Part 1 Fundamental Principles: 1 Needle Electromyography 257

Contents
Part 1 F U N D A M E N T A L PRINCIPLES
1 Nerve and Muscle Anatomy and Physiology 3

Daniel Dumitru, M.D., Ph.D., and Andrew J. Gitter, M.D.
2 Electrical Sources and Volume Conduction 27
Daniel Dumitru, M.D., Ph.D., Dick E Stegeman, Ph.D.,
and Machiel Zwarts, M.D., Ph.D.
Appendix The Leading/Trailing Dipole Model and Near-Field/Far-Field 54
Waveforms
Daniel Dumitru, M.D., Ph.D., Dick F. Stegeman, Ph.D.,
and Machiel Zwarts, M.D., Ph.D.
3 Instrumentation 69
Daniel Dumitru, M.D., Ph.D., and Machiel J. Zwarts, M.D., Ph.D.
Appendix Basic Electricity Primer 98
John C. King, B.S.E.E., M.D.
4 Peripheral Nervous System's Reaction to Injury 115
Daniel Dumitru, M.D., Ph.D., Machiel J. Zwarts, M.D., Ph.D.,
and Anthony A. Amato, M.D.
Part I! BASIC A N D A D V A N C E D T E C H N I Q U E S
5 Nerve Conduction Studies 159
Daniel Dumitru, M.D., Ph.D., Anthony A. Amato, M.D., and
Machiel Zwarts, M.D., Ph.D.
6 Special Nerve Conduction Techniques 225
1 Needle Electromyography 257
8 Quantitative EMG 293
Sanjeev D. Nandedkar, Ph.D., Erik V Stdlberg, M.D., Ph.D,
and Donald Sanders, M.D.
9 Somatosensory Evoked Potentials 357
Daniel Dumitru, M.D., Ph.D., Lawrence R. Robinson, M.D.,
and Machiel J. Zwarts, M.D., Ph.D.
Yii
viii —. CONTENTS
10 Magnetic Stimulation of the Central and Peripheral Nervous Systems . . 415

Lawrence R. Robinson, M.D
11 Quantitative Sensory Testing: Basic Principles and Clinical Applications 429
Gill Wolfe, M.D.
12 Intraoperative Neurophysiology Monitoring 439
John C. King, B.S.E.E., M.D., Jaime R. Lopez, M.D.,
and Tod B. Sloan, M.D., Ph.D
13 Chemical Denervation 479
Joyce R. Grissom, M.D.
Part IH P A T I E N T CARE-RELATED ISSUES
14 The Electrodiagnostic Medicine Consultation: Approach and Report . . 515

Generation
Daniel Dumitru, M.D., Ph.D.f and Machiel J. Zwarts, M.D., Ph.D.
15 Electrodiagnostic Medicine Pitfalls 541
Part IV C L I N I C A L A P P L I C A T I O N S
16 Disorders Affecting Motor Neurons 581

Daniel Dumitru, M.D., Ph.D., and Anthony A. Amato, M.D.
17 Focal Cranial Neuropathies 653
18 Radiculopathies 713
19 Brachial Plexopathies and Proximal Mononeuropathies 777
20 Lumbosacral Plexopathies and Proximal Mononeuropathies 837
21 Approach to Peripheral Neuropathy 885
Anthony A. Amato, M.D., and Daniel Dumitru, M.D., PAD.
22 Hereditary Neuropathies 899
Anthony A. Amato, M.D., and Daniel Dumitru, M.D., Ph.D.
23 Acquired Neuropathies 937
24 Focal Peripheral Neuropathies 1043
25 Neuromuscular Junction Disorders 1127
CONTENTS — ix
26 Introduction to Myopathies and Muscle Tissue's Reaction to Injury . . . 1229
27 Hereditary Myopathies 1265
28 Acquired Myopathies 1371
29 Electrodiagnostic Medicine Evaluation of Children 1433
Maureen R. Nelson, M.D.
30 A AEM Glossary of Terms in Electrodiagnostic Medicine 1449
and Illustrations of Selected Waveforms
Index , 1489
CD-ROM: Needle Electromyography Inside back cover
Contributors
A n d r e w Gitter, M . D .
Associate Professor, Department of Rehabilitation Medicine, University of Texas Health Science Center,
San Antonio, Texas
Joyce Grissom, M . D .
Chief of Movement Disorders and Chemodenervation Clinic, Wilford Medical Center, San Antonio, Texas
J o h n C. King, M . D .
Associate Professor, Department of Rehabilitation Medicine, University of Texas Health Science Center,
San Antonio, Texas
J a i m e R. Lopez, M . D .
Assistant Professor, Department of Neurology and Neurological Sciences, Stanford University School of
Medicine, Stanford University Medical Center, Stanford, California
Sanjeev D. N a n d e d k a r , Ph.D.
Clinical Applications Manager, Oxford Instruments, Hawthorne, New York
M a u r e e n Nelson, M . D .
Associate Professor, Department of Physical Medicine and Rehabilitation, Baylor College of Medicine;
Chief, Physical Medicine and Rehabilitation, Texas Children's Hospital, Houston, Texas
Lawrence R. R o b i n s o n , M.D.
Professor and Chair, Department of Rehabilitation Medicine, University of Washington School of
Medicine, Harborview Medical Center, Seattle, Washington
Donald B. S a n d e r s , M . D
Professor, Department of Neurology, Duke University Medical Center, Durham, North Carolina
T o d B. Sloan, M . D . , Ph.D.
Professor, Department of Anesthesiology, University of Texas Health Science Center, San Antonio, Texas
E r i k V. Stalberg, M.D., Ph.D.
Professor and Chairman, Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala,
Sweden
Dick F. Stegeman, P h . D .
Professor, Department of Neurophysiology, Institute of Neurology, University Medical Center Nijmegen,
N ij megen, The Netherl ands
Gil I. Wolfe, M . D .
Associate Professor, Department of Neurology, University of Texas Southwestern Medical Center, Parkland
Hospital, Zale Lipshy University Hospital, Texas Scottish Rite Hospital for Children, Dallas, Texas
x
Chapter 24
Focal Peripheral Neuropathies

Daniel Dumitru, M.D., Ph.Q
Machiel J. Zwarts, M.D., Ph.D.
CHAPTER OUTLINE
Electrophysiologic Correlates of Focal The Lower Limb
Neuropathies Peroneal Nerve and Branches • Tibial Nerve and Branches
Axonal Loss • Focal Demyelination • Sural Nerve
Electrodiagnostic Medicine Evaluation Electrodiagnostic Medicine Consultation
History * Physical Examination • Nerve Conduction Studies Pitfalls
• Needle Electromyography Anatomic Variations • Reference Values • Temperature
• Stimulation • Inadequate Study
The Upper Limb
Median Nerve and Focal Median Nerve Neuropathies Illustrative Cases
• Ulnar Nerve and Focal Ulnar Nerve Neuropathies • Radial Hand Numbness/Arm Pain • Hand Numbness/Elbow Pain
Nerve and Focal Radial Nerve Neuropathies • Finger Extensor Weakness • Footdrop
Focal compromise of peripheral nerves secondary to entrap- ELECTROPHYSIOLOGIC CORRELATES O F

ment within a compartment of relatively fixed size, compres- F O C A L PERIPHERAL NEUROPATHIES
sion by an internal or external source, repetitive trauma and
overuse, or some other etiology affecting a nerve over a finite Focal peripheral nerve lesions result in a limited number of
segment is one of the most common lesions evaluated by an pathologic responses to injury. The nerve may undergo com-
electrodiagnostic medicine consultant. Those entrapment neu- plete neural transection with ensuing Wallerian degeneration
ropathies affecting the distal portions of major peripheral secondary to direct trauma or energy dissipation; axonal loss,
nerves are discussed in this chapter, while the more proximally with varying degrees of connective tissue preservation from
located focal lesions have been detailed in those chapters ad- traction or compression; and myelin derangement with
dressing the brachial and lumbosacral plexi. In addition to axonal preservation. Each process reflects a unique electro-
neural entrapment, additional causes of focal neuropathies are physiologic presentation during the electrodiagnostic medi-
also examined. cine examination.
This chapter is structured to optimize the discussion of indi-
vidual nerve lesions affecting both the upper and lower limbs. AXONAL LOSS
Because multiple nerves traversing quite diverse regions of the
body are addressed, the pertinent anatomy for each nerve is Regardless of the degree of damage to the supporting connec-
first presented with special attention given to potential areas of tive tissue, once axonal loss occurs at a specific site along the
neural compromise based on the surrounding anatomic struc- nerve, the remaining portion of the nerve distal to the lesion un-
tures. The clinical presentation and differential diagnosis for dergoes Wallerian degeneration. This process is essentially the
specific syndromes are considered with the appropriate electro- same in both motor and sensory fibers. The primary difference,
diagnostic medicine evaluation. The pathophysiology and however, is the lack of a neuromuscular junction in the sensory
degree of injury characterization for focal neural compromise fibers, thus resulting in the preservation of a sensory nerve
secondary to compression or transection have been detailed action potential (SNAP) for approximately 9-10 days while a
previously (see Chapter 4), and the reader is urged to review compound muscle action potential (CMAP) disappears by day
this material prior to attempting to diagnose individual nerve 7-8 because of neuromuscular junction transmission failure
disorders. (see Chapter 4). The major importance of supporting connective
1043
1044 — PART IV CLINICAL APPLICATIONS
tissue preservation is with respect to prognosis of successful week time frame is rather variable and depends upon the dis-
reinnervation by way of the original endoneurial tubes. tance between the lesion site and muscle tissue. For example,
Loss of axons in the peripheral nervous system's sensory por- a lesion at the fibular head may produce membrane instability
tion depends upon the lesion's location. Disruption of axonal (positive sharp waves and fibrillation potentials) in the tibialis
continuity proximal to the dorsal root ganglion results in degen- anterior within 7-10 days, while an L5 radiculopathy may re-
eration of the nerve's central extension with preservation of the quire 3 or 4 weeks to produce the same result. The time delay
peripheral portion extending into the limb. The SNAP remains between lesion initiation and needle examination is necessary
preserved in this instance, as is the case in radiculopathies and for the hallmarks of denervation, positive sharp waves, and
preganglionic brachial plexopathies. Most focal peripheral fibrillation potentials to become manifest. Of course, attempt-
nerve lesions, however, are at some location distal to the dorsal ing to observe voluntary motor units (reduced recruitment)
root ganglion, thereby resulting in a loss of the SNAP within within this short time frame may also be useful prior to the de-
about 10 days of the insult following a case of complete neural tection of membrane instability. These findings are sought in a
transection. The exact time of SNAP loss is directly dependent peripheral nerve distribution, thus confirming the SNAP and
upon the nerve segment length between the injury and recording CMAP findings. It may not be possible to always obtain a
sites. Partial lesions obviously result in some preservation of the SNAP or CMAP from sufficient nerves to confirm a particular
SNAP response. SNAP amplitude, therefore, is a relatively peripheral nerve injury. In this case, the needle electromyo-
good predictor of axonal loss because it regains amplitude usu- graphic examination is particularly useful. In addition to mem-
ally only through regrowth of the damaged axons and little in brane instability, the presence of voluntary motor units is also
the way of peripheral sprouting, although this may occur to a important to document because it signifies that the lesion is in-
small degree. Unfortunately, mild to moderate axonal loss is complete and neural integrity is at least partially preserved.
difficult to assess accurately because of the wide variation in This finding typically implies a much more satisfactory prog-
normal SNAP amplitude. Also, side-to-side amplitude variation nosis compared with complete axonal disruption. A complete
can approach 3(MK)% in normal persons (authors' observation), nerve transection is assumed when there is an absent CMAP to
thereby requiring an amplitude difference approaching 50% to stimulation distal to the lesion site, membrane instability to
be considered significant prior to definitively concluding that varying degrees depending upon the duration of injury, and no
axonal loss is present. Clinically, in both pre- and postgan- detectable voluntary motor units distal to the site of injury. 1
glionic lesions, the patient complains of diminished sensation in The corresponding SNAP, when available, may be present or
the distribution of the injured nerve. This is usually not mani- absent depending upon a preganglionic or postganglionic
fested in a distinct peripheral nerve distribution unless there is lesion, respectively. In the case of a very proximal lesion
moderate to profound axonal loss. where no CMAP can be elicited, for example, it should be re-
As noted previously, the CMAP may require about 7-8 days alized that signs of membrane instability combined with ab-
to disappear following complete axonal disruption. Partial nerve sence of voluntary recruited motor units do not necessarily
injuries should stabilize within this time frame regarding a se- indicate a complete axonal lesion is present. The absence of
quential decline in the CMAP amplitude. This implies the focal voluntary motor units can also be due to a complete conduc-
lesion is a static and not progressive type of disorder. Most focal tion block. This situation may occur because the site of neural
peripheral nerve lesions are either static or slowly progressive, activation can be problematic in so far as the site of nerve
thereby complying with the above time frames as detected by stimulation may be proximal to the lesion's location.
CMAP amplitude over the course of days or weeks. In slowly Alterations in the morphology of voluntary motor unit action
progressive lesions, the CMAP may continue to drop when potentials (MUAPs) such as amplitude, phases, duration, and
evaluated over weeks to months, but collateral sprouting limits recruitment abnormalities can also be observed depending
this parameter as a completely accurate predictor of axonal loss upon the severity of axonal loss and the timing of the exami-
after several weeks. Similar to SNAPs, the CMAP is a relatively nation with respect to axonal injury.
good indicator of axonal loss in moderate to profound lesions.
Again, the wide variation of normal and side-to-side CMAP FOCAL DErffELlNATION
amplitude differences requires about a 50% side-to-side varia-
tion to validate a conclusion of axonal loss. This approximation In addition to axonal loss, the peripheral nerve insult may-
must be used with caution because of poorly defined individual result in injury only to the enveloping myelin (see Chapter 4).
variations and categorically cannot be used for SNAP ampli- Myelin alteration over a localized segment is referred to as focal
tudes obtained more than a few centimeters apart, because demyelination. Peripheral nerve injuries can produce action
prominent phase cancellation may result in amplitude reduc- potential blockade (conduction block) with or without a de-
tion. Collateral sprouting complicates axonal loss based on myelinating component as well as demyelinative differential
CMAP amplitude analysis. In partial lesions, intact nerves can or synchronized impulse slowing. In conduction block, either
send out collateral neural sprouts to reinnervate neighboring all or some portion of the neural impulses are prevented from
denervated muscle fibers. This process may take several weeks crossing the lesion site. This block of neural conduction may be
to months prior to achieving functional neuromuscular trans- a result of localized ischemia or demyelination. Regarding both
mission. Once this occurs, however, the CMAP is no longer an cases, the block of propagation is temporary. In the former, con-
adequate predictor of axonal loss because of a lack of a one-to- duction is restored when blood flow returns provided the axon
one correspondence between the number of axons lost and the has not experienced ischemia of a sufficient degree to result in
CMAP amplitude (see Chapter 4). axonal loss. The later case of conduction return requires the de-
As with most neural lesions resulting in axonal loss, the myelinated segment to be remyelinated. Either of the preceding
needle electromyographic portion of the evaluation is particu- pathologic processes spare the axon, thus preventing Wallerian
larly helpful in delineating the lesion's extent when performed degeneration distal to the injury site. Because the neural ele-
about 3-4 weeks after the presumed neural insult. This 3-4 ments are preserved distal to this focal region of conduction
Chapter 24 FOCAL PERIPHERAL NEUROPATHIES — 1045
block, a normal response is anticipated to both motor and sen- the presence of conduction block in these instances is extremely
sory stimulation when performed below the lesion. Stimulating difficult and most likely cannot be accomplished beyond a rea-
proximal to the area of focal neural blockade, however, results sonable doubt.
in a reduction in both the recorded SNAP and CMAP ampli-
tude. In these cases, the recording electrodes are assumed to be
located distal to the lesion. By comparing the CMAP above and ELECTRODIAGNOSTIC MEDICINE
below the presumed site of injury with the same muscle's EVALUATION
CMAP from the contralateral side, it is possible to estimate both
the degree of conduction block and axonal loss when the proce- HISTORY
dure is performed several weeks following the insult. For exam-
ple, the CMAP from an unaffected abductor digiti minimi is The electrodiagnostic medicine evaluation of focal peripheral
observed to be 10.0 millivolts (mV) with stimulation of the neuropathies is no different than the assessment of possible
ulnar nerve at a location several centimeters below and above injury to any other portion of the peripheral nervous system. A
the medial epicondyle. Stimulating in the same locations on the thorough history directed at eliciting potential precipitating fac-
affected limb generates CMAPs of 2.5 mV from above the tors or incidents likely to generate a focal neural dysfunction
elbow and 5.0 mV below the elbow. In this instance, there are should always be performed. Success requires that the physi-
data to support a conclusion that about half of the axons have cian be familiar with the historical presentation and pathophysi-
experienced axonal loss (5 mV versus 10 mV) and about half of ology of the various disorders likely to affect the peripheral
the remaining axons (25% of the total axonal number) across nervous system.
the elbow are affected by a conduction block (2.5 mV versus The initial presentation of the patient's symptoms is impor-
5.0 mV). A reduction in nerve conduction velocity (NCV) tant to establish, particularly with respect to an acute or insidi-
across the injury site may be documented. It is a questionable ous disease process. This is of paramount importance with
practice to rely solely on the NCV because it is highly possible respect to the therapy of the nerve lesion. In principle, all com-
that two different fiber populations are being compared. A sig- pressive nerve lesions that develop acutely should be treated
nificant portion of the faster conducting fibers, for example, conservatively, even if severe. 508 An association with acute or
may be blocked and not reach the recording electrode. The am- repetitive trauma is an important factor to determine. Repetitive
plitude reductions noted above are meant to be rough approxi- motion disorders such as carpal tunnel syndrome are relatively
mations and apply only if the CMAP's duration is similar above common in the industrial setting, and a patient's work history
and below the presumed lesion site. If the duration of the must be investigated. This includes individuals who do not con-
CMAP above the lesion is quite a bit longer than that obtained sider themselves formally employed, but work as a domestic or
from below the lesion, conduction block may not be the etiol- child caretaker on a part-time basis. Related diseases such as di-
ogy of the amplitude reduction, which may be due instead to abetes mellitus, connective tissue disorders, or other diseases
temporal dispersive effects. predisposing persons to peripheral nerve compromise should
If a focal demyelinating lesion produces a synchronized also be discussed.
slowing of all neural impulses propagating across the affected Patients usually complain of paresthesias such as numbness,
segment, there should be little change in the relative temporal tingling, pins-and-needles sensations, and other descriptors
relationships of the action potentials to each other. This is mani- when addressing their symptoms. These sensations typically,
fested as a focal slowing of NCV. The CMAP appears quite sim- though not always, involve at least the anatomic distribution of
ilar above and below the damaged portion of nerve with respect the peripheral nerve affected. It is not uncommon, however, for
to its general morphology regarding duration and phases. The these spontaneous sensations to subjectively involve more than
amplitude may be diminished somewhat but not in excess of the presumed territory of the injured nerve. This is particularly
that anticipated (0-20%). This finding justifies a conclusion that true of pain. For example, persons with carpal or cubital tunnel
the observed slowing is likely due to a focal demyelinative syndrome may complain of the entire hand being numb as well
process generating a similar degree of slowing in all neural as pain radiating into the shoulder and occasionally the neck
fibers. On the other hand, if the morphology of the CMAP is al- region. There is usually also a complaint of motor dysfunction
tered in comparison with that obtained distally from the per- in some form. When the hand is the affected portion, dropping
spective of a prolonged duration, with or without multiple objects or diminished ability to button clothes is a common
phases/turns, and marked reduction in amplitude across the af- complaint. In lower limb disorders, ambulating in the dark at
fected segment (> 20%, for example), one cannot conclude that night when attempting to find the lavatory may be a problem, as
conduction block is the primary physiologic response to injury. the visual clues that usually compensate for diminished sensa-
The alteration in the CMAP is the important finding suggesting tion are absent. Soliciting a history for all of the above and more
that there is a differential slowing of neural impulse propagation is important in attempting to define the most appropriate elec-
crossing the affected portion of nerve. The prolonged duration trophysiologic investigation to perform.290-682-763
and, if present, increased number of phases/turns imply a de-
crease in the synchronous arrival of the impulses at the muscle. PHYSICAL EXAMINATION
This desynchronization is manifested as a CMAP distributed
over a longer segment of nerve, which increases the chance of In combination with the history, the physical examination is
phase cancellation leading to the CMAP's increased duration critical to forming a preliminary diagnosis as well as solidifying
and phases. Whenever a normal appearing potential distal to a the most appropriate course of action with respect to the elec-
lesion site is observed, but proximal stimulation results in a trodiagnostic medicine consultation. An effective physical ex-
CMAP that is markedly increased in duration, reduced in ampli- amination can be performed only if the practitioner is familiar
tude, and comparatively polyphasic, a demyelinating process with the neural innervation of the limb's skin and musculature,
resulting in differential focal slowing is suggested. Teasing out particularly with respect to testing each muscle's function. Once
this knowledge is mastered, it is possible to demonstrate the distance is of greater value than amplitude comparison for left
manifestations of the neural lesion as it is physically reflected in elbow versus wrist stimulation. In those instances, when focal
paresis or abnormal body postures. In mild lesions, sensory al- lesions affect nerves without a routine SNAP technique, so-
teration may be rather difficult to detect. By using modalities matosensory evoked potentials (SEPs) may be of assistance (see
such as pin prick, touch, vibration, and proprioception in a care- below). The utility of specific SNAP techniques is discussed
ful manner, it is usually possible to map out the affected periph- with respect to individual nerve lesions.
eral nerve distribution. Assessing muscle tone and deep tendon v Motor Nerve Conduction Studies. For evaluating focal pe-
reflexes is an important aspect of the physical examination, as ripheral neuropathies, the CMAP and nerve conduction velocity
these are rather good guides to general functioning of the pe- are perhaps the two most useful parameters of motor conduc-
ripheral nervous system. Of course, all of the above assumes a tion studies routinely performed. The CMAP amplitude pro-
cooperative patient. In persons who have an altered sensorium vides information regarding the number of functional axons
secondary to trauma or other factors, the electrophysiologic ex- especially when compared with the comparable response on the
amination may be extremely revealing when performed during unaffected side. Amplitude reductions across defined limb seg-
the most opportune time. ments in excess of that normally anticipated usually signify
axonal loss or conduction block provided temporal dispersion
NERVE CONDUCTION STUDIES secondary to asynchronous focal slowing is absent. It is cer-
tainly possible for a slowly progressive lesion such as neural
Nerve conduction studies are extremely important in evaluat- compression to result in primarily an insult to the myelin com-
ing focal peripheral neuropathies. In addition to documenting ponent of the nerve. In this case, one would not anticipate an
segmental nerve conduction velocities, it is also necessary to amplitude reduction provided the myelin is affected uniformly
determine the response's magnitude at various stimulation sites thus producing a synchronous slowing of impulse conduction
and distal latencies. Essential to the diagnosis is the localized across the affected neural segment. In this instance, the practi-
slowing (motor and sensory) of conduction or conduction block tioner is alerted to the problem not by means of abnormal am-
(only motor) over a relatively short nerve segment. This implies plitude reduction, but through a focal slowing of neural
stimulation of the nerve at multiple places, both proximal and conduction. An entire segment of nerve may reveal an abnor-j
distal of the demyelinative lesion. Although this may seem ob- mally slow NCV. It is possible, through the application of shortn
vious, numerous studies fail to fulfill these criteria, e.g., in segment stimulation (10-15 cm, for example) or incremental
carpal tunnel syndrome (see Table 24-3) where only stimulation stimulation every centimeter, to better localize a focal lesion.
proximal to the possible site of the compressive lesion is per- Both conduction velocities and latencies can be used to assess
formed. The only exception is the SNAP amplitude across long neural conduction. Conduction velocities in some sense obviate
body segments—elbow to wrist, for example. The propensity of the necessity of the uniform distances required for optimal com-
sensory impulses to undergo phase cancellation secondary to parisons when using only latency measurements. The minor
temporal dispersive effects over long distances normally results limitation of using velocities is the potential for inaccurate mea-
in significant amplitude reductions. Side-to-side SNAP ampli- surement of the distances required for the calculation. Latency
tude comparisons over similar distances, however, are a valid comparisons require only the reporting of time per unit distance,
method of assessing potential sensory fiber axonal loss (see but are of less comparative value between different practitioners
below). If it is not possible to measure a localized slowing, for who may record the latency over different distances. Whether
example, owing to the proximal and deep lying position of the one uses velocities, latencies, or both is usually a matter of per-
nerve, perhaps an acceptable alternative is to demonstrate sec- sonal preference.
ondary axonal loss in a distribution confined to one nerve or a H-Reflex. The H-reflex is of little use in attempting to local-
branch of the nerve in question. ize focal peripheral nerve lesions distal to the root level. The
Sensory Nerve Conduction Studies. Performing sensory long pathway of impulse conduction renders it susceptible to
nerve conduction studies should always be done in persons sus- compromise at any location along the afferent or efferent con-
pected of having focal peripheral neuropathies. This is because duction course. It may be of value in alerting the practitionei
the sensory fibers are usually, though not always, affected first that a lesion is present at some location, but more selective tech-
and to a more significant degree. It is also helpful to obtain niques are required to establish a precise location. A rather pro-
SNAPs from the lower limbs even with exclusively upper limb found limitation of the H-reflex is its limited distribution to
complaints whenever there is a clinical suspicion of a possible primarily the tibial and median nerves.
concomitant peripheral neuropathy. This may be important in F-Wave. The most useful aspect of the F-wave is its long
attempting to determine an underlying etiology or predisposi- neural pathway in that it is capable of alerting one to the fact
tion in some patients who develop multiple entrapment neu- that a lesion is present at some location. This is manifested by a
ropathies. Of note, exploring the medial plantar nerve may be of slowing of latency in excess of that predicted for the patient's
assistance in defining the presence of peripheral neuropathy limb length. Unfortunately, there are a number of limitations to
when the sural nerve is found to be normal.170 the F-wave, minimizing its utility in the diagnosis of focal neu-
Fortunately, the vast majority of focal neuropathies, particu- ropathies. The very nature of its long pathway renders this pro-
larly those due to chronic entrapment, affect nerves with readily cedure nonspecific with respect to location. Although a number
obtainable SNAPs. The amplitude of these responses are of of techniques have been developed to localize the region of po-
value when compared with the unaffected side as obtained from tential slowing to specific limb segments, they have not gained
the same anatomic stimulus site. However, comparing a proxi- much popularity aside from the centers that developed them.
mal and distal amplitude in the same limb is of less value be- Also, most techniques use the shortest F-wave of multiple trials.
cause of the previously noted phase cancellation effects. For This tends to predispose the results to a normal study, poten-
example, comparing left and right median SNAPs from the third tially missing subtle abnormalities early in the disease course.
digit as obtained from wrist stimulation over a standardized In short, the F-wave is of limited use in the routine assessment
of most focal neuropathies, but may occasionally be of some affecting others partially. Membrane instability also tends to be
value in difficult cases to establish a lesion's presence, but not self-inhibiting in that various amounts of denervated fibers may
necessarily its exact location. be fibrillating at any one time. Also, if the needle electrode is
Somatosensory Evoked Potentials (SEPs). Occasionally, placed in a partially denervated muscle and not located in the
SEPs may be of diagnostic use with respect to focal peripheral portion of this muscle containing the denervated fibers, little in
neuropathies. This is particularly true when more routine sen- the way of membrane instability may be detected. Anomalous
sory techniques are not available. In the lower limb, the lateral innervation can also result in confusing patterns of denervation,
femoral cutaneous and saphenous nerves may be more such as the all-median or all-ulnar hand mediated through a
amenable to evaluation with SEPs, while the lower lateral cuta- combination of the Martin-Gruber and Riche-Cannieu anasto-
neous or posterior cutaneous nerve of the forearm is an example moses. Combining all of the above factors and possibly others
in the upper limb. The exact relationship between axonal loss can result in patients with "typical" nerve injuries not conform-
and cortically recorded potentials is unclear because the central ing to "typical" patterns of denervation.
nervous system's amplification effect on peripheral stimuli is Motor unit action potential morphologic changes and alter-
not quantified as of yet. This limits the SEP to primarily identi- ations in recruitment may also be of assistance in diagnosing
fying a lesion as present or absent and not to the degree of focal peripheral neuropathies. These alterations are those antici-
axonal loss. Both latency and amplitude are criteria utilized to pated from a remodeled motor unit. In partial nerve injuries, col-
determine the presence of pathology, with latency being some- lateral sprouting allows preserved motor units to increase their
what more quantifiable. Significantly more work is required to muscle fiber content. A combination of immature collateral
adequately characterize the exact role of SEPs in diagnosing sprout conduction velocity plus a possible increased end-plate
focal peripheral nerve lesions. zone's longitudinal expanse, and slowed muscle fiber conduc-
Mixed Nerve Stimulation. It is possible to stimulate a tion summate to generate a decrease in the synchronous addition
mixed nerve containing both motor and sensory fibers and of voltages generated by the total population of muscle fibers for
record the ensuing response from the same mixed nerve at a dis- each motor unit that is activated. The net result is a long-dura-
tance. For example, it is possible to stimulate the median nerve tion, polyphasic, increased-amplitude potential. In profound dis-
trunk at the wrist and record the mixed nerve action potential ease, these potentials are relatively easy to identify because they
from the median nerve at the antecubital fossa. The exact fiber are usually the only functional motor units. The problem arises
population contributing to the potential's onset, fastest conduct- in more subtle injuries when there is little if any membrane in-
ing fibers, is unclear and may be a mixture of motor and sensory stability and only a few motor units may be abnormal. Because a
axons, or pure sensory axons. Despite this uncertainty, a number statistical mean is used to define an abnormality, one cannot state
of techniques employ a mixed nerve response in order to assist with assurance as to the presence of abnormal potentials unless
in the diagnosis of specific disorders. Activation of the median 20 simple (nonpolyphasic) motor units are assessed and the
and ulnar nerves in the palm while recording over each nerve at above-noted parameters of duration and amplitude exceed the
the wrist, or the medial and lateral plantar nerve in the sole of reference criteria. It is also necessary to quantify the total per-
the foot and recording over the tibial nerve proximally, is a pop- cent of polyphasic potentials. Merely observing a free running
ular method of using mixed nerve responses to characterize the trace or even a "frozen" screen is not an acceptable method of
conduction over potential entrapment sites. quantitatively characterizing motor unit action potentials.
Fortunately, in such instances, the lesion is of a partial nature and
NEEDLE ELECTROMYOGRAPHY surgical intervention is not usually contemplated.
The needle electromyographic examination is an extremely
useful technique that complements nerve conduction studies. As SECTION I: T H E UPPER LIMB
with the majority of other disorders, the most reliable finding is
that of positive sharp waves and fibrillation potentials in a dis- In this section we shall consider focal lesions affecting the
tribution compatible with an individual peripheral nerve as op- median, radial, and ulnar nerves. Disorders of the axillary, mus-
posed to a root or plexus pattern. A thorough knowledge of the culocutaneous, and proximal aspects of the radial, median, and
sequential innervation of the muscles supplied by individual pe- ulnar nerves are discussed in the chapter addressing brachial
ripheral nerves allows one to localize the suspected lesion to a plexopathies (see Chapter 19).
particular level in the affected limb. For example, detecting ab-
normalities in the brachioradialis muscle and all muscles dis-
tally, but not in any portions of the triceps muscles, strongly MEDIAN NERVE
suggests that the pathology affecting the radial nerve is distal to
the innervation of the triceps but proximal to the brachioradialis ANATOMY
muscles, i.e., the spiral groove of the humerus. This same rea-
soning can be applied to most peripheral nerves in both the Anatomic Course. In the axilla, the lateral and medial cords
upper and lower limbs. Given this general rule, caution must be each give off a major terminal branch, lateral and medial root
exercised when the above-noted "textbook" finding is absent of the median nerve, respectively, which fuse about the axil-
and not all muscles distal to the lesion display an abnormality. lary artery to form the median nerve (Fig. 24-1 ).n5'299-763 The
In this instance, one must remember that peripheral nerve trunks lateral root is the larger of the two and is composed of fibers
contain multiple funiculi with axons destined to innervate spe- from spinal levels C5, C6, and C7, while the medial root con-
cific nerves, and these funiculi continually change their fiber re- tributes fibers from the C8 and Tl spinal levels. Proximal to the
lationships. At any level of the peripheral nerve trunk, it is origin of the median nerve, the musculocutaneous nerve courses
possible for a lesion to result in damage to only a portion of sev- laterally to enter the substance of the coracobrachialis muscle,
eral funiculi, thereby sparing some muscles entirely and only while posteromedially the ulnar nerve travels distally on the
At the elbow, the median nerve lies on the brachialis tendon,
which separates the nerve from the elbow joint. Lateral to the
median nerve is the biceps brachii tendon, anteriorly the bicipital
aponeurosis (lacertus fibrosus) and anterior division of the medial
antebrachial cutaneous nerve, and medially lies the pronator teres
muscle (Figs. 24-1 and 24-2). The median nerve enters the fore-
arm by passing between the two heads of the pronator teres
muscle. In the forearm, the nerve is located between and posterior
to the tendonous arch of the radial and humero-ulnar origins of
the flexor digitorum superficial is muscle. Posterior to the nerve
are located the deep forearm flexor muscles. Approximately 5 cm
proximal to the flexor retinaculum at the wrist, the tendons of the
flexor digitorum sublimis become distinct and the median nerve
lies radial to these tendons.763 At this region, the median nerve can
be easily located because it lies just medial to the flexor carpi ra-
dialis and lateral to the palmaris longus tendons and maintains
this relationship as the nerve passes into the hand. When the pal-
maris longus muscle is absent, the median nerve is just ulnar to
the flexor carpi radialis tendon. In this area just proximal to the
wrist joint, the nerve and above-noted tendons are superficial,
Ulnar n. while posterior to these structures are located the flexor pollicis
longus, flexor digitorum profundus to the second digit, and the
^rs Superior ulnar pronator quadratus muscles.
collateral a.
radialis**
— Brachial a.
Radial Pronator teres,
Basilic v.
recurrent a. humeral head
Flexor carpi radialis
Deep and super- and palmaris longus
ficial branches-
_ Pronator teres,
\ y x Inferior ulnar of radial n.
ulnar head
collateral a. -—Ulnar n.
Ant. and post,
ulnar
Extensor carpi
recurrent aa.
radialis longus
—Ulnar a.
_ Common
interosseous a.
Figure 24-1. Median nerve in the arm. The median nerve is Posterior and
anterior
formed by the fusion of the medial and lateral roots from the medial and interosseous aa.
lateral cords, respectively. Note how the median nerve is closely in- Anterior
vested with the axillary artery and ulnar nerve to form a neurovascular interosseous n.
bundle. The ulnar and musculocutaneous nerves are observed to be as-

sociated with the median nerve as terminations of the medial and lateral
cords. (From Hollinshead WH: Anatomy for Surgeons:The Back and
Limbs,Vol. 3,3rd ed. Philadelphia, Harper & Row, 1982, with permission.)
medial head of the triceps muscle. At the level of the coraco-

brachialis muscle's insertion, the medial brachial and ante-
brachial cutaneous nerves depart from the medial cord and Dorsal branch of
proximity of the median nerve to pierce the deep fascia, becom- ulnar n.
ing subcutaneous. The median nerve trunk, in association with

the axillary/brachial artery, continues distally into the arm. At ap-
proximately the level of the coracobrachialis muscle, the neu- Ant. inferos*
seous a. and n.
rovascular bundle courses somewhat anteriorly from the axilla, '•Ulnar a. and n.
over the brachialis muscle and medial intermuscular septum, until Pronator
quadratus
it reaches the antecubital fossa. Because of the median and other Abductor pollicis
nerves' pathways noted above, by the mid-arm level the median longus
.~4- Median n.
nerve is no longer closely associated with any other neural struc-

tures (Fig. 24-1). The course of the nerve is important, as it is at
first laterally located, but then gradually crosses the artery to lie Figure 24-2. Median nerve in the forearm. Relationship of the
medial to it. This anatomic course may be of importance when at- median nerve to the various superficial and deep muscles in the fore-
tempting to stimulate the nerve in the arm region. arm is depicted. (From Hollinshead WH: Anatomy for SurgeonsrThe
In the antecubital fossa, the median nerve is associated with the Back and Limbs,Vol. 3, 3rd ed. Philadelphia, Harper & Row, 1982, with
brachial artery and prepares to course deeply into the forearm. permission.)
Tendon of flexor carpi radialis
Tendon of flexor pollicis longus / Abductor pollicis

Tendon of palmaris longus brevis
I I Opponens pollicis
Tendons of long flexors of fingers / Tendon of abductor
pollicis longus
Figure 24-3. Wrist cross-section. A cross-sec- .Trapezium
Palmar branch
tion through the carpal bones depicts the various of ulnar n A
tendons and nerves traversing the wrist region into Tendon of extensor
the hand. Of particular interest is the ligamentous 'pollicis brevis
and bony structures forming the carpal tunnel. Superficial branch
Note how the 10 structures (median nerve and 9 of radial n.
flexor tendons) are confined in an unyielding space — -Radial a.
completely surrounded by bone and ligament. Tendon of extensor
(From Hollinshead WH: Anatomy for Surgeons:The pollicis longus
Back and Limbs,Vol. 3, 3rd ed. Philadelphia, Harper Tendon of extensor
& Row, 1982, with permission.) carpi radialis longus
Trapezoid
Dorsal branch Tendon of extensor carpi

Tendons of radialis brevis
of ulnar n.
extensor digitorum \
Tendon of extensor x
^ Capitate
digiti minimi
Tendon of extensor indicis
The main trunk of the median nerve enters the hand by pass- There are usually multiple branches to the pronator teres
ing through the carpal tunnel. The carpal bones form a concav- muscle, with the more proximal ones innervating the superficial
ity that is covered by the transverse carpal ligament anteriorly, head while the distal branches supply the deep head. The next
thus forming a compartment through which pass the median muscular branch off the median nerve is to the flexor carpi ra-
nerve, eight tendons of the superficial and deep finger flexors, dialis muscle. There is usually a single branch arising from the
and the the flexor pollicis longus tendon (Fig. 24-3). This com- main trunk of the median nerve below the medial epicondyle;
partment is known as the carpal tunnel. The transverse carpal however, it is not uncommon for this branch to share a common
ligament (flexor retinaculum/anterior annular ligament) is a point of origin with other neural branches destined for either or
thick structure with sharp proximal and distal edges that at- both the pronator teres and flexor digitorum superficialis mus-
taches to the pisiform and hook of the hamate bones medially, cles. When present (87% of the population), the palmaris
and the scaphoid (navicular) tubercle and trapezium bones later- longus muscle is usually innervated by a branch snaring its
ally. Thus the medial, lateral, proximal, and distal margins of origin with that for the flexor carpi radialis. 630 Forceful wrist
the carpal tunnel's anterior extent can be palpated rather easily flexion against resistance usually allows this muscle's tendon to
in most hands. The significance of the above-described anatomy be readily observed just medial to the flexor carpi radialis
is that the floor, walls, and roof of the carpal tunnel is composed tendon, and its absence is readily detected by this maneuver.
of tough ligaments and bones that form an unyielding tunnel The flexor digitorum superficialis muscle is then innervated
conveying the nine tendons and one nerve. Any increase in pres- by either a separate branch from the main median nerve trunk,
sure within the canal is not compensated by an expansion of the or from multiple branches supplying the flexor carpi radialis
space, but transmitted internally to the contained structures. The and occasionally the pronator teres muscles. Occasionally, the
lateral margin of the transverse carpal ligament splits prior to anterior interosseous nerve (see below), in addition to those
inserting onto the trapezium, forming a separate compartment fibers from the main median nerve, also contributes innervation
for the tendon of the flexor carpi radialis, which is, therefore, to the flexor digitorum superficialis muscle, particularly that
strictly speaking not in the same compartment as the median portion supplying the second digit.
nerve. After exiting the carpal tunnel, the median nerve splits Approximately 2-8 (mean 5.1) cm distal to the medial epi-
into multiple branches to innervate the cutaneous aspect of the condyle, the relatively large anterior interosseous nerve origi-
hand as well as several hand intrinsic muscles. nates from the median nerve trunk to course distally and
Neural Branching. From its origin just distal to the axilla, superficial to the flexor digitorum profundus muscle.428,763 This
through its course in the arm, the median nerve does not provide nerve then runs between the flexor digitorum profundus and
any muscular or neural branches until just proximal to the flexor pollicis longus muscles to course on the interosseous
medial epicondyle. The first muscular branch to arise from the membrane. The first muscle supplied by the anterior in-
median nerve is to the pronator teres muscle. Several small terosseous nerve is the flexor digitorum profundus muscle.
sensory branches are usually provided to the elbow joint upon Typically, the muscle bellies destined to supply the second and
passing this region (Fig. 24-4). In approximately 40-58% of in- third digits are innervated by the anterior interosseous nerve;
dividuals, the branch to the pronator teres muscle originates however, multiple variations may occur (see below). The flexor
proximal to the medial epicondyle. In 13-20% of persons, the pollicis longus muscle is then innervated by multiple branches
nerve to this muscle arises at the medial epicondyle, while 40-45% not uncommonly originating with those supplying the flexor
of the population has this nerve arise distal to the epicondyle.133-763 digitorum profundus muscle. The anterior interosseous nerve
terminates by innervating the pronator quadratus muscle.
Several branches are also provided to the wrist joint. The ante-
rior interosseous nerve is occasionally referred to as a pure
motor nerve. This is inaccurate because it contains afferent
fibers from not only the wrist joint, but also the muscle spindles
from the muscles innervated by this nerve. It is more correct to
state that the anterior interosseous nerve does not provide any
cutaneous innervation to the limb.
The last branch given off by the main trunk of the median nerve
in the forearm is the palmar cutaneous branch of the median
nerve. It originates from the radial side of the median nerve, on
average 8.4 cm proximal to the distal wrist crease.136-296-476-482-809
From its origin, the nerve courses distally along with the median
nerve between the palmaris longus and flexor carpi radialis ten-
dons. The palmar cutaneous branch of the median nerve pierces
the antebrachial fascia near the distal wrist crease to enter a short
tunnel (9-16 mm) formed in the mass of the transverse carpal lig-
ament just medial to the tunnel conveying the flexor carpi radialis
Pronator teres-^.j tendon.95-774 After exiting its tunnel, the nerve divides into rela-
Flexor digitorum tively large radial and smaller ulnar branches, which then further
subdivide to provide cutaneous sensation to the bases of the thenar
sublimis and hypothenar eminencies as well as a small area of skin in the
mid-palm region. The nerve usually continues distal to the wrist
Flexor pollicis crease for about 4.5 cm. It has variable extensions medial and lat-
eral to an axis formed by the third digit and median nerve at the,
longus wrist. It is a common misconception that this nerve supplies the'
FlexorproFundus
digitorum entire thenar eminence. Only a variable portion of the base and
muscle pad of the thenar eminence is supplied by this nerve.169
The palmar cutaneous nerve may share its innervation to the
Pronator thenar eminence's proximal aspect with the lateral antebrachial
cutaneous (musculocutaneous) and superficial radial nerves and
quadratus- occasionally with the palmar cutaneous branch of the ulnar
Abductor nerve.420-727-763 It may also be completely absent, in which case any
pollicis
Opponens brevu or all of the above-noted nerves provide sensibility to this area.
pollicis The primary significance of this nerve is that it may be injured
Superfic. during surgical releases for carpal tunnel syndrome, subsequently
headcfi
tumbrii causing pain due to neuroma formation.
flexor The main trunk of the median nerve continues distally to
pollicis
brevis
Figure 24-4. Median nerve branching. Median nerve course and enter the hand, but prior to doing so, it must traverse the carpal
neural branching in the upper limb. Note the cutaneous innervation of
1st anterior
£ 2m and posterior portions of the hand (insert). (From tunnel. As noted above, the carpal tunnel is bounded by four
the carpal bones and a tough transverse carpal ligament. Before en-
Haymaker W,Woodhall B: Peripheral Nerve Injuries. Philadelphia,W.B. tering the carpal tunnel, the median nerve is roughly cylindrical
Saunders, 1953, with permission.) to oval in shape. Upon entering the carpal tunnel, however, a
Median Nerve
Transverse Carpal Ligament
Sublimis 3 Figure 24-5. Median nerve tissue rela-

Sublimis 2 tionships. Sagittal section of the forearm,
wrist, and hand along the axis of the third
metacarpal facing ulnarly. Note the profound
flattening of the median nerve as it crosses the
narrowest portion of the carpal tunnel beneath
the thickened transverse carpal ligament.
(From Robbins H: Anatomical study of the
median nerve in the carpal tunnel and etiolo-
gies of carpal tunnel syndrome. J Bone Joint
Profundus 2 Surg 1963;45A:953-966, with permission.)
Pronator Quadratus
Adductor Pollicis
Puronu'a SjmcM' (with Fat)
Figure 24-6. Palmar neuromuscular structures. A dissection of the palm of the hand depicting the neural innervation of the hand by the
median and ulnar nerves. Note the communicating ramus between the median and ulnar nerves. (From Clemente CD: Gray's Anatomy of the
Human Body. Philadelphia, Lea & Febiger, 1985, with permission.)
dramatic flattening of the nerve occurs. The nerve flattening is In the palm, the median nerve's lateral limb becomes the first
maximal approximately 2.0-2.5 cm distal to the proximal edge common palmar digital nerve. This nerve then divides into
of the transverse carpal ligament (Fig. 24-5). 643 This is the nar- three proper digital nerves with two branches supplying the
rowest portion of the carpal tunnel, which is shaped somewhat volar aspect of the first digit and thenar eminence, and a third
like an hourglass in the plane of the palm. Coincidentally, the innervating the radial portion of the second digit (Fig. 24-6).
transverse carpal ligament is also quite thick in this region. The third proper palmar digital nerve also provides innervation
Just prior to reaching the distal edge of the transverse carpal to the first lumbrical muscle. The median nerve's medial limb
ligament, the median nerve splits into lateral and medial limbs. divides into two divisions, the second and third common
At the level where these two divisions arise, a thenar or recur- palmar digital nerves. Continuing distally, the second
rent (motor) branch of the median nerve originates to course common palmar digital nerve first provides innervation to the
distally for a short distance to then enter a tunnel in the traris- second lumbrical muscle and then splits into proper digital
verse carpal ligament just beyond this ligament's thickest nerves to supply cutaneous sensation to the adjacent sides of the
region.338 It then proceeds proximally to pass into the substance second and third digits. Lying most medial, the third common
of the thenar mass. The distal edge of the transverse ligament can palmar digital nerve innervates the skin between the third and
be approximated by flexing the fourth digit so that the finger tip fourth digits supplying the radial half of the fourth digit. There
encounters the base of the thenar eminence. Flexing the third is usually a communication between this nerve and the ulnar
digit adjacent to the fourth defines the arborization of the recur- nerve in the mid-palm region. Occasionally, a small branch
rent branch into the substance of the thenar muscles. This nerve from this nerve provides some innervation to the third lumbri-
innervates the abductor pollicis brevis, opponents pollicis, and cal, in which case this muscle is dually innervated. All of the
superficial head of the flexor pollicis brevis muscles. proper digital nerves provide cutaneous sensibility to the palmar
surface of the digits and the dorsal skin of the terminal phalanx ulnar direction secondary to the unopposed action of the flexor
of their respective digits. Communication with the terminal dig- carpi ulnaris muscle. When the patient attempts to make a fist,
ital branches of the superficial radial nerve occurs about the the first two digits fail to flex, while the third may flex slightly.
more proximal regions of the digits toward their dorsal surface. The fourth and fifth digits usually function quite normally. This
hand posture is referred to as the benediction sign (Fig. 24-7).
FOCAL MEDIAN NERVE NEUROPATHIES It is important to note that this posture is assumed only upon at-
tempted forced flexion of the digits, while at rest the hand's po-
The median nerve can be compromised at multiple locations sition may appear quite normal. With time, the thenar eminence
from its formation in the axilla proximally to the carpal tunnel usually demonstrates profound wasting and appears hollowed
distally. Axillary median nerve lesions have already been pre- out. Palmar abduction of the thumb (movement of the thumb at
sented in conjunction with brachial plexopathies. In this section, right angles to the palm) is severely limited, as the abductor pol-
relatively well-localized lesions affecting the median nerve licis brevis and superficial head of the flexor pollicis brevis
distal to the axilla are discussed. muscles are no longer functional. There may be limited abduc-
tion because the deep head of the flexor pollicis brevis can gen-
Arm Region erate some palmar abduction. Radial thumb abduction may still
Clinical Features. Lesions affecting the median nerve in the be possible to a minor degree, as the abductor pollicis longus is
arm may arise secondary to humeral fractures, lacerations, bullet intact (radial nerve). Thumb opposition to the fifth digit is im-
wounds, brachial artery-cephalic vein fistulas, and compression possible, and the movement observed is one of thumb adduction
from: prolonged tourniquet application, rifle slings, anomalous from the adductor pollicis and flexor pollicis brevis muscles
muscles, hanging over chair backs (sleep/Saturday night palsies), (ulnar nerve). Sensory loss is in the typical distribution of the
and a person's head (honeymoon palsies). 42 ' 54 - 59 - 460 ^ median nerve affecting the palmar aspect of the hand and first
Any one of these lesions can result in either complete or partial three and one-half digits as well as the dorsal surfaces of the
nerve injuries with a corresponding loss in the hand's functional distal phalanx of these digits.
ability and sensation. It is important for the practitioner to be aware of how patients
A complete median nerve injury in the arm results in loss of with complete median nerve injuries can still perform appar-
median innervation to muscles distal to the lesion site beginning ently appropriate maneuvers. For example, an individual with a
with the pronator teres. The patient demonstrates an inability to complete median nerve injury in the arm region can continue to
pronate the arm against gravity. Similarly, any attempt at wrist pronate the forearm despite a complete absence of voluntary
flexion results in the hand weakly flexing, and deviating in the motor units and florid membrane instability on needle elec-
tromyography in the median innervated muscles. The answer is
"trick" movements in which muscles innervated by intact
nerves substitute for the denervated muscles. 763 When substitu-
tion is utilized to achieve a given motion, the patient cannot
overcome resistance, but the observed motion can mislead the
examiner into thinking only a partial, as opposed to a complete
lesion, is present. In the above example, the brachioradialis
muscle is capable of pronating the forearm from the completely
supinated position to just enough pronation to where gravity
completes the pronation activity. Sunderland's excellent text-
book on peripheral nerve injuries reviews how to examine pa-
tients properly and eliminate muscle substitutions during
manual muscle testing.763
Electrophysiologic Evaluation and Findings. In evaluating
median neuropathies, it is possible to record a median SNAP
from digits 1-4. The first and fourth compared with the second
and third digits generate relatively smaller responses. This is be-
cause the fourth digit shares its innervation with the ulnar nerve,
while the first digit has a major sensory contribution from the
radial nerve. For most focal median neuropathies proximal to
the wrist, it is sufficient to examine a single digit with either the
second or third being the most commonly studied. A number of
techniques use an anatomic landmark such as the distal wrist
crease, but a standard distance such as 14 cm is preferred, par-
ticularly when one will also record the amplitudes, as they are
especially sensitive to distance. Either antidromic or ortho-
dromic sensory evaluations can be used, but antidromic tech-
niques usually yield more easily obtained responses. It can be
Figure 24-7. Benediction sign. Hand posture following median anticipated that lesions proximal to the above-noted site of pe-
nerve injury with inability to flex the thumb and radial two fingers, i.e., ripheral nerve stimulation result in preferential amplitude re-
the first three digits.The diagram to the right of the figure depicts reductions with mild prolongations in latency. One does not
gions of anesthesia (black) and hypesthesia (lined). (From Haymaker W, anticipate an alteration in latency unless there is asynchronous
Woodhall B: Peripheral Nerve Injuries. Philadelphia, W.B. Saunders, slowing distal to the site of stimulation, or when a significant
1953, with permission.) number of preferentially faster conducting axons have undergone
Wallerian degeneration. Side-to-side comparisons of both am- the anterior interosseous nerve, as its branch arises in the proxi-
plitude and latency (conduction velocity) are the two important mal forearm. Performing the needle examination prior to the de-
parameters evaluated. A lesion located in the arm should result velopment of membrane instability only reveals recruitment
in a median SNAP from the second or third digit displaying a abnormalities provided the lesion has affected a sufficient
reduced amplitude and possibly prolonged latency. If there is number of axons.
profound axonal disruption, a SNAP may be unobtainable from As previously stated for sensory studies, both the motor con-
any of the first four digits. It is important to document the pres- duction studies and needle electromyographic evaluation should
ence of an ulnar SNAP to support the diagnosis of a focal be performed on more than just median-innervated muscles. A
injury to just the median nerve. If the ulnar SNAP is also ab- CMAP for the ulnar nerve to the abductor digiti minimi (ADM)
normal, it is then necessary to pursue a concomitant ulnar and the radial nerve to the extensor indicis proprius (EIP) mus-
nerve injury or peripheral neuropathy. Because the radial nerve cles are a good idea. Multiple muscles innervated by both the
is relatively close to the median nerve in the arm, a complete ulnar and radial nerves in addition to the median-innervated
electrophysiologic sensory examination involves an analysis of muscles are important to evaluate with a needle electromyo-
the superficial radial SNAP as obtained from the hand's dorsal graphic electrode. A normal ulnar or radial nerve CMAP and
aspect. The SNAPs from these three nerves allows one to gain SNAP do not obviate the need to perform a needle investigation
a general idea as to the lesion's extent. Also, the SNAPs help of radial and ulnar innervated muscles. The needle examination
the practitioner plan the most appropriate muscles to examine is quite sensitive to mild axonal loss, while the wide variation in
during the needle electromyographic and motor conduction normal for CMAP and SNAP amplitudes may not reflect a loss
portions of the examination. of less than a moderate amount of axons. It is entirely possible
Recording a CMAP from the APB is the most common to find positive sharp waves and fibrillation potentials in radial
median motor nerve technique. A lesion in the arm would be ex- and ulnar innervated muscles despite corresponding "normal"
pected to result in a CMAP reduction when obtained from wrist CMAPs and SNAPs. A similar statement regarding sensitivity
stimulation and as compared with the contralateral side. The can also be made with respect to the clinical examination.
distal motor latency to wrist stimulation may or may not be ab- Frequently, mild ulnar or radial nerve lesions about the arm may
normal, depending upon the number of fast conducting fibers be missed on clinical examination while needle electromyogra-
injured and time since injury. In profound injuries, a more pro- phy demonstrates evidence of axonal loss.
longed latency can be expected. Subtracting the wrist from the
antecubital fossa median nerve latencies allows one to calculate Distal Arm/Proximal Forearm Region
a forearm median nerve conduction velocity. Again, if a suffi- Median nerve injuries can result from a number of etiologies
cient number of fast conducting fibers are lost, this velocity can in the distal aspect of the arm or proximal forearm area, i.e.,
be abnormal. In arm lesions, it is a good idea to stimulate in the about the elbow. A number of these median lesions can arise be-
axilla as well as in the antecubital fossa or just proximal to this cause of gunshot wounds and fractures/dislocations of the
site, i.e., the distal arm. Using these two stimulus sites, one at- elbow resulting in both direct and indirect neural trauma,
tempts to localize the lesion between the proximal and distal median nerve lacerations, and nerve compression from the
points of neural activation. If the CMAP obtained with axilla bicipital aponeurosis (lacertus fibrosus), supracondylar spur/lig-
stimulation is significantly less than 80% of that with elbow ex- ament of Struthers, pronator teres muscle, or the proximal edge
citation, consideration should be given to the presence of a con- of the flexor digitorum superficialis fibrous ridge. Bullet
duction block. This type of lesion has a relatively good wounds and lacerations from sharp objects are typically quite
prognosis for recovery provided the offending lesion resolves. obvious, and the main purpose for the electrodiagnostic medi-
When the pathology is such that the brachial segment of the cine consultation is to provide an assessment of remaining
median nerve displays a drop in conduction velocity when com- neural function as well as establish the integrity of associated
pared with the forearm or contralateral arm, some form of de- neural structures. The remaining etiologies of median nerve
myelination is likely present. A reduced amplitude at all compression about the elbow region can at times pose a diag-
stimulation sites, but no drop in NCV across the arm, is sugges- nostic challenge and are worth discussing in some detail.
tive of an injury producing primarily axonal loss. Examining a
partial lesion several months or years following the inciting in- Fractures and Dislocations
cident may result in no abnormality if the process of collateral Clinical Features. Fractures of the humerus and radius/ulna
sprouting has successfully reinnervated the previously dener- as well as dislocations of the elbow joint can result in axonal
vated muscle fibers, and there is sparing of some fast conduct- injury to any of the three main nerves traversing the arm.
ing fibers. A normal NCV combined with a relatively normal Supracondylar fractures of the humerus usually produce a com-
CMAP is expected, thus obliterating any hint of a previous bination of axonal loss and reduced conduction affecting pri-
lesion as judged solely by nerve conduction techniques. The marily the radial nerve, less commonly the median nerve, and
wide range of normal CMAP amplitude allows for considerable only occasionally the ulnar nerve.434-812 Several studies, how-
variation with respect to side-to-side differences. ever, note that median nerve injuries may be more common than
It is best to wait about 2-4 weeks prior to performing the ulnar and occasionally radial nerves.i85-268-292,341-729 Following
needle electromyographic examination depending upon the dis- elbow dislocations, the median and ulnar nerves can rarely be
tance between the lesion and muscle tissue. This is a slightly injured or entrapped between the bony elements.278-481-617-737
shorter time than recommended for radicular injuries because The mechanism of injury is usually traction in mild to moder-
focal peripheral nerve lesions are usually more distal and closer ate injuries and compression or laceration from bony fragments
to their respective muscles. In the case of median nerve arm in- in more severe trauma. It is also possible for a delayed median
juries, membrane instability can be expected in all muscles in- nerve injury to occur following the application of orthopedic
nervated by the median nerve beginning with the pronator teres stabilization hardware, or through repetitive trauma and com-
muscle. This comment also refers to the muscles innervated by pression by bony callus formation. 261763 Involvement of the
median nerve is usually obvious based on physical signs and is that a fibrous or fibro-osseous ligament (ligament of
symptoms. Struthers) usually extends distally from the spur to attach to
Electrophysiologic Evaluation and Findings. The electro- the medial epicondyle of the humerus (Fig. 24-8). Rarely, only
physiologic examination may be of value in clearly defining the the ligament is present and an obvious spur is absent.711-756-764
extent of the neural injury in the affected limb. Obvious median The median nerve, with or without the brachial artery, usually
nerve injuries are present, but concomitant radial or ulnar nerve passes through the opening between the humerus and the fibro-
lesions may also be detected, but not readily appreciable on osseous ligament. Although this situation does not necessarily
clinical examination. Nerve conduction or needle electromyo- lead to a problem, some patients can develop compromise of the
graphic studies may reveal evidence of axonal loss or conduc- median nerve as it passes through the above-noted open-
tion block in the clinically suspected as well as unsuspected ing 32.37i.5i i,767 When present, it is not unusual for the pronator
neural lesions. Also, documenting obtainable responses and vol- teres muscle to arise from the fibro-osseous bridge, which may
untary motor units defines a nerve lesion as incomplete. If the further add to compression of the median nerve.833
patient has absent clinical function in the median nerve distribu- Patients usually complain of an insidious onset of weakness
tion but obtainable SNAPs and CMAPs greater than 10 days primarily affecting the hand's ability to hold onto objects as
after the injury, it is likely that some component of conduction well as difficulty flexing the wrist against resistance. Numbness
block is present. Membrane instability on needle examination can affect any portion of the hand's volar aspect from selective
should be looked for in muscles innervated by the different involvement of one of the first four digits to the entire surface of
major nerves of the affected limb. It is possible to detect signs the palm and the first three and one-half digits. A deep, aching
of denervation in nerve distributions not suspected by clinical type of pain is localized about the proximal forearm, which may
examination. Following appropriate treatment for the fracture or be exacerbated by repetitive pronation and supination.
dislocation, one can follow any nerve injury from the perspec- Occasionally, this pain can radiate proximally to the shoulder or
tive of functional return and reinnervation. The disappearance distally to the hand. On physical examination, the deep tendon
of membrane instability combined with increases in muscle reflexes are usually preserved except for hand pronation and
strength suggests that muscle reinnervation is progressing. finger flexion to the second and third digit. This absence is usu-
Should neural function deteriorate secondary to compromise of ally noted only in patients with profound nerve damage present
the nerve by exuberant callus formation, the electrophysiologic for quite some time. Muscle wasting of the APB may be noted j
examination may be of assistance in documenting this func- on hand inspection. Attempts at manual muscle testing of the
tional decline. pronator teres and flexor carpi radialis muscles may aggravate
the patient's pain complaints. A Tinel's sign can be present at
Supracondylar Spur and Ligament of Struthers the elbow region, or just proximal to the medial epicondyle.
Clinical Features. Approximately 3-6 cm proximal to the Muscle testing reveals mild to moderate weakness, depending
humerus' medial epicondyle, a bony spur less than 2 cm in upon the degree of median nerve axonal loss, of the wrist and
length can arise from the anteromedial aspect of the humerus in finger flexors (superficial/deep innervated by median nerve) as
0.7-2.7% of the population.52-306-407-754-755-756-778-779 Occasionally well as forearm pronation and thumb abduction/opposition. It is
this bony process can be found bilaterally.475-833 Of importance important to test the flexor pollicis longus muscle because it is
innervated by the anterior interosseous nerve and when affected
in combination with the hand intrinsic/extrinsic muscles implies
a lesion proximal to the formation of this nerve, i.e., arm or
proximal forearm. The appearance of the hand may be quite
similar to that in median nerve lesions occurring in the more
proximal regions of the arm (see above). Only rarely is a bony
spur palpated, but in such patients where a proximal median
nerve lesion is suspected, it is a good idea to attempt to feel for
this bony anomaly. An inability to palpate this structure, how-
ever, does not imply that it is absent, as radiographic evaluation
frequently reveals this anomaly when none could be palpated on
physical examination.
Electrophysiologic Evaluation and Findings. A profound
compromise of the median nerve as it passes between the
humerus and ligament of Struthers results in a number of char-
acteristic findings.764 An absent or markedly abnormal median
SNAP can be anticipated as recorded from any of the first four
digits. The CMAP from the APB reveals a reduced conduction
velocity over the segment from approximately mid-arm to the
antecubital fossa when demyelination is present. If there is a
component of conduction block, one may expect to find a sig-
nificantly smaller CMAP to mid-arm stimulation than when ex-
citing the nerve in the antecubital fossa or wrist provided a
Figure 24-$. Ligament of Struthers.The median nerve is shown supramaximal stimulus is applied to all sites. The evoked CMAP
passing through an opening between the humerus and ligament of from the APB at all stimulus sites is smaller than when elicited
Struthers. Note how the median nerve can be compressed in this tight from comparable regions on the contralateral limb. Needle elec-
space. (From Liveson JA: Peripheral Neurology: Case Studies in tromyographic evaluation of the affected upper limb demon-
Electrodiagnosis. Philadelphia, F.A. Davis, 1991, with permission.) strates abnormalities only in the median-innervated muscles.
Specifically, all median-innervated muscles in the affected limb median nerve wrist stimulation is reduced, but the forearm con-
including the pronator teres muscle reveal membrane instability. duction velocity can be normal provided significant axonal loss
This includes those muscles innervated by the anterior in- has not yet occurred. Stimulating both above and below the
terosseous nerve. The above description is consistent with a elbow region demonstrates a slowing of conduction in chronic
severe lesion proximal to the origin of the anterior interosseous cases where there has been demyelination/remyelination
nerve and has the same presentation as a median nerve injury at changes. In patients who present with an acute event, it is possi-
any location between the axilla and the origin of the muscular ble to note a component of conduction block by observing a
branch to the pronator teres muscle. In less severe compromise drop in CMAP amplitude across the elbow region. Needle elec-
of the median nerve from a ligament of Struthers, there may be tromyographic examination is important, as it should demon-
an absence of conduction block or overt slowing of neural con- strate membrane instability in the forearm and hand muscles
duction across the affected segment. A mild to moderate reduc- innervated by not only the main trunk of the median nerve but
tion in SNAP and CMAP amplitudes may be observed. Not all also the anterior interosseous nerve. Of most importance is de-
muscles reveal membrane instability. It is nevertheless very im- tecting abnormalities in the pronator teres muscle, which docu-
portant to examine the pronator teres and flexor pollicis ment a median nerve injury within or proximal to the pronator
longus/pronator quadratus muscles in suspected median nerve teres muscle. Unfortunately, a lesion at any level from the axilla
lesions even if carpal tunnel syndrome is the obvious clinical di- to the elbow can produce the electrophysiologic findings noted
agnosis. This is because the median nerve may be injured at a above. Combining the history, physical examination, and elec-
more proximal site in addition to the more obvious distal loca- trophysiologic findings can at least narrow the likely site of
tion. Therapeutic intervention directed only to a single region lesion to be at or about the elbow region and include the liga-
may result in unsatisfactory results because the second lesion ment of Struthers and lacertus fibrosus as likely structures to
site is missed. consider in the differential diagnosis. As with the ligament of
Treatment for median nerve compression by a ligament of Struthers, surgical exploration has been recommended to both
1 Struthers may be conservative or surgical depending upon the definitely assess the situation and decompress the median nerve
severity of the lesion. Most chronic compressions with electro- by sectioning the offending structure.
diagnostic medicine evidence of axonal loss or profound clini-
cal symptoms should probably be operated upon to relieve the Pronator Teres Syndrome
neural compromise. From time to time, there may be an associ- Clinical Features. Just distal to the proximal edge of the
ated fracture of the supracondylar spur from trauma or muscular bicipital aponeurosis, the median nerve passes between the two
forces, and if associated with neural injury, again operative in- heads of the pronator teres muscle in 83-95% of arms dissected
tervention should be considered.161'390-449-547 Most patients and travels either beneath both heads or through one of them in
demonstrating median nerve damage appear to respond quite the remaining limbs (Fig. 24-9).36-326-412-713 The median nerve then
well to surgical release of the ligament of Struthers and regain
relatively good limb function.
{Bicipital Aponeurosis (Lacertus Fibrosus)
Clinical Features. A thickening of the antebrachial fascia that
serves to attach the biceps brachii muscle to the ulna is referred to
as the bicipital aponeurosis or lacertus fibrosus."8456545728766 It
is believed to assist in elbow flexion and overlies the median nerve
and flexor muscle mass in the proximal forearm region. Although
this anatomic structure is present to varying degrees of develop-
ment in most persons, it only rarely compresses the median nerve.
The few patients reported to have been diagnosed with this type of
anatomic compression of the median nerve have clinical com-
plaints similar to those previously described for neural compro-
mise secondary to a ligament of Struthers.I92-243-339-408'477-766
The patient usually complains of elbow pain with associated
pain radiating to the wrist and occasionally the proximal arm.
There is numbness in the distribution of the median nerve af-
fecting any or all of the digits and palmar surface of the hand.
An inability to use the hand such as gripping and buttoning
shirts is typically noted. Onset of symptoms is insidious if
repetitive activities are the cause, but may be acute in manual
laborers who perform a strenuous precipitating lifting event.
Physical examination demonstrates weakness in all the median-
innervated muscles including the pronator teres. In profound A B
disease, both thenar muscle atrophy and a benediction sign can
be observed. A Tinel's sign can usually, though not always, be Figure 24-9. Sublimis bridge. The median nerve is shown de-
elicited at the elbow region. It is usually possible to demonstrate scending beneath the sublimis bridge after traversing the space be-
decreased sensation in the typical median nerve distribution. tween the two heads of the pronator teres. N o t e that the nerve is
Electrophysiologic Evaluation and Findings. Median depicted compressed at the sublimis bridge. (From Kopell HP,
nerve SNAPs are typically of reduced amplitude and can be Thompson WAL: Pronator syndrome: A confirmed case and its diagno-
absent in long-standing disease. The thenar CMAP amplitude to sis. N Engl J Med 1958;259:713-715, with permission.)
immediately passes beneath the so-called sublimis bridge or fi- motor fibers experience axonal loss. Median NCV over the fore-
brous arch of the flexor digitorum superficialis muscle and con- arm segment can be abnormal; however, this is not a consistent
tinues distally under cover of this muscle. The median nerve is finding, particularly in less than severe cases.111J89'525'535 Active
known to become compromised as it passes through the pronator isometric forearm pronation is used to produce abnormal neural
teres muscle, or about the sublimis bridge, either through "kink- conduction supposedly through a mechanism of reversible con-
ing" on passage through this region or by constricting anomalous duction block; however, this has not been proved to be a worth-
fibrous bands crossing the two heads of the flexor digitorum su- while maneuver. 535 814 Sequential needle excitation of the
perficialis muscle (Fig. 24-9).227-285-364-392-395 The median nerve median nerve in 1-cm segments while recording the APB's
can be compressed at this level by a number of causes such as CMAP may reveal a region of conduction block in or about the
hypertrophied pronator teres muscle, repetitive prona- pronator teres muscle. 80
tion/supination motion, acute forceful pronation, anomalous ar- Needle electromyographic examination can be particularly
teries penetrating the median nerve about the pronator teres useful when examining patients with a suspected pronator teres
muscle, and postoperative scarring.4l-,34-,89J44-382-689'823 A related syndrome. Membrane instability can be anticipated in all
median nerve compression in the proximal forearm that may pre- median-innervated muscles distal to the pronator teres muscle.
sent similar to a pronator teres syndrome is compression of the The pronator teres muscle is reportedly spared because this
median nerve by carrying a heavy bag with the arm flexed (gro- muscle is innervated by axonal branches prior to the median
cery-bag neuropathy).625 The weight of the heavy bag is distrib- nerve trunk entering the main substance of the muscle, thereby
uted over the small surface area of the handles of the bag, which escaping compromise. na243,816 This is not an invariable finding,
acts as a guillotine on the forearm and compresses the median and it is possible for individuals with surgically proven compro-
nerve with a potential for axonal loss. mise of the pronator teres muscle whose symptoms resolve after
Patients with pronator teres syndrome usually note in retro- surgery to have membrane instability in the pronator teres
spect upon questioning an insidious onset of a diffuse type of muscle.7-285 This finding is most likely a result of at least some
dull, aching pain about the proximal forearm exacerbated by portion of the pronator teres muscle being innervated by neural
forced forearm pronation. Occasionally, a few patients may note branches arising distal to the site of compression (see above
an acute onset of a more sharp pain in the proximal forearm as- anatomy section).298
sociated with strenuous muscular effort involving pronation. Treatment consists of initially attempting a conservative regi-
Repetitive pronation/supination results in subjective complaints men of avoiding the offending repetitive trauma, rest, and corti-
of not only pain but also easy fatigue of the forearm and hand costeroid infiltration of the pronator teres muscle.525 If this fails
muscles as well as diffuse numbness of the hand most com- to resolve the patient's symptoms, surgical release of the prona-
monly involving the second or third digit. Unlike carpal tunnel tor teres muscle and any constricting bands should be consid-
syndrome, nocturnal awakening secondary to pain and pares- ered. Fortunately, differentiating between a ligament of
thesias is absent or occasional. These somewhat vague clinical Struthers, lacertus fibrosus, and pronator teres muscle as the of-
complaints may or may not be associated with significant phys- fending agent is essentially a moot point, as the surgical release
ical findings. The complaint of forearm pain should always is generally in the area of all three structures and best deter-
prompt palpation of the proximal flexor muscle mass particu- mined by direct exploration of the area.7
larly about the median nerve as it passes beneath the lacertus fi-
brosus and through the pronator teres muscle. More proximal Comment
palpation for a supracondylar spur and nerve tenderness is also The electrodiagnostic distinction of various proximal focal
important. Pronator teres muscle tenderness is the most median neuropathies can be quite challenging. The above de-
common finding in patients with suspected compromise of the scriptions are of severe median nerve injuries where there is
median nerve by this muscle. Forceful pronation of the forearm little question of axonal loss or the findings of membrane insta-
against resistance usually reproduces the patient's complaints of bility on needle electromyographic examination. In patients
pain, and paresthesias when present. Noting aTinel's sign about with acute or chronic disease of a mild nature, there may be
the elbow is a rather common finding. Occasionally, in long- little in the way of electrophysiologic abnormalities. This is
standing cases of a severe nature, muscle wasting may be noted simply a limitation of the investigation. Even in instances of
in the region of the common flexor muscle mass and thenar em- severe disease, the above three syndromes may appear identical,
inence. Manual muscle testing can reveal weakness in the fore- particularly if a patient's pronator teres is innervated within the
arm flexor muscles; however, pain on testing usually obviates a substance of the muscle by at least a few axonal twigs. Neither
completely accurate assessment of strength. Objective sensory motor/sensory nor needle electromyographic findings are of as-
loss in the median nerve distribution is usually not detected until sistance. When patients present with a history of forearm pain,
the syndrome has been present for some time or an acute inci- paresthesias, and associated complaints of hand and forearm
dent has severely injured the median nerve. weakness, the above-noted syndromes should be considered.
Electrophysiologic Evaluation and Findings. Unfortunately, The practitioner may occasionally find that the lacertus fibro-
the above somewhat vague clinical presentation is not always sus, pronator teres, and sublimis bridge compressions of the
clarified by the electrodiagnostic medicine evaluation. In rela- median nerve are collectively referred to as "pronator syn-
tively severe compromise of the median nerve, one can antici- dromes." This concept simply reflects one's inability to ade-
pate a number of electrophysiologic findings. Compression of quately distinguish between the above-noted possibilities. The
the median nerve by the pronator teres muscles and/or the sub- practitioner is urged to alert the referring physician to any of the
limis aponeurosis results in the diminution or absence of above-noted syndromes as possible causes for proximal focal
median evoked SNAPs from the first through fourth digits. median neuropathies when there is a lack of obvious traumatic
Sensory latencies to these digits should not be abnormal until insult.
such time only the slowly conducting fibers remain. A reduced Perhaps one of the most important functions the electrodiag-
CMAP amplitude to the APB is also expected when median nostic medicine evaluation performs is an assessment of both
the distal and proximal aspects of the peripheral nervous
system. The presence of a concomitant carpal tunnel syndrome
must always be considered (see below). Because it is so
common, there is a distinct possibility that both a proximal and
distal focal median neuropathy may be present. Treating only
one disorder is a prescription for continued patient discomfort
and unsatisfactory therapeutic results. There is also a possibility
that a cervical radiculopathy may be coexistent with a median
neuropathy at the elbow. Again, failing to properly treat both
nerve lesions will result in persistent patient discomfort. As al-
luded to previously, the radial and ulnar nerves can be injured to
variable degrees in a number of disorders causing primarily a
median neuropathy. Finally, individuals with generalized pe-
ripheral neuropathies are susceptible to the development of mul-
tiple focal peripheral neuropathies, and this possibility should Figure 24-10. "OK" sign. Patient capable of demonstrating a
always be evaluated. normal "OK" sign with the right hand while a similar attempt on the
left produces the characteristic posture of an anterior interosseous
Anterior Interosseous Nerve (Kiloh-Nevin Syndrome) nerve lesion secondary to weakness of the long finger flexors of the
Clinical Features. Isolated paresis or paralysis of the flexor thumb and second digit. (From Sunderland S: Nerve and Nerve
pollicis longus, pronator quadratus, and flexor digitorum profun- Injuries. Edinburgh, Churchill Livingstone, 1978, with permission.)
dus to the second and third digit is usually a result of a focal an-
terior interosseous neuropathy. A number of etiologies have
been implicated in this disorder and include spontaneous (idio- the flexor pollicis longus and digitorum profundus muscles to
pathic), neuralgic amyotrophy, forearm/humeral fractures, mus- the first and second digit cannot touch just the pulps of the
cular exertion of the forearm muscles, injection injuries, gunshot finger tips. Instead, the entire volar surfaces of these digits are
wounds, elbow arthroscopy, lacerations, pregnancy, and anom- in contact. Also, the metacarpophalangeal joint of the first digit
alous fibrous band compression or accessory head of the flexor and interphalangeal joint of the second digit are excessively
pollicis longus muscle (Gontzer's mUscle).73-197-261-294-483-495^ flexed while these digits' interphalangeal joint is hyperex-
635,672.724.727.801.808 j persons with spontaneous onset of anterior in-
n tended. It is possible for some patients to present with preferen-
terosseous neuropathy, an aching type of pain can occasionally tial weakness of the flexor pollicis longus and variable sparing
be noted in the forearm muscle mass prior to the onset of weak- of the pronator quadratus and profundi muscles suggesting a
ness. 340.585.635.655.672.724.725.727.8Ol.808.838
T n e l WCakneSS IS quite
m u S C e partial anterior interosseous syndrome. Although this is cer-
characteristic in that only three muscles demonstrate evidence of tainly a possibility, one must also consider that it is likely that
paresis: flexor pollicis longus, pronator quadratus, and flexor the long finger flexors were primarily innervated by the ulnar
digitorum profundus to the second and third digits. Patients usu- nerve and the pronator quadratus muscle is overwhelmed by the
ally complain of difficulty in attempting to pick up small objects pronator teres muscle because of poor testing procedures or
with the first two digits. There is a distinct lack of sensory com- other reasons. Sensation testing should reveal no deficits in a
plaints. Similar complaints are noted by those individuals sus- pure anterior interosseous nerve injury. Rarely, the fascicles
taining obvious trauma to the limb resulting in a pure anterior destined to become the anterior interosseous nerve may be pref-
interosseous nerve injury aside from the trauma-induced pain. erentially injured more proximally in the median nerve where
Physical examination is relatively straightforward in persons they are tightly grouped. 817 These cases present exactly like a
with pure focal lesions of this nerve. Sensation should be intact lesion more distally affecting solely the anterior interosseous
in the affected limb. Manual muscle testing must be properly nerve despite an injury to the proximal median nerve trunk such
performed to elicit weakness in the appropriate distribution. For as in humeral fractures. Forearm MR imaging using short inver-
the first digit, the metacarpophalangeal joint is braced in extension-recovery (STIR) can reveal muscle denervation in only the
sion by the examiner and the patient is asked to flex just the anterior interosseous nerve distribution.259 The full utility of this
distal phalanx. A similar maneuver is performed for the remain- technique remains to be realized.
ing digits while also stabilizing the proximal interphalangeal Electrophysiologic Evaluation and Findings. The electro-
joint. This procedure eliminates the flexor digitorum superfi- diagnostic medicine examination can be quite helpful in confirm-
cialis muscle and isolates the flexor digitorum profundus ing a suspected anterior interosseous nerve syndrome.I2a230-294-539-551 •
muscle's action on the terminal phalanx. A patient with a lesion A |j SNAPs in the affected upper limb are normal. If
62o.687.74o.8i8
to the anterior interosseous nerve will be unable to exert much an abnormal SNAP is found, it is due to some other lesion and
in the way of terminal phalanx flexion. The most reliable not the anterior interosseous nerve injury. Motor conduction
muscle, however, for testing a lesion of this nerve is the flexor studies can be quite useful, particularly if performed with sur-
pollicis longus and usually the flexor digitorum profundus, as face conduction techniques. 534 The most appropriate technique
the first digit is always, and the second digit usually, innervated at this time appears to be recording from the pronator quadratus
by the median nerve, while the remaining deep finger flexors muscle where the surface-active recording electrode is posi-
can be innervated by the ulnar nerve.763 The pronator quadratus' tioned 3 cm proximal to the ulnar styloid midway between the
clinical function is difficult to isolate from the pronator teres, but radius and ulna on the dorsal surface of the forearm. The refer-
this can be attempted by flexing the forearm and asking the pa- ence is located on the ulnar styloid with a ground just proximal
tient to resist supination. A useful clinical test is to ask the patient to the active electrode. The median nerve is excited at the ante-
to forcefully approximate the finger pulps of the first and second cubital fossa as for most routine studies. A mean onset latency
digits in the "OK" sign (Fig. 24-10). Persons with weakness of for the CMAP is 3.6 ± 0.4 ms (2.9-4.4 ms) with a side-to-side
difference of 0.0-0.4 ms. The baseline-to-peak amplitude is 3.1 Treatment for the anterior interosseous entrapment syndrome
± 0.8 mV (2.0-5.5 mV) with a side-to-side difference of is at first conservative. If spontaneous improvement does not
0-25%. The CMAP duration with this technique is 7.7 ± 1.3 ms occur by 6-8 weeks, consideration should be given to surgical
(5.5-10.4 ms) with a side-to-side difference of 0-2.4 ms. exploration.409-724-725'727-815 Those patients with spontaneous focal
Techniques employing needle recordings for latency are accept- neuropathies of this nerve have been found to have various con-
able, but those using surface recordings are much more satisfactory nective tissue bands apparently compromising the nerve.
for recording CMAP amplitudes and durations representative of Following external neurolysis, these patients made an unevent-
the entire muscle depolarizing. Needle electromyography ful recovery. If surgical decompression fails to resolve the
should demonstrate evidence of membrane instability in the weakness, tendon transfers may be considered. There is a sug-
three muscles innervated by the anterior interosseous nerve. A gestion that some patients demonstrate a more rapid recovery if
single case has been reported in which the pronator teres muscle surgery is not performed. 539 Because of the small number of
revealed membrane instability secondary to an anomalous in- cases, further studies are required to define the best treatment
nervation of this muscle by a neural branch from the anterior options.
inerosseous nerve. 21 It is good practice to always examine the
flexor pollicis longus whenever a focal median neuropathy is Forearm Nerve Lesions
suspected, even if a carpal tunnel is clearly present. From time Clinical Features. The main trunk of the median nerve can be
to time, a subclinical focal neuropathy of the anterior in- injured at any location between the elbow and wrist as a result of
terosseous nerve can be detected. The electrodiagnostic medi- a number of causes. A few of the reported etiologies include ele-
cine evaluation is also quite useful for following neural vated pressures in the flexor forearm compartment (Volkmann's
recovery. ischemic contracture) secondary to hemorrhage in hemophiliacs
It is important to recall that the anterior interosseous nerve is from arterial/venous punctures, and generalized trauma, nerve en-
the primary means whereby the Martin-Gruber anastomosis con- trapment in radius/ulna fracture fragments, direct needle injuries,
veys fibers to the ulnar nerve. These cross-over fibers usually in- and arteriovenous fistulas.229-260-279-307-388-444-701-703-746-834-842 In frac-
nervate the first through third dorsal interossei as well as the tures, the etiology of a median nerve injury is quite obvious. In
adductor pollicis and occasionally the abductor digiti minimi many of the other forearm lesions, particularly those resulting
muscles.464 Should an anterior interosseous lesion exist proximal from elevated forearm pressures, the immediate cause may not be
to the origin of the anastomosis to the ulnar nerve, additional readily detectable. Patients may or may not complain of pain, but
clinical and electrophysiologic findings can be anticipated in ad- the motor and sensory consequences of median nerve insult are
dition to the above-noted classic presentation. There may be as- noted quite easily. Physical examination demonstrates diminished
sociated weakness of second and fifth digit abduction as well as sensation in the hand consistent with a median nerve injury, as
adduction of the first digit. Membrane instability is observed not does weakness of the thenar muscles innervated by this nerve.
only in the anticipated three muscles innervated by the anterior The degree of forearm muscular involvement depends entirely
interosseous nerve, but also in the ulnar-innervated hand intrin- upon the level at which the median nerve is affected. Obviously,
sic muscles. Finding abnormalities in the ulnar hand intrinsic proximal lesions result in wrist and finger flexion weakness. The
muscles should prompt a thorough exploration of the possible anterior interosseous nerve may be concomitantly affected, re-
ulnar nerve lesions at the elbow and wrist, but consideration sulting in the additional dysfunction of the muscles supplied by
should also be given to the possibility of a Martin-Gruber anas- this nerve. In fractures and elevated forearm compartment pres-
tomosis in conjunction with an anterior interosseous nerve sures, immediate operative intervention is suggested to provide
injury. In this instance, the ulnar nerve's palmar digital and optimal neural preservation.
dorsal ulnar cutaneous SNAPs are normal, as is conduction Electrophysiologic Evaluation and Findings. The electro-
across the elbow. Stimulation of the median nerve at the elbow diagnostic medicine evaluation should demonstrate abnormali-
results in CMAPs evoked from the ulnar-innervated hand in- ties in the median evoked SNAPs from the digits. Reduction in
trinsic muscles. The median innervated thenar muscles are the APB's CMAP is to be anticipated following lesions severe
completely normal on needle electromyography. It is also pos- enough to produce axonal loss. Needle electromyographic ex-
sible for the anterior interosseous nerve to supply partial inner- amination will reveal membrane instability in the muscles in-
vation to the flexor digitorum superficialis in about 30% of nervated distal to the lesion site. In sparing of the anterior
limbs.727-741 This muscle may not be particularly weak because interosseous nerve, the supplied muscles should demonstrate an
of its dual innervation in certain individuals, despite displaying absence of abnormal spontaneous activity. It may be necessary
membrane instability on needle electromyography. This possi- to carefully examine the forearm muscles sequentially inner-
bility should be kept in mind so as not to arrive at an erroneous vated by the median nerve in order to localize the level of neural
conclusion. Although these findings are no doubt rare, when compromise.
found they are certainly a sterling example of penultimate di-
agnostic skills. Wrist Injuries: Carpal Tunnel Syndrome
As noted above, it is possible for median nerve lesions at Clinical Features. The prototypical injury of the median
more proximal levels due to misplaced injections or fractures to nerve at the wrist is either an acute or chronic compressive
have the same appearance as a focal anterior interosseous nerve lesion referred to as carpal tunnel syndrome (CTS). The
lesion.212-359-409-817 It is also possible for patients with rheumatoid prevalence of this disorder in the general population for a com-
arthritis to experience painless tendon ruptures of the flexor pol- munity in the Netherlands is 0.6% for men and 6.8% for
licis longus and flexor digitorum profundus muscles to the women.142 In the United States, the exact prevalence is unknown
index finger, thus simulating an anterior interosseous nerve in the general population; however, based on patients seen with
injury.294-465-540 In patients with weakness secondary to a tendon this disorder in large medical practices, it is estimated to ap-
rupture, the nerve conduction studies and needle electromyog- proximate 55-125 cases per 100,000.97-596-742 A more recent
raphy do not suggest a neural injury. study has concluded that approximately 2.7% of the population
has both clinically and electrophysiologically documented carpal quite well to conservative therapy consisting of an injection of
tunnel syndrome.25 Women are considerably more prone to this 1 % triamcinolone or other corticosteroid preparations, and lido-
disorder in a ratio of 3:1 to about 10:1 J42-596 CTS is bilateral in caine without epinephrine followed by wearing a resting hand
up to 87% of patients clinically and approximates 50% through splint for about 3 weeks. 236 In 76% of these patients, complete
neurophysiologic testing.5753 Risk factors associated with carpal symptom relief occurs by 6 weeks. Unfortunately, by 18 months
tunnel syndrome include repetitive activities requiring wrist flex- only 22% of all patients are asymptomatic. Of these patients,
ion, wrist extension, a combination of wrist flexion and exten- 40% who had mild symptoms were asymptomatic, whereas 89%
sion, hysterectomy without oophorectomy, last menstrual period of persons with a severe symptom presentation have a recurrence
in menopausal women 6-12 months ago, relatively shorter by 18 months. This study suggests that individuals with mild
height, elevated body weight, and crash diets.141 No association symptoms should be treated early to achieve the best results with
could be found with oral contraceptives, age at menopause, dia- conservative treatment. It is possible, however, for an attempted
betes, thyroid dysfunction, rheumatoid arthritis, or typing. This therapeutic injection to end up injuring the nerve.775
information reflects the general population in the Netherlands, Individuals who best fit an intermediate type of CTS classifica-
and different factors may be operative in the United States. tion complain of continuous diminished sensation in the median
Previous studies have suggested a strong correlation with dia- nerve distribution, reduced ability to manipulate fine objects such
betes mellitus, 1285297,4 thyroid disorders, 533 615 and rheumatoid as buttoning clothes, and occasionally dropping objects such as
arthritis504-538-579; however, the general population as a whole was glasses of water or coffee cups. Associated complaints of burning
not statistically sampled. Further comprehensive epidemiologic sensations about the hand as well as a feeling of fullness and in-
studies in the United States sampling the general population as ability to make a tight fist are also noted. There is also a signifi-
opposed to those considering large medical practices need to be cant increase in the pain within the wrist or hand that radiates to
performed to arrive at a true prevalence rate in addition to true the elbow and even shoulder regions.106 Mild or moderate com-
risk factors. Groups of industrial workers may require a different plaints may also be described affecting the contralateral hand.
set of reference values compared with nonindustrial workers,665 The patient is particularly troubled by the paresthesias and pain in
and the natural course of nerve conduction parameters may be the evening requiring significantly more effort than patients in the
different in this population.542 Prior to concluding that the partic- previous category to relieve the symptoms. Sensory complaints
ular job performed is exclusively responsible for the CTS, unrec- can involve the entire palmar surface of the hand and not just the
ognized medical conditions predisposing the patient to the median nerve distribution. 438 Physical examination reveals de-
median neuropathy should be thoroughly investigated.24 It is also creased sensation in the median nerve distribution, and some pa-
important to recognize that various neurologic disorders may tients also show reduced sensibility in the ulnar nerve area. Mild
present with symptoms suggestive of CTS.833a thenar wasting can also be found. The above-noted physical ma-
Patients can be placed into three categories with respect to neuvers continue to result in symptom reproduction in a number
clinical presentation and for guidance regarding prognosis and of patients. Both abnormal motor and sensory findings are usu-
treatment: (1) early, (2) intermediate, and (3) advanced carpal ally detected on electrodiagnostic testing. Although conservative
tunnel syndrome. 140142 Individuals having early carpal tunnel intervention consists of nonsteroidal anti-inflammatory medica-
syndrome usually complain of numbness, paresthesias, and pain tion combined with immobilization in a resting hand splint, these
in the median nerve distribution. 596 These symptoms are inter- persons appear to respond best to surgical release of the trans-
mittent and typically worse at night where the patient is awak- verse carpal ligament. The reason is that most of the individuals
ened from sleep and relieves the discomfort by vigorously in this category have some form of job-related exacerbation of
shaking the hand. With time, the night-time complaints begin to symptoms and cannot continue to earn a living with their hand
occur during the day and of progressively increasing frequency, immobilized for weeks at a time as well as the distinct possibility
as they are associated with activities requiring repetitive use of of symptom recurrence.236 The low surgical complication rate in
the hands. Although patients often have difficulty localizing the competent hands combined with a good outcome suggests
sensory disturbances to only the median innervated digits, phys- surgery is the most expeditious treatment route in well-selected
ical findings should be limited to this nerve's distribution. Phys- patients.639-684-763
ical examination may at first reveal little in the way of objective Patients with advanced CTS have had the disorder for quite
sensation loss, but with disease progression, some alteration of some time. Sensory loss and muscle atrophy are usually severe,
sensation beginning in the tip of the third or second digits can and hand function is expectedly compromised. Conservative
be found.140-596 Various physical maneuvers designed to stress therapeutic intervention in these patients is likely of little bene-
the median nerve in the carpal tunnel (Phalen's test, reverse fit. The most appropriate course of action is surgical decompres-
Phalen's, etc.) may exacerbate symptoms. Additional clinical sion of the transverse carpal ligament.239-595-598-639 Several studies
testing can include a Tinel's sign with percussion of the median have documented that even in patients with severe CTS, approx-
nerve about the wrist, Semmes-Weinstein monofilaments, vi- imately one third of individuals have significant improvement
brometry assessment, and two-point discrimination. These in symptoms with one half regaining thenar muscle mass.
physical tests are of variable discriminatory value in the major- Unfortunately, the extensive neural destruction and fibrosis
ity of patients with CTS.361-362-403-768-770 Tinel's sign in particular limit the amount of recovery possible, and some patients with
may be abnormal in 45-60% of patients with CTS and in about extensive axonal damage may receive little in the way of benefit
30% of patients without CTS.596-745 Measuring intracanal pres- from any therapeutic intervention.
sures with a wick catheter is abnormal in patients with carpal The pathophysiology and etiology of CTS are the subject of
tunnel syndrome; however, this is not a practical diagnostic test continued and extensive investigation. Essentially, the carpal
at this time.237-445-446-769 The best objective diagnostic test contin- tunnel is a rigid structure surrounded by bone and tough liga-
ues to be a carefully performed electrodiagnostic medicine eval- mentous tissue. Confined within the tunnel are the nine tendons
uation performed by an expert (see below). Patients in this noted previously, the median nerve, and associated vasculature.
category who initially present with mild symptoms respond Any abnormality resulting in a reduction in available space
1060 PART IV CLINICAL APPLICATIONS
Table 24-1. Factors Associated with Carpal Tunnel Syndrome Development
I. Idiopathic VI. Trauma/wrist positioning
II. Congenital/anatomic Cumulative trauma
Anomalous flexor digitorum superficialis muscle Repetitive wrist flexion/extension
Proximal lumbrical muscles in tunnel Repetitive grasp/torsion
Reversed palmaris longus muscle, abnormal Repetitive finger motion with wrist extended
insertion of palmaris longus Typing, musical instruments
Anomalous flexor pollicis longus tendon slip Weight bearing with wrist extended
Palmaris profundus Paraplegia, cycling, crutches
Thickened, transverse carpal ligament Immobilization with wrist flexed
Familial Colles' cast, sleeping position
Carpal bone abnormalities Distal radius fracture (acute, fracture, callus, malunion)
III. Metabolic/fluid hemostasis Displaced carpal fractures, dislocations
Acromegaly malalignment, bony abnormalities
Hyperparathyroidism Scaphoid, lunate, perilunate
Hyperthyroidism fractures/dislocations
Myxedema Hook of hamate fracture
Pregnancy and post partum Hematoma (hemophilia, leukemia,
Oral contraceptives anticoagulation therapy, trauma)
Menopause Radial artery catherization
Diabetes Burn
Raymond's disease Compartment syndrome
Dialysis, renal failure Insect bite
Arteriovenous fistula for dialysis Hand vibration for prolonged periods
Obesity Injections
IV. Tumor VII. Degenerative
Ganglion Carpal collapse, Kienbock's disease
Neuroma Osteoarthritis, osteophytes
Neurofibromatosis VIII. Neuropathic
Fibroma Diabetes mellitus
Lipoma Alcoholism
Myoma Amyloidosis
Hamartoma of median nerve Proximal median nerve lesion (double crush)
V. Inflammatory IX. Infection
Tenosynovitis, hypertrophic synovium Abscess
Rheumatoid arthritis Tuberculous tenosynovitis
Gout Leprosy
Dermatomyositis X. Vascular
Scleroderma Persistent or thrombosed median artery
Amyloidosis Aneurysm
Lupus Anomalies, arteriovenous shunt, hemangioma
From Szabo RM, Madison M: Carpal tunnel syndrome. Orthop Clin North Am I992;23:l03-I09;and von Schroeder HP, Botte MJ: Carpal tunnel syndrome. Hand
Clinics 1996;12:643-655.
within the tunnel such as space occupying lesions or inflamma- and (2) palmar bowing of the flexor retinaculum at the level of
tory processes necessarily results in an increase in carpal tunnel the hamate bone.65-517 There is also a suggestion that the MRI
pressure. There are a multitude of conditions believed to be as- may have an ability to stage the severity of the disease
sociated with and predisposes patients to developing carpal process. 385 These radiographic evaluations have been recom-
tunnel syndrome, all doing so by reducing the amount of space mended as diagnostic procedures for identifying patients at risk
available for the nerve (Table 24-1). This postulate is verified by for CTS, but the expense and lack of physiologic assessment of
individuals with carpal tunnel syndrome apparently more prone the nerve's dynamic function limit their utility at this time. The
to any alteration in carpal tunnel pressure because of a less than most vulnerable structure to any pressure alterations in the
capacious anatomic carpal tunnel as evidenced by CT, MR1, and carpal tunnel is the median nerve.
sonographic evaluations.76-77-143-499-500-501 Not all CT investiga- Sunderland has postulated a pathophysiologic mechanism for
tions agree, however, that CTS patients have abnormal carpal median nerve compromise based on abnormal tunnel pressures
canals.831 Continued advances in various MRI techniques sug- and the nerve's microcirculation. 763 The relevant pressures in
gest that there are primarily two imaging findings suggestive of the nutrient vessels of the median nerve in the carpal tunnel are
carpal tunnel syndrome: (1) an approximate increase of the in the epineurial arterial pressure (P A ), intrafunicular capillary
median nerve size of 50% compared with a control population, pressure (P c ), intrafunicular tissue pressure (P F ), epineurium's
venular pressure (P v ), and finally the pressure within the carpal
tunnel external to the median nerve (P T ). It can be appreciated
that all of these pressures are physiologically related, with P A
the highest and P T the lowest so as to maintain circular blood
flow from the arterial system through the nerve and thus drain-
ing into the venous system. Should P T become elevated above
P v as a result of any the above-noted causes, there will be a
back-up of fluid pressures impeding this circular flow, thereby
altering the nerve's nutrition and removal of metabolic waste
products (Fig. 24-11). Reduced epineurial blood flow has been
demonstrated to result in the first detectable manifestations of
neural compromise at pressures of 20-30 mmHg. 662 Axonal
transport is compromised at pressures of 30 mmHg with resul-
tant elevations in endoneurial fluid pressures.131-452'661 Patients
with carpal tunnel syndrome are known to have increased carpal
tunnel pressures, and individuals with experimentally elevated
carpal tunnel pressures are found to have symptoms characteris- Figure 24-11. Microvascular compression hypothesis of
tic of CTS.237-445'446'451-769 If experimental compression of 50 carpal tunnel.The carpal tunnel is pictured with the various pres-
mmHg is maintained about a nerve for about 2 hours, epineurial sures denoted.The large dark circle within the carpal tunnel repre-
edema is formed, while an 8-hour compression results in not sents the median nerve. Normally PA > P c > PF > P v > PT, but when P T
only axonal transport blockade, but also a dramatic increase in > P v , the pressure backs up with diminished nutritional flow to t h e
endoneurial fluid pressure.131'450-452-660-661662 In the human being, median nerve and ensuing clinical symptoms. PA, intraneural arterial
60 mmHg of compression leads to complete sensory and motor pressure; P c , intrafunicular capillary pressure; PF, intrafunicular pres-
impulse conduction blockade.238-451 At higher levels of compres- sure; P v , epineurial venous pressure; PT, pressure within the carpal
sion, intraneural vascular trauma accompanied by endoneural tunnel. (From Sunderland S: Nerve and Nerve Injuries. Edinburgh,
edema is noted, which likely results in still further compression Churchill Livingstone, 1978, with permission.)
about the nerve.
The degree of neural compromise is related to the magnitude Sensory Techniques. Sensory nerve conduction studies as
of the compressive force, its duration of application, and onset opposed to motor conduction techniques are more likely to
rate with faster compared with slower onset being more detri- reveal an abnormality of median nerve action potential propaga-
mental to the long-term viability of neural tissues. Initially, is- tion because the sensory fibers are usually affected first and to a
chemia may result in conduction block and some degree of
motor and sensory latency prolongations.373 Continued pressure Table 24-2. Etiology of CTS in Children and Adolescents
elevation and in particular deforming forces within the carpal without Trauma
tunnel may result in morphologic neural alteration with com- Idiopathic
pression resulting in the nodes of Ranvier invaginating into the Increase in athletic activity
paranodal region followed by demyelination and remyelination. Genetic/Metabolic disorders
A more chronic compressive lesion may lead to a "tadpole" ap- Familial carpal tunnel syndrome
pearing demyelination with the "tails" of the tadpole pointing Mucopolysaccharidosis
away from the compression site (see Chapter 4).553-554
The pediatric and adolescent population is particularly im- Hurler/Scheie
portant to consider when the diagnosis of a median mononeu- Hunter
ropathy at the wrist is entertained. A number of median nerve Sanfilipo
wrist lesions are obvious and due to some type of trauma in- Morquio
cluding fractures, crush injuries, and electrical burns. 8127155 Maroteux-Lamy
However, nontraumatic or so-called idiopathic lesions are very Beta-Glucuronidase deficiency
rare and most likely a result of a systemic disorder such as mu- Keratan and heparan sulfaturia
copolysaccharidoses or mucolipidosis. When young persons are Mucolipidosis
encountered with CTS, a thorough differential should be con- Sialidosis (infantile onset)
sidered (Table 24-2), to institute therapy as expeditiously as "I" cell disease
possible. Pseudo-Hurler polydystrophy
Electrophysiologic Evaluation and Findings. The electro- Dejerine-Sottas disease
physiologic procedures designed to assist in the diagnosis of Weill-Marchesani syndrome
carpal tunnel syndrome can be quite helpful in defining the Leri's pleonosteosis
functional status of both motor and sensory fibers through the Melorheostosis
carpal tunnel. The sensitivities of electrodiagnostic methods Space occupying lesion within carpal tunnel
have ranged between 49% and 84% with specificities of 95% or Median nerve lesion: lipofibromatosis, hamartoma, hemangioma,
higher.12-323 There are a significant number of different methods tumors
available to evaluate a patient for median nerve compromise at Anomalous muscles or other lesion not affecting the median nerve
the carpal tunnel (Table 24-3). It is impossible to discuss all of Hemophilia
the available methods published for determining whether Congenital abnormalities: hypoplastic scaphoid, congenital bands
median nerve conduction is disturbed. Only those studies more From Al-Qattan MM.Thomson HG, Clarke HM: Carpal tunnel syndrome in chil-
commonly performed are evaluated. dren and adolescents with no history of trauma. J Hand Surg 1996;21B: 108— I I I.
Table 24-3. Carpal Tunnel Electrodiagnostic Medicine Techniques
Technique DSL DML (ms) Amp (uV) NCV (m/s)
MOTOR STUDIES
Median Motor333497
Stimulate median nerve 8 cm proximal to APB; 2.2^.2 5000-25000 50-60
record from APB
Median Motor: Mid-Palm214 256 378
Stimulate recurrent branch of median nerve in palm Mid-palm amp 5-25% > wrist amp
conduction block: > 20% drop
where ring finger touches base of thenar eminence compared to the wrist amp
Ulnar Motor333497 2.3-4.0
Stimulate ulnar nerve 8 cm proximal to ADM;
record from ADM 1.0
Median DML - Ulnar DML203-204 1.0
Same hand 1.0
Opposite hand (median nerve)
Opposite hand (ulnar nerve) <0.4
Lumbrical/lnterossei576
Stimulate median/ulnar nerves separately and > 0.3 (no units)
record latencies; then calculate the difference 1.3-2.6
Terminal Latency Index705
Distance * (NCV x DML)
Residual Latency353 354400
A mathematical calculation using median motor DML, 2.9-3.6 10-100 48-65
distance, and NCV: RL = DML - (80 mm + NCV)
SENSORY STUDIES 2.6-4.1
Median Sensory333 497 (Antidromic)
Ring electrodes on 2nd or 3rd digit with stimulation
of median 14 cm proximal to active recording electrode <0.5
Ulnar Sensory333 (Antidromic) <0.5
Ring electrodes on 5th digit with stimulation of ulnar
nerve 14 cm proximal to active recording electrode <0.6
Median DSL - Ulnar DSL203 204
Same hand
Opposite hand
Ring Finger334 (Antidromic)
Ring recording electrodes on 4th digit with stimulation Single peak: normal;
median and ulnar nerve 14 cm proximal to active Double peak: abnormal
recording electrode. Difference between the 2 DSL is
basis for diagnosis.
Ring Finger794 (Orthodromic)
Ring electrodes placed as for antidromic technique except
they are used for stimulation and recording electrode > 0.46 per I cm segment
located between FCR and FCU to pick up volume
conducted response from both nerves simultaneously
"Inching"3'4379
Antidromic median sensory as noted above with stimu- <3.5 (14 cm)
lation in I cm increments from proximal to distal to < 1.9(7 cm)
the carpal ligament. Record from either 2nd or 3rd digit. A t < 1.6 129% mid palm:wrist
Mid-Palm125 378839 (Antidromic)
Ring electrodes on 2nd or 3rd digit with median nerve < 2.2 (median)
stimulation 7 cm and 14 cm proximal to active < 2.2 (ulnar)
recording electrode. < 0.3 (median - ulnar)
Mid-Palm137 510743 (Orthodromic) < 0.5 (median right/left
Median and ulnar nerves are excited between the 2nd difference)
and 3rd and 4th and 5th metacarpals respectively in the
mid-palm. Recording is with bar electrode over the < 2.9 (Median)
median and ulnar nerves 8 cm proximal to mid-palm < 2.8 (Radial) 34
cathode. < 0.5 (Median - radial) 15
Median/Radial11 U35.W6.589.709 (Antidromic)
Ring electrodes on I st digit. Radial nerve excited 10 cm
along radius. Median nerve excited 10 cm following Usually single peak,
course similar to motor, i.e., from 1st digit to mid-wrist when double peak < 0.5 ms
Sensory latencies FCR
then between measured
and PLto tendons
peak. APB,over
abductor
medianpollicis
nerve.brevis; ADM, abductor digiti minimi; FCR, flexor carpi radialis; PL, palmaris longus; RL, residual latency;
DSL: distal sensory latency; DML, distal motor latency;
Also, stimulate between median and radial nerves Amp, amplitude in microvolts (uV). NCV, nerve conduction velocity in meters/second (m/s).
to activate both nerves simultaneously.
greater degree than motor fibers. The technique preferred by of questionable value in these persons.43-574 Finally, one cannot
one of the authors (DD) is to perform antidromic sensory use the ulnar nerve sensory latency as a reference point unless it
recordings from the third digit while stimulating the median is normal. This implies a lesion of the ulnar nerve cannot be pre-
nerve 14 cm proximal to the active recording electrode (Table sent at the elbow, wrist, or some other location potentially affect-
24- 3).333-497-822 This technique allows one to obtain easily obtaining its distal sensory latency.
able SNAPs, and rarely is there a problem with motor artifact. A similar strategy of short-segment conduction across the
Should technical difficulty arise secondary to motor artifact, the carpal tunnel can be applied with orthodromic studies. A simple
active recording electrode can be moved slightly more distal on technique is to stimulate both the median and ulnar nerves in the
the finger to avoid the volume-conducted motor response from mid-palm region and record an orthodromic response 8 cm prox-
the hand (probably a lumbrical muscle response), or the patient imal over the main trunk of the median and ulnar nerves (Table
can be asked to abduct the fingers during stimulation in an at- 24- 3).79-137-510743 This technique shares the same advantages as
tempt to suppress the motor artifact. It is crucial to ensure the those noted above for mid-palm antidromic stimulation localiz-
patient's hands are 31-32°C or greater prior to recording data ing a lesion to primarily the involved segment. The absolute la-
for any sensory technique, as lower temperatures can result in a tency is frequently compared with the ulnar nerve over a similar
prolonged SNAP response potentially suggesting a median neu- short segment. This is important because one does not have a
ropathy at the wrist. This test alone is insufficient to diagnose segment with which to compare the median nerve. It is certainly
carpal tunnel syndrome. It is absolutely necessary to include an possible for a patient with a peripheral neuropathy that has pro-
additional stimulation site to improve the sensitivity of this gressed to affect more than just the very distal segment of the
technique, i.e., a mid-palmar stimulation.125-378-839 Exciting the digital nerve resulting in an abnormal conduction across the
median nerve between the first two tendons of the finger flexors carpal tunnel and this patient does not necessarily have CTS. A
7 cm proximal to the active recording electrode allows one to normal ulnar mid-palm-to-wrist combined with abnormal
subtract this latency from the 14-cm wrist latency, thereby median mid-palm-to-wrist latency most likely suggests a CTS,
having two important latencies; the time of conduction across while slowing of both nerves may be a result of a peripheral neu-
the carpal tunnel so as to compare it with the time from the mid- ropathy or some other type of ulnar nerve lesion, and CTS. When
palm to the digit. This is important because the practitioner can the ulnar latency is abnormal, this technique becomes limited
isolate the potentially injured segment of nerve and localize it to with respect to detecting a focal median neuropathy at the carpal
the carpal tunnel region. When using only the 14-cm latency, tunnel, and the above-noted antidromic 14/7 cm test should be
one cannot be sure that a prolonged conduction is not a result of performed because it does not rely on the ulnar nerve and com-
distal slowing from the mid-palm to digit as opposed to wrist to pares both the distal and carpal tunnel regions. In a strict sense,
mid-palm. The time across the carpal tunnel should always be the 8-cm mid-palm orthodromic technique is really a mixed-
less than the time for the distal segment. This is most likely a nerve response. This is because both the median motor fibers and
result of larger diameter nerve fibers proximally. The recording the deeper ulnar motor fibers traversing the palm of the hand
of both a mid-palm and wrist latency can be quite helpful in pa- may be activated particularly in pathology when one increases
tients with a peripheral neuropathy. When using only the 14-cm the current intensity to ensure activation of all pathologically in-
latency in patients with a known peripheral neuropathy, one volved fibers. In this instance, a mild sensory fiber dysfunction
cannot know if the observed median nerve slowing is because of might be masked by normal motor conduction from the lumbri-
carpal tunnel, peripheral neuropathy, or both. Using split times cal or recurrent branch of the median nerve fibers. Additionally,
can distinguish if patients with peripheral neuropathies have activation of the deeper ulnar motor fibers could be recorded
CTS because this segment can be isolated and compared with from the ulnar nerve at the wrist through volume conduction
reference values (Table 24-3). Additionally, in persons with even though the active recording electrode is located over the
mild slowing, the absolute 14-cm latency can still be within the median nerve, as they are not that far from each other.171 In these
range of normal limits. Comparing the transcarpal time with instances, completely normal responses may be recorded despite
that for the distal segment allows one to detect mild slowing abnormal or absent median sensory conduction.
across only this segment. An additional advantage of the mid- Several sensory conduction techniques using digits dually in-
palm stimulation is that amplitudes for above and below carpal nervated can be used as a "screening" method of identifying pa-
tunnel stimulation can be compared, thereby investigating the tients with CTS. The primary value in these techniques is that
possibility of conduction block. These studies can be used for conduction is recorded from another digit that may be more in-
either the second or third digit and possibly the fourth. volved than the one initially investigated. They can also be used
The above-noted 14-cm median nerve stimulation technique more as a confirmatory measure to validate more definitive
can be combined with a 14-cm ulnar nerve excitation latency for methods in cases of borderline slowing. Despite these state-
comparison purposes (Table 24-3). A difference of greater than ments, the techniques are discussed because they are worth-
0.5 ms between the median and ulnar nerve sensory latencies in while for the practitioner to perform occasionally. The first
the same hand is recommended as the criterion for concluding if method concerns measuring the median and radial sensory la-
CTS is present (Table 24-3 ).203-204-205 This technique may be of tencies to the first digit (Table 24-3). ,4 ,!1-245-335-336-573m709 A peak
some assistance in a few patients. There are several difficulties latency difference of greater than 0.5 ms is suggestive of median
with this technique. The original study did not apparently control nerve compromise. In addition to the individual nerve action
for temperature, nor was this critical factor measured. It may be potentials, it is advocated to perform this technique by simulta-
possible for both the median and ulnar nerves to be at different neously exciting both the radial and median nerve by placing
temperatures between the two hands as well as within the same the cathode midway between the two nerves while recording
hand. When latencies and amplitudes are used between two from the first digit. If two peaks are noted with the above peak
limbs, it is important to maintain the same conditions for both latency difference, CTS is likely present. This can be a useful
limbs. Also, approximately 61% of patients have bilateral CTS, technique provided one is aware of its shortcomings. In patients
thus implying that side-to-side median latency comparisons are with profound CTS and an absent median SNAP, only one peak
is detected because the radial nerve continues to function nor- technique can be useful in exactly localizing the lesion site,
mally. This should not be mistaken as confirmatory evidence whether it is more sensitive than the above-described techniques
that CTS is absent. In patients with symptoms who only have and justifies the additional time and potential errors has not been
one peak similar to that anticipated in normals, a mid-palm conclusively demonstrated to justify its widespread acceptance.
technique should be performed. Also, it is possible for the When performing any sensory study, it is crucial to ensure
median nerve to not innervate the first digit. In patients with this the patient's hands are greater than 31-32°C, as reduced tem-
anomaly and CTS, only one SNAP is generated that is normal. perature can result in an artificially prolonged latency. When the
Again, in patients with symptoms suggestive of CTS and a hand is less than the desired temperature, it is advisable to warm
normal median/radial study, further studies must be performed. the limb rather than using latency/velocity correction factors,
Another possible problem with the simultaneous activation of since abnormal nerves do not always respond to temperature al-
both median and ulnar nerves is that the radial nerve can be ac- terations in the same way as normal nerves.22 Also, irrespective
tivated closer to the recorded electrode when the cathode is of one's favorite technique, the most symptomatic finger must
moved from directly over the nerve to between the median and always be examined. For example, if the patient complains of
radial, thus generating a shorter peak latency.208 This has the symptoms in the first digit, but only the third digit is examined,
effect of artifactually increasing the inter-peak latency and pos- it is certainly possible to miss a diagnosis of CTS if the third
sibly predisposing toward a false-positive study. The reason for digit is not yet affected. In other words, a patient with classic
the earlier radial nerve activation is likely a result of the current CTS symptoms and a normal study to a particular digit should
spreading out further as the cathode is moved toward the not be dismissed. All digits innervated by the median nerve
median nerve (away from the radial nerve), thereby activating should be examined if necessary. Also, several techniques may
the radial nerve closer to the recording electrode. A radial nerve be appropriate to verify the presence or absence of pathology.
lesion or peripheral neuropathy can also limit the utility of this There is a suggestion that the third digit may be the optimal
technique. A second dual-innervation digit technique (anti- finger to study in patients with suspected CTS. 457 The third digit
dromic or orthodromic) involves the fourth digit, as it is inner- is suggested despite finding slightly higher abnormalities in the
vated by both the median and ulnar nerves (Table fourth digit, as the fourth digit is dually innervated and can be
24-3).i26.334.79o.79i.794 R a m e r good success is claimed with respect misleading for the reasons already noted. The second digit is
to detecting mild CTS with the ring finger technique compared least likely to be involved in CTS because its fibers may be
with mixed-nerve mid-palm studies.791 Similar concerns regard- more protected from compressive injury in the carpal tunnel be-
ing an absent response with respect to anomalous innervation cause they lie more posterior compared with the anterolateral
and true pathology apply to this technique as noted for the location for the sensory fibers to the remaining digits.763 In pa-
median/radial method. 90a The sensory innervation to the ring tients with normal sensory latencies, provocative median nerve
finger has been shown to rarely display an innervation pattern stress testing may result in a transient conduction abnormality
other than discussed by standard anatomic texts, suggesting that that is manifested only after compression.470-679 Latency is typi-
comparison studies using the fourth digit should not be compro- cally described as the primary parameter considered when at-
mised by a concern regarding anatomic variations.414 In the case tempting to diagnose CTS. Axonal loss or stimulation above a
of a moderate to severe CTS and absent sensory responses of lesion site should result in diminished median SNAP ampli-
the median nerve, there is a risk of coactivation of the ulnar tudes. SNAP amplitudes, however, can vary considerably in
nerve at the wrist while increasing stimulus strength in an at- normal persons, and the range of normality no doubt overlaps
tempt to obtain a median sensory response. This could lead the with abnormality, particularly in mild cases. SNAP amplitude
unwary investigator to think that a normal median sensory re- ratios between different fingers can be used, but care must be
sponse is present. This pitfall can be easily circumvented by exercised that a standard interelectrode recording distance as
using a dual-channel recording with an extra ring electrode well as stimulus distance is used.437 Both of these parameters
around the fifth finger to exclude any ulnar coactivation.414 can affect both latency and amplitude. Refractory periods are
A recommended method for diagnosing CTS is to use a so- prolonged in CTS and can be used as a diagnostic technique,
called inching technique in which one either records from the but this requires special equipment and may not yield a higher
second or third digit and stimulates the median nerve from the sensitivity than that from more simple techniques.248-771
wrist into the mid-palm along multiple sites, or stimulates the An interesting approach utilizing three different techniques
nerve above the wrist and records from multiple electrodes along with a high test-retest reliability (median/ulnar difference to the
the course of the nerve into the hand (Table 24-3).3I4-379-688-688a A ring finger (< 0.4 ms}; median/ulnar mixed-nerve mid-palm
short intersegmental latency difference exceeding that antici- difference f<0.3 ms}; median/radial to thumb difference {< 0.5
pated in normal persons is suggestive of CTS. Despite the re- ms}) to derive a combined sensory index (CSI) has been sug-
ported sensitivity for this test,341 there are a number of difficulties gested.4243-646 After performing these three tests, the summated
with this method that render it somewhat impractical. First, irre- latency difference for each test is documented and should be <
spective of the technique, multiple recordings are necessary, 0.9 ms. If the CSI exceeds 0.9 ms, the patient likely has CTS.
which can be quite time consuming. This is especially true for The CSI has a sensitivity of 83.1% and a specificity of 95.4%,
adequate preparation of the palmar tissue so as to reduce the im- which were better than the combined sensitivity and specificity
pedance sufficiently to obtain clearly recognizable responses. If for any one of the three tests alone. A combination of these three
stimulation is applied along multiple locations, one must recall tests is different than simply doing three independent tests and
that the median nerve travels beneath considerable tissue in the picking one that is abnormal upon which a diagnosis of CTS is
palmar region. This may necessitate the use of rather strong cur- based. In effect, the greater the number of tests done, the more
rent intensities or durations that may result in an inaccurate la- likely by chance one is going to be abnormal. The CSI, how-
tency measurement because of exciting the nerve more distally ever, combines all three tests to derive a single number, thereby
than anticipated. Also, multiple stimulations in addition to "diluting" out any statistical chance of randomly arriving at an
recordings can be rather time consuming as well. Although this abnormal parameter. Further work needs to be done, particularly
taking into consideration the cost-effectiveness of multiple tests preferential compression of intraneural motor fibers preferen-
versus one reliable test. Irrespective of what techniques are tially positioned in a volar-radial region within the carpal canal,
used, practitioners are advised to become familiar with a or in some patients the recurrent branch of the median nerve may
number of techniques and develop their own reference data. lie within a separate tunnel and be subjected to compression.636
Motor Techniques. Although routine motor nerve conduc- At this point, it is important to note that some persons may
tion studies to the APB are less sensitive than SNAPs, it is still have a congenital absence of the thenar muscles that presents
important to perform them in order to assess the extent of the with complete "wasting" or "atrophy" of the thenar muscle
pathologic involvement with respect to the motor fibers (Table mass associated with an inability to move the thumb as expected
24_3).333.497.78o j ^ g ^stal m otor latency to the APB is the primary for these median-innervated muscles.317-467-643-832 These patients
parameter examined by most practitioners. A distal motor latency may have either a congenital absence of the recurrent branch of
delay in excess of that expected from normals suggests patho- the median nerve or, more likely, a congenital absence of the
logic involvement of motor fibers in the carpal tunnel. The practi- median-innervated thenar muscles. As expected, the median
tioner should also be familiar with stimulating the recurrent sensory response is anticipated to be normal; however, there is a
branch of the median nerve (Table 24-3).214-256-378 This nerve can complete absence of a median CMAP from the thenar muscles
be easily activated by stimulating the site where the patient's and no MUAPs from these muscles because they are not pre-
fourth digit touches the base of the thenar eminence. 338 sent. This may look very similar to a "pure" motor carpal tunnel
Comparing the CMAP above and below the carpal tunnel can syndrome. One may also find this rarely associated with a tho-
help determine if conduction block affecting the motor fibers is racic outlet syndrome. 824 One can only speculate as to this diag-
present. It is also possible to compare the median and ulnar nerve nosis unless surgical intervention verifies the complete absence
motor latencies to define if there is an abnormality of motor con- of these muscles or the recurrent branch of the median nerve.
duction through the carpal tunnel (Table 24-3). This can be of Perhaps one of the most vexing problems with respect to di-
some assistance in questionable cases of slowing. The validity of agnosing CTS arises when a patient presents with a diabetic pe-
this technique has been challenged.5833 The proximity of the re- ripheral neuropathy and electrophysiologic findings suggestive
current branch of the median nerve and the deep ulnar nerve can of median neuropathy at the wrist.9-802 Failure to document either
frequently result in co-activation of both nerves, resulting in ulnar or median sensory potentials irrespective of technique fre-
median "pseudoneurapraxia" and hence an erroneous conclusion. quently arises in this patient group. Additionally, the distal
One may also study motor conduction to the first or second motor latency to the APB is markedly prolonged compared with
lumbrical muscle and compare this latency to that from the the ulnar hypothenar response. This situation has been aptly de-
second interosseous muscle.151-214-611-844 In general, the recording scribed: "In Aristotelean terms, focal electrophysiologic abnor-
electrode is placed directly over the first or second lumbrical malities may be necessary, but not sufficient to diagnose a
muscle in the mid-palm region just radial to the flexor tendon to syndrome such as the carpal tunnel syndrome. Unfortunately
the second or third digit. A reference electrode is positioned on for the patient, if the electrophysiologic abnormalities do not
the corresponding digit. The median and ulnar nerves are stimu- represent the sole and sufficient cause of the focal nerve
lated at the wrist identical distances from the active recording damage, treating the focal nerve damage will not help the pa-
electrode. The onset latencies to the respective muscles corre- tient." 288 An investigation attempting to address this patient
sponding to the nerve excited are measured and a latency differ- group found that the best technique to define patients with pe-
ence calculated. The interlatency difference between the two ripheral neuropathy and CTS was the second lumbrical/second
muscle responses should not exceed 0.4 ms. Interestingly, this interossei technique.802 This latency difference was prolonged in
technique has been found to not only be abnormal in persons the CTS patient population as well as the peripheral neuropathy
with abnormalities on the more routine studies in carpal tunnel plus CTS population, but not in the peripheral neuropathy popu-
syndrome, but also suggesting motor fiber involvement when lation. The distal motor latency to the APB, however, was
studies to the APB were still normal.695-786 prolonged in all populations. This may be of significant electro-
When activating the median nerve at the wrist for any motor physiologic help in this patient population. However, it is im-
technique, it is a good idea to pay attention to the waveform's portant to keep the above quote in mind: if the patient is
morphology. It is easy to co-activate the ulnar nerve at the wrist, asymptomatic, finding focal abnormalities is of no help; how-
particuarly when the median nerve is pathologically affected ever, if the patient is symptomatic and has electrophysiologic
and may have a relatively high stimulus threshold. 92 The ulnar evidence of a focal median neuropathy, a diagnosis of CTS is
nerve may only be 5 mm from the median nerve at the wrist.5363 likely present and documented. Additionally, patients with both
This caution also applies when stimulating the recurrent branch a peripheral neuropathy and CTS have been documented to ben-
in the palm because the deep branch of the ulnar nerve lies in efit from surgical intervention. 523 As always, the history and
close proximity to it. physical are paramount and assisted by diagnostic tests.
Motor techniques may be helpful in some patients with pref- A particularly interesting finding is the reduced median fore-
erential slowing of motor fibers with sparing of sensory fibers, arm conduction velocity noted in patients with CTS.79-80-1033-376-379
i.e., the latency to the APB may be abnormal, but all sensory This slowing has been attributed to retrograde degeneration of
studies are spared. These so-called pure motor carpal tunnel the median nerve based on animal studies.591-749 The possibility
syndromes are very rare but should be looked for when symp- of this being the case based on available information is highly
toms do not correlate with sensory study findings.376-394-636-743 unlikely. This is because both human and animal studies of the
Specifically, when patients complain of signs and symptoms of median nerve have revealed histologic evidence of neural
CTS but routine motor and sensory studies are normal, consid- changes only in cases of axonal loss and not pure demyelina-
eration should be given to performing the above-described lum- tion.226-781 Additionally, retrograde changes more than a cen-
brical/interossei technique. It may be the only abnormality early timeter proximal to the flexor retinaculum have not been
in the disease process for some patients.787 The physiologic ex- demonstrated.15-781 It is doubtful that a 1-cm segment proximal
planation for pure motor CTS is unknown, but may be related to to the flexor retinaculum that may not even be included in the
section of nerve stimulated could alter the entire forearm con- is not particularly revealing in the majority of CTS cases until
duction velocity. A more likely explanation is the block or loss rather late in the disease process. Because of this, some investi-
of the fastest conducting fibers at the carpal tunnel (see Chapter gators have concluded needle electromyography should not be
4 for a more complete discussion). In this case, only the slower routinely performed in the evaluation of early carpal tunnel syn-
conducting fibers can progress to the APB to generate a CMAP drome.28-119-484-782-799 However, if one neglects the needle exami-
and thus yield a slow NCV. This controversy continues with nation, there is the possibility of missing the more aggressive
studies favoring either conduction block 830 or retrograde degen- lesions and concomitant pathology as discussed below.251
eration. 1 3 215 When the forearm conduction velocity falls below In some patients, there may be a rapid progression of axonal
47 m/s, however, consideration should be given to a superim- loss that is revealed during the needle examination as profound
posed process such as a peripheral neuropathy.164 Further work membrane instability. This suggests that if an offending agent is
needs to be done to more fully elucidate this interesting finding. present, such as compression or a space occupying lesion, it
Calculating the residual latency has been suggested as means should be dealt with in an aggressive manner. Also, florid mem-
of improving the sensitivity of the electrodiagnostic medicine brane instability can also be observed in long-standing disease
evaluation of CTS.353-354-400 The fact that this technique uses with significant muscle wasting. As time progresses in this situ-
motor latencies renders it inherently less sensitive than any of ation, however, the membrane instability will diminish as the
the above-noted sensory techniques. 345 Additionally, in patients muscle tissue atrophies and is replaced by connective tissue, at
with a Martin-Gruber anastomosis, motor nerve conduction ve- which time there is little in the way of membrane instability and
locity can no longer be used because it is commonly erroneous. only decreased insertional activity. In long-standing axonal loss
In this anatomic anomaly, the response is contaminated by a lesions, there may be some membrane instability present, but
distal motor latency most likely arising from a volume-con- one is more likely to detect an alteration in the morphology of
ducted ulnar motor response. The utility of the residual latency motor unit action potentials (MUAPs) such as increased dura-
technique has not been found to be of much value in diagnosing tion, amplitude, and phases, with a decreased MUAP recruit-
CTS.404-786 ment (reduced MUAP numbers firing at rapid rates). Once
A variation on the residual latency technique is known as the collateral sprouting is no longer effective, not only are increased
terminal latency index (Table 24-3).705-706 This is a mathematical numbers of positive sharp waves and fibrillation potentials ob-
manipulation of data routinely acquired during the assessment served, but also the CMAP begins to decline significantly.
of median motor nerve function. The median nerve terminal la- Remember, as long as collateral sprouting is effective and can
tency index is calculated as follows: terminal distance (wrist to keep pace with the loss of axons, there should be little in the
recording electrode) 4- (forearm conduction velocity x distal way of CMAP alterations. Of note, approximately 11 % of pa-
motor latency). The defined reference value for the terminal la- tients with carpal tunnel syndrome may reveal the firing of
tency index is equal to or greater than 0.34. Although this tech- spontaneous and rhythmic MUAPs, or the same MUAP firing
nique is claimed to be highly diagnostic, further work is several times within a few tenths of a millisecond, i.e., multi-
required to establish its diagnostic utility more fully. plets (doublets, triplets, etc.).718
Needle Electromyography. The needle electromyographic Perhaps the value of the needle examination is in the detec-
examination is less sensitive than nerve conduction studies in tion of additional lesions at a more proximal level that may be
general and sensory studies in particular with respect to detect- coexistent with the CTS. In particular, a C6 or C7 radiculopathy
ing early CTS. This is primarily because the main pathologic may also be present in patients with CTS. Approximately 11%
neural alteration in early CTS is demyelination causing slowing of patients with CTS have a concomitant cervical radiculopa-
of sensory action potential propagation across the carpal tunnel thy.845 This dual neural compromise is termed the double crush
region with prolongation of the SNAP latency. Axonal loss of syndrome.308-480-571-792 The double crush syndrome was intro-
sensory fibers is minimal in mild carpal tunnel syndrome, reduced to explain why some persons with a proximal nerve
sulting in SNAP amplitude reduction that may be missed be- lesion may be more prone to common entrapments at a more
cause of the wide range of normal amplitudes and the normal distal location along the same nerve. This originally applied to a j
variation of side-to-side amplitude differences. Motor fiber cervical radiculopathy of the C6/C7 or CS7T1 nerve roots with ]
pathology is also reflected in demyelinative slowing, and later the development of a CTS or ulnar nerve lesion at the elbow. It
in the disease process as axonal loss. If motor axonal loss is is theorized that the proximal nerve insult compromises the de-
slowly progressive, the denervated muscle fibers can be reinner- livery of appropriate axoplasmic substances to more distal loca-
vated by neighboring intact axons through the process of collat- tions in the nerve. A nerve that is subjected to minor trauma at a
eral sprouting. In this way, there may be a slow formation of common entrapment site, and would normally be unaffected,
denervated muscle fibers that are reinnervated relatively rapidly, now succumbs to this relatively minor insult because it cannot
thus minimizing the total number of orphaned muscle fibers at adequately respond with appropriate reparative processes. In
any time. Locating an electromyographic needle into the APB this way, patients eventually develop two neural lesions. The
or opponens pollicis (OP) muscles may require significant prob- significance of this type of injury is that both must be treated to
ing prior to finding the few denervated muscle fibers present. In address the patient's complaints completely. This can be accom-
other words, a slowly progressive lesion may demonstrate sig- plished only if there is a high index of suspicion for a dual
nificant alterations in SNAP latency and amplitude with moder- lesion. It is not uncommon for patients to have their CTS treated
ate motor conduction prolongation of the distal motor latency, appropriately, only to complain of continued symptoms in the
but little in the way of membrane instability (positive sharp affected hand. This may prompt unnecessary re-exploration of
waves and fibrillation potentials). This suggests that membrane the wound to ensure a complete carpal ligament release. The
instability is not a prominent finding in CTS until such time that needle electromyographic examination is capable of diagnosing
the rate of axonal loss progresses at a pace that is more rapid both a CTS and cervical radiculopathy provided there is axonal
than the nervous system's ability to compensate through collat- loss in the appropriate myotomal distribution. A needle elec-
eral sprouting. This is indeed the case, and the needle examination tromyographic examination performed on a select number of
C6/C7-innervated muscles ensures that a second lesion will not that described in the above sections. These are individuals who
be missed. The pronator teres or flexor carpi radialis muscles have complained of the symptoms characteristic of CTS for at
are quite sensitive for C6/C7 nerve root pathology in the au- least several months and demonstrate both delayed SNAP laten-
thors' experience and should be examined in all patients with a cies and amplitude abnormalities as well as possibly distal
suspected diagnosis of CTS. motor latency changes with occasional needle electromyo-
Although not particularly common, it is possible for a patient graphic changes. It is no doubt possible for some patients with
to have a dual lesion affecting the median nerve at the wrist and chronic CTS to have normal SNAP parameters; however, the
a radiculopathy. Confusion may arise, and less than optimal exact incidence of this finding is questionable, but most likely is
treatment may be delivered. However, a number of investiga- only a few percent of patients with true CTS.
tions have called into question the entire hypothesis of the The acute form of CTS is usually the result of severe trauma
double crush.37-521-637-828 These investigations support the finding to the wrist region or distal forearm with a resultant fracture of
that occasionally a single individual may have a dual lesion that the distal radius (e.g., Colles' fracture) or carpal bone. Elevated
requires ah astute practioner to diagnose properly, but that there pressures in the carpal tunnel, median nerve traction secondary
is no physiologic support for the concept of a lesion at one to bony displacement, or direct neural insult from energy trans-
locale predisposing the nerve to a second lesion at another fer or bony impingement can all lead to median nerve dysfunc-
region. tion. Following appropriate bony reduction, continued pain or
Electrodiagnostic Medicine Evaluation. The optimal way worsening of symptoms suggestive of median nerve compro-
to evaluate a patient electrophysiologically is certainly open to mise warrants consideration for emergent carpal tunnel re-
debate; however, the manner in which the authors approach a pa- lease.162'770 Compartment syndromes may also develop and
tient suspected with CTS is presented. To be sure, there may be require not only fasciotomy but also carpal tunnel release.
additions and deletions depending upon the specific patient. The Electrophysiologic studies in these cases are usually not consid-
history and physical examination are performed to completely ered because of the patient's symptoms being of such magni-
address not only the potential CTS, but also additional com- tude that surgery is an emergent concern. One may speculate
plaints that may suggest other diagnostic categories of impor- that conduction block is most likely a major component with
tance. Prior to beginning any electrophysiologic testing, the the potential for axonal loss in lacerating injuries or unrelieved
patient's mid-palm temperature of both hands is recorded. pressure in the carpal tunnel.
Additionally, the hands are felt by the examiner to get an impres- Subacute CTS is usually less than a few months' duration
sion ogverall temperature. If the recorded temperature is below typically resulting from work-related injuries requiring highly
3 1 - 3 2 ^ , the hands are warmed and temperature is again mea- repetitive motions with the hands, i.e., cumulative trauma dis-
sured. A convenient way to warm the hands is to run warm water order.57-94-21*-273*13 Of all the neural injuries resulting from cu-
over the patient's hands for several minutes, monitoring the mulative trauma disorders, carpal tunnel is the best known and
water to ensure it is not too warm. While one limb is being ex- no doubt the most common. In these individuals. SNAP laten-
amined, the patient is instructed to place the other hand under the cies, even when evaluated just across the carpal tunnel or com-
buttock to keep it from cooling. An antidromic median nerve pared with more distal latencies, may not be the most sensitive
SNAP is obtained from the third digit with stimulation at both 7 indicator of pathology. There is a suggestion that amplitude for
and 14 cm. The split times are compared, as are the amplitudes. both motor (wrist vs mid-palm CMAP comparison—see above)
A motor nerve conduction velocity is then obtained with careful and sensory fibers when compared above and below the carpal
attention paid to the distal motor latency. An ulnar sensory la- tunnel might be an early sensitive indicator of conduction block.
tency is also recorded. Finally, a needle electromyographic ex- There may be sparing of sufficient fast conducting fibers to
amination of the APB, pronator teres, and flexor pollicis longus maintain all recorded latencies within normal parameters, but a
muscles is performed. A median nerve SNAP similar to de- sufficient population of axons may experience conduction block
scribed above is also performed on the contralateral hand even if to reveal a significant amplitude difference.256 It is important for
asymptomatic because of the high incidence of bilateral CTS. If practitioners to consider electrophysiologic parameters other
the patient complains of bilateral symptoms suggestive of CTS, than latency such as amplitude and possibly duration in certain
the above-described procedure is performed on both limbs. circumstances to improve the diagnostic ability of the electrodi-
When the above electrophysiologic tests reveal equivocal find- agnostic medicine examination.
ings, additional tests such as orthodromic mid-palm,
median/radial studies to the first digit (stimulation performed to Special Considerations and CTS: Indications
each nerve individually), and median/ulnar studies to the fourth for an Electrodiagnostic Consultation
digit are considered, as is a latency difference to the second lum- There are no electrophysiologic parameters that when ex-
brical/interossei muscles. If an abnormality is noted in the ulnar ceeded, indicate that conservative intervention has failed and
sensory response, motor and sensory conductions are performed surgery is now indicated. The primary indications for an elec-
to evaluate the patient for an ulnar nerve lesion at the elbow. A trodiagnostic medicine consultation are: (1) to resolve any un-
sural SNAP and peroneal motor NCV are considered if the pa- certainties regarding the diagnosis; (2) to evaluate the
tient's history or the electrophysiologic findings are suggestive possibility of additional lesions such as concomitant upper limb
of a peripheral neuropathy. This description of the examination entrapment neuropathies, peripheral neuropathies, and double
essentially allows one to consider a number of possibilities that crush syndromes; (3) to follow conservative treatment effective-
should be accounted for in thejdifferential diagnosis of patients ness; and (4) prior to operative intervention to confirm the diag-
with a history suggestive of CTS, i.e., peripheral neuropathy, nosis and provide a baseline for further future follow-up.
cervical radiculopathy, and other entrapment neuropathies. especially in cases in which surgical intervention has failed to
Acute/Subacute CTS. For the purposes of this discussion, resolve the symptoms.140 It is important to recognize that the
CTS is considered to take the form of acute, subacute, and electrodiagnostic medicine evaluation is frequently considered
chronic manifestations. The chronic form of CTS is primarily of little assistance because of its lack of sensitivity or specificity
IQ63 — PART IV CLINICAL APPLICATIONS
with respect to diagnosing mild CTS.361-770 This is primarily a degree, the abductor digiti minimi muscles.770a-7893 Since these
result of these investigators' lack of knowledge with respect to are all ulnar-innervated muscles, one may well ask of what im-
the most appropriate studies to use when developing protocols portance is this to CTS, which is a pure median nerve lesion.
to investigate patients suspected of having CTS. 56590 Any The answer lies in a consideration of volume conduction ef-
prospective investigation that does not include some form of fects. It is known that the distal motor latency in CTS is fre-
sensory mid-palm studies with respect to both amplitude and la- quently prolonged. In patients with a Martin-Gruber
tency considerations is simply a suboptimal study, and the sub- anastomosis and a prolonged median distal motor latency, the
sequent conclusions drawn are of questionable merit. The median nerve's NCV can be normal or even quite high, ap-
electrodiagnostic medicine consultation is highly dependent proaching 100 m/s or more. It is even possible to have a nega-
upon the skill and expertise of the practitioner. Individuals who tive conduction velocity if the distal motor latency is longer
are less than well trained can quite easily perform a substandard than the proximal latency. These findings occur because the
study. Unfortunately, it is these individuals who then taint the proximal motor latency is essentially normal or even slightly
entire arena of electrodiagnostic medicine. These are not trivial faster than anticipated. Subtracting a prolonged distal motor la-
factors, as they influence the perception of the entire medical tency from a proximal motor latency that is only a few millisec-
community. The electrodiagnostic medicine evaluation of pa- onds longer results in a very small number, which is divided
tients with suspected carpal tunnel syndrome is quite valuable. into the forearm distance, hence a very fast NCV. The key lies in
Good prospective studies using mid-palm stimulation, however, understanding the fast proximal motor latency.
are still required to more fully document the utility of neural In most instances, if the distal motor latency is prolonged,
stimulation in relation to the clinical impression. one would anticipate that the proximal latency would also be
Electrophysiologic Changes Following Surgery. Follow- longer than normal, as the neural fibers have to conduct across
ing surgical decompression of the transverse carpal ligament in the abnormal portion of nerve beneath the carpal tunnel. The
CTS, there is known to be an improvement of neural conduction only way the proximal latency can be normal or shorter than
in some patients within approximately 30 minutes.191 302 This normal is to somehow bypass the slowing in conduction through
finding is highly dependent upon the severity of the CTS, which the carpal tunnel. If the APB's CMAP is recorded at a low sen-
is another way of saying that if conduction improves rapidly, sitivity of 5000 pV/div, it appears as though the proximal motor
some component of ischemic conduction block is present.843 latency is indeed somehow bypassing the carpal tunnel.
One would not anticipate an immediate decrease in conduction Increasing the instrument's sensitivity reveals that the initial
times across the carpal tunnel after surgical release if severe de- onsets of the two potentials are quite different. Stimulation at
myelination and axonal loss were the only components of the wrist produces a CMAP with an initial negative onset (Fig.
neural injury. This type of pathology requires considerable time 24-12C). Median nerve activation at the elbow results in a
to remyelinate the damaged segment or for the axon to regrow CMAP with an initial positive onset prior to describing the large
across the damaged segment once the offending pressure is re- negative phase (Fig. 24-12D). This initial positive phase implies
lieved. If conduction block is present, indeed relief of pressure that the observed voltage contributing to the recorded CMAP
should result in a comparatively more rapid return of neural originates not from solely median innervated muscles, but from
conduction in addition to eventual resolution through the above some other source. The only other muscles in the vicinity of the
noted neural regenerative processes. The more commonly ob- recording electrode arc the adductor pollicis. deep head of the
served pattern of improvement of conduction times over weeks flexor pollicis brevis, and first dorsal interosseous muscles. One
to months255-365-496-699 is more likely a result of remyelination and can now appreciate that at low sensitivities the CMAP deviates
axonal regrowth. Despite the complete resolution of symptoms, from the baseline at an earlier than anticipated interval because
some patients continue to display altered neural conduction. it is arising from the neural fibers activated at the elbow while
This is to be expected, particularly if profound demyelination contained in the median nerve. These neural impulses then de-
and axonal loss occurred. The remyelinated axons may fail to scend in the forearm to cross over to the ulnar nerve and pass to
regain a normal thickness of myelin. This finding, combined the adductor pollicis, deep head of the flexor pollicis brevis, and
with an increased number of internodes following remyelina- first dorsal interosseous muscles. Because they were not de-
tion, can be expected to result in some persistent conduction layed at the carpal tunnel, they arrived at the thenar region and
slowing. The greater the original insult and amount of axonal generated a voltage that volume conducted to the recording
damage, the less eventual recovery one can anticipate. The con- electrode. This voltage resulted in an earlier than anticipated
sequences of peripheral nerve repair—less than optimal myeli- CMAP onset, especially when viewed with low amplifier sensi-
nation and increased internodes—can result in diagnostic tivities. If one were to increase the amplifier sensitivity to 500
difficulty in patients with surgical intervention and recurrent uV/div. for example, an initial positive deflection would be ob-
symptoms. If a latency delay across the carpal tunnel is present, served only for the CMAP arising from elbow stimulation.
the question then becomes: is this delay a result of a recurrent Although the neural fibers destined for the APB and OP really
median neuropathy, residual from the previous median neuropa- never bypassed the carpal tunnel, it appears as though they did
thy, or a combination of both? Patient history, physical exami- because of artifactual error. One cannot assume that because a
nation, and electrophysiologic findings must be combined to recording electrode is located over a certain group of muscles, it
provide an educated diagnostic opinion. cannot record voltages from nearby muscles. It is crucial to un-
Martin-Gruber Anastomosis. One potential significant derstand that the ulnar fibers traveling with the median nerve in
cause for confusion during the electrodiagnostic medicine eval- the arm that crossed over to the ulnar nerve do not innervate the
uation of CTS is the presence of a Martin-Gruber anastomosis. APB or OP. They continue to innervate the usual ulnar inner
This neural communication is typically from the anterior in- vated muscles that make up the thenar eminence (adductor pol-
terosseous nerve to the ulnar nerve 3-10 cm distal to the medial licis, first dorsal interosseous, and deep head of the flexor
humeral eipcondyle, and conveys fibers that usually innervate pollicis brevis muscles). It is simply a volume-conducted re-
the adductor pollicis, first dorsal interosseous, and, to a varying sponse from the ulnar innervated muscles that allows one to
erroneously conclude the APB's CMAP is normal to proximal
stimulation.
By using an amplifier sensitivity of 5000 jiV/div, one can
note an additional interesting finding. If one compares the
CMAP amplitudes when stimulating at the wrist with those at A
the elbow, it can be seen that the CMAP from wrist stimulation
is comparatively smaller (Fig. 24-12C and D). This is exactly
opposite than normally observed. Because of temporal disper-
sion, the proximal CMAP is usually slightly smaller than that
from the wrist. The fact that the proximal CMAP is larger sug-
gests that it somehow contains more voltage, i.e., more muscle
fibers. As noted above, this is in fact exactly the case. It is the B
voltage generated by the adductor pollicis and possibly first
dorsal interosseous muscles contributing to the APB and OP
CMAP that causes it to appear larger. One should suspect a
Martin-Gruber anastomosis in a patient with CTS when any of
the following are observed: (1) a thenar CMAP with an initial C
positive deflection following elbow but not wrist stimulation,
(2) comparatively larger or possibly the same CMAP amplitude
with median nerve elbow excitation, and (3) a median nerve
conduction velocity of about 70 m/s or greater, or a negative
conduction velocity.i24-270-319,377-825 One may not always observe D
an initial positive deflection with elbow stimulation because on
rare occasions, the motor point of the adductor pollicis and/or
deep head of the flexor pollicis brevis muscles can align with
that of the APB. In this instance, a CMAP with an initial nega- Figure 24-12. Martin-Gruber anastomosis. (A) Median nerve
tive onset is generated. Also, from time to time, the temporal stimulation at the wrist results in a CMAP with a normal distal motor
dispersion from proximal to distal conduction is just offset by latency. (B) Median nerve activation at the elbow generates a CMAP
the added voltage from a small adductor pollicis muscle such with an initial negative deflection but larger amplitude than at the
that the proximal CMAP is not larger but essentially the same wrist.This is the typical electrophysiologic finding in a patient with a
size as that recorded at the wrist. When a Martin-Gruber anasto- Martin-Gruber anastomosis but normal conduction across the wrist.
mosis exists, calculating the median nerve NCV is meaningless (C) In a patient with CTS, the CMAP derived from wrist stimulation is
because two different fiber populations are compared. It is suffi- prolonged. (D) The CMAP generated from median nerve activation at
cient to just record the median nerve's distal motor latency. One the elbow reveals a larger amplitude than for the wrist (C) and an ini-
must be vigilant for the possibility of this anomaly because in tial positive deflection (arrow).This is the typical electrophysiologic
mild carpal tunnel syndrome of primarily the motor type, the finding in a patient with a CTS and Martin-Gruber anastomosis.
only abnormality may be a positive deflection with proximal
median nerve stimulation.271 more generalized peripheral neuropathy. In a retrospective study,
The above situation of a combined CTS and Martin-Gruber 46% of patients were found to have electrophysiologic evidence
anastomosis is to be compared to a person without CTS but of an ulnar neuropathy and attributed directly to the CTS. 96
having a Martin-Gruber anastomosis. In this case, the only atyp- There are several shortcomings in this study. Temperature could
ical finding is a larger proximal compared with distal CMAP not be controlled because of the very nature of the study. Also,
(Fig. 24-12A and B). An initial positive deflection is absent ulnar neuropathy at the elbow was not completely evaluated in
from the proximal CMAP because the median fibers are not all patients. The lack of localizing any of the ulnar nerve lesions
slowed across the carpal tunnel, thereby arriving at the median to a focal lesion at the wrist does not support the claim of the
innervated thenar muscles prior to the crossover ulnar fibers study. Clearly, prior to assuming the carpal tunnel is an etiology
reaching the ulnar innervated thenar muscles. The distal motor for concomitant findings of ulnar neuropathy, one must establish
latency is normal, as would be anticipated. Hence, the median that a peripheral neuropathy is not present, temperature is care-
nerve conduction velocity is also normal. fully controlled, and there is a lack of any lesion at the elbow
Ulnar Neuropathy and CTS. There is a suggestion that the combined with definite ulnar pathology at the wrist. Despite the
ulnar nerve may be concomitantly injured in those patients with lack of any well-controlled electrodiagnostic medicine studies
CTS, thus accounting for the observation that some persons also examining this supposition of ulnar neuropathy at the wrist asso-
complain of symptoms in the ulnar nerve distribution as well as ciated with CTS, there is a surgical study of interest. In patients
the median nerve. Careful electrophysiologic studies have in- with complaints of both ulnar and median nerve symptoms with
deed documented that 15-39% of patients with CTS also have documented CTS, surgical release of the transverse carpal liga-
objective abnormalities involving the ulnar nerve.80-681 Similar ment resulted in significant improvement of ulnar nerve symp-
findings of 36% of patients with CTS demonstrated vibratory toms in most patients.702 Further, following carpal tunnel release,
evidence of ulnar nerve involvement were noted.313 It is impor- pressure measurements in the canal of Guyon were reduced
tant to understand that these reports did not claim the carpal compared with the preoperative levels.1 Certainly, patients with
tunnel syndrome as the etiology of the ulnar nerve dysfunction. CTS frequently complain of symptoms in the ulnar nerve distrib-
It is certainly possible that these patients may have had an ulnar ution as well.267-744 Additional controlled studies utilizing the
nerve lesion at the elbow region because of a predisposition to above criteria combined with surgical outcome evaluations are
multiple entrapment neuropathies, or some may have had a needed to fully explore this interesting association.
Grading severity. Unfortunately, there are no generally trauma, antebrachial fascia compression, or anomalous muscles
agreed upon criteria or standards for diagnosing CTS, nor are can also result in damage to this nerve.683-727-739-748 There is con-
there universally accepted criteria for grading disease severity. siderable overlap of cutaneous sensation about the hand, and the
The recommendation of Stevens 743 to utilize both the primary loss of sensation secondary to a complete injury to this
history/physical and electrodiagnostic medicine findings when nerve is in the proximal mid-palm region at the base of the
making a diagnosis of CTS appears reasonable. He has also rec- thenar eminence, not the entire thenar eminence.
ommended a CTS grading scheme based on the following elec- Electrophysiologic Evaluation and Findings. At present, a
trophysiologic findings: technique to examine the palmar cutaneous branch of the
Mild: Prolonged (relative or absolute) sensory or median nerve most likely does not exist. Several investigators
mixed-nerve action potential distal latency (or- have claimed to have developed a technique to assess this nerve
thodromic, antidromic, or palmar) ± SNAP am- electrically; however, this is likely not the case.169-350-447
plitude below the lower limit of normal. Normally, if one increases the amplifier's sensitivity to about 20
Moderate: Abnormal median sensory latency as above, and pV/div while performing a median motor study, a small nega-
(relative or absolute) prolongation of median tive potential (10-15 |iV) appears just prior to the negative
motor distal latency. onset of the median CMAP. At times, this potential can be rather
Severe: Prolonged median motor and sensory distal la- large and result in an artifactual appearing positive deflection
tencies, with either an absent SNAP or mixed prior to the median CMAP. This sensory response is referred to
(nerve action potential) NAP, or low-amplitude as the pre-motor potential and most likely represents a far-field
or absent thenar CMAP. Needle examination potential derived from the digital sensory branch innervating the
often reveals fibrillations, reduced recruitment, first digit. 169173 211 An orthodromic technique stimulating the
and motor unit potential changes. base of the thenar eminence may be a more promising attempt
to excite the palmar cutaneous branch of the median nerve. 101
Recurrent Branch of the Median Nerve The close proximity of median nerve fibers beneath the carpal
Clinical Features. Distal to the carpal tunnel, the various ligament warrants caution to ensure these fibers are not also ac-
motor and sensory branches travel to their individual regions of tivated. Further study of this technique with selective nerve
innervation. The main motor nerve, recurrent branch of the block is needed to prove that the observed potential is indeed
median nerve, acutely changes direction to innervate the APB, arising from the palmar cutaneous branch of the median nerve.
OP, and one half of the flexor pollicis brevis, and at times it may
pierce the transverse carpal ligament proximal to this structure's Digital Branches
distal edge. It is possible for this nerve to become preferentially Digital branches of the median nerve can be selectively in-
injured.45-339 727 In this instance, the patient presents with an injured in the hand secondary to various kinds of trauma. 763
ability to use the first digit properly, possible wasting of the Altered sensation to either one half of the digit or possibly an
thenar muscles in advanced cases, and normal sensation in the entire digit is possible and usually correlates with the history. It
median nerve distribution. Physical examination is consistent may be possible for ganglia to preferentially damage one of the
with the above symptoms and reveals only weakness of the median nerve's digital branches with a localized region of sen-
median-innervated thenar muscles. sory abnormality. Although electrophysiologic documentation
Electrophysiologic Evaluation and Findings. The electro- of such lesions are limited, 108 one can examine the individual
diagnostic medicine evaluation demonstrates normal sensory digits of the median nerve sequentially to median nerve stimula-
studies. Median nerve forearm conduction velocity may be tion at the wrist. It is possible to locate a bar electrode or spe-
normal or abnormal depending upon the degree of loss regard- cially prepared ring electrodes on each side of the digit and
ing the fast conducting fibers. This is also true for the CMAP selectively record from the digital nerves as they innervate the
and depends on the degree of axonal loss, reinnervation through radial or ulnar side of each digit to better localize which digital
collateral sprouting, and time of the examination with respect to branch is affected. Both wrist and midpalm studies may be at-
symptom duration. Needle electromyography reveals mem- tempted. Caution must be exercised with this technique, how-
brane instability and altered recruitment in only the thenar mus- ever, as a volume-conducted spread of the intact potential to
cles innervated by the median nerve. The remaining intrinsic recording electrodes may very easily occur, obscuring the
hand muscles are normal. This disorder is rare, but should be degree of true axonal loss.
kept in mind when only motor symptoms are observed. One
must consider this disorder versus a pure motor carpal tunnel
syndrome when the above patient presentation and electrophys- ULNAR N E R V E
iologic findings are found. Sufficient patients have not been de-
scribed to completely characterize the electrophysiologic ANATOMY
differences between a pure motor carpal tunnel syndrome
versus a recurrent branch of the median nerve focal neuropathy Anatomic Course. The ulnar nerve is formed in the axilla
aside from an obvious palmar injury. after the medial cord gives off a branch, the medial branch to
the median nerve, to help form the median nerve (see Fig. 24¬
Palmar Cutaneous Branch of the Median Nerve 1). In essence, the ulnar nerve is simply the continuation of the
Clinical Features. The palmar cutaneous branch of the medial cord into the upper limb. Root levels C8 and Tl are the
median nerve is usually spared in CTS, thus implying patients primary constituents of the ulnar nerve; however, there is usu-
should have undisturbed sensation in the proximal mid-palm ally a contribution from the C7 level. In the axilla, the ulnar
and medial aspect of the thenar base. This pure sensory branch nerve is initially posterior to the axillary vessels. As the nerve
of the median nerve can be injured during carpal tunnel release descends into the proximal arm, it is positioned medial to the
surgery if the incision is improperly located.95-774 Also, ganglia, brachial artery, while the median nerve is located lateral to this
vessel, thus forming a common neurovascular bundle. This neu-
rovascular bundle can be easily located because it lies in the
groove between the coracobrachialis muscle laterally and the
three heads of the triceps muscle posteriorly. At approximately
the midportion of the upper arm, where the coracobrachialis
muscle inserts, the ulnar nerve departs from the neurovascular
bundle, which is anterior to the intermuscular septum, and
enters the posterior compartment of the arm by piercing this
septum. The intermuscular septum is a connective tissue struc-
ture that separates the arm's musculature into anterior and pos-
terior compartments; it is rather thick distally at its attachment
to the medial epicondyle and supracondylar ridge. As the septum
ascends, it thins out considerably near its proximal attachment,
which lies posterior to the coracobrachialis muscle near the infe-
rior border of the teres major muscle's insertion on the humerus.
The region of the septum just proximal to where it is pierced by
the ulnar nerve is known as the internal brachial ligament.
After traversing the septum, the ulnar nerve lies on the medial
surface of the medial head of the triceps muscle. The ulnar nerve
is located in a deep groove within the medial triceps muscle and
covered by .a tough fascial plane that covers the nerve from the
upper surface of the triceps muscle to the intermuscular septum
Figure 24-14. Ulnar nerve in postcondylar groove.The ulnar

nerve lies first in the postcondylar groove between the medial epi-
condyle of the humerus and the olecranon process. It then passes be-
tween the two heads of the flexor carpi uinaris muscle and enters the
cubital tunnel. (From Liveson JA: Peripheral Neurology: Case Studies in
Electrodiagnosis. Philadelphia, FA Davis, 1991, with permission.)
and is referred to as the arcade of Struthers (Fig. 24-13). This

anatomic description is relevant because the ulnar nerve is rela-
tively free prior to piercing the intermuscular septum; however,
it is tightly bound to the medial head of the triceps muscle by
the above noted arcade of Struthers.
Just proximal to the elbow region, the triceps muscle nar-
rows for its insertion to the olecranon. The ulnar nerve departs
from the triceps muscle proximal to the olecranon to lie poste-
rior to the medial humeral epicondyle and medial to the ulnar
collateral ligament and olecranon process, i.e., the postcondy-
lar groove. As the nerve passes distally, it travels between the
humeral and ulnar heads of the flexor carpi uinaris muscle (Fig.
24-14). A tendonous/fibrous arch between the two heads of the
flexor carpi uinaris muscle overlies the ulnar nerve. The com-
Figure 24-/3. Arcade of Struthers.The ulnar nerve is depicted bination of this fibrous arch and the underlying skeletal and lig-
traversing the arcade of Struthers to enter the posterior compart- amentous structures form the cubital tunnel. Distal to the
ment of the arm. Inset:The arcade of Struthers has been sectioned to cubital tunnel, the ulnar nerve then lies deep to the flexor carpi
reveal the ulnar nerve and its relationship to the internal brachial liga- uinaris muscle but superficial to the flexor digitorum profundus
ment. (From Spinner M, Kaplan EB:The relationship of the ulnar nerve muscle. In the forearm, the ulnar nerve remains in its position
to the medial intermuscular septum in the arm and its clinical signifi- beneath the flexor carpi uinaris muscle until it reaches the
cance. Hand 1976;8:239-242, with permission.) wrist.
ULNAR N. (Fig. 24-16). A reappraisal of the canal of Guyon's anatomic
VOLAR CARPAL
boundaries suggests that the lattermost confine is not the hamate
LIGAMENT bone, but rather the transverse carpal ligament's midportion. 712
TRANSVERSE
CARPAL LIGAMENT
In some persons, a portion of the ulnar nerve may pass lateral to
the hook of the hamate. The superficial branch of the ulnar
nerve innervates the palmaris brevis muscle. The deep branch
of the ulnar nerve travels between the abductor digiti minimi
and flexor digiti minimi muscles. It then passes through a fibro-
osseous tunnel formed by the piso-hamate ligament posteriorly,
musculotendonous arch anteriorly, pisiform bone medially, and
Figure 24-15. Canal of Guyon. Relationships of the ulnar nerve as hook of the hamate laterally, to then curve laterally to traverse
it is located between the transverse carpal ligament and volar carpal the palm of the hand deep to the flexor tendons (Fig. 24-17).
ligament forming Guyon's canal.The tendonous insertion of the flexor This deep branch of the ulnar nerve splits into its terminal
carpi radialis muscle and pisiform bone form the medial wall of the branches upon reaching the adductor pollicis muscle.
structure, while the hook of the hamate is the lateral wall. (From
Kleinert H, Hayes JE:The ulnar tunnel syndrome. Plastic Reconstr NEURAL BRANCHING
Surg 1971 ;47:21-24, with permission.)
There are rarely any neural branches arising from the ulnar
nerve in the upper arm (Fig. 24-18). In only 5% of cadaver dis-
Immediately proximal to the wrist region, the flexor carpi ui- sections, there is noted to be a muscular branch to the flexor
naris muscle narrows to form its tendon, which inserts onto the carpi uinaris muscle arising proximal to the medial epi-
pisiform bone (Fig. 24-2). Because of this tendonous narrow- condyle. 726763 It is the rule, with few exceptions, that the flexor
ing, the ulnar nerve is subcutaneous and lies between the medi- carpi uinaris muscle is the first muscle innervated by multiple
ally located flexor carpi uinaris and laterally placed flexor branches from the ulnar nerve, and these branches typically
digitorum superficialis tendons. The ulnar nerve then enters the arise distal to the medial epicondyle. 763 The flexor digitorum
hand by passing superficial to the transverse carpal and pisoha- profundus muscle to the fourth and fifth digits is the next mus-
mate ligament, but deep to the rather thin volar carpal ligament cular branch from the ulnar nerve, and it arises within a few
and palmaris brevis muscle, and between the hook of the centimeters distal to the medial epicondyle just below the mus-
hamate laterally and pisiform bones laterally (Fig. 24-15). This cular branch to the flexor carpi uinaris muscle. This muscle can
fibro-osseous compartment through which the ulnar nerve be variably innervated by both the median and ulnar nerves. At
passes is referred to as Guyon's canal. In or about Guyon's a variable distance distal to the mid-forearm level, but proximal
canal, the ulnar nerve divides into a superficial and deep branch to the dorsal ulnar cutaneous nerve, the palmar cutaneous branch
Figure 24-16. Ulnar nerve In canal of Guyon.The

main ulnar nerve trunk is shown splitting into its superfi-
cial and deep branches as it enters Guyon's canal between
the pisiform and hook of the hamate bones. (From Liveson
JA: Peripheral Neurology: Case Studies in Electrodiagnosis.
Philadelphia, FA Davis, 1991, with permission.)
Chapter 24 FOCAL PERIPHERAL NEUROPATHIES — 1 0 7 3
Figure 24-/7. Deep branch of ulnar nerve.The deep branch of

the ulnar nerve is shown giving a branch to the abductor digiti minimi
prior to passing through a fibro-osseous tunnel formed by the piso-
hamate ligament, musculotendinous arch of the hypothenar muscles,
and the pisiform and hook of the hamate bones. (From Uriburu EJF,
Morchio FJ, Marin JC: Compression syndrome of the deep motor
branch of the ulnar nerve (piso-hamate hiatus syndrome). J Bone Joint
Surg 1976;58A: 145-147, with permission.)
of the ulnar nerve arises to course distally and supply a vari-

able portion of the skin overlying the hypothenar eminence
(Fig. 24-18).' 86482 There can be considerable overlap of cuta-
neous innervation to this region by branches from the palmar
cutaneous branch of the median nerve, superficial terminal divi-
sions of the ulnar nerve in the hand, and the medial antebrachial
cutaneous nerve. Approximately 5-10 cm proximal to the wrist,
the dorsal ulnar cutaneous nerve branches from the main
trunk of the ulnar nerve to pass posteriorly between the ulna and
tendon of the flexor carpi uinaris muscle, thus reaching the
dorsal aspect of the hand. 763 Upon attaining the ulnar styloid,
this nerve splits into a variable number of dorsal digital nerve
branches. The most medial of these branches supplies the dor-
solateral aspect of the hand and continues distally to innervate Figure 24-18. Ulnar nerve. Course of the ulnar nerve and its vari-
the fifth digit's dorsum to approximately the fingernail (Fig. 24- ous neural branches are depicted.The first branches are usually muscu-
18).413 The next most medial branch then courses in the fourth lar in the proximal arm to the flexor carpi uinaris and digitorum
metacarpal interspace to divide and innervate the lateral aspect profundus (digits 3 and 4). Next, cutaneous branches known as the
of the fifth digit to the fingernail and also innervate the medial palmar cutaneous branch of the ulnar nerve (I) and dorsal ulnar cuta-
aspect of the fourth digit to the middle phalanx. The most neous nerve (2) are given off. In the hand, the superficial (3) and deep (4)
medial branch has a variable course over the remaining aspect terminal ulnar nerve branches are formed. Intrinsic hand muscle inner-
of the hand's dorsum to the mid-axis of the fourth digit with oc- vation is shown in the figure. (From Haymaker W,Woodhall B: Peripheral
casionally extensions more laterally. Nerve Injuries. Philadelphia,W.B. Saunders, 1953, with permission.)
Approximately 0.4-2.0 cm distal to the radial styloid, the
main trunk of the ulnar nerve splits into its superficial and deep between the superficial and deep divisions. In about 25% of ca-
divisions (Fig. 24-16). The branch to the palmaris brevis usually daveric specimens, the abductor digiti minimi receives its inner-
arises from the superficial ulnar nerve 1-4 cm distal to the divi- vation directly from the main trunk of the ulnar nerve prior to its
sion of the superficial and deep ulnar nerves. Hypothenar divisions, while in the remaining 25% of hands, the abductor
muscle innervation is somewhat complex primarily because of digiti minimi is supplied by a branch arising at the site of divi-
its variability, which can be quite important with respect to sion between the two main ulnar nerve divisions in the hand.
lesion localization. 427 Approximately 50% of the time, the The flexor digiti minimi muscle is characteristically innervated
branch innervating the abductor digiti minimi emanates from by the deep branch of the ulnar nerve, and the opponens digiti
the deep branch of the ulnar nerve just distal to the branch point minimi muscle is the next in sequence innervated by the deep
branch. The fourth lumbrical muscle is typically innervated by a lesion attributed solely to an arcade of Struthers compression,
nerve twig from the branch innervating the flexor digiti minimi but this entity should be considered in the differential diagnosis
muscle. Palmar and dorsal interossei are sequentially innervated of ulnar nerve arm injuries.
by the deep branch of the ulnar nerve with each respective For discussion purposes, let us assume a complete lesion such
palmar interossei muscle innervated prior to its associated as a transection from a knife wound affects solely the ulnar
dorsal interossei muscle. The third and fourth lumbrical mus- nerve in the arm region. In this instance, the patient will com-
cles are also innervated by nerve twigs from the deep branch. plain of immediate loss of sensation in the distribution of all
The last muscles of the deep branch to be innervated are the sensory branches of the ulnar nerve: base of hypothenar emi-
transverse portion of the adductor pollicis and first dorsal in- nence (palmar cutaneous branch), dorsum of the hand's medial
terosseous muscles. Individual variations can place ekher one or aspect (dorsal ulnar cutaneous), and volar aspect of medial palm
both of these muscles as the last muscle innervated by the deep and medial fifth and half of the fourth digits (superficial
branch of the ulnar nerve. Along its course, the ulnar nerve pro- branches) (Fig. 24-18). Unless the medial brachial and ante-
vides articular branches to the elbow, radio-ulnar, carpal, car- brachial cutaneous nerves are also injured, there should be
pometacarpal, and metacarpophalangeal joints as well as preservation of sensation along the medial aspect of the arm and
various associated arterial branches. forearm proximal to the wrist region. All muscles innervated by
The superficial branch of the ulnar nerve emerges deep to its the ulnar nerve are rendered nonfunctional. Physical examina-
distal border to divide into a proper palmar digital branch tion reveals absent sensation in the above-noted distributions
and a common palmar digital branch. The proper palmar dig- with sparing along the lateral aspect of the hand's dorsum (su-
ital branch innervates the medial aspect of the fifth digit, while perficial radial nerve territory) and first three and one-half digits
the more common palmar digital branch splits to supply the cu- as well as the lateral aspect of the palm of the hand and thenar
taneous aspects of the lateral surface of the fifth and medial eminence (median nerve). Wrist flexion results in radial devia-
region of the fourth digits (see Fig. 24-6). Recall that this lateral tion because the flexor carpi ulnar muscle is impaired, leaving
division usually forms a communicating loop with a digital the flexor carpi radialis muscle unopposed. Flexion of the ter-
branch of the median nerve. minal phalanges of the fourth and fifth digits is no longer possi-
ble because the flexor digitorum profundus is denervated. This
FOCAL ULNAR NEUROPATHIES can be a variable finding, however, as the slips of muscle to
these digits may be totally or partially innervated by the anterior
Similar to the median nerve, the ulnar nerve can also be com- interosseous branch of the median nerve. All of the hand intrin-
promised in the axilla from crutches, hanging the arm over sic muscles are nonfunctional except for the opponens pollicis,
sharp edges, or gunshot wounds. 748 This region of ulnar nerve abductor pollicis brevis, and one half of the flexor pollicis
injury is discussed with brachial plexus lesions (see Chapter brevis muscles as well as the first two lumbrical muscles.
19). In this section, we shall concentrate on focal ulnar nerve Flexion of all digits is still possible secondary to the flexor digi-
damage beginning in the arm and progressing distally. torum superficialis muscle.
Observation of a patient with a complete ulnar nerve lesion
Arm Region reveals that the fifth digit tends to be slightly more abducted
Clinical Features. Focal ulnar neuropathies in the arm when compared with the nonaffected hand. This is believed to
region are relatively rare in comparison with more distal regions occur because of absence of the third palmar interosseous
of the upper limb. Fractures, tourniquet applications for pro- muscle, which adducts the fifth digit, combined with an unop-
longed periods, lacerations, missile wounds, focal neural hyper- posed pull from radial nerve—innervated extensor digiti minimi
trophy, crutch palsy, and other traumatic incidents can result in and extensor digitorum communis to the fifth digit, i.e., a dy-
ulnar nerve injuries.599-762-763 A number of patients have been re- namic muscle imbalance referred to as Wartenberg's sign.811 It
ported to have experienced high ulnar nerve lesions following is important to realize that persons who sustain a significant ab-
removal of a subdermal contraceptive.471-710 Particular care must duction injury to the fifth digit with compromise to the radial
be exercised in patients undergoing surgical procedures, be- sagittal band, radial collateral ligament, and junctura tendinum
cause the ulnar nerve can be preferentially compressed in the about the fifth metacarpophalangeal joint region may present
upper to mid-arm region as the limb hangs over the operating with an identical appearance despite normal ulnar nerve func-
table.'86-806,807.8ii Because of the proximity of the median and tion.441 Patients may complain of "catching" the fifth digit when
radial nerves, it is not uncommon to also find concomitant attempting to put the hand into a pocket. A hollow or guttering
damage to these neural structures, which has been referred to as is usually observed between the metacarpal bones because of
a triad neuropathy. 472 interosseous muscle wasting. This is particularly prominent for
An often discussed but rarely documented cause of ulnar neu- the first dorsal interosseous muscle. There may also be some
ropathy in the arm can occur about the arcade of Struthers, flattening of the thenar eminence as the adductor pollicis
which is anatomically present in about 70% of individuals (Fig. muscle atrophies. This is also true of the hypothenar region as
24-13).552a-805 This fibrous structure may act to directly compress these muscles atrophy. As noted above, the patient is quite capa-
or prevent optimal sliding of the ulnar nerve during elbow flex- ble of flexing all the digits, but has difficulty on attempting to
ion and extension. 727 The major importance of this structure open the hand. There is noted to be a characteristic position of
may be more related to its relationship to the ulnar nerve in sur- the hand on attempted finger extension where there remains par-
gical transpositions. When the ulnar nerve is transposed anteri- tial flexion of the proximal and distal interphalangeal joints
orly, the arcade of Struthers can act to tether the nerve and limit with exaggerated extension of the metacarpophalangeal joints
its mobility. Sectioning this structure during a transposition to the fourth and especially the fifth digits. This is the so-called
procedure assists in freeing the nerve and allowing it sufficient ulnar claw hand (Fig. 24-19). The hyperextension at the fourth
mobility during elbow flexion and extension. The authors are and fifth metacarpophalangeal joints is attributed to the unop-
unaware of electrophysiologic documentation of an ulnar nerve posed pull of the extensor digitorum communis muscle fibers to
these digits because of denervation to the third and fourth lum-
brical as well as the interossei muscles. Hyperflexion at the
second and third metacarpophalangeal joints is absent because
of median nerve innervation to the first two lumbrical muscles.
Flexion occurs in the fourth and fifth digits upon opening the
hand in ulnar nerve lesions proximal to the flexor digitorum
profundus muscle innervation. This is because of some inherent
muscle tone in the flexor digitorum profundus and superficialis
muscles as these muscle fibers are stretched over the metacar-
pophalangeal joints owing to the hyperextension by extrinsic
muscle pull. Clawing is particularly noted, however, when the
flexor digitorum profundus muscle is spared. Care must be ex-
ercised when examining a patient because the claw deformity
can be eliminated if the hand is placed against a hard surface
(Fig. 24-19). The ulnar claw hand can at times appear quite sim-
ilar to a median benediction sign if one is not careful in observ-
ing the patient. The median nerve benediction sign occurs when
the patient is asked to close the hand, whereas the ulnar claw
occurs during attempted hand opening.
In a complete ulnar nerve lesion in the arm, the ability to
abduct and adduct the fingers should be totally lost; however, it
may be possible for the patient to perform these functions par-
tially. This is accomplished to a small degree by the extensor
digitorum communis muscle having a limited abduction capa-
bility and substituting for the dorsal interossei. Similarly, if the
fingers are slightly flexed, the palmar interossei can be substi-
tuted for by the remaining finger flexors. If the digits are ex-
tended, this motion cannot be performed because the muscle is Figure 24-/9. Ulnar claw hand. Note the hyperextension of the
now at a mechanical disadvantage. Even though the adductor fourth and fifth metacarpophalangeal joints with flexion of the inter-
pollicis muscle function is lost, patients can still palmarly and phalangeal joints.The claw deformity can be eliminated by the patient
ulnarly adduct the thumb. This movement is different than that extending the fingers with the dorsum of the hand braced against a
normally observed and can be brought out by having the patient hard surface. (From Haymaker W, Woodhall B: Peripheral N e r v e
grasp a piece of paper between the thumb and radial side of the Injuries. Philadelphia,WB. Saunders, 1953, with permission.)
second digit of both hands and attempt to pull the paper apart.
The affected hand will demonstrate flexion of the distal phalanx
of the thumb, while the unaffected thumb remains extended. presumed lesion site a definite response is observable, this may
The flexor pollicis longus muscle serves to adduct the thumb by be of some value in documenting conduction block. This find-
a substitution movement, and the extensor pollicis longus also ing is the exception, however, and not the rule.
helps to a small degree. This is the so-called Froment's signe
de journal (Froment's sign) (Fig. 24-20).
Electrophysiologic Evaluation and Findings. With com-
plete ulnar nerve lesions in the arm region, one can anticipate
the absence of SNAPs as obtained from the dorsal ulnar cuta-
neous nerve and digital terminal nerves to the fourth and fifth
digits. As with the median nerve, either orthodromic or an-
tidromic techniques can be used, but a standard distance is pre-
ferred because of how the SNAP'S amplitude varies with
distance. A preferred method of evaluating the ulnar SNAP is to
position recording ring electrodes on the fifth digit and stimu-
late the ulnar nerve at the wrist a standard distance from the
active electrode. Onset/peak latency or conduction velocity is
usually the parameter used to assess the SNAP. In partial lesions,
a variable-amplitude SNAP is anticipated but the onset/peak la-
tencies should remain normal until the response completely dis-
appears in a progressive traumatic injury. Stimulating above and
below the lesion is possible to assess the proximal portion of the
ulnar nerve for any component of conduction block. This study Figure 24-20. Froment's sign.The patient with an ulnar nerve
is limited in most persons, however, because of the previously lesion is asked to pull a piece of paper apart with both hands. Note the
noted dependence of SNAP amplitude on distance. The long affected side (right hand) uses the flexor pollicis longus muscle to pre-
conduction distance between arm and fifth digit results in sig- vent the paper from slipping out of the hand, thus substituting for the
nificant phase cancellation of the individual waveforms, render- adductor pollicis muscle and generating the so-called Froment's sign.
ing this technique of little value. If one notes that immediately (From Haymaker W, Woodhall B: Peripheral Nerve Injuries. Phila-
above a focal injury no response is detectable, but just below the delphia, W.B. Saunders, 1953, with permission.)
Obtaining a CMAP from the hypothenar muscles is much more ulnar nerve is spared following a supracondylar fracture, it is
feasible in attempting to evaluate the possibility of a proximal possible for percutaneous cross-pinning of the fracture to then
ulnar nerve lesion. Immediately following an ulnar nerve transec- injure the ulnar nerve 453 Fortunately, most of these injuries re-
tion in the arm, stimulation proximal to the lesion site fails to cover spontaneously. In addition, on rare occasions a supra-
evoke a response. Distal to this injury, a normal response can still condylar spur and ligament of Struthers affects both the
be obtained within the first few days following the insult. By about median and ulnar nerves.216-511 These lesions result in variable
day 8, the CMAP has declined significantly and fails to be evoked symptoms depending upon the degree of neural insult. In the
any longer because of neuromuscular junction and terminal neural case of fractures, the inciting traumatic incident is obvious.
disintegration. In an incomplete lesion, stimulating the ulnar nerve Unfortunately, the ensuing neural damage may be missed if it is
at the wrist, for example, and comparing this CMAP with the unless than severe. Patients with mild symptoms should be as-
affected contralateral CMAP allows one to roughly approximate sessed electrophysiological^ to completely evaluate not only
the amount of axonal loss. Combining this study with proximal the ulnar, but also the median and radial nerves. The rarity of
stimulation sites above and below the lesion helps assess the nerve supracondylar spurs suggests that this potential lesion should
for not only axonal loss, but also conduction block. Let us assume certainly not be high on the list of potential causes of ulnar
that a knife penetrated our hypothetical patient in the mid-ai m nerve lesions about the elbow region. Nevertheless, it should be
region and the patient complained of numbness in the ulnar nerve considered when more common ulnar nerve insults have been
distribution with a typical claw hand. At 10 days following the in- addressed. Although not always sensitive, simply palpating
cident, a CMAP from the affected abductor digiti minimi reveals a along the medial epicondyle and distal third of the medial
baseline-to-peak amplitude of 3 mV, while that from the other side humerus may reveal the presence of a supracondylar spur. Even
is 6 mV to wrist stimulation. Above the injury, there is a complete if this bony anomaly is found, it is not necessarily the cause of
absence of any response. These findings imply there is about a ulnar nerve compromise.
50% loss of axons in the ulnar nerve ({6 mV-3 mV) -f 6 mV = Electrophysiologic Evaluation and Findings. Electro-
0.5) with 100% of the remaining intact fibers experiencing con- physiological^, stimulating in short, 1 -cm increments may help
duction block in the arm. This patient has a relatively good prog- localize a conduction block if present when the ulnar nerve is
nosis, as the fibers blocked should regain function as well as send compromised by a supracondylar spur. Essentially, one looks
out collateral sprouts to reinnervate the denervated muscle fibers. for a rather significant change in amplitude over a small seg-
If a compressive lesion in the mid-arm generates some demyelina- ment. If only axonal loss is present with minimal demyelina-
tion of the fastest conducting fibers, a preferentially reduced tion, one may not be able to localize a lesion to this region. If
neural conduction across the arm segment may be observed. This axonal loss is present, needle electromyographic findings are
finding is detected if one stimulates the ulnar nerve in the proxi- anticipated in all ulnar muscles, as they are innervated distal to
mal arm above the presumed lesion and just proximal to the this region. Unfortunately, a profound lesion at the elbow re-
medial epicondyle that is below the injury. A focal lesion resulting sults in quite similar findings. Typical ulnar nerve lesions at the
in differential demyelination can produce a temporally dispersed elbow, however, do not characteristically result in abnormalities
CMAP to proximal stimulation because of an asynchronous con- in the flexor carpi uinaris muscle. Abnormalities in the dorsal
duction through the lesion site. ulnar cutaneous and digital SNAPs are important, but suggest
After about 2-3 weeks, a needle electromyographic examina- only that a lesion is proximal to the origin of the dorsal ulnar
tion should be performed on muscles in the affected upper limb. cutaneous nerve in the proximal antebrachium and do not local-
It is very important to examine not only the ulnar innervated ize the lesion over a focal segment. With respect to humeral
muscles, but also those muscles innervated by the median and fractures, needle electromyographic findings cannot only docu-
radial nerves. This is because the radial, and in particular the ment the extent of an ulnar nerve lesion, but also document the
median nerves are in close proximity to the ulnar nerve. With integrity of both the median and radial nerves that may be con-
respect to the ulnar nerve, the flexor carpi uinaris muscle and all comitantly injured by the fracture. Both CMAP and SNAP ab-
those distal muscles should reveal signs of denervation, i.e., normalities are anticipated depending upon the lesion's severity.
membrane instability consisting of positive sharp waves and fib-
rillation potentials. In partial lesions, each muscle may demon- Elbow Region
strate variable degrees of denervation as well as reductions in Clinical Features. Ulnar nerve compromise about the elbow
voluntary MUAPs and recruitment abnormalities. region is second only to CTS with respect to frequency of occur-
It is important to perform SNAPs of the median nerve and rence regarding focal neuropathies in the upper limb. Individuals
radial nerve to complete the study of the three major nerves in with ulnar nerve damage at the elbow usually first complain of
the affected limb. After about 3-6 weeks, the process of collat- paresthesias and hypesthesias in the volar aspects of the fourth
eral sprouting adds the previously denervated muscle fibers to and fifth digits and hypothenar eminence. These symptoms are
the remaining motor units. This process renders the use of typically exacerbated by prolonged elbow flexion. At first, par-
CMAPs for estimating the amount of axonal loss less than opti- ticularly observant patients may note that avoiding elbow flexion
mal. As more muscle fibers are reinnervated by collateral reduces the symptomatic complaints. Those persons who must
sprouting, the CMAP increases in amplitude and begins to ap- repetitively flex and extend the elbow as a result of their work re-
proximate that from the contralateral side. Even though the quirements note an increase in symptoms with this activity as
nerve has not yet regrown across the injury site, collateral well as awakening at night as the disorder progresses. Depending
sprouting minimizes one's ability to estimate the degree of on the etiology of neural compromise, the symptoms may
axonal loss after the above-noted time period. progress at variable rates and eventually reach a level at which
the discomfort is continually present. Pain may also develop at
Distal Arm and Supracondylar Region various stages of the disorder and radiate proximally to the
Clinical Features. Fractures of the distal third of the humerus shoulder and/or distally to the wrist and hypothenar eminence.
can result in preferential injury to the ulnar nerve.268-434-812 If the The above chronic progression is more common for ulnar nerve
compromise at the elbow; however, acute falls and other trau- crease with the more proximal portions of the limb innervated
matic incidents also occur. These two presentations usually dic- by the medial antebrachial cutaneous nerve. The patient's elbow
tate how patients seek medical attention. should be flexed and extended several times while the examiner
Acute insults of a minor degree to the ulnar nerve at the palpates for the ulnar nerve to remain in the postcondylar
elbow are quite common. This is because the exposed ulnar groove. In some persons, elbow flexion results in the ulnar
nerve in the postcondylar groove is subject to frequent traumatic nerve escaping from the ulnar groove to snap across the medial
events when the elbow is bumped into objects. These minor an- epicondyle. Elbow extension results in the ulnar nerve snapping
noyances usually resolve quickly, and no further thought is over the medial epicondyle to regain the postcondylar groove.
given to them. When significant trauma occurs and paresthe- This can generate chronic irritation to the ulnar nerve.
sias/numbness does not abate, or hand intrinsic weakness The motor examination can be conveniently performed by
ensues, patients usually seek medical attention. It is much more considering the ulnar nerve's muscle function from four per-
common for an insidious onset of minor paresthesias and numb- spectives: (1) thumb to second digit lateral pinch, (2) thumb to
ness to progress over the course of months to years. These digit precision pinch, (3) synchronous digital flexion for grasp,
symptoms are tolerated by most patients, as they are slowly pro- and (4) power grip. 140 When examining lateral pinch for the
gressive and the median nerve provides most of the cutaneous thumb, the patient is asked to hold a piece of paper in the first
sensation to the hand. When weakness or muscle wasting be- web space between the thumb and second metacarpal bone with
comes manifested, particularly in persons needing a power grip both hands and attempt to pull the hands apart while firmly
such as hammering or using a screw driver, a physician is then grasping the paper. Patients without ulnar intrinsic muscle
sought. It is not unusual for some individuals to be primarily weakness can perform this maneuver quite well without the
concerned with weakness and discuss sensory complaints only need to flex the distal phalanx of the thumb. When the ulnar-in-
when specifically questioned. nervated hand intrinsic muscles are weak, however, there is a
The physician should pursue a history of repetitive trauma characteristic hand posture required to hold onto the paper, the
secondary to repeated elbow flexion/extension. Also, persons so-called Froment's sign (Fig. 24-20). Reduced power in the
who drive for their livelihood, such as truck drivers or salesper- adductor pollicis and flexor pollicis brevis deep head muscles
sons, may spend hours with their elbows flexed and hands results in an unstable metacarpophalangeal joint to the first digit
firmly grasping the steering wheel. Elbow flexion for prolonged that produces hyperextension of this joint upon resistance to
periods tends to decrease the volume of the space available for pulling the above-noted piece of paper. Furthermore, the paper
the ulnar nerve as it courses beneath the flexor carpi uinaris can be retained in the affected hand only with flexion of the
muscle. Further, elbow flexion serves to decrease the cross-sec- flexor pollicis longus and contraction of the extensor pollicis
tional area of the cubital tunnel as well as increase intraneural longus and brevis muscles, both of which press the thumb and
pressure within this region.241 Also, gripping the steering wheel hence the paper into the second metacarpal bone. The thumb
tightens the flexor carpi uinaris muscle about the ulnar nerve, hyperextension and distal phalanx flexion are characteristic of
further tending to compromise it. Similarly, some professionals intrinsic hand muscle weakness. Because the interossei and
and students spend many hours leaning on their nondominant medial two lumbrical muscles are no longer functional, coordi-
elbow while writing with the dominant hand. This type of exter- nated abduction and adduction of the digits are impossible for
nal compression can also injure the ulnar nerve. An old elbow the patient to perform. Also, flexion and extension must now be
injury such as a dislocation or fracture can cause callus forma- performed solely by the hand extrinsic muscles without assis-
tion that impinges upon the ulnar nerve and may also be importance from the hand intrinsic muscles, which results in a some-
tant to the patient's present complaints. A single investigation what clumsy appearance to this motion. This deficit is
suggests that men are more likely than women to have an ulnar particularly noted when the patient attempts to gently grasp a
neuropathy in the elbow region.63811 A risk factor among men ap- relatively small object. Clawing of the fourth and fifth digits is
pears to be advancing age, but body mass index (BMI) is not. particularly noticeable in profound ulnar nerve lesions at the
Women with a BMI < 22.0 were more likely to have an ulnar elbow, as the hand intrinsic muscles are preferentially affected
neuropathy than women with a BMI > 22.0. Further work is re- compared with the flexor carpi uinaris and digitorum profundus
quired in the area of risk factors. muscles. The inherent tone of the flexor digitorum profundus
Physical examination should concentrate on the following as- muscles generate marked flexion of the interphalangeal joints
pects. A careful sensory examination is important to delineate when combined with an extension force from the extrinsic digi-
an ulnar from median nerve insult. Differentiating between the tal extensors (see above). Also, abduction of the fifth digit may
terminal digital and dorsal ulnar cutaneous branches is very im- be noted (Wartenberg' sign). This is typically observed by
portant. If there is noted to be diminished sensation along the asking the patient to put his or her hand in a pocket. Finally,
volar aspect of the fourth and fifth digits but sparing on the power grasp as measured by any one of multiple commercially
dorsum of the hand medially, a lesion affecting the ulnar nerve available gripping devices is significantly compromised.
distal to the takeoff of the dorsal ulnar cutaneous nerve should Normal males and females can exert up to 140 and 60 pounds of
be considered. An insult to the ulnar nerve at the elbow should pressure, respectively, during a power grasp. 140 This value may
result in altered sensation along the distribution of the dorsal drop by as much as 80% with ulnar nerve lesions.
ulnar cutaneous nerve as well as that for the terminal cutaneous Ulnar nerve injuries at the elbow can be categorized into
branches to the digit's volar aspect. It is recommended to first three groups: (1) intermittent symptoms of mild paresthesias
begin testing sensation from the region of worst deficit and and hypesthesias; (2) persistent sensory complaints with some
work proximally, i.e., pads of the fourth and fifth digits to the degree of intrinsic muscle weakness; and (3) marked sensory
hypothenar eminence and wrist.140 All modalities—light touch, loss, weakness, and muscle atrophy.140 The causes of ulnar
pain, vibration, two-point discrimination, and temperature— nerve compromise at the elbow leading to the above-noted three
should be tested. In the majority of patients, sensory abnormali- categories are multiple (Table 24-4). Additionally, five anatomic
ties due to an ulnar nerve lesion stop at about the distal wrist sites of potential ulnar nerve compromise have been identified:
Table 24-4. Etiology of Ulnar Neuropathies at the Elbow result in significant neural damage. Similarly, prolonged leaning
1. Pressure on the elbow can damage the ulnar nerve at the elbow. Patients
A. External undergoing various surgical procedures are particularly prone to
Single event ulnar nerve injury, as the upper limb may rest for long periods on
Repetitive events
the operating table.506-803'806-807 Patients should be positioned with
B. Internal the forearm supinated so that the olecranon process bears the
Soft tissue masses
forearm weight and with the elbow cushioned. With the forearm
pronated, the ulnar nerve is compressed between the hard surface
Fibrosis following trauma and its bony groove. Pressure also may be applied to the ulnar
Anomalous muscles nerve from any object that acts to reduce the amount of space
II. Bony deformity available for the ulnar nerve as it traverses the postcondylar
A. Acute groove or cubital tunnel regions. One group of space occupying
Fracture/dislocation lesions is various soft tissue masses such as ganglia, lipomas, or
B. Chronic epidermoid cysts.31-68-797 An anomalous muscle, the anconeus
Healed fractures epitrochlearis muscle, which arises from the olecranon process
Medial epicondyle and triceps muscle tendon to insert onto the medial epicondyle,
Lateral epicondyle can act to compress the ulnar nerve.132-478-727-845 This muscle is
Supracondylar noted to be present in about 8% of cadavers.103 Ulnar nerve com-
Additional elbow joint deformities pression, which is believed to occur in only a few individuals with
Rheumatoid arthritis this muscle, can be diagnosed only by surgical exploration of the
Valgus deformity and shallow postcondylar groove area; the muscle cannot be palpated.733 When the ulnar nerve is
Supracondylar spur (ligament of Struthers) compromised by this muscle, only surgical resection can resolve
III. Cubital tunnel syndrome the symptoms. Repetitive trauma of a chronic nature can also
IV. Chronic subluxation
result in fibrous thickening of the nerve, which further reduces
the space available, thus adding to further neural compromise.569
V. Idiopathic Leprosy is a rare cause of ulnar neuropathy at the elbow, and
Modified from Stewart748 and Dawson et al.1 neural swelling predisposes it to compression.663 It is possible for
patients with hemophilia to sustain a focal ulnar nerve lesion at
(1) intermuscular septum, (2) medial epicondyle region, (3) epi- the elbow secondary to neural compression from a hematoma.102
condylar groove, (4) cubital tunnel, and (5) ulnar nerve exit Various bony deformities about the elbow can result in pref-
from flexor carpi ulnar muscle (Fig. 24-21). Externally applied erential insult to the ulnar nerve. Immediate damage to the ulnar
pressure from either a single event or repetitive compressive nerve can arise in conjunction with elbow joint dislocations or
episodes can injure the ulnar nerve, which is vulnerable and ex- fractures.434-763 Perhaps one of the more familiar causes of ulnar
posed about the elbow. A single fall of sufficient magnitude may neuropathy at the elbow occurs months or more typically years
Site 5: Exit of ulnar nerve from flexor carpi uinaris

Compression caused by
• Deep flexor-pronator aponeurosis
Triceps
Site 1: Intermuscular septum

Compression caused by
• Arcade of Struthers
• Medial intermuscular septum Flexor carpi uinaris
• Hypertrophy of the medial head
Aponeurosis of the flexor carpi uinaris
of the triceps
• Snapping of the medial head Flexor digitorum profundus
of the triceps
Site 2: Area of medial epicondyle Site 3: Epicondylar groove

Site 4: Cubital tunnel
Compression caused by Compression caused by
• Lesions within the groove Compression caused by
• Valgus deformity of the bone
• Conditions outside the groove • Thickened Osborne's ligament
• Subluxation or dislocation of the nerve
Figure 24-21. Anatomic sites of ulnar nerve compromise. Five possible anatomic sites of ulnar nerve compression are depicted. (From
Posner MA: Compressive ulnar neuropathies at the elbow: I. Etiology and diagnosis. J Am Acad Orthop Surg 1998;6:282-288.)
after a distal humeral fracture associated with the development of
a cubitus valgus deformity, i.e., tardy ulnar palsy.81-578 As this
descriptive name implies, the ulnar palsy is a late sequela of a pre-
vious bony injury. In young persons, a fall arid subsequent frac-
ture of the capitulum can result in less than full development of
the lateral humeral epiphysis. The resultant lack of capitulum for-
mation allows for the development of a cubitus valgus deformity,
which in turn places an abnormal tension on the ulnar nerve, pre-
disposing it to a stretch injury.807 A similar malalignment defor-
mity can result from a less than optimal healing of a Figure 24-22. Ulnar nerve compression. The ulnar nerve is
supracondylar fracture. Additional deformities arising from bony shown to be compressed at the proximal edge of the cubital tunnel
osteophytes can impinge upon the ulnar nerve during its course in beneath the arcuate ligament with subsequent bulging of the nerve.
the postcondylar groove or cubital tunnel. It is also possible for (From Osborne GV: Compression neuritis of the ulnar nerve at the
persons with rheumatoid arthritis, osteoarthritis, and Paget's dis- elbow. Hand 1970;2:10—13, with permission.)
ease to suffer disruption of the normal elbow architecture and
subject the ulnar nerve to further insult.98-579-748-763 Persons with a examined) demonstrated a focal mononeuropathy. 88 Of these 10
congenitally shallow postcondylar groove combined with cubitus patients, 4 individuals had ulnar neuropathies about the elbow.
valgus are also prone to ulnar nerve compromise at the elbow.490 The etiology was attributed to intraoperative compression or
An etiology believed to account for a significant number of some form of blunt trauma.
ulnar nerve lesions at the elbow is the cubital tunnel syn- Arguably, the majority of ulnar nerve lesions at the elbow may
drome.201 .386.568.570 fhe proposed etiology of ulnar nerve compro- be classified as idiopathic in that an exact cause of ulnar nerve
mise in the cubital tunnel syndrome is a compression of the compromise cannot be definitively identified. Surgical resection
nerve either beneath or at the proximal edge of the flexor carpi of the arcuate ligament in proposed cubital tunnel syndromes has
uinaris aponeurosis or arcuate ligament (Fig. 24-22). During revealed "proximal swelling" of the nerve. 201 •46K568>570-829 A ca-
elbow flexion, the anatomic distance between the olecranon daver study, however, revealed that about 50% of 400 limbs
process and medial epicondyle increases by approximately 1 cm, demonstrated a similar fusiform swelling of the ulnar nerve in
thus stretching and tightening the arcuate ligament.17 201592 As a the region of the medial epicondyle.101 The significance of ulnar
result of ligamentous tightening, the pressure exerted on the nerve swelling observed during operation, therefore, is likely not
ulnar nerve is increased, thereby potentially resulting in a com- a reliable indicator of arcuate ligament compression of the ulnar
pression neuropathy. It is also possible that repetitive flexion and nerve. A careful history and physical examination are important
extension of the elbow may chronically irritate the nerve through in accurately characterizing the type of lesion producing a focal
this mechanism or result in hypertrophy of the arcuate ligament, ulnar neuropathy at the elbow. Magnetic resonance imaging and
thereby further compressing the nerve.461-505 An additional factor in particular short tau inversion recovery sequencing (STIR), as
that may contribute to ulnar nerve compression within the cu- well as sonographic assessment of potential ulnar nerve lesions
bital tunnel during elbow flexion is the observation that the at the elbow, can be quite helpful.66-374-614 The electrodiagnostic
medial collateral ligament of the elbow buckles medially. This medicine examination can be of considerable value in properly
medial bulge combined with the tightened arcuate ligament can diagnosing an ulnar neuropathy at the elbow.
act to compress the ulnar nerve between these two structures.763 Electrophysiologic Evaluation and Findings. The practi-
A number of athletic activities have been implicated in caus- tioner must be familiar with the possible causes of ulnar neu-
ing ulnar nerve problems at the elbow. One etiology in particu- ropathy at the elbow to properly localize and diagnose this focal
lar is any throwing activity. Angular velocities up to 7000 neuropathy. Not all ulnar neuropathies are cubital tunnel syn-
degrees per second have been documented in some throwing drome, and careful electrophysiologic testing may assist in ac-
maneuvers. 700 Pressures within the cubital tunnel have been curately defining the exact cause of the ulnar nerve dysfunction.
documented to increase between three and six times during dif- Three distinct locations about the elbow have been proposed to
ferent aspects of a throwing activity.592 Additional sports impli- account for the majority of ulnar nerve lesions: (1) retroepi-
cated in ulnar neuropathies include weightlifting, various condylar (postcondylar) groove; (2) humero-ulnar aponeurotic
racquet sports, and skiing.602 arch (so-called cubital tunnel; the ulnar nerve passes between
In approximately 16% of the population, the ulnar nerve can the arcuate ligament, spanning the two heads of the flexor carpi
sublux from the postcondylar groove and slip over the medial uinaris muscle); and (3) flexor-pronator aponeurosis (where the
epicondyle to varying degrees. 107 It is possible for the nerve to ulnar nerve exits from beneath the flexor carpi uinaris muscle). 87
completely enter the anterior aspect of the arm or only partially The importance of distinguishing these three regions is that the
sublux and approximate the medial epicondyle. This finding first and third areas of compromise require simple surgical sec-
may or may not be present with a shallow postcondylar groove tion of the constricting tissues, whereas the second lesion site
or cubital valgus deformity. This type of abnormality can pre- may be treated by either nerve transposition or ligamentous sec-
dispose a person to an ulnar neuropathy because of repeated ir- tioning. Unfortunately, the routine electrodiagnostic medicine
ritation to the nerve with elbow flexion and extension.,9-20-763 evaluation is not always capable of clearly distinguishing
Also, when the nerve is outside of the postcondylar groove, it is among these three potential sites of focal compromise. 86 Let us
susceptible to compression against firm surfaces. The majority first begin by attempting to define the presence of an ulnar
of persons with this deformity are asymptomatic; however, the nerve lesion localized to the elbow segment and then attempt to
susceptibility of the nerve to trauma can be a predisposing better define its exact location.
factor that should be considered in ulnar nerve neuropathies. We may begin our evaluation of the patient with a suspected
A prospective investigation of patients undergoing orthotopic ulnar nerve lesion at the elbow by first placing the individual
liver transplantation revealed that 10% of patients (100 patients supine. From this point forward, the controversy begins as to
how one should best assess the neurophysiologic status of the confirmed by a subsequent study.4363 Further work is required t
ulnar nerve. Instead of delving into the controversy surrounding confirm and explain this finding.
the most "efficacious" techniques to use, the preferred studies Sensory Techniques. Sensory nerve conduction studies ar«
by the authors are presented with reference made to other meth- performed first. This is certainly consistent with most patients
ods, thus allowing the practitioner to be aware of the multiple complaints in that sensory symptoms are noted prior to moto
recommendations and pursue appropriate literature citations weakness.483 Both antidromic and orthodromic sensory as well;
when deemed necessary. The first major controversy to tackle is mixed nerve action potential techniques have been advocated ii
elbow position. The elbow can be completely extended, fully evaluating ulnar neuropathies at the elbow as having a higher diag
flexed to comfort, or placed at any angle in between these two nostic yield than motor studies.247-315-375-432-587-588-623-772 Orthodromic
extremes. The importance of this issue lies in the fact that the techniques have several drawbacks. Surface responses are rathe
ulnar nerve is redundant in the elbow extended position and small and may not be present in patients with mild amplitude re
measurement across the skin does not accurately reflect the true ductions, thus requiring the placement of near-nerve needle
anatomic length of the nerve. Similarly, when the elbow is fully recording electrodes at the above-designated locations over the
flexed, the nerve may be physiologically extended, but skin nerve. Although these techniques are not difficult, they require
measurements across the bent elbow can be somewhat difficult multiple needle placements, which limits the acceptance of this
to measure with respect to the "preferred" path that most closely method. Antidromic SNAP evaluations are preferred by the au-
follows the nerve. A number of elbow positions have been sug- thors as they are easy to perform and yield readily obtainable re-
gested as most closely representing the nerve's anatomic length sponses in most patients unless the response is absent, in which
versus least velocity variation,48-105-184'206-281-546 whereas others case further abnormalities are likely to be found in other electrodi-
have found that the fully flexed elbow produces the least statis- agnostic techniques. Standard ring electrodes are located on the
tical variation in the calculated data and highest diagnostic fifth digit, and the ulnar nerve is supramaximally activated at the
yield. 380381396 Flexed elbow positions yield conduction veloci- above-noted stimulation sites. The amplitude is anticipated to drop
ties with higher values (> 50 m/s) than extended elbows (> 35 precipitously as one excites the nerve more proximally, limiting
m/s) because of the surface-to-anatomic distance discrepancy. A the SNAP'S amplitude as a diagnostic parameter. Conduction ve-
further complicating factor in this regard is related to the pa- locity is calculated for the forearm and across-elbow segment
tient's weight, with an increase in across elbow velocities re- using the onset latency of the SNAPs. Peak latencies are fine for
lated to how overweight the patient is based on a body mass standard distances distally, but they are unacceptable for conduc-
index.704 This finding is most likely due to a surface measure- tion velocity determinations. Commercially available instruments
ment error with respect to the nerve's actual length. The most have no difficulty in recording clear take-offs for the sensory re-
important aspect to remember about this entire issue is that it sponse, and if necessary, several averages can be performed to
really does not matter what elbow position is used provided one "clean up" the waveform. Objections have been raised to the an-
is thoroughly familiar with the technique and uses reference tidromic techniques in that a motor response may obscure the
data based solely upon the position utilized. 50 It is not valid to SNAP. This is an overstated problem and rarely occurs. When this
mix and match normal values from one technique to another.123 is the case, moving the recording electrodes slightly more distal on
The preferred patient position by these authors is supine, with the digit usually solves the problem. Further, having the patient
the arm abducted 90° and the elbow comfortably but fully voluntarily abduct and extend the fingers can result in a substantial
flexed approximating 135° (see Chapter 5). This affords a close reduction in the motor artifact contaminating the sensory re-
approximation between the anatomic length of the ulnar nerve sponse.659 A conduction velocity of less than 50 m/s for the sen-
and the surface skin measurements. With respect to surface sory response across the elbow (above-elbow to below-elbow
measurements, the ulnar nerve is stimulated in at least three lo- segment) is considered abnormal.381
cations: (1) at the wrist 8.0 cm proximal to the active recording In addition to calculating the ulnar SNAP across the elbow
electrode over the abductor digiti minimi's motor point, (2) 4.0 segment, analysis is also performed on the 14-cm response. Not
cm distal to the medial epicondyle, and (3) 4.0-8.0 cm proximal uncommonly, the latency or amplitude of the distal sensory re-
to the medial epicondyle.7943 Occasionally, a fourth stimulus site sponse may be abnormal in elbow lesions. However, a focal
in the proximal arm or axilla is used. This arm position exposes lesion at the elbow may not result in an abnormal response dis-
all stimulus sites, which is not always the case with a fully ex- tally, particularly if the primary mechanism of injury is conduc-
tended elbow. The distances across the elbow are performed tion block or focal demyelination with little axonal loss, as is
several times to ensure accuracy prior to stimulation, and the likely early in the disease process. A second important SNAP to
tape measure is traced over the course of the ulnar nerve poste- obtain in all patients suspected of having ulnar nerve elbow le-
rior to the medial epicondyle. A reference to any standard sions is the dorsal ulnar cutaneous response.324 In lesions ranging
anatomy text and some practice should obviate concern about from moderately severe to severe, this response can be absent,
not accurately measuring this distance. Also, ring recording strongly suggesting that an ulnar nerve lesion is not only present,
electrodes are placed on the fifth digit with a mark made on the but also located proximal to the origin of this nerve. The likely
patient's skin overlying the ulnar nerve at the wrist 14.0 cm cause of an absent dorsal ulnar cutaneous SNAP is a lesion about
proximal to the active recording electrode (standard antidromic the elbow region. An investigation has documented a normal re-
SNAP technique). sponse for the dorsal unlar cutaneous nerve in 60% of ulnar
A single report suggests that wrist position can affect both the nerve lesions at the elbow involving either axonal loss or de-
forearm and across elbow conduction even though the forearm myelination.7983 When the ulnar SNAP to the fifth digit is absent,
and elbow remained fixed.658 The forearm velocity and across this suggests a profound axonal loss insult to the sensory fibers
elbow velocity increased and decreased, respectively, when the to this digit and does not permit nerve conduction calculations
wrist was changed from a fully flexed to an extended position. across the elbow. In this instance, it is paramount to document
A mean drop of 5.8 m/s was documented for the across-elbow the status of the dorsal ulnar cutaneous nerve despite the above
segment when the wrist was flexed. This finding was not comments. An absent fifth digit SNAP combined with a normal
dorsal ulnar cutaneous SNAP suggests that the lesion is distal to the drop in amplitude in excess of 20-30% is encountered when
take-off of the dorsal ulnar cutaneous nerve, i.e., a lesion is poten- stimulating above compared to below the elbow. This is not a
tially present at the wrist as opposed to the elbow. Although this is particularly common finding, especially in patients suffering
not totally foolproof, it certainly raises a suspicion of a lesion lo- from a chronic ulnar neuropathy. 87 When an amplitude drop is
cated distal to the origin of the dorsal ulnar cutaneous nerve. When found, serious consideration should be given to concluding that
an absent or low-amplitude sensory responses to the fifth digit is there is a lesion producing at least in part some form of conduc-
noted, comparing the distal latencies and amplitudes of the sensory tion block. The authors do not make much of comparative veloc-
median and ulnar responses with the fourth digit may be of diag- ity reductions with the arm or forearm, as these comparisons are
nostic help. Usually these amplitudes are comparable, and this prone to problems. For example, suppose an axonal lesion af-
technique gives a clear indication of the amount of axonal loss and fecting the fastest fibers were present at the elbow region. All of
the integrity of the sensory responses outside the ulnar distribution. these fibers would undergo Wallerian degeneration and no
It may be difficult to differentiate an epicondylar ulnar neu- longer be subject to neural activation. Irrespective of stimulus
ropathy from a cubital tunnel neuropathy. An innovative tech- site (axilla, arm, forearm, or wrist), only the remaining slowly
nique using near-nerve needle electrodes located 4 cm above, conducting fibers would reach the abductor digiti minimi or first
and 1.5 cm and 6 cm below, the medial epicondyle permits de- dorsal interosseous. The end result is a uniform subpopulation of
termination of sensory nerve conduction velocities over these slowly or relatively slowly conducting fibers that may not
focal segments. 555 Preliminary investigations suggest this may demonstrate the expected "drop" in conduction velocity over the
be a valid method of approaching this difficult problem. elbow segment, especially if there is a lack of focal demyelina-
Motor Techniques. The most popularly performed tech- tion at this region. Similarly, if a conduction block is present in
nique is the determination of a motor conduction velocity. There or about the elbow, conduction velocities are of minimal value,
are a number of ways one can gain insight into the physiologic as one is considering two different fiber populations at the
status of the motor fibers in suspected ulnar nerve damage at the above- versus below-elbow stimulations. It is not valid to com-
! elbow. One can record a CMAP from either the abductor digiti pare these different fiber types to arrive at a "representative" con-
minimi or first dorsal interosseous (FDI) muscles with the arm duction velocity across the elbow. One should instead perform
flexed or extended and using across-elbow or above-elbow-to- segmental latency measurements (see below) to better localize a
wrist conduction velocity determinations. 149-,83-184--w focal conduction block and not worry about velocities.
509,556.601.641.675,707 Calculating the ulnar nerve's segmental conduc- Whether a drop in amplitude is noted or not, an alternative
tion velocity across the fully flexed elbow is the authors' pre- method to better localize a focal lesion is to perform multiple
ferred technique.380 A nerve conduction velocity less than 49 m/s stimulations in 1-cm segments several centimeters proximal
is considered abnormal. Finding a difference of 10 m/s or greater and distal to the medial epicondyle and compare each sequen-
between the arm and above-elbow-to-wrist segment is consid- tial latency.69-70-351-507 A series of CMAPs are obtained, and a
ered to be of significance, as is a latency exceeding 9 ms from an jump of 0.4 ms or greater designates a focal lesion producing
above-elbow stimulation. 183 The recommendation of a 10-m/s slowing. 87 The so-called inching techniques may be of more
difference is made on arbitrary grounds, as a number of normal value with respect to ulnar nerve lesions than in carpal tunnel
1 persons had difference in excess of this value. Differences of 20 syndrome, as the ulnar nerve remains superficial about the
m/s have been found for the across-elbow segment versus either elbow than the median nerve does in the palm, unless needle
the arm or forearm region. 772 Absolute conduction velocities stimulation is employed. The location where a prolonged la-
with respect to reference data are more reliable than comparisons tency is noted is identified as the problem site. This technique
with proximal or distal segments. 50 Considering only a latency produces results that correlate somewhat with intraoperative
from above-elbow to hypothenar eminence dilutes the abnormal- findings, but not always. One can also look for an alteration in
ity across too much normal nerve, raising a question as to the va- the general morphology of the waveform, particularly with re-
lidity of this technique. If the conduction velocity across the spect to an increase in temporal dispersion or more phases. 512
elbow segment is normal as recorded from the abductor digiti This technique requires further study to better define signifi-
minimi muscle, the same procedure is performed for the first cant alterations in the waveform's morphology. Finally, one
dorsal interosseous, i.e., stimulating at the above-designated lo- can stimulate the ulnar nerve 2.0 cm proximal to the medial
cations to calculate a conduction velocity for this muscle in case epicondyle and locate a needle recording electrode in the
its fibers are more profoundly affected.483-772 One investigation flexor carpi uinaris muscle 10 cm distal to the medial epi-
found that 8 1 % compared with 7 1 % of patients demonstrated condyle. A latency greater than 4.0 ms is diagnostic of an
abnormal across-elbow conduction studies while recording ulnar nerve lesion in or about the elbow region. 44
from the first dorsal interosseous versus abductor digiti minimi Needle Electromography. The number and extent of mus-
muscles, respectively.399 Repeating the motor study to the first cles that should be investigated depend on the results of the
dorsal interosseus has three advantages: (1) it gives the exam- nerve conduction studies. If the examiner is confident that a
iner confidence that a focal slowing is indeed present and not focal ulnar neuropathy is present because of nerve conduction
due to a possible measurement error, (2) measurements to the slowing at the elbow, ulnar-innervated muscle can be investi-
first dorsal interosseus may have a higher yield of abnormali- gated to show the presence and amount of axonal loss.
ties,399-747 and (3) because this muscle is the most distally inner- Especially in severe and longstanding lesions, nerve conduction
vated, it can show severe abnormalities in cases of a distal studies are often not revealing with respect to localizing the dis-
entrapment of the nerve at the wrist or hand, while the findings order. In this case, it is crucial to investigate other C8/T1 and
to the abductor digiti minimi may be normal. This study399 re- lower plexus muscles such as the abductor pollicis brevis and
vealed that motor studies were abnormal more frequently than extensor pollicis brevis and longus. Membrane instability is
mixed nerve studies. sought in the flexor carpi uinaris, flexor digitorum profundus,
During the performance of the motor conductions, velocity is abductor digiti minimi, and first dorsal interosseous muscles.
not the only waveform parameter to consider. Occasionally, a The needle examination is not particularly revealing, especially
in mild and chronic cases. In mild disorders, there is little in identification. Magnetic resonance imaging may also be of con-
the way of axonal loss, and abnormalities are more likely to be siderable benefit with respect to imaging lesions in the region.
found on sensory or motor nerve conductions. In chronic dis- Treatment. Treatment can be divided into conservative
orders, any axonal loss, unless profound, is likely to be com- and surgical approaches. An acute blow to the elbow with a
pensated for by collateral sprouting, thereby minimizing resultant ulnar neuropathy in the absence of any bony disrup-
membrane instability. Acute lesions resulting in significant tion is best treated conservatively with rest and splinting the
axonal loss, however, are likely to result in membrane instabil- elbow in extension. In more chronic forms of the disorder,
ity of a noticeable degree. There is noted to be sparing of the mild lesions should also be treated conservatively with
flexor carpi uinaris muscle both clinically and with respect to splinting and rest. This simple recommendation can be se-
membrane instability. An explanation originally provided is verely limiting to individuals who must work with their
that the branch innervating the flexor carpi uinaris muscle hands. This is especially true of persons whose job entails
originates proximal to the medial epicondyle.44-375-657 This is repetitive flexion and extension of the elbow. Staying home
simply not the case, however, as only rarely does the branch to from work for 2-3 months is simply not practical, nor is the
this muscle arise proximal to the medial epicondyle (see recommendation to change jobs. In these persons, surgical
above). Two alternative explanations have been offered to intervention may be considered for definitive treatment prior
account for sparing of the flexor carpi uinaris muscle, i.e., in- to the symptoms and signs progressing to profound muscle
traneural topography85-"2-322-763 and axoplasmic flow abnormal- wasting and weakness. There are multiple surgical proce-
ities.483-488 The individual neural fibers destined to innervate dures possible for focal ulnar neuropathies at the elbow.
the flexor carpi uinaris muscle are situated medially and some- These operative interventions include resection of the arcu-
what protected from external trauma, while the sensory fibers ate ligament, medial epicondylectomy, and transposition of
and intrinsic hand motor fibers are located laterally, thereby the ulnar nerve anteriorly into various tissue planes. Each
more subject to external compression and trauma. The alterna- surgical procedure is designed for a particular problem that
tive explanation is that externally applied pressure would com- may not be fully appreciated until the time of operation. A
promise axoplasmic flow and preferentially affect the longest complete review of the surgical options and indications is
fibers, resulting in a "dying-back" type of phenomenon. The beyond the scope of this text, and the reader is referred to
sparing of the flexor carpi uinaris muscle with respect to other works on the subject.4-• 40,150.221.223.422.468.493.543.588.603.763
axonal loss appears contradictory with respect to finding ab-
normalities in conduction to this muscle (see above). The con- Forearm Region
duction versus needle electromyographic findings can be Clinical Features. The ulnar nerve is rarely compromised
reconciled if one considers that axonal loss is necessary for between the elbow and wrist regions. A few of the more com-
membrane instability but demyelinative conduction slowing monly observed lesions in this region preferentially affecting
does not result in positive sharp waves and fibrillation poten- the ulnar nerve are lacerations, fractures, and missile wounds. 763
tials. Therefore, it is certainly possible for the flexor carpi ui- Two rather unusual groupings of focal ulnar neuropathies have
naris muscle to not have membrane instability yet continue to been reported, which require a high index of suspicion by elec-
demonstrate altered conduction latencies in ulnar nerve com- trodiagnostic medicine practitioners. The first focal ulnar neu-
promise not producing significant axonal loss. ropathy occurs between 3 and 7 cm (average 5 cm) distal to the
Summary. The complete electrodiagnostic medicine evalua- medial epicondyle where the ulnar nerve exits the flexor carpi
tion of the ulnar nerve consists of a number of studies designed uinaris muscle." This anatomic region deserves special mention
to increase the diagnostic accuracy of the consultation. Both because there is a connective tissue structure referred to as the
motor and sensory studies are performed across a flexed elbow. deep flexor-pronator aponeurosis located superficial to the
Motor studies are performed to both the abductor digiti minimi flexor digitorum profundus but deep to the flexor digitorum su-
and first dorsal interosseous looking for both nerve conduction perficialis muscles and flexor carpi uinaris muscle. It serves as
velocity and amplitude changes across the elbow segment. an additional point of origin for these three muscles and can act
Absolute values instead of comparative values to the arm or to compress the ulnar nerve at the above-noted distances distal
forearm segment are used. The dorsal ulnar cutaneous nerve is to the medial epicondyle. "-82-83-86 This is an important site to
also important to help establish a lesion proximal to the wrist. If keep in mind, as patients can present with symptoms and have
an amplitude drop is noted or the clinical examination clearly physical findings identical to those of a lesion in the postcondy-
suggests a focal elbow ulnar neuropathy but the electrophysio- lar groove or in the cubital tunnel beneath the arcuate ligament
logic studies noted are unrevealing, short-segment stimulation (see above). Magnetic resonance imaging of the forearm can be
is attempted to better localize the lesion. This may be of assis- of considerable help in defining the presence of a mass lesion
tance in mild focal lesions because minor slowing may be "di- affecting the ulnar nerve.291
luted" over a segment 10 cm or more in length. Needle A potential pitfall is the presence of a Martin-Gruber anasto-
examination of the above-noted ulnar-innervated muscles is also mosis, the crossing-over of motor nerves from the median nerve
performed particularly with respect to additional lesions that to the ulnar in the forearm innervating the ulnar muscles result-
may be present. ing in a lower CMAP when stimulating the ulnar nerve distal of
In addition to the electrodiagnostic medicine assessment of the elbow. This suggests a conduction block in the forearm to
ulnar nerve function across the elbow region, plain radiographs the unsuspecting examiner. Stimulating the median nerve at the
have also been used to visualize the elbow's bony anatomy. 734 elbow can resolve this problem and show the presence of a
This technique may be of some value in identifying abnormal CMAP over the ulnar muscles with an amplitude approximating
bony anatomy; however, the important aspect is the ulnar the difference between the wrist and elbow responses to ulnar
nerve's physiologic status irrespective of the bony anatomy. stimulation. The same electrodiagnostic methodology noted
Also, the majority of ulnar nerve lesions appear to be a result of above for ulnar nerve lesions about the elbow region is em-
soft tissue abnormalities and thus not amenable to radiographic ployed. The major difference is that there is a lack of findings to
suggest an alteration in either motor or sensory conduction mass. Significantly more current is usually required to excite
across the elbow segment. It appears the best way in which to the nerve, which can result in considerable spread of electric
define this proximal forearm entrapment is to stimulate the current from the presumed site of the cathode. This can produce
ulnar nerve in 1 -cm increments beginning above the medial epi- an unexpected latency shift and even change the CMAP mor-
condyle and "inching" distally while recording from the abduc- phology if the nerve is stimulated at a less than supramaximal
tor digiti minimi or first dorsal interosseous. At about 3-7 cm level because of its depth. If there is any doubt, a monopolar
distal to the medial epicondyle, one hopes to detect either an ab- needle with a current duration of 0.05 ms can be situated close
normal shift in sequential latency approximating 0.4 ms or to the nerve just above and below the presumed site of conduc-
greater, or a marked alteration in the CMAP's waveform with tion abnormality as determined by surface stimulation to
respect to amplitude or morphology. Also, the proximal location double-check these results. Maximizing the CMAP to both
of the lesion should result in an abnormal dorsal ulnar cuta- proximal- and distal-needle stimulation should reduce the
neous SNAP as well as an abnormal SNAP to the fifth digit. amount of stimulus necessary and minimize current spread as
Similarly, membrane instability on needle electromyography well as ensure a supramaximal response, thus diminishing an
can be anticipated in the ulnar-innervated hand intrinsic mus- erroneous conclusion upon which a patient may receive surgery.
cles and possibly the flexor digitorum profundus. The flexor
carpi uinaris muscle should be spared. If the lesion is severe Wrist Region (Guyon's Canal)
enough, a reduced conduction velocity in the forearm segment Clinical Features. The second most common site for local-
may be noted as well as prolonged F-waves; however, these re- ized compromise of the ulnar nerve is about the wrist region ap-
sponses are of little value in localizing the lesion. proximating Guyon's canal. Patients with lesions in this area
A second possible focal lesion affecting the ulnar nerve may be classified as having one of three types, based on symp-
occurs in the distal forearm 5-7 cm proximal to the ulnar sty- toms, signs, and physical examination (Table 24-5).694
loid. 84.283.3oi Rarely, the muscular fibers of the flexor carpi ui- A patient with a Type I lesion complains of diminished sen-
naris muscle may continue to originate from this muscle's sation on the volar aspects of the fifth and medial one half of the
tendon quite distally in the forearm and act to compress the fourth digits as well as the medial palmar surface. Additionally,
ulnar nerve just proximal to the ulnar styloid. The clinical pre- the palmar and dorsal interossei are weak, as are the hypothenar
sentation is somewhat similar to a lesion at the elbow region in muscles. Sparing of sensation on the hand's medial dorsal
that the dorsal ulnar cutaneous nerve may be involved as well as aspect is the rule, as the dorsal ulnar cutaneous nerve is spared
the terminal sensory fibers to the digits. The palmar cutaneous because of its origin proximal to Guyon's canal. In profound
branch of the ulnar nerve may or may not be affected, however, axonal loss lesions, a prominent ulnar claw deformity is noted
this nerve can be inconstant, thus accounting for variable find- because of the unopposed pull of the flexor digitorum profun-
ings in the sensation to the base of the hypothenar eminence.186 dus to the fourth and fifth digits. In ulnar nerve lesions proximal
Needle electromyographic examination reveals membrane in- to the innervation to this muscle, the claw deformity is mild be-
stability in the hand intrinsic muscles with sparing of the flexor cause of little tension generated in the ulnar-innervated profun-
digitorum profundus muscle and flexor carpi uinaris muscle, but dus muscle. Physical findings are commensurate with the above
this pattern is also seen in ulnar nerve lesions at the elbow. description because the lesion is situated in the proximal extent
Nerve conductions across the elbow should be normal, but fore- of Guyon's canal and affects the main trunk of the ulnar nerve
arm conductions can be abnormal, as is ulnar-evoked F-waves prior to it dividing into the superficial and deep branches. This
from the abductor digiti minimi muscle. Performing sequential type of lesion is reported to be the most common form of ulnar
stimulation along the course of the ulnar nerve in 1 -cm intervals nerve compromise in the wrist region (Table 24-5).516
is used to localize a focal lesion to the distal portion of the ulnar In Type II neuropathies, persons may complain only of a loss
nerve.84 An alteration in the CMAP's amplitude, morphology, or of fine dexterity of the fingers and an inability to spread or ap-
abrupt change in latency is significant for a lesion in this region. proximate the fingers with preservation of normal sensation
As with all "inching" techniques, great care must be taken when (Table 24-5). Physical examination reveals normal sensation in
stimulating any nerve, particularly as it travels beneath a muscle the superficial ulnar nerve distribution, but weakness of all ulnar
Table 24-5. Classification of Ulnar Neuropathies at the Wrist

Neuropathy Type I Type II Type III
Lesion Location Proximal or in In Guyon's canal; In Guyon's canal;
Guyon's canal hook of hamate at at hook of hamate;
origin of ADM and FDM; in PB
in ODM muscle.
Type IIA: Distal
to hypothenar muscles
Portion of Nerve Superficial and deep Deep branch only Superficial branch only
Affected branch
Signs/Symptoms Sensory/motor Motor loss only Sensory loss only
loss
Percent of 30-48 44-52 8-18
Occurrence
ADM, abductor digiti minimi; FDM, flexor digiti minimi; ODM, oppenens digiti minimi; PB, palmaris brevis. Percent of occurrence refers to frequency of individual
types of ulnar nerve lesions at the wrist compared to total number of reported cases in literature. Modified from Shea and McClain694 and Moneim.516
innervated intrinsic hand muscles except possibly the abductor with any of the above-noted types of ulnar nerve compro-
digiti minimi. This muscle can be spared because its neural mise 159.1so.280.575 j m s j s primarily a result of forcefully gripping
branch may originate at the region of division between the deep the handlebars with the wrists either radially or ulnarly deviated
and superficial ulnar branches within Guyon's canal. In Type II for prolonged periods. These individuals recovery uneventfully,
lesions, only the deep branch of the ulnar nerve is compromised as they are usually young persons in excellent health. Finally,
in the distal region of Guyon's canal close to the hook of the there are a number of reports of persons with carpal tunnel syn-
hamate, at the origin of the abductor digiti minimi muscle and drome developing a concomitant ulnar nerve compression at the
flexor digiti minimi muscle, or within the opponens digiti wrist (see above).96-681702 The difficulty with these studies is that
minimi muscle. This explains the preservation of normal sensa- there are insufficient evaluations performed to categorically rule
tion along the volar aspect of the hand. During abduction of the out an ulnar nerve lesion at the elbow accounting for the ulnar
fifth digit, the palmaris brevis muscle also contracts and acts to nerve symptoms. Further, carefully controlled studies must be
wrinkle the skin overlying the hypothenar eminence (palmaris performed prior to concluding that CTS can of itself generate a
brevis sign). When this sign is observed, one can be assured lesion of the ulnar nerve in Guyon's canal.
that there is significant sparing of the superficial branch of the Electrophysiologic Evaluation and Findings. The specific
ulnar nerve.320-604 Again, a marked claw hand deformity can be type of electrophysiologic abnormality detected is dependent
noted. In both Type I and II injuries, the motor examination of upon the location of the ulnar nerve lesion as outlined above.
the hand is quite similar to a lesion at the elbow except for spar- One of the most important aspects of assessing potential ulnar
ing of the flexor digitorum profundus muscle. Recall that the nerve compromises at the wrist is to first evaluate the ulnar
flexor carpi uinaris muscle is typically spared in both elbow and nerve about the elbow region. These two disorders can appear
wrist insults. Type II lesions occur with a similar or slightly less quite similar clinically and at times may be difficult to distin-
frequency compared with Type I injuries. A subtype of Type II guish. Performing both motor and sensory studies across the
injuries (Type IIA) may exist in which the deep branch of the elbow segment in an attempt to define a focal slowing or con-
ulnar nerve is compromised distal to the innervation of all hy- duction block in this area is mandatory (see above). The SNAP
pothenar muscles. In this instance, the hypothenar muscles are to the fifth digit may be normal or abnormal in both elbow and
spared, as is sensation, but all of the interossei, ulnar innervated wrist lesions. This is nevertheless one of the first sensory stud-
lumbricals, as well as the adductor pollicis and one half of the ies that must be documented. If there is noted to be an abnor-
flexor pollicis brevis muscles are weak. mality to this response, one should consider an elbow, or
The least common form of ulnar neuropathy at the wrist is a proximal/distal Guyon canal lesion. Recall that a focal lesion in
Type III lesion in which only the superficial branch of the ulnar the proximal extent of Guyon's canal may affect the ulnar nerve
nerve is compromised (Table 24-5). Patients complain only of prior to its dividing, while a lesion in the distal confines of the
diminished sensation in the volar aspect of the hypothenar emi- canal can just injure the ulnar nerve's sensory branch. Although
nence and regions of the fifth and fourth digits supplied by this the fifth digit's SNAP is important, little can be concluded from
nerve. Physical examination reveals only the above loss of sen- this response in isolation. Performing a SNAP to the dorsal
sation with preservation of all hand intrinsic and extrinsic mus- ulnar cutaneous nerve is extremely important. An abnormal
cles supplied by the ulnar nerve. In this case, the skin wrinkling SNAP to this nerve allows one to conclude that a lesion is pre-
noted above due to contraction of the palmaris brevis muscle is sent proximal to the wrist region and most likely at the elbow. A
lacking despite normal abduction of the fifth digit. A very focal normal response, however, is still compatible with either an
lesion is necessary to affect only the superficial and not deep elbow, although unlikely, or wrist lesion. Finding normal dorsal
branch of the ulnar nerve. This may occur at the distal portion ulnar cutaneous but abnormal fifth digit SNAPs begins to pro-
of the Guyon's canal, or external trauma to only the superficial vide information compatible with a lesion at the wrist.
branch may result in the above-described presentation. As noted above, motor studies across the elbow should be
The etiology of Guyon canal insults can be understood if one performed in all suspected ulnar nerve lesions at the wrist. This
considers the anatomy of this region. Guyon's canal is essen- study is best performed to both the abductor digiti minimi and
tially a closed space surrounded by the volar and transverse first dorsal interosseous when attempting to define the presence
carpal ligaments with medial and lateral bony margins (see of conduction slowing or block across the elbow segment.
Figs. 24-15 and 24-16).263 In addition to the ulnar nerve, there is Short-segment stimulation may also be necessary. Finding a
an ulnar artery and vein contained in the canal. Essentially any focal lesion at the elbow does not necessarily allow one to con-
lesion within this region has the potential to compress either the clude that a search for a wrist lesion is unwarranted. In moder-
main ulnar nerve trunk proximally in the canal, or one of its two ate to profound ulnar nerve lesions at the wrist, a particularly
branches more distally in the canal. The main determination of helpful technique may be to compare the latencies and ampli-
symptoms is the specific location of the lesion with respect to tudes between the abductor digiti minimi and first dorsal in-
the various portions of the nerve. About half of all ulnar nerve terosseous muscles to ulnar nerve wrist stimulation.93179-566-707
lesions at the wrist occur because of some type of acute or Specifically, when stimulating the ulnar nerve at the wrist, de-
chronic trauma most likely but not exclusively related to an oc- tecting a latency difference of greater than 2.0 ms between the
cupation.289-343-411-532-694-766-793-797 Depending upon one's practice, abductor digiti minimi and first dorsal interosseous in the same
the next most common cause of ulnar neuropathies at the wrist hand or a left/right first dorsal interosseous latency difference in
is due to a ganglion. 694 Some additional causes of ulnar neu- excess of 1.3 ms is suggestive of ulnar nerve motor fiber com-
ropathies at the wrist include ulnar artery disease,175-348 carpal promise in the wrist or hand. This may be of significant help in
bone fractures,220-305 metacarpal bone fractures,305 distal radius defining a lesion at the wrist. Unfortunately, this is of little help
fractures,608-851 anomalous muscles,552-666-765 rheumatoid ar¬ when a pure sensory nerve lesion is under consideration or the
thritis,146 776 and lipoma.489 Two additional reported causes of ulnar nerve is only mildly affected.
focal ulnar neuropathy at the wrist require comment. Persons who Consideration should be given to incremental stimulation
ride bicycles either for exercise or competitively may present across the wrist region in 1 -cm increments while recording from
the first dorsal interosseous muscle similar to across elbow stud- of assistance in localizing a second site of compression. Care
ies in attempting to define conduction block.491-576 It may be pos- should be exercised in using the forearm nerve conduction ve-
sible in some patients to actually define a conduction block locity. This can be abnormal in both elbow and wrist lesions. An
lesion in or about the canal of Guyon region. axonal loss lesion in the elbow can result in loss of the fastest
A good examination to add to the protocol for suspected conducting fibers resulting in reduced conduction velocities
ulnar nerve lesion about the wrist region is the latency differ- when recording from the abductor digiti minimi and first dorsal
ence between the CMAPs evoked from the second lumbrical interosseous. Similarly, a conduction block, demyelinating, or
muscle (median nerve) and second interosseous (deep ulnar axonal loss lesion at the wrist can diminish conduction through
nerve).397-398-696 The active electrode is located just lateral to the the wrist region, so that only the slower fibers reach the muscle,
third metacarpals midpoint (approximates the midpalm) with again yielding a reduced forearm conduction velocity. In at-
the reference electrode located dorsally on the second metacar- tempting to arrive at an electrophysiologic diagnosis with re-
pophalangeal joint. The median and ulnar nerve are sequentially spect to localizing potential ulnar nerve pathology, all of the
activated at the wrist using the same distance to each nerve with above-noted techniques must usually be performed to collect as
CMAP onset latency interpotential differences anticipated to be much data as possible. Once these data are analyzed, a particu-
less than 0.4 ms. If the interosseous latency is longer than that lar pattern may emerge based upon the greatest focal abnormal-
to the lumbrical muscle, consideration should be given to a ity consistent with the findings. On the other hand, despite all of
ulnar nerve lesion. this information, one may simply be forced to conclude that an
Needle electromyographic evaluation of the affected limb ulnar nerve lesion is definitely present, but a deficit at the wrist
should demonstrate membrane instability in only the hand in- may or may not be present, particularly when there is definite
trinsic muscles when the ulnar nerve is injured in the wrist abnormalities detected at the elbow.
region. This same pattern, however, can also be found in ulnar An important adjunct to the electrodiagnostic medicine ex-
nerve lesions at the elbow. When the flexor carpi uinaris or amination of ulnar neuropathies at the wrist is radiographic
flexor digitorum profundus muscle to the fourth and fifth digits imaging of the affected area. Plain films of the wrist region, par-
reveal abnormalities, one can be comfortable in concluding a ticularly in instances of trauma, may reveal signs of fractured
lesion proximal to the wrist is present. As noted above, ulnar carpal bones producing the ulnar nerve injury. Of potentially
nerve damage at the elbow must be rather severe before these greater diagnostic assistance is the addition of high-resolution
muscles demonstrate membrane instability. If the abductor CT and MRI. The CT scan can provide considerable detail re-
digiti minimi only is spared while the remainder of ulnar-inner- garding the bony anatomy surrounding Guyon's canal as well as
vated hand intrinsic muscles are denervated, consideration delineate soft tissue compromise of the ulnar nerve. 249
should be given to a Type II wrist lesion. One can attempt to ap- Astonishing anatomic detail of both the bony and soft tissue
proximate the lesion location by serially investigating all of the confines of Guyon's canal can be achieved by MRI of the hand
dorsal interossei and noting when membrane instability is first region. 761849 The course of the nerve, anomalous muscles, and
detected. 841 Care should also be taken to examine not just the surrounding tissues are clearly shown such that any anatomic
abductor digiti minimi muscle, but also the remaining hy- cause of neural impingement can be immediately recognized.
pothenar muscles. Remember that the deep branch of the ulnar Continued work needs to be done in this area to better define the
nerve may be injured at any location from its separation from MRI parameters of normality such that ulnar nerve compromise
the main nerve to its termination in the adductor pollicis muscle. can be detected.
When a superficial branch injury is considered, needle elec-
tromyographic examination of the palmaris brevis can be at- Dorsal Ulnar Cutaneous Nerve
tempted to document abnormalities in this muscle suggesting a Clinical Features. As previously noted, the dorsal ulnar cu-
lesion to the superficial branch of the ulnar nerve proximal to taneous nerve emerges from the ulnar nerve in the forearm to
the branch innervating this muscle.109 wind around the ulna and innervate the dorsum of the hand and
As can be concluded from the above discussion, there are portions of the medial two digits. It is very rare for this nerve to
times when all of the necessary findings are present and it is rel- be injured in isolation. Acute trauma to the ulnar portion of the
atively easy to conclude that a focal lesion affecting the ulnar forearm, particularly about the ulnar styloid, may result in injury
nerve at the wrist is present. Normal sensory and motor conduc- to this nerve.140 Similarly, persons who are left handed and com-
tions across the elbow combined with an abnormal sensory re- press the ulnar portion of the distal forearm onto a hard surface
sponse to the fifth digit but normal dorsal ulnar cutaneous when writing may produce a chronic type of injury to this
SNAP are important findings to this end. Also, first dorsal in- nerve.727 Occasionally, the nerve may become adherent to the ex-
terosseous to abductor digiti minimi latency differences coinci- tensor tendon of the fifth digit, thus irritating the nerve during
dent with membrane instability in only some or all of the flexion and extension-of the digit. A few reports have suggested
ulnar-innervated hand intrinsic muscles are confirmatory for an that the nerve may be compressed by the distal portion of the
ulnar lesion in the wrist or hand. At other times, it may be quite flexor carpi uinaris tendon, or a ganglion.242-443-487,653
difficult to firmly conclude whether the ulnar nerve is injured at The clinical presentation of individuals with selective injuries
the wrist, elbow, or both regions. It is certainly possible for a to the dorsal ulnar cutaneous nerve is relatively straightforward
person to have an ulnar nerve compromise at both the elbow and provided the clinician is aware of this potential problem. Pain
wrist regions. In this case, the most fruitful techniques for defin- and/or paresthesias with numbness in the distribution of the
ing these two lesions is conduction abnormalities. Specifically, nerve on the medial dorsal aspect of the hand are rather charac-
one should concentrate on examining sensory and motor neural teristic. On physical examination, there is diminished sensation
conduction across the elbow segment and observe for slowing, in the nerve's cutaneous distribution with normal sensation on
conduction block, or both. Similarly, performing the ulnar the volar aspect of the hand associated with a normal manual
nerve latency comparisons to the first dorsal interosseous and muscle test of the limb. There may be a Tinel's sign along the
abductor digiti minimi bilaterally with wrist stimulation can be course of the nerve where it is injured.
Electrophysiologic Evaluation and Findings. The electro- may have both an ulnar nerve insult at the elbow, for example,
diagnostic medicine findings are of an abnormal or absent and a CS7T1 radiculopathy. Unless the practitioner is suspicious
dorsal ulnar cutaneous SNAP with a normal SNAP to the fifth for both lesions by performing not only a complete needle ex-
digit as well as normal ulnar sensory and motor conductions amination, but also segmental conductions of the ulnar nerve
across both the elbow and wrist. Needle electromyographic ex- across the elbow, one or the other lesion may be missed. In this
amination of the hand intrinsic muscles is also normal. instance, less than optimal treatment is delivered and the patient
continues to suffer from the missed lesion.
Ulnar Nerve Lesions: Differential Diagnosis In persons with peripheral neuropathies, it may simply be im-
A number of conditions must be considered when first evalu- possible to tease out a focal ulnar nerve compromise from the
ating a patient with a suspected lesion of the ulnar nerve. As more generalized neural disorder. It is hoped that patients may
noted above, elbow, forearm, and wrist lesions should all be complain of a particular set of symptoms suggestive of a super-
considered in the differential diagnoses of each other, as all can imposed focal neuropathy. SNAPs may be of little help in per-
have similar presentations. When a person is seen to present sons with moderate or greater peripheral neuropathies.
with what appears at first glance to be an ulnar claw hand, care Similarly, needle electromyographic abnormalities may be pre-
must be exercised to examine the patient properly. Begin with sent in all the distal limb muscles. It may be of some assistance
the hand completely relaxed and ask the patient to first close the in considering degrees of abnormality in which generally the
hand. If the medial two digits close but the first three do not, the peripheral neuropathy produces 1 -2 + membrane instability but a
benediction sign of a high median nerve injury (proximal to the focal neuropathy generates 3-4+ membrane instability in a select
innervation of the finger flexors) is present. When the patient is population of muscles. This can be misleading, however, as
asked to open the hand maximally, there is no difficulty in per- membrane instability is dependent not only upon the amount of
forming this maneuver. If on attempting to close the hand the denervation, but also the location of the needle with respect to
distal phalanges of the fourth and fifth digits cannot be buried the denervated fibers. Caution must always be exercised when
into the palm of the hand, there is likely to be an ulnar nerve attempting to diagnose a focal problem in the face of a general-
injury. When asked to open the hand fully, these persons will ized neural disorder. Select slowing of motor conduction can
display the typical ulnar claw hand with some hyperextension at often be of help in localizing a lesion of the peripheral nerve. In
the medial two metacarpophalangeal joints. In a low ulnar nerve this case, one should look for an asymmetric prolongation of
injury, this deformity is maximal because of the inherent tone of conduction across the elbow or the first dorsal interosseous
the flexor digitorum profundus muscle. Finally, if a patient dis- compared with the abductor digiti minimi muscles.
plays what appears to be an ulnar claw hand with less than com- Amyotrophic lateral sclerosis can occasionally present with
plete extension of the fourth and fifth digits on hand opening, an asymmetric wasting of the hand intrinsic muscles.530 Initially,
but has normal function of all hand intrinsic muscles, a partial it may be difficult to determine if a deep ulnar nerve lesion is
radial nerve lesion or tendon rupture of the extensor tendons present because the sensory studies should generally be normal
may be present. Specifically, a partial lesion to the radial nerve in motor neuron disorders. The presence of fasciculations ac-
innervating the extensor muscles to the fourth and fifth digits companied by membrane instability on needle electromyogra-
results in an inability to extend these digits; however, there is a phy in more than just the ulnar nerve distribution is suggestive
lack of hyperextension at the metacarpophalangeal joints.346-469-653 of a more widespread disorder. Also, there should be a lack of
Similarly, laceration to these tendons secondary to trauma or focal conduction slowing across the elbow or wrist regions.
rupture associated with rheumatoid arthritis (Vaughan- There may also be abnormalities on needle electromyography
Jackson syndrome) may present with the pseudoulnar claw of the opposite limb or one of the lower limbs. A careful physi-
hand.727-798 In these latter two instances, the electrodiagnostic cal examination should be performed of both the upper and
medicine evaluation demonstrates normal ulnar nerve motor lower limbs in any atypical case of ulnar neuropathy so as to not
and sensory studies unless a superimposed peripheral neuropa- miss an unusual presentation of a well-known disorder. If doubt
thy is present. An evaluation of the radial-innervated muscles continues, the picture should clear within several months as the
should be explored with the possibility of finding a posterior in- motor neuron disorder begins to affect more regions of the body.
terosseous nerve injury. The above comments apply equally well to spinal cord disor- '
Cervical radiculopathies affecting primarily the CS nerve root ders such as syringomyelia as well as various tumors.
should be considered in all patients presenting with numbness Occasionally, thoracic outlet syndrome may be considered to
of the fifth digit and weakness of the hand intrinsic muscles. In present in a similar manner to an ulnar neuropathy. In this disor-
these cases, patients usually complain of neck and arm pain, a der, one can anticipate needle electromyographic abnormalities
diminished triceps reflex may be noted, and weakness extends in both the median- and ulnar-innervated intrinsic hand mus-
outside of the ulnar nerve distribution to include the median-in- cles. It can be distinguished from a cervical radiculopathy by
nervated hand intrinsic muscles as well as C8-innervated mus- normal paraspinal electromyographic findings and an abnormal
cles proximal to the hand. Normal sensory responses combined ulnar sensory response. There should also be a lack of focal
with clearly diminished sensation suggest a preganglionic conduction slowing across either the elbow or wrist areas.
lesion. The most revealing electrodiagnostic medicine examina- Finally, a loss of sensation may be detected along the inner
tion in suspected radicular lesions is the needle electromyo- aspect of the arm outside of just the ulnar nerve distribution. An
graphic assessment. In all patients with suspected ulnar nerve abnormal medial antebrachial cutaneous SNAP is highly sug-
lesions at either the elbow or wrist, a complete needle examina- gestive of a lesion affecting either the medial cord or lower
tion of the limb must be performed, including the median-inner- trunk of the brachial plexus. Along with thoracic outlet syn-
vated hand muscles. Also, it is recommended to examine the drome, a superior sulcus tumor should be considered. Again, the
pronator quadratus and/or extensor pollicis muscles, as these medial cord of the brachial plexus is affected, leading to similar
are good C8-innervated muscles. It is certainly possible for a findings noted above. Additionally, a Horner's syndrome may
so-called double crush syndrome to be present in which a patient be present.
R A D I A L NERVE in direct contact with the bone that renders it particularly sus-
ceptible to neural injury during radius fractures. The posterior
ANATOMY interosseous nerve terminates by providing several branches to
the carpal joints.
Anatomic Course. After the axillary nerve departs from the In the proximal forearm, the superficial radial nerve de-
posterior cord of the brachial plexus, the posterior cord's con- scends under the brachioradialis muscle. It then passes superfi-
tinuation is the largest branch of the plexus comprised of spinal cial to the supinator, and radial aspects of the flexor digitorum
levels C5-C8 (Tl) and is known as the radial nerve. Within the superficialis and flexor pollicis longus muscles. At about the
axilla, the radial nerve is located posterior to the axillary artery lower two thirds of the forearm, this nerve becomes superficial.
and is sequentially superficial to the subscapularis muscle, latis- The superficial radial nerve crosses the wrist joint across the ex-
simus dorsi tendon, and teres major tendon. At the brachio-ax- tensor retinaculum to divide into multiple branches and supply
illary angle, inferior border of axilla where there is a union of the lateral aspect of the hand's dorsum. The cutaneous distribu-
the latissimus dorsi and long head of the triceps muscles, the tion of the superficial radial nerve covers a territory demarcated
radial nerve enters the arm on this fibro-tendinous structure. The by a line approximating the middle of the third digit's metacar-
nerve then descends in a groove between the long and medial pophalangeal joint to the wrist extending laterally to the
heads of the triceps muscle. It continues in this depression until thumb's dorsum and the second digit's first interphalangeal
reaching the humerus' spiral groove between the insertion of the joint (Figs. 24-23 and 24-24). 413
above-noted two muscles. During its course in the spiral groove,
the radial nerve is deep to the lateral head of the triceps muscle.
Upon reaching the lateral margin of the humerus, the nerve Radial n.
pierces the lateral intermuscular septum approximately 10 cm
proximal to the humerus' lateral epicondyle 763 and enters the Post cut. n_ of arm
arm's anterior compartment. The radial nerve is rather superfi-
cial as it reaches the lateral aspect of the arm and is just below Lower lat cu Lrtcf arm
the deltoid muscle's insertion, after which it continues distally
between the brachialis and brachioradialis muscles.
In its course along the distal one third of the arm, the nerve Post cut a of
forearm
descends under the cover of the following muscles: brachioradi-
alis, extensor carpi radialis longus, and extensor carpi radialis
brevis. Near the formation of the brachialis muscle's tendon, the
radial nerve traverses the elbow joint to then divide into the su-
perficial radial and posterior interosseous nerves just prior to
the supinator muscle.
The posterior interosseous nerve enters the substance of the
supinator muscle between its humeral and ulnar origins. Within
this muscle, the nerve courses around the proximal one fourth
of the radius to exit the supinator muscle distally, but remains
beneath the superficial forearm extensor muscles to provide in-
nervation to them. While coursing about the radius, the nerve is
Figure 24-24. Radial nerve. Neural branching of the radial nerve

Figure 24-23. Superficial radial nerve cutaneous distribution. from its origin in the axilla to the termination of its motor and sen-
Cutaneous innervation from the median nerve (white area), ulnar sory branches.The insert demonstrates the cutaneous distribution of
nerve (light shading), and radial nerve (dark shading). (From Concannon the various sensory branches of the radial nerve. (From Haymaker W,
MJ: Common Hand Problems in Primary Care. Philadelphia, Hanley & Woodhall B: Peripheral Nerve Injuries. Philadelphia, W.B. Saunders,
Belfus, 1999, with permission.) 1953, with permission.)
NEURAL BRANCHING epicondyle, but there can also be branches distal to this point.
Below the elbow, the radial nerve divides into the superficial
The branch pattern of the radial nerve is important to under- radial and posterior interosseous nerves.
stand because it can be of significant help in localizing a lesion The next muscle innervated is the extensor carpi radialis
to a particular segment of the radial nerve or its major divisions brevis. It is consistently innervated below the lateral epicondyle
(Fig. 24-24). The first branches to emerge from the radial nerve and can receive innervation from the main trunk of the radial
do so in the axilla and usually innervate the long head of the tri- nerve, superficial radial nerve, or posterior interosseous nerve.
ceps muscle. Rarely, a branch in the axilla also innervates the The particular division of the radial nerve from which this
lateral and medial heads of this muscle. Upon reaching the bra- muscle is innervated appears to depend on the exact point of
chio-axillary angle, the radial nerve typically gives rise to sev- neural branching of the main radial nerve. When the radial
eral branches that innervate not only the long head, but also the nerve extends for some distance, it innervates this muscle,
lateral and medial heads of the triceps muscle. The neural whereas a high origin of the posterior interosseous nerve predis-
branches to the lateral and medial heads of the triceps, though poses to the muscle being innervated by one or both of the radial
separate, usually accompany the radial nerve trunk into the nerve's terminal divisions.763
proximal portion of the spiral groove prior to branching to their Distal to the elbow, the posterior interosseous nerve is usu-
respective muscles. Of note, there is usually a collateral branch ally well formed. Prior to entering the supinator muscle, this
from the ulnar nerve in the brachio-axillary angle that inner- nerve supplies the supinator muscle usually by several
vates the medial head of the triceps but is of apparently little branches. The supinator muscle is also innervated by collateral
clinical significance. 763 The neural branch innervating the tri- branches from the posterior interosseous nerve as it courses
ceps' medial head also provides a branch to innervate the an- through the muscle's substance. 763 Upon emerging from the
coneus muscle. With respect to the serial innervation of the supinator muscle, the posterior interosseous nerve breaks into
tricep muscle's three heads, the long head is always innervated multiple smaller nerve branches to supply the various forearm
first, while the lateral head is innervated next in about half of muscles, making it difficult to clearly delineate an exact se-
examined cadavers.763 quential pattern of innervation. A single common neural branch
A number of sensory branches are also given off the radial distal to the supinator muscle provides innervation to the fol-
nerve in its course from the axilla to spiral groove. In or about lowing muscles: extensor digitorum communis, extensor carpi
the axillary outlet region, the posterior cutaneous nerve of the uinaris, and extensor digiti minimi. These muscles are also in-
arm originates either independently or in conjunction with one nervated by additional neural branches at more distal levels.
of the muscular branches to the triceps muscle (Fig. 24-24). The abductor pollicis longus and extensor pollicis brevis mus-
This nerve innervates the posterior aspect of the arm as far dis- cles are then innervated by a common stem from the posterior
tally as the area of the olecranon. As the radial nerve crosses the interosseous nerve distal to the supinator muscle. Similarly, a
brachio-axillary angle, the posterior cutaneous nerve of the separate branch from the posterior interosseous nerve also sup-
forearm separates to travel independently with the radial nerve plies the extensor pollicis longus and extensor indicis proprius
into the spiral groove. Just inferior to the deltoid muscle's inser- muscles.2-64 Although there is significant individual variation
tion, this nerve appears between the triceps' lateral head and with respect to serial innervation patterns, it may be useful to
brachioradialis muscles to descend posterior to the humerus' have a general idea of this pattern. A general rule of reinnerva-
lateral epicondyle and traverse the forearm's midline. The ter- tion with respect to the radial nerve distal to the spiral groove
minal aspects of this nerve intermingle with the terminations of can be thought of as follows regarding the muscles' functional
the medial and lateral cutaneous nerves of the forearm. The return: brachioradialis, extensor carpi radialis longus, extensor
region of cutaneous supply for this nerve is the posterior aspect carpi radialis brevis, extensor digitorum communis = extensor
of the forearm with occasional fibers to the lateral and posterior carpi uinaris, abductor pollicis longus, extensor digiti minimi,
aspect of the lower arm. The final cutaneous nerve arising from extensor pollicis longus, extensor pollicis brevis, extensor indi-
the main trunk of the radial nerve in the arm region is the lower cis proprius. 763
lateral cutaneous nerve of the arm. This nerve arises as either
a separate branch in the spiral groove or in common with the ANATOMIC VARIATIONS
posterior cutaneous nerve of the forearm. The skin overlying the
lower arm's anterior and lateral aspect is innervated by this A number of neural variations may occur with respect to the
nerve. The branch to the anconeus muscles also supplies a few radial nerve that may be of clinical consequence to practition-
articular branches to the elbow joint. ers. In addition to C5-C8 spinal nerve contributions, approxi-
Prior to the formation of the radial nerve's two main terminal mately 11% of the population may contain fibers from Tl. 369761
divisions, the main trunk provides neural innervation to several Rarely, the posterior interosseous nerve may traverse the super-
muscles above the lateral epicondyle. The first branch arising ficial aspects of the supinator muscle as opposed to passing be-
from the radial nerve distal to the spiral groove is a small motor tween this muscle's two heads. 837 Similarly, the posterior
and sensory branch to the brachialis muscle, thus providing dual interosseous nerve may divide into two branches with one pass-
innervation to this muscle from both the radial and musculocu- ing superficial to the supinator muscle with the other entering
taneous nerves. Its origin averages about 6 cm proximal to the its substance. The superficial branch may then innervate the ab-
lateral epicondyle.763 The next branch or branches departing the ductor pollicis longus, extensor pollicis longus and brevis, and
radial nerve distal to the spiral groove is destined to innervate the extensor indicis proprius muscles.401-803 It is possible for the
the brachioradialis muscle. All of the neural branches to this posterior interosseous nerve to terminate by innervating any one
muscle arise from the radial nerve proximal to the lateral epi- or all of the lateral three dorsal interossei muscles through the
condyle. Several branches may originate from the radial nerve so-called Froment-Rauber nerve.224-622 This could be of im-
to then innervate the extensor carpi radialis longus muscle. portance in ulnar nerve lesions with sparing of the first and pos-
These nerve branches usually originate proximal to the lateral sible second and third dorsal interossei muscles or their
involvement with radial nerve injury. Finally, it is possible for occur following exertional throwing of objects, particularly
the region of the hand innervated by the superficial radial nerve during baseball games.557 During the fracture, the nerve may be
to be replaced by other nerves. For example, the ulnar and su- damaged by the trauma itself, or lacerated by the bony frag-
perficial radial nerves can displace each other to variable de- ments, and occasionally during attempts to reduce the frac-
grees. The lateral antebrachial cutaneous nerve can replace to a ture.228-693 Rarely, children are born with radial nerve palsies
great extent the superficial radial nerve's innervation to the acquired in utero secondary to amniotic bands, umbilical cord
hand's dorsum.18-293 It is also possible for the posterior cuta- constriction of the arm, or possibly uterine bands, as well as ac-
neous nerve of the arm to replace a large portion of the superfi- quiring these injuries from various traumatic etiologies in child-
cial radial nerve's cutaneous distribution.309 hood and adolescence.121-188-202-421-522-651 It is also possible for
traumatic deliveries to result in humeral fractures of the infant
FOCAL RADIAL NERVE NEUROPATHIES with secondary radial nerve damage. Additionally, it is possible
for an isolated posterior antebrachial cutaneous nerve (posterior
It is possible for the radial nerve to be injured in the axilla cutaneous nerve of the forearm) to be injured in isolation. 99100
either in isolation or in conjunction with the median or ulnar This is a pure sensory nerve, and the diagnosis is best made
nerves. These focal neuropathies are discussed in the chapter clinically, although a nerve conduction technique is available.455
dealing with brachial plexus injuries (see Chapter 19). In this The patient's clinical presentation depends primarily upon
section, we shall explore radial nerve injuries in the arm and the level at which the radial nerve is compromised. 642 High in
distal regions of the upper limb. the axilla, neural dysfunction results in loss of triceps function;
however, most lesions distal to the axilla spare at least some
Arm Region fibers to the various heads of the triceps muscle. Persons who
Clinical Features. Between the axilla and elbow, the radial sustain radial nerve injuries about the midshaft of the humerus
nerve is susceptible to damage from a number of causes. As approximating the spiral groove usually do not complain of
with all focal peripheral neuropathies, bullet wounds, lacera- elbow extension weakness. Also, there is typically sparing of
tions from sharp objects, inappropriate use of crutches, and sensation to the lower lateral and posterior aspects of the arm.
direct blunt trauma can injure the radial nerve at any location in Elbow flexion is somewhat diminished because of weakness af-
the arm. One of the more common injuries likely to be encoun- fecting the brachioradialis muscle, but the biceps brachii and
tered by the practitioner is a compression insult to the radial brachialis muscles continue to be the primary elbow flexors.
nerve and its branches. 616 The radial nerve is frequently com- The ability to extend the wrist and fingers is reduced. The pa-
promised in association with some form of unconsciousness re- tient also has difficulty supinating the forearm, but the biceps
sulting from a deep sleep secondary to extreme fatigue, alcohol brachii muscle continues to perform some of this function. A re-
or drug intoxication, i.e., the so-called Saturday night duction in sensation over the hand's medial dorsal aspect and
palsy.210-508 Typically, the individual lies with the upper limb in posterior region of the arm is noted.
an awkward position such as over a sharp ledge/back rest of a On physical examination, the triceps reflex is usually spared,
chair, or rests the head on the lateral surface of the arm. A par- as is the strength of this muscle. It is entirely possible, however,
ticular form of radial nerve insult may occur when a person for the neural branches to the medial and possibly lateral heads
allows another to rest his or her head on the middle third of the of the triceps muscle to be injured, producing some elbow
arm while caressing that person. In this instance, the radial extension weakness. Testing the brachioradialis muscle is par-
nerve can be compressed in the groove between the brachialis ticularly important in radial nerve injuries. This can be accom-
and forearm extensor muscles against the shaft of the humerus, plished with difficulty by asking the patient to flex the elbow
the so-called honeymooner's palsy. Also, persons confined to a against resistance with the forearm positioned midway between
wheelchair may incur radial nerve injuries about the arm region full supination and pronation, and looking for a prominence
secondary to resting the arm over the backrest of the chair, con- about the lateral aspect of the antecubital fossa, i.e., a bulging of
tinually using this portion of the chair to shift body weight, or the brachioradialis muscle. Finding evidence that this muscle is
even in elite wheelchair athletes.60-284-708 Occasionally, the radial nonfunctional suggests that the lesion is proximal to its innerva-
nerve can be compressed during general anesthesia if the arm is tion, i.e., about the spiral groove or proximal to this region. If
permitted to hang over the edge of the operating table or reside the muscle is functional but the remaining muscles distal to it
in the outstretched position for any length of time.157-584-819 are paretic or nonfunctional, the lesion is distal to the brachiora-
Pneumatic tourniquets or Esmarch bandages can also be a cause dialis muscle's innervation, which is at least at the distal third of
for isolated as well as combined radial and median/ulnar nerve the arm. Carefully testing sensation along the posterior aspect
injuries in the arm.49-58-72-513-785 From time to time, strenuous of the forearm (posterior cutaneous nerve of the forearm) helps
muscular exercise particularly involving forceful elbow exten- to place the lesion with respect to the spiral groove. Radial
sion can result in an isolated radial nerve injury about the spiral nerve lesions in the arm also produce wrist drop and inability to
groove region. The mechanism of nerve injury is unclear, but extend the fingers because of denervation to the extensor carpi
there is most likely a stretch and/or compression factor possibly radialis longus/brevis and extensor carpi uinaris, and the exten-
as the radial nerve pierces the lateral intermuscular septum and sor digitorum communis, extensor indicis proprius, extensor
a portion of the triceps muscle.29-295-440-466-753-763 Misplaced injec- digiti minimi, and extensor pollicis longus/brevis muscles, re-
tions into the upper limb can damage the radial nerve when spectively. Some residual finger extension can be carried out by
placed too far posteriorly into the triceps muscle or distal to the the ulnar-innervated hand intrinsic muscles, and the wrist
deltoid muscle. Typically, these persons complain of acute onset should be dorsiflexed to help isolate the radial finger extensors.
of pain and weakness, although occasionally delayed symptoms Electrophysiologic Evaluation and Findings. The electro-
can occur.67-190-235-303-429 Anywhere from 2% to 16% of humeral diagnostic medicine evaluation of radial nerve injuries can be
fractures result in radial nerve injury.372-550-572-763 A number of quite challenging. Irrespective of the presumed lesion site, one
humeral fractures with resultant radial nerve injury can also common assessment to begin with is the superficial radial
SNAP. There are a number of techniques, with the two most One of the most valuable portions of the electrodiagnostic
common being antidromic excitation of the nerve on the radius medicine consultation regarding focal radial neuropathies is the
while recording distally either from the first digit with ring elec- needle electromyographic examination. 544 Detecting membrane
trodes, or directly over the nerve as it crosses the extensor polli- instability in various muscles permits a relatively accurate deter-
cis longus tendon.123166-454-458-691 698 Because orthodromic mination of lesion location. For example, in a radial nerve mid-
excitation yields much smaller responses and is more techni- humerus or spiral groove lesion, all three of the triceps muscle's
cally demanding,78-492-783 the authors prefer the antidromic tech- heads should be normal, but the brachioradialis muscle and all
nique. Performing this study bilaterally allows one to roughly muscles distal will have evidence of denervation. If the brachio-
infer the amount of axonal damage by comparing side-to-side radialis muscle is spared along with the various heads of the tri-
amplitudes. A completely absent response obviously suggests ceps muscle but the extensor carpi radialis longus muscle and all
there has been significant Wallerian degeneration affecting the muscle distal are denervated, the lesion is obviously in the distal
superficial radial sensory fibers at some level. It is also possible arm between the innervation to the brachioradialis and extensor
to attempt a posterior cutaneous nerve of the forearm SNAP, al- capri radialis longus muscles. This same logic can be applied
though this is a somewhat technically demanding study because equally well along the entire course of the radial nerve provided
of the small size of the potential and the variable anatomy of one is familiar with the sequential innervation of muscles in the
this nerve.455 In lesions proximal to the spiral groove, this SNAP limb, given individual variations of neural innervation.
should be absent. Prior to concluding the SNAP'S absence is Partial nerve lesions in the arm can be approached using the
secondary to pathology and not technically related, the con- above methods to determine not only the lesion's location with
tralateral unaffected side must be examined. If the SNAP is not respect to the serial innervation of muscles, but also the degree
present bilaterally despite good technique, then one can only of nerve injury. If there is a complete absence of an evoked re-
conclude that the response is unobtainable because of a lesion sponse above a particular site, but a readily obtainable response
as opposed to a technical reason. A unilateral absence of the distally, one can conclude that some degree of conduction block
SNAP allows one to feel more comfortable regarding true is present. A totally absent response to stimulation distal to the
pathology. presumed site of injury implies complete Wallerian degenera-
Motor studies are also usually performed, but all techniques tion to the nerves innervating the muscle under investigation.
leave much to be desired with respect to measuring CMAP am- This is supported by finding florid membrane instability on
plitudes for axonal loss approximations. The difficulty lies in the needle electromyographic examination. Of course, with time
fact that there simply is no well-isolated muscle far from other the amount of membrane instability can be expected to decrease
radially innervated muscles. For example, in the hand the thenar either because of reinnervation or muscle atrophy. If reinnerva-
and hypothenar muscles are relatively well isolated in that they tion occurs, an evoked CMAP should be detected while muscle
are small and localized to a particular region with well-defined atrophy and replacement with connective tissue continue to
motor points. However, the distally located radially innervated yield a completely absent CMAP. If there is noted to be an
muscles such as the extensor indicis proprius are not isolated, absent superficial SNAP, the lesion is proximal to the division
but surrounded by other radially innervated muscles, as is their of the superficial radial and posterior interosseous nerves. The
nerve supply. Placing a surface recording electrode over this authors have seen a number of proximal radial nerve lesions
muscle results in a volume-conducted response not only from particularly in the distal arm that produced significant axonal
this muscle, but also from all of the other forearm muscles inner- loss in the posterior interosseous nerve distribution with relative
vated by the radial nerve. Stimulating the nerve at more distal lo- sparing of the superficial radial nerve. This may be a result of a
cations results in less muscle tissue being activated with the rather high division of these two nerves or a localized lesion
potential for a slightly different response at each stimulus site. sparing the fascicles of the superficial radial nerve despite a
Herein lies the difficulty with recording surface responses and radial nerve trunk injury. All of the above-noted techniques are
using them for side-to-side amplitude comparisons.158-297-692 It is required to fully assess the radial nerve and attempt to localize
difficult to consistently obtain similar responses at the various the lesion site.
stimulation sites along the radial nerve's course. Also, the
CMAP's initial deflection can often be positive, suggesting the Forearm Region
recording electrode is off the muscle's motor point. This is the Clinical Features. There are primarily two major focal
reason for the majority of radial nerve techniques utilizing radial neuropathies in the forearm region affecting the posterior
needle recording electrodes placed usually though not exclusively interosseous nerve. The first is known as the radial tunnel syn-
in the extensor indicis proprius rnuscle.233-329-330-347-455-676-783-784 drome, while the second is frequently referred to as a supina-
Using stimulation sites at Erb's point, axilla, posterior arm, lat- tor syndrome (see below). Additionally, it is possible for
eral aspect of the distal arm between the brachialis and triceps isolated ganglia, fibromas, hemangiomas, or lipomas to prefer-
muscles, and in the forearm proximal to the active electrode can entially affect the posterior interosseous nerve after its forma-
yield good approximations of conduction velocities across the tion but proximal to the supinator muscle.31-62-156-519-597-692-840
various segments defined above between stimulation points. Missile fragments and lacerations are also observed to cause
Because needle recording electrodes are used, however, the am- isolated posterior interosseous nerve injuries. 763 A particular
plitude of the evoked response is not appropriate for attempting type of fracture/dislocation, Monteggia fracture, can also pref-
to approximate the degree of axonal loss. Additionally, needle erentially affect this nerve.35-524-722-727-738-751 In the Monteggia
stimulation may be more successful than surface stimulation at fracture, the trauma produces a fracture of the proximal ulna
all of the above-noted sites except for Erb's point. When surface combined with a posterior dislocation of the head of the radius.
stimulation is used, the depth of the radial nerve beneath the skin It is also possible for more extensive trauma to result in fracture
requires firm pressure and long pulse durations prior to conclud- of the radius' head with secondary neural insult. More distal
ing the response is absent. If there is any doubt about the validity fractures of the mid-shaft of the radius and ulna can also pro-
of the stimulation, a needle cathode should be employed. duce posterior interosseous nerve injuries. Similar to tardy ulnar
Brachialis Superficial radial
Biceps nerve
Radial tendon
Figure 24-25. Radial tunnel. The radial tunnel is nerve Pronator teres
shown in cross-section as extending from the lateral in-
termuscular septum region to the supinator muscle.
The radial nerve or its posterior interosseous division
is proposed to be compressed by various structures
along the length of the radial tunnel. (From Roles NC,
Maudsley RH: Radial tunnel syndrome: Resistant tennis
elbow as a nerve entrapment. J Bone Joint Surg
Humerus Superficial
1972;54B:499-508, with permission.) Deep
Triceps
Brachioradialis Portions of
supinator
palsy, a fracture of the radius/ulna or elbow joint may result in be a part of the radial tunnel. However, most definitions of the
the bone healing in excessive angulation with a resultant stretch supinator syndrome (see below) include the arcade of Frohse as
of the posterior interosseous nerve and the development of the proximal part of the supinator muscle and hence by defini-
tardy radial palsy years after the original traumatic incident or tion a potential cause of radial nerve entrapment in the supina-
possibly osteomyelitis.300-425 It is possible to confuse a posterior tor syndrome. After an extensive literature review, these authors
interosseous nerve compression with a tendon rupture to the conclude that the radial tunnel should not include the arcade of
finger extensors in patients with rheumatoid arthritis.503 In real- Frohse because this structure is more appropriately involved
ity, the nerve is injured because of a compression neuritis result- with the supinator syndrome. The exact anatomic structure re-
ing from a bulging of the elbow joint synovium into the sponsible for the signs and symptoms of radial tunnel syndrome
substance of the supinator muscle. In addition to the above- remains to be unquestionably defined.
noted lesions, the radial tunnel and supinator syndrome require Clinically, the so-called radial tunnel must be differentiated
further discussion. from a lateral epicondylitis (Table 24-6) versus a supinator syn-
Radial Tunnel Syndrome. The radial tunnel is a controver- drome. The complaint of pain in the lateral forearm and lateral
sial entrapment neuropathy described as originating from where elbow region can be rather diffuse and at times hard to localize
the radial nerve pierces the lateral intermuscular septum to lie despite suggestions to the contrary. Arguably, a rather simple
between the brachialis and brachioradialis muscles, and to end approach is first to define if true muscle weakness is present.
at the point where the posterior interosseous nerve enters the Documenting finger extensor weakness is highly suggestive of a
supinator muscle (Fig. 24-2S).647 Three structures in the radial supinator syndrome. Weakness of finger extensors should not
tunnel are proposed to result in entrapment of the radial or pos- be present in lateral epicondylitis or radial tunnel syndrome. If
terior interosseous nerves. These structures are (1) fibrous
bands about the anterior margin of the radial head; (2) radial re-
current fan of vessels; and (3) the sharp tendonous edge of the Table 24-6. Radial Tunnel Syndrome vs. Lateral
extensor carpi radialis brevis rnuscle.435-527'644-647-668'670-730 Individ- Epicondylitis
uals who are supposed to fall into this category of neural entrap- Radial Tunnel Lateral Epicondylitis
ment are those with resistant tennis elbow not responsive to
conservative treatment. The diagnosis of radial tunnel syndrome Maximum pain Mobile was/cannot Lateral epicondyle
is made by (1) having a patient unresponsive to conservative location localize
measures for typical tennis elbow, (2) reproduction of painful Pain Dull, aching Sharp
symptoms with resisted extension of the third digit during characterization
elbow extension, and (3) local tenderness along the course of Pain reproduction Active wrist extension Passive wrist flexion
the radial nerve about the radial head. There is an absence of and supination greater greater than active
objective motor weakness or sensory loss in the distribution of than wrist flexion and wrist extension and
the radial nerve or its branches. The treatment of choice is a sur- pronation supination
gical procedure in which the extent of the radial tunnel is Mobile wad Lateral epicondyle
opened and any adhesions about the radial head, proximal edge Maximum tenderness
of the extensor carpi radialis brevis, tendonous origin of the Middle finger extension +
supinator muscle, or other "suspicious" structures are sectioned. test
The surgical literature reports that approximately 66-95% of Resisted supination ++ ±
patients respond favorably to surgery with respect to pain ++
relief.328-435-644 Passive wrist flexion ±
Not all investigators agree on the boundaries comprising the EMG/NCV
radial tunnel. There appears to be disagreement as to whether Response to LE injection -
the supinator muscle is part of the so-called radial tunnel.33-141-142 Response RT injection +
Most authors agree that the distal margin of the radial tunnel is EMG, electromyography; NCV, nerve conduction velocity; LE, lateral epicondyle;
the proximal border of the supinator muscle including the RT, radial tunnel. (Modified from Barnum M, Mastey RD,Weiss A-RAkelman E:
arcade of Frohse. Others consider the entire supinator muscle to Radial tunnel syndrome. Hand Clin 1996;12:679-689.)
the patient responds to an injection at the lateral epicondyle, lat- beneath a sharp fibrous opening in the superficial head of the
eral epicondylitis is obviously present. However, failure to re- supinator muscle. Specifically, the proximal portion of the su-
spond to an injection at the lateral epicondyle without finger perficial head of the supinator muscle originates from the tip of
extensor weakness would lead some to conclude that the radial the lateral epicondyle, and arches inferiorly in a semi-circular
tunnel syndrome is manifested in that patient. As always, more manner to then swing superiorly again and attach to the medial
clinical work is required to better define these various entities. tip of the lateral epicondyle (Fig. 24-26).723-763 In about 30% of
The above radial tunnel syndrome is primarily a clinical spec- individuals, the opening in the supinator muscles is completely
ulation based on little in the way of objective data. Patients do fiorous and presents quite a sharp edge to the posterior in-
not demonstrate any documented loss of strength or sensation in terosseous nerve as it pierces this muscle. The fibrous opening
any branches of the radial nerve. There is also no detailed docu- in the superficial head of the supinator muscle is known as the
mentation through electrophysiologic means of neural dysfunc- arcade of Frohse. 222 The posterior interosseous nerve can
tion. In undisputed focal entrapment neuropathies, there is at become entrapped at the opening of the supinator muscle as it
least an occasional report of denervation in the nerve's distribu- abuts against the arcade of Frohse or possibly within the sub-
tion suggesting true axonal loss. This finding has never been stance of the supinator muscle itself.34-55-75-252-274-286-356-548-692-723-736
documented in the above-noted radial tunnel syndrome. Rarely, a ganglion in the substance of the supinator muscle may
Similarly, detailed electrophysiologic studies have failed to also cause a lesion identical to that of compression at the arcade
reveal conduction slowing or block suggesting a focal demyeli- of Frohse. A proposal has been made, primarily on electrophys-
native lesion.796-800 The surgery is directed at cutting anything in iologic grounds, to distinguish the supinator syndrome from the
the way of the radial nerve and has not been scientifically di- more generic category of posterior interosseous nerve syn-
rected at attempting to define a focal lesion. Patient response dromes. If the supinator muscle reveals no evidence of mem-
has also been variable regarding the suggested operative inter- brane instability, it is suggested that this patient has the
vention. Failure has been claimed to be the result of poor patient supinator syndrome while denervation in this muscle represents
selection as opposed to a failure to identify a true entrapment a more "proximal" lesion of the posterior interosseous nerve.91
syndrome. The existence of the radial tunnel syndrome must be This type of designation is questionable because the selective
questioned on multiple grounds.827 Until there are careful con- involvement of the supinator muscle may be more a result of its
trolled surgical studies directed at identifying a focal compro- innervation pattern or a less than adequate exploration of the
mise of the radial nerve by electrophysiologic means, muscle with a needle electrode. It is unwise to categorically
particularly intraoperative studies demonstrating focal conduc- state that the lesion does not involve the posterior interosseous
tion abnormalities, credibility can not be given to this supposed nerve prior to it entering the supinator muscle, as this may
entrapment syndrome. simply be "pushing" the limits of the needle examination.
Supinator Syndrome. After innervating the extensor carpi
radialis brevis muscle, the posterior interosseous nerve descends Posterior Interosseous Nerve
Clinical Presentation. The clinical presentation of persons
with posterior interosseous nerve compromise is somewhat
variable depending upon the location of neural insult.122 In the
majority of persons, this nerve is affected after the extensor
carpi radialis longus muscle and usually the extensor carpi radi-
alis brevis muscle are innervated, and the superficial radial
nerve has departed. Persons can complain of a dull or at times
sharp pain in the deep extensor muscle mass just distal to the
radial head. Cutaneous sensation is spared, but the major com-
plaint is one of an inability to use the hand.
On physical examination, there is preservation of all sensory
modalities in the peripheral nerves of the upper limb. The af-
fected limb displays radial deviation of the hand when wrist ex-
tension is attempted. This is because the extensor carpi uinaris
muscle is nonfunctional and does not dynamically balance the
action of the extensor carpi radialis longus and brevis muscles.
Wrist extension is not normal secondary to this loss of muscle
power. In complete neural lesions, there is an inability to extend
the digits of the affected limb. Partial paralysis of the nerve can
produce a decreased ability to extend the fourth and fifth digits
leading to a pseudbclaw hand (see above). It is possible for this
neural injury to progress to a complete lesion of the posterior in-
terosseous nerve. Loss of innervation to the finger and thumb ex-
tensor muscles leads to the passively flexed posture of the digits
Figure 24-26. Supinator muscle. The superficial head of the through a tenodesis effect during wrist extension. If there is
supinator muscle is shown with its fibrous opening for the posterior noted to be complete wrist drop, the extensor carpi radialis
interosseous nerve. N o t e how the nerve to the supinator muscle is longus and brevis muscles must be assumed to be affected. This
seen to also travel beneath the fibrous arch referred to as the arcade can occur in rare instances of posterior interosseous neuropathies
of Frohse. (From Spinner M: Injuries to the Major Branches of when these muscles are innervated more distally; however, con-
Peripheral Nerves in the Forearm. Philadelphia, W.B. Saunders, 1978, sideration should be given to a radial nerve injury at a higher
with permission.) level. In this instance, the brachioradialis muscle should be carefully
assessed, as should sensation in the superficial radial nerve dis- and extensor carpi radialis longus/brevis muscles should be
tribution. When wrist extension is absent, but the brachioradialis spared. The supinator muscle may or may not be affected de-
muscle is functional, there is usually a radial nerve injury about pending upon the lesion location. If there is neural dysfunction
the distal arm or proximal elbow region with an accompanying proximal to the muscle or at the arcade of Frohse, the supinator
loss of sensation over the hand's dorsum. Supination can be very muscle can be expected to display signs of denervation.
difficult to evaluate because not only is the supinator muscle es- Compromise of the nerve within the substance of the supinator
sentially impossible to isolate, but also forced supination may muscle can continue to yield evidence of denervation, as neural
cause pain with a secondary hesitation to producing full force. branches to this muscle arise not only proximally, but also
The biceps brachii muscle can substitute for supination, and the within the substance of the muscle. In partial nerve lesions, the
arm should be flexed maximally at the elbow by the examiner as extensor carpi uinaris muscle and fourth and fifth digit exten-
well as the arm flexed 90°.366 In radial nerve lesions, the biceps sors can be preferentially affected, thus sparing the thumb and
brachii muscle cannot maintain the forearm fully supinated in second/third digit extensors, although small amounts of positive
this position. If the posterior interosseous nerve is damaged sharp waves and fibrillation potentials may be detected in these
proximal to the supinator muscle, this muscle should be affected. relatively spared muscles. Obviously, in complete posterior in-
On the other hand, if the nerve is compromised within the sub- terosseous nerve lesions, all of the muscles innervated distal to
stance of the muscle, the supinator muscle can still be weak be- the supinator muscle are denervated. As with all nerve lesions, it
cause it continues to receive neural innervation while in the is important for the practitioner to observe not only for mem-
substance of the muscle.763 In long-standing cases, there is usu- brane instability but also for the presence of voluntary motor
ally atrophy of the muscles distal to the supinator demonstrating units. Voluntary motor units distal to the presumed site of injury
a marked scalloping or transition between those muscles inner- suggest that there is a lesion in continuity.
vated and those denervated.168 Two electrophysiologic techniques have been developed to
Mild neural compression may simply present with proxi- assess conduction through the radial tunnel. The first involves
modorsal forearm pain particularly with resisted supination. recording a CMAP from the brachioradialis and extensor carpi
There are no clear-cut objective physical findings of weakness uinaris muscles following radial nerve stimulation at the elbow
or muscle wasting. This is an especially important category of (axilla stimulation can also be used).686 A latency difference be-
patients, as they present with symptoms quite indistinguishable tween these two muscles of 1.3 ms is anticipated with a side-to-
from, "tennis elbow." There is usually discrete tenderness along side difference of 0.4 ms. This technique has not been
the proximal radius to deep palpation. This pain is reproduced demonstrated of value in patients with clinical signs and symp-
with the patient extending the arm and third digit while the ex- toms suggestive of radial tunnel syndrome. The second tech-
aminer attempts to flex the third digit. Persons who do not re- nique involves activating the radial nerve at the elbow in the
spond to conservative therapy should be considered to have a intermuscular groove between the brachioradialis and biceps
possible posterior interosseous neuropathy. There may be some brachii muscles while recording a CMAP from the extensor dig-
mild slowing of neural conduction in the radial nerve, particu- itor communis. 406 The recordings are performed to the muscle
larly with forced supination during conduction testing.650-813 with the forearm in three different positions: (1) neutral, (2)
Needle electromyographic findings may be completely normal. maximal forearm supination, and (3) maximal forearm prona-
Additional radiographic studies should also be performed to tion. The recordings were performed after the forearm had been
assess the limb for the possibility of a soft tissue mass or other in the required position for 30 seconds. The normal interposi-
space occupying lesion potentially resulting in neural compro- tional latency was found to be less than 0.12 ms. When this
mise. As can be seen from the above description, it may quite same technique was performed in persons with a clinical diag-
difficult if not impossible to always distinguish between a nosis of radial tunnel syndrome, an interpositional latency of
simple tennis elbow and focal neural compromise. 0.44 ms was found. When this same technique was tried postop-
Electrophysiologic Evaluation and Findings. Posterior in- eratively in persons undergoing a radial tunnel release, the inter-
terosseous nerve lesions result in a normal superficial radial positional latencies were all less than 0.07 ms. Considerable
SNAP. The CMAP for a muscle innervated by this nerve may work is required to replicate these findings as well as justify
result in a drop in conduction or amplitude when stimulated at physiologically the mechanism of conduction slowing for such
(1) the distal arm between the brachialis and brachioradialis short periods of supposed positional compression.
muscles, and (2) the distal forearm region just proximal to the After documentation of the physiologic status of the nerve
extensor indicis proprius recording site. Recall that a CMAP and the presumed site of damage, computed tomography of the
can be assessed only if surface electrodes are used. There may affected region may be of assistance in planning the surgical
be amplitude or CMAP morphology changes because of pathol- procedure. 548 When an obvious mass is absent, it is recom-
ogy or the above-noted difficulties with this technique. A con- mended to wait approximately 8-12 weeks for any signs of
servative approach is to recognize the shortcomings of assessing spontaneous recovery. Following this time, exposure of the pos-
the radial nerve and utilize a needle recording electrode in the terior interosseous nerve with removal of the offending soft
extensor indicis proprius muscle, for example, and calculate a tissue structure or sectioning the proximal tendonous portion of
conduction velocity only for the posterior interosseous nerve.194 the supinator muscle or constricting fibrous bands is usually
Slowing of conduction may be detected across the supinator preferred.
region if a sufficient degree of axonal loss or demyelination is
present. Superficial Radial Nerve
Perhaps the best technique with respect to localizing the Clinical Features. The superficial radial nerve can be injured
lesion is needle electromyography. Observing for membrane in- in isolation from a number of causes. In the distal forearm or
stability is usually the easiest manner in which to determine the wrist region, the superficial radial nerve may be compressed by
location and grossly the completeness of the lesion. In typical such objects as wristwatch bands, too tightly applied handcuffs,
posterior interosseous nerve injuries, the triceps, brachioradialis, fractures, a venous cutdown, lacerations, and blunt trauma.
When the nerve is affected at the wrist, it is sometimes referred to blunt trauma, or penetrating injuries. It is possible to investigate
as cheiralgia paresthetica.63-165-182-424-43^ It is also the individual branches of the superficial radial nerve as they
possible for the median and ulnar nerve to be affected in lesions as course in the intermetacarpal spaces.720 Simply, the radial nerve
a result of circumferential pressure application such as forcefully is stimulated 10 cm proximal to the base of the first digit, and in
applied handcuffs.259a The superficial radial nerve can also become the forearm along the radius while recording electrodes are
entrapped in the distal forearm between the tendons of the bra- placed in the intermetacarpal regions between the first four
chioradialis and extensor carpi radialis longus tendons where the digits.
nerve pierces the fascia connecting these two tendons.148 " Motor conduction velocities to the radial nerve and posterior
Patients with isolated compromise of the superficial radial interosseous nerve should be normal. The needle electromyo-
nerve usually complain of a burning, numbnessror tingling graphic examination of the radial-innervated muscles is also
about the dorsoradial aspect of the hand. Plamar and ulnar flex- normal. As with all electrodiagnostic medicine consultations, a
ion as well as forceful pronation of the forearm exacerbates the needle and nerve conduction study should also be performed on
symptoms. There is usually objective sensory loss in the distrib- the median and ulnar nerve in the affected limb. This is neces-
ution of the superficial radial nerve, although this loss can be sary to evaluate the possibility of lesions such as radiculopathies
less than anticipated. It is important to keep in mind that the lat- or peripheral neuropathies simulating a focal neuropathy or co-
eral antebrachial cutaneous nerve can supply a rather substan- existing with it.
tive portion of the hand's dorsum and replace in part or whole Peripheral nerve anesthetic blockade of first the lateral ante-
the superficial radial nerve.459 Weakness of the radial-innervated brachial cutaneous nerve followed by the superficial radial
muscles should be absent. A positive Tinel's sign may be pre- nerve may be of assistance in differentiating between a lesion
sent at some point along the course of the nerve. The nerve affecting these two nerves. Conservative treatment of rest and
should be percussed from the mid-forearm distally to include nonsteroidal anti-inflammatory medication may provide com-
the above-noted potential entrapment site. There may be an as- plete relief. If this trial is unsuccessful, surgical exploration of
sociated Finkelstein sign. Because of this finding, patients may the nerve's course may be indicated, looking for focal entrap-
be misdiagnosed as having deQuervain's tendonitis. In persons ments or neuroma formation.178
with pure tendonitis, there is normal sensation over the hand's
dorsum. It is certainly possible, however, for patients to have
both a tendonitis and superficial radial neuropathy. Proper diag- SECTION II: T H E LOWER LIMB
nosis of radial nerve compromise is important because it can be
quite disturbing to some patients, particularly if it progresses to Focal lesions affecting the lumbosacral plexus' branches have
reflex sympathetic dystrophy. been previously detailed in the chapter discussing lumbosacral
Electrophysiologic Evaluation and Findings. The proper plexopathies. In this chapter we shall address only lesions af-
evaluation of potential compromise of the superficial radial fecting the peroneal and tibial nerves as well as their various
nerve is rather straightforward. Fortunately, it is relatively easy branches. The detailed anatomy of the neural course and mus-
in normal persons to elicit a superficial radial SNAP. A slight cular branches are not presented for the tibial and peroneal
variation on the above-described techniques for this nerve is nerves as this has been previously described (see Chapter 20).
employed in suspected cases of focal compromise to the super- However, a brief anatomy section begins each section with re-
ficial radial nerve. Because of a possible entrapment site in the spect to pertinent surrounding structures which may contribute
distal forearm proximal to the wrist where the nerve pierces the to focal neural compromise.
superficial fascia, a nerve conduction technique has been rec-
ommended.721 One records the radial SNAP from the base of the
first digit while stimulating this nerve 10 cm proximal to the PERONEAL NERVE AND BRANCHES
active recording electrode along the radius, and the main trunk
of the radial nerve in the antecubital fossa medial to the brachio- THIGH AND KNEE REGION
radialis muscle. This allows one to calculate not only a distal
sensory latency, but also a forearm conduction velocity (62.1 ± Common Peroneal Nerve
4.2 m/s; left/right difference < 7.0 m/s) across the above-noted Clinical Features. At approximately the middle to distal one
site of potential entrapment. It is recommended to also stimulate third of the thigh region, the peroneal portion of the sciatic nerve
the lateral antebrachial cutaneous nerve while recording from becomes a distinct nerve, the common peroneal nerve, and de-
the base of the thumb. If a SNAP is obtained, there may be a scends toward the popliteal fossa, innervating the short head of
lesion of this nerve as opposed to the superficial radial nerve. the biceps femoris muscle.763 It travels in the lateral aspect of the
This is because of the above-noted anatomic variations between distal thigh beneath the cover of the long and short heads of the
these two nerves. The rationale for performing a distal latency biceps femoris muscle to gain the region of the fibular head.
(conduction velocity) as well as a proximal velocity determina- Proximal to the fibular head, the common peroneal nerve gives
tion is to evaluate the nerve not only distally, but also across the off two branches: the sural communicating branch, to assist in
possible entrapment site in the forearm. If the response is com- the formation of the sural nerve with a branch from the tibial
pletely absent, it is difficult to localize the lesion. A normal nerve; and the lateral cutaneous nerve of the calf, which pro-
distal latency or velocity, however, suggests that a lesion is not vides cutaneous sensation to the proximolateral aspect of the leg.
present. The normal distal latency/velocity, however, may be The common peroneal nerve then courses around the fibular
present with a concomitant slowing of conduction in the fore- neck and passes through a fibro-osseous opening in the superfi-
arm segment because of a focal segment of demyelination and cial head of peroneus longus muscle. This opening can be quite
possible axonal loss. tough and result in the nerve angulating through it at a rather
Rarely, individual peripheral branches of the superficial radial acute angle. Also, there is significant fibrous connective tissue
nerve may be injured in the dorsal web spaces from ganglia, securing the nerve to this proximal portion of the fibula, acting to
potentially compromise the nerve particularly when it is stretched
as in ankle inversion. Distal to this so-called fibular tunnel, the Common peroneal
common peroneal nerve divides into the superficial and deep
peroneal nerves. The superficial peroneal nerve provides inner-
vation to the peroneus longus and brevis muscles and then travels Deep peroneal
down the leg to pierce an opening in the deep fascia at about the
distal one third of the anterior leg (Fig. 24-27). This superficial
sensory peroneal nerve splits into the medial and lateral termi- ~~.y-*-Tibialis anterior
nal sensory branches to pass anterior to the ankle and innervate
most of the foot's dorsum except that region between the first and 'Extensor digitorum
longus
second toes. The deep peroneal nerve descends along the leg be-
tween the tibialis anterior and extensor hallucis longus muscles, •Extensor hallucis
innervating them as well as supplying the extensor digitorum Ion
longus and peroneus tertius muscles (Fig. 24-28). This nerve ongus
crosses the ankle by passing posterior to the extensor retinaculum
and divides into a motor branch to innervate the extensor digito-
rum brevis (EDB) muscle and a sensory branch to provide cuta-
neous sensation to the region between the first and second toes.
Approximately 28% of the population has a branch from the su- 'Peroneus tertius
perficial peroneal nerve, the accessory peroneal nerve, that pro-
vides a variable amount of innervation to the EDB. 269 Although Extensor digitorum
brevis
the figure of 28% is given in the literatue, is has been these au-
thors' experience that most patients do not display this anomaly
during routine lower limb testing. The true electrophysiologic '1st dorsal interosseous
presence of this anomaly is still to be accurately defined.
Dorsal digital
Figure 24-28. cutaneous
Deep peroneal nerve.The deep rt
peroneal nerve
Lateral cutaneous n. arises from the common peroneal nerve distal to the fibular head and
Jj~\\,^'''' of calf innervates the anterior compartment muscles of the leg.A small cuta-
Common peroneal rv neous nerve provides sensibility to the region of skin between the first
and second toes. (From Haymaker W, Woodhall B: Peripheral N e r v e
Injuries. Philadelphia, W.B. Saunders, 1953, with permission.)
Deepr^peroneal
(cue;n The common peroneal nerve can be injured at any location
Superficial along the thigh to the fibular head region by various kinds of
trauma such as bullet wounds, lacerations, femur fractures,
peroneal n.-l 393,763 The majority of peroneal nerve injuries, however, occur
about the fibular head. Perhaps the most common form of
e t c
Fbrvneuslongus~ \ neural compromise about the fibular head is some form of

compression secondary to habitual leg crossing, debilitated pa-
Peroneus brevis tients with the nerve compressed against a hard mattress or
bedrailing, comatose patients during general anesthesia, or sec-
ondary to a drug-induced stupor as well as various forms of
Medial cutaneous trauma. 232 - 349 - 416 ' 53 ^ Excessive weight loss is
branch" often a precipitous factor in patients with compressive peroneal
nerve lesions (slimmer's paralysis).140-697-731 Occasionally, per-
Lateral cutaneous sons may present with peroneal nerve compression secondary
branch // to an occupation such as picking strawberries (strawberry
pickers' palsy) or planting/harvesting crops by walking in the
squat position or spending long hours in this posi-
tion. 2 5 0 - 3 9 1-669.685 xhe cause of this insult is most likely a com-
pression of the common peroneal nerve about the fibular head
as it penetrates the fibro-osseous opening in the peroneus
Figure 24-27. Superficial peroneal nerve.The superficial per- longus muscle in persons with a particularly fibrous or tight
oneal nerve is shown to arise from the common peroneal nerve just peroneal tunnel.193 Additional causes of common peroneal nerve
distal to the fibular head and innervate the peroneus longus and brevis injury about the fibular head include ankle sprains, proximal
muscles. It then descends as a pure sensory nerve to innervate the fibula fractures, knee dislocations, 1 °-494-549 752 tibial osteotomies,
dorsum of the foot except for that region between the first and total hip565 and knee arthroplasties (prevalence of 0.3^%), 23 - 129 -
second toes. (From Haymaker W, Woodhall B: Peripheral Nerve 310,383.518.671 a s w e u a s arthroscopies 153593 and compression from
Injuries. Philadelphia,W.B. Saunders, 1953, with permission.) ganglions and vascular abnormalities.51,167'357-528-735-789 Rare
etiologies of common peroneal nerve insult include those asso- is then asked to dorsiflex the foot as well as invert it to optimally
ciated with natural childbirth in which the woman compresses test the tibialis anterior muscle. From the neutral position, ankle
both peroneal nerves at the fibular head by pulling back on her eversion is then assessed and patients can have relative sparing
knees with her wrists resting on the fibular head during of these muscles. This does not necessarily imply that only the
birthing. 6 The nerve may also be injured during childbirth in deep peroneal nerve is affected, but that the superficial per-
the squatting position.27-629 Further, lower-limb lengthening oneals nnervated muscles tend to be less affected than those in-
procedures, 606 anorexia nervosa, 370 and paraneoplastic syn- nervated by the deep peroneal nerve. Sensory loss is rather
dromes389-654 can all result in focal peroneal mononeuropathies. variable and depends upon the level of injury. In profound fibu-
A single patient has been reported with a peroneal nerve injury lar neck injuries, there is complete absence of sensation on the
having an intrauterine onset with electrodiagnostic confirmation anterodistal portion of the leg and entire dorsum of the foot.
of the lesion 18 hours after birth.342 Also, peroneal mononeu- There may be sparing of the lateral calf sensation if the lesion is
ropathy can occur with hyperthyroidism, diabetes mellitus, below the nerve to this region. The short head of the biceps
vasculitic disorders, leprosy, and some sporting activi- femoris muscle is spared in neural insults at the knee, but it
ties.53-200-2183 !2-520-529-663 Finally, a large number of persons simply cannot be tested in isolation.
develop peroneal palsy with no clearly identifiable antecedent Electrophysiologic Evaluation and Findings. The electro-
cause and fall into the idiopathic category. 193 Of interest, per- diagnostic medicine evaluation is arguably the best method to
oneal nerve injuries are the most common peripheral nerve in- assess a potential peroneal nerve insult about the fibular head
jured in the lower limb following multiple trauma, particularly region. This is primarily because it can be extremely difficult
after motor vehicle accidents. 550 Magnetic resonance imaging from a clinical standpoint to localize a lesion affecting the per-
of the peroneal nerve can be of considerable assistance in oneal nerve to a specific site along its course. As noted above,
defining the presence of a mass lesion.439 the manual muscle test is limited because of an inability to test
It is also possible for either the deep peroneal or superficial the short head of the biceps femoris muscle, which is a critical
peroneal nerves to be compromised in isolation with sparing of muscle to evaluate. An abnormality detected in this muscle de-
the other. The deep peroneal nerve may be compromised in the fines a lesion proximal to the knee and causes concern for a
anterior tibial compartment syndrome. This is a disorder in more proximal lesions involving the sciatic nerve, lumbosacral
which the deep branch of the tibial nerve and muscles contained plexus, or even a radicular/intraspinal process. The electrodiag-
within the anterior compartment of the leg are compromised nostic medicine examination can provide significant informa-
secondary to ischemia resulting from trauma, profound exertion with respect to localizing a lesion.
cise, or direct vascular occlusion.648-748 The superficial per- Sensory Techniques. The superficial peroneal SNAP is very
oneal nerve may be preferentially affected in the peroneal important. An abnormality in this response implies the lesion is
compartment syndrome, which is similar to the anterior com- distal to the dorsal root ganglion, although the occurrence of a
partment syndrome described above.433-448,634 Elevated compart- reduced sensory response due to L5 radiculopathy is described,
ment pressures associated with necrosis of only the peroneal possibly because the dorsal root ganglion is sometimes posi-
muscles and dysfunction of the superficial peroneal nerve are tioned within the spinal canal. It is relatively easy to obtain this
observed. The causes of this rare disorder are the same as for response by recording from the ankle and stimulating along the
the previously described anterior compartment syndrome. distal lateral aspect of the leg.321-325-423 A loss in amplitude of this
Persons with lesions of the peroneal nerve about the knee response implies there has been some axonal loss affecting either
region or distal thigh usually complain of altered ambulation the common peroneal nerve or its superficial division. One
secondary to paretic/paralyzed ankle dorsiflexors.46-360-717-757'826 cannot determine which portion of the nerve is injured by just
The loss of sensation in the cutaneous distribution of the super- considering the superficial peroneal SNAP. Comparison of both
ficial and deep peroneal nerves is a minor annoyance, but it is the latency and amplitude of this response with the contralateral
the muscle weakness that results in the greatest concern. Pain limb is mandatory in order to define in at least an approximate
about the knee is highly variable and typically associated with manner the degree of axonal loss. One criterion suggests a loss
the etiology of the peroneal nerve compromise. Idiopathic and of greater than 50% compared with the nonaffected side prior to
most compressive lesions secondary to leg crossing do not concluding that an axonal loss lesion is present.360-826
result in significant pain. Musculoskeletal and space occupying Motor Techniques. When peroneal nerve injuries are evalu-
lesions may produce pain in some persons about the knee ated, the most commonly performed test is determining per-
region, especially resulting from the trauma generating the oneal conduction in both the leg and across the fibular head as
anatomic disruption. Observation of the patient ambulating re- recorded from the EDB.104-331 The peroneal nerve is usually
veals a so-called steppage gait in which the affected foot is stimulated at the ankle, several centimeters below the fibular
lifted excessively off the ground during swing phase in order to head, and about 10 cm proximal to the fibular head just medial
clear the foot, which is no longer capable of dorsiflexing. This to the biceps femoris tendon. This allows one the opportunity to
produces excessive knee and hip flexion such that the patient calculate a conduction velocity across the presumed lesion site
appears to be "stepping over" an object in his or her pathway. (fibular head region) and compare it with the leg segment.
Also, on heel strike, there is noted to be a relatively loud slap of Similarly, the same measurements can be performed on the con-
the foot, as the ankle dorsiflexors cannot produce a controlled tralateral limb for comparison reasons. Unfortunately, there are
descent of the foot toward the floor. Examination usually re- two major shortcomings to this technique: (1) the EDB may be
veals a variable pattern of weakness. The EDB is typically pro- so severely affected that one cannot obtain a response, and (2)
foundly affected; however, this muscle is difficult to test in axonal loss and conduction block lesions do not necessarily
isolation. Ankle and toe dorsiflexion can be significantly af- result in conduction slowing.
fected, and in profound disorders there may be a complete in- To better evaluate lesions about the fibular head and avoid
ability to dorsiflex the foot. When testing dorsiflexion, it is missing those rare disorders preferentially affecting fibers in-
helpful to begin with the ankle in a neutral position. The patient nervating either the tibialis anterior or EDB, it is recommended
to assess the amplitude of the response as obtained from both nerve. Perhaps the most valuable aspect of the needle examina-
the EDB and tibialis anterior with stimulation above and below tion is defining the proximal extent of the lesion. If there is a
the fibular head.71-154198-360-419-717-826 This method has a number of lack of amplitude drop across the fibular head but the tibialis
advantages. First, there is rarely conduction slowing across the anterior CMAP is lower than the unaffected side suggesting
fibular head and when it is present, an accompanying reduction axonal loss, it is difficult to localize the lesion to the fibular
in amplitude across the fibular head may be found.600 Because head even though this may be the most common site for per-
the EDB tends to be more severely affected than the tibialis an- oneal nerve injuries. In any peroneal nerve injury irrespective of
terior, recording from the latter muscle ensures obtaining a re- suspected level, it is paramount to examine the short head of the
sponse and being able to comment on the patient's condition. biceps femoris muscle. If this muscle demonstrates membrane
Also, the patient's major complaint is footdrop, which is a result instability, the lesion must be proximal to the fibular head.
of tibialis anterior weakness. It is also important to perform the Similarly, it is necessary to evaluate not only muscles in the per-
same stimulations on the contralateral limb. If the contralateral oneal nerve distribution, but also those muscles innervated by
responses are normal, one can gain a rough appreciation as to the tibial nerve. In particular, the flexor digitorum longus and
the degree of axonal loss by expressing the affected side's tibialis posterior muscles should be evaluated because they are
CMAP as a percentage of the nonaffected side. This is applica- at about the same level as the peroneal muscles and contain pri-
ble to both the EDB and tibialis anterior muscles. The amount marily L5 neural innervation from the tibial nerve. Although
of percentage drop above compared with below the fibular head controversy exists regarding needle placement in the tibialis
is debatable. Changes considered significant range between posterior muscle, there are a number of techniques available.418
20% and 50%.360'600-826 A change of 50% is extremely conserva- If a radicular process is present, both the peroneal- and tibial-in-
tive, but one may be able to use the 20% value in attempting to nervated muscles should demonstrate membrane instability.
define a conduction block. If there is noted to be a significant This examination is extremely important if there is a possibility
drop in amplitude of the CMAP to either of the above-noted of a lesion at more than one level, for example, an L5 radicu-
muscles, there is an implication that a subpopulation of fibers lopathy and peroneal nerve injury at the fibular head. Should
are subjected to a conduction block, most likely of a demyeli- there be an absence of an amplitude drop at the fibular head and
nating type. Although the patient may be weak, the documenta- no conduction slowing, and an L5 radiculopathy, it may be im-
tion of a significant conduction block suggests that the patient possible to define the exact site of a concomitant lesion. In this
has a relatively good prognosis for recovery. case, an absent superficial peroneal SNAP suggests that there is
Obtaining the CMAP amplitude from both the EDB and tib- a secondary lesion in addition to the L5 radiculopathy, but one
ialis anterior muscles on the affected as well as unaffected limb cannot be sure as to the location. One may assume that the most
allows one to draw several inferences about the patient's lesion. common location for an isolated peroneal nerve injury is at the
These conclusions are predicated on the examination occurring fibular head, However, one should clearly state that this is only
at least 10 days after the insult to allow maximal Wallerian de- a guess when firm data are lacking. When conduction slowing
generation and the associated reduction in the CMAP. Let us across the fibular head is present, the diagnosis becomes rather
suppose that the CMAP from the affected limb's tibialis anterior straightforward.
muscle above and below the fibular head is 5 mV and 10 mV, Putting It Together. Combining the above studies allows
respectively. The contralateral values from the unaffected limb one to formulate five major electrodiagnostic medicine patterns
are 14 mV and 15 mV. This information permits us to make sev- (Fig. 24-29): (1) The most common is a partial or complete
eral rough approximations regarding the patient's condition and axonal loss lesion with little if any conduction block. The
prognosis. By comparing the CMAP from the left and right tib- needle electromyographic examination is the most helpful in at-
ialis anterior muscles, to stimulation below the fibular head tempting to localize the lesion. Because there is considerable
there appears to be about a 33.3% loss of fibers due to axonal distance between the fibular head and innervation to the biceps
loss ({15 mV - 10 mVj 4- 15 mV = 0.333 x 100 = 33.3% loss). femoris, one can only conclude that the lesion is most likely at
Of the remaining 66.7% of fibers, about 50% of them have ex- the fibular head, but may also be anywhere between this site and
perienced conduction block ({10 mV - 5 mV) -f 10 mV = 0.5 x just distal to the biceps femoris muscle's innervation. These per-
100 = 50%). This patient would be predicted to have a good sons also have abnormal superficial sensory SNAPs. (2) A
chance of functional recovery because the fibers presently expe- second pattern is either partial or complete conduction block
riencing conduction block should recover with minimal residual with some small degree of axonal loss. These lesions are recog-
deficits provided the offending agent is no longer present. With nized by the obvious reduction in amplitude above compared
time, those relatively small fibers undergoing Wallerian degen- with below the fibular head as recorded from either or both the
eration should also regrow, as the endoneurial tubes are still EDB and tibialis anterior muscle. Needle electromyographic ex-
intact if this has not been a significantly disruptive lesion. In amination demonstrates some degree of membrane instability,
other words, this patient should display a biphasic recovery with as it is difficult to generate significant conduction block without
an initial return in several weeks secondary to conduction block a concomitant axonal loss lesion. The degree of axonal loss,
resolution, with further return in several months because of col- however, is relatively insignificant compared with the amount
lateral sprouting. of conduction block. This type of lesion may not be observed as
Needle Electromyography. This exam confirms the pres- frequently as the first because it can resolve by the time patients
ence of axonal loss and helps to assess the degree of involve- are referred and receive their electrodiagnostic medicine exami-
ment of the muscles innervated by the superficial peroneal nation. The superficial peroneal SNAP is usually normal in
nerve. As noted above, this portion of the nerve is usually, these individuals. (3) A not uncommon pattern is a combination
though not always, less severely involved than the deep per- of relatively significant axonal loss and conduction block. These
oneal nerve. It is also possible to localize the lesion to just the individuals demonstrate a reduction in CMAP amplitude
deep or superficial portion of the peroneal nerve if appropriate above compared with below the fibular head in addition to
abnormalities are detected in the proper distribution for each having a significantly smaller distal amplitude compared with
2Kt/\ «VVl/^
Figure 24-29. Five major patterns of electro-

diagnostic medicine findings with peroneal
mononeuropathies about the fibular head. (A)
Normal pattern of large CMAP from the tibialis an-
terior without drop across the fibular head and a
large superficial peroneal SNAP. (B) Partial conduc-
tion block lesion at the fibular head. Drop in ampli-
tude to the tibialis anterior with sparing of
superficial peroneal SNAP. (B-1) Complete conduc-
tion block across the fibular head. (C) Mixed lesion
with both conduction block and axonal loss. (D)
Partial axonal loss injury without conduction block.
(D-1) Complete axonal loss damage to the peroneal
nerve. (E) Axonal injury to the deep peroneal nerve
only. (From Katirji MB,WiIbourn AJ: Common per-
oneal mononeuropathy:A clinical and electropysio-
logic study of 116 cases. Neurology 1988;38:1723¬
1728, with permission.)
;zsSi^
the unaffected side. The needle electromyographic examination examination will demonstrate denervation in all muscles inner-
is consistent with a notable axonal loss lesion from the perspec- vated by this nerve except for relative sparing of the EDB. As
tive of demonstrable positive sharp waves and fibrillation poten- noted above, one would anticipate that the EDB would be pro-
tials. One can anticipate a marked reduction in the superficial foundly affected, yet in this instance it is spared because of pref-
peroneal SNAP amplitude. The recovery in these persons is erential innervation by the accessory deep peroneal nerve. An
biphasic in nature with resolution first of the conduction block injury to the distal superficial peroneal nerve would be expected
followed by collateral sprouting. (4) A relatively rare presenta- to yield only a reduced or absent superficial peroneal SNAP, yet
tion is an isolated deep peroneal nerve injury. Any of the above when the accessory deep peroneal nerve is present, denervation
four combinations can be seen depending upon the type of can be found in the EDB. Similarly, a proximal injury to the su-
lesion present and its duration. In all cases, however, the super- perficial peroneal nerve generates denervation in the peroneus
ficial peroneal SNAP can be expected to be normal. The defin- longus and brevis muscles with an absent superficial peroneal
ing study is the needle electromyographic examination in that SNAP. In the case of anomalous innervation to the EDB, it too
there is noted to be membrane instability in all of the muscles contains positive sharp waves and fibrillation potentials. This
innervated by the deep peroneal nerve; however, the peroneus anomaly should be kept in mind whenever the peroneal nerve is
longus and brevis muscles are spared. Thus, sparing of these examined and an unexpected pattern of findings is noted.
two muscles combined with a normal superficial peroneal Peroneal neuropathies at the fibular head are treated based
SNAP suggests an injury affecting the deep peroneal nerve only. upon the etiology of the injury. If there is acute trauma with a
Care must be taken to also evaluate the patient for an L5 radicu- suggestion of nerve section, operative intervention should be
lopathy by assessing the tibial innervated muscles as well. (5) considered. 748763 An incomplete nerve insult is typically fol-
The authors have observed two patients with an isolated superfi- lowed conservatively, as spontaneous return is anticipated. A
cial peroneal nerve injury secondary to a compartment type syn- failure of the patient to improve within about 8-12 weeks sug-
drome. These individuals had sparing of the muscles innervated gests surgical exploration may be indicated. With a blow to the
by the deep peroneal nerve. The peroneus longus and brevis knee, these types of neural insult are best managed conserva-
muscles demonstrated significant membrane instability with tively, as there may be a significant component of conduction
minimal sparing of motor units. As would be expected, the su- block. In most persons, there is some form of compressive
perficial peroneal SNAP was completely absent. episode, and the patient is then advised to avoid further injury to
An accessory deep peroneal nerve can present a somewhat the nerve. Those persons who present with a history suggestive
confusing picture to the unwary practitioner. Recall that this of progressive peroneal neuropathy should be aggressively in-
nerve arises from the superficial peroneal nerve and courses vestigated for some type of neural compressive lesion, with sur-
around the lateral malleolus to innervate entirely or typically a gical exploration seriously considered. If there is a compartment
portion of the EDB. If this anomaly is present in a patient with a syndrome suspected, this is considered a medical emergency
peroneal nerve lesion, atypical findings can be noted. 269 If a and the patient should be immediately decompressed. The ap-
deep peroneal nerve injury occurs, needle electromyographic plication of a plastic ankle-foot orthosis (AFO) usually assists
most patients with ambulatory footdrop. Care should be exer- can be found. The superficial peroneal and sural SNAPs are
cised when prescribing such an orthosis because it must be usually although not always normal.
properly fitted to avoid further compression of the peroneal
nerve about the fibular head from the proximal retaining strap. Lateral Cutaneous Nerve of the Calf
The lateral cutaneous nerve of the calf can occasionally
Differential Diagnosis become compromised either from direct compression 213 or an
When a patient presents with footdrop, first consideration entrapment as the nerve passes through a fascial opening about
should be given to a peroneal nerve injury about the fibular the popliteal fossa.272-276 Persons with diabetes who sit with their
head. This should always be evaluated irrespective of the pa- legs crossed beneath them or assume other awkward positions
tient's clinical history. The second disorder to be thought of is a may directly compress the lateral cutaneous nerve of the calf
severe L5 radiculopathy. There is usually an associated history against a hard surface. Also, a group of patients have been de-
of back pain with weakness in an L5 myotomal distribution, al- scribed with tenderness about the lateral popliteal fossa region
though this may not always be easy to define. These persons with pain radiating distally along the lateral side of the calf as
should have weakness of foot inversion, as the tibialis posterior well as proximally to the thigh region. This latter syndrome is
muscle is innervated by the tibial nerve and is out of the per- apparently an entrapment of the nerve as it pierces the fascia
oneal nerve's distribution. Persons with an L5 radicular lesion along the lateral aspect of the leg. Symptom relief is provided
may have altered sensation above the level of the lateral calf, by injection of local anesthetic into the region of tenderness at
thus demonstrating abnormalities proximal to the superficial the lateral popliteal space. This nerve can be assessed by either
peroneal nerve distribution. The majority of L5 radiculopathies antidromic or orthodromic sensory techniques.81 a
do not result in complete paralysis of the foot dorsiflexors be-
cause there is innervation from the L4 nerve root as well as L5. DISTAL LEG AND ANKLE AND FOOT REGION
A complete footdrop, therefore, suggests a profound lesion of
the peroneal nerve and not a typical L5 root insult in most but Superficial Peroneal Nerve
not all patients. Clinical Features. Approximately 10-13 cm proximal to
Occasionally, persons incur sciatic nerve injuries particularly the lateral malleolus, the superficial peroneal nerve pierces the
following fracture/dislocations of the hip joint or after various deep fascia to become subcutaneous. 5 It splits into two major
surgical procedures on the hip. The peroneal portion of the sci- terminal branches either prior to exiting, or just after leaving,
atic nerve is more prone to injury than is the tibial division. the fascial opening to pass anterior to the extensor retinaculum
These individuals present with a classic footdrop and little in at the ankle and innervate most of the foot's dorsum. This
the way of weakness or sensory deficit in the tibial nerve distri- nerve can be injured as a result of trauma, lipoma, ankle
bution. It can be quite difficult to clinically distinguish a partial sprain, and muscle herniation through the fascial defect as
sciatic from a peroneal nerve injury. In this instance, the best well as from ankle arthroscopies.30-130-209'231-368-442-485-758-760
method of lesion localization is through the needle electromyo- Patients can complain of pain in the region of the distal leg
graphic examination. Finding membrane instability on needle with radiation into the lateral ankle and foot. Physical exami-
examination of the short head of the biceps femoris strongly nation should be directed at palpating along the lateral margin
suggests a high peroneal or sciatic nerve injury. Additionally, of the leg in the hope of feeling herniated muscle tissue or
the tibial-innervated muscles may demonstrate subtle degrees of other soft tissue masses. This palpation should be performed
membrane instability when these muscles are quite strong clini- in the supine as well as the standing position. Firm palpation
cally. The sural nerve SNAP may be abnormal in addition to a along the superficial peroneal nerve may also reproduce the
diminished-amplitude superficial peroneal SNAP, thus pointing patient's symptoms at the region of the fascial defect. When
toward a sciatic nerve insult. Similar findings to sciatic nerve the nerve is injured subsequent to an ankle sprain, there may
damage can be found with a lumbosacral plexopathy. Care not be a fascial defect or herniation of muscle tissue, but pain
should be exercised to fully assess the abdominal and pelvic re- may be elicited with palpation along the nerve's course.
gions with appropriate imaging studies. Sensory examination can demonstrate a decreased sensation
Patients with diabetes mellitus frequently have a superim- along the dorsum of the foot and that region of skin just proxi-
posed mononeuropathy on their generalized peripheral neuropa- mal to the ankle. A Tinel's sign can be found over the nerve as
thy. Electrophysiologic abnormalities may be found in both the it exits the fascial ring. Muscle strength is normal. Sensation
upper and lower limbs. The key in this instance is finding ab- should be intact between the first and second toes (deep per-
normalities in the peroneal nerve region out of proportion to the oneal nerve territory; Fig. 24-30).
concomitant findings in the other nerve's territory. Similarly, The mechanism of injury to the superficial peroneal nerve
some families are predisposed to developing multiple pressure is believed to be related to its passage through the small fas-
palsies. At some point in their lives, they tend to manifest this cial opening 10-13 cm proximal to the lateral malleolus. The
hereditary susceptibility to neural compression as a peroneal nerve is firmly bound in this position and can be the focal
mononeuropathy. 39138405 point for stress forces to be directed during an inversion
A remote possibility of motor neuron disease should always ankle sprain. Also, it is not uncommon for muscle tissue to
be in the differential diagnosis when a patient presents with herniate through the fascial opening and concomitantly com-
footdrop. Although the individual may present with the major press the nerve as it passes over the sharp edge of this fascial
complaint of footdrop, a careful history and physical examina- opening.
tion usually demonstrate other abnormalities such as weakness Electrophysiologic Evaluation and Findings. This focal
in the contralateral leg or distal upper limb. Also, there may be a neuropathy is readily amenable to documentation through elec-
history of widespread fasciculations in both lower limbs. On trodiagnostic medicine means. The superficial peroneal sensory
electrodiagnostic testing, widespread findings in both lower SNAP usually demonstrates a reduction in amplitude compared
limbs in not only the peroneal but also tibial nerve distributions with the contralateral limb. Onset and peak latencies may be
MOO — PART IV CLINICAL APPLICATIONS
Extensor retinaculum
Extensor digitorum Tibialis anterior

longus
Medial malleolus
Lateral malleolus
Extensor hallucis longus Figure 24-30. Anterior tarsal tunnel. The anterior
Sural nerve Dorsalis pedis artery tarsal tunnel region is depicted with the deep branch of the
Deep peroneal nerve
peroneal nerve passing beneath it. Note that this nerve
splits into a motor branch to the EDB and a sensory
branch providing cutaneous sensation to the region be-
tween the first and second toes. (From Liveson JA:
Peripheral Neurology: Case Studies in Electrodiagnosis.
Extensor digitorum
brevis
Sensory a r e a -
deep peroneal nerve
prolonged, but amplitude reduction is the more common find- of the deep peroneal nerve. Tapping the nerve gently along its
ing.732 Motor conduction studies of the deep peroneal nerve to course may reveal a Tinel's sign about the ankle region. If the
the EDB and tibialis anterior muscle are normal. Needle elec- motor portion of the nerve is affected, one cannot readily test
tromyographic examination of all peroneal innervated muscles the EDB. The patient can be asked to dorsiflex the toes, how-
is also normal. ever, and the lateral margin of the foot can be palpated for the
Fascial release of the ring surrounding the superficial per- mound of tissue formed by the EDB. A flat region on the lateral
oneal nerve usually results in complete symptom relief. The foot during toe dorsiflexion suggests this muscle is wasted.
electrophysiologic studies of the superficial peroneal nerve typ- The etiology for this syndrome has not been clearly delin-
ically lags behind the patient's symptomatic recovery. A high eated. In persons who develop this syndrome following trauma,
index of suspicion confirmed with the relatively simple sensory the mechanism of neural insult is easy to understand. The nerve
conduction technique leads to an accurate diagnosis and appro- lies on top of the hard bony surface of the foot. Dropping a
priate patient treatment. heavy object on the foot clearly injures the nerve between the
object and the underlying bone. In those persons with sponta-
Deep Peroneal Nerve neous development of the syndrome, a less than clear explana-
Clinical Features. Compromise of the deep peroneal nerve tion is available. This entrapment is often seen in farmers
as it passes beneath the extensor retinaculum at the ankle has wearing wooden shoes with a rigid edge. Plantar flexion at the
been referred to as the anterior tarsal tunnel syndrome (Fig. ankle with dorsiflexion of the toes is found to stress the deep
24-30).61395.402.473,852 Either the sensory or motor branches, or peroneal nerve as it courses beneath the extensor retinaculum.61
both, may be affected. Patients with an anterior tarsal tunnel This is the very position assumed by women who wear high
syndrome usually only have sensory complaints with numbness heel shoes and is believed to be one reason for producing the
and paresthesias limited to the region between the first and anterior tarsal tunnel syndrome.244-402
second toes. This is understandable given that weakness of the Electrophysiologic Evaluation and Findings. It is possible
EDB is of little consequence for most patients. The difficulty to perform a deep peroneal SNAP by stimulating the peroneal
lies in the fact that the patient may still have pain about the nerve at the ankle and recording from its sensory branch by lo-
ankle region if only the motor division is affected. Most patients cating an active electrode in the interspace between the first and
complain of being awakened at night secondary to ankle and second toes.16-417-609-610 This is a small SNAP, and averaging is re-
foot pain often associated with numbness and tingling between quired to obtain the response. It is important to perform this
the first two toes. technique bilaterally. If the response is absent on both sides but
Physical examination in these persons reveals diminished the patient is symptomatic on only one side, caution should be
sensation in the region of the foot supplied by the terminal portion exercised prior to concluding that the patient has anterior tarsal
tunnel syndrome based on electrodiagnostic findings alone. The the hamstring muscles with sparing of the gluteal muscles and
small nature of the SNAP suggests that it may be too small to lumbosacral paraspinal region imply a sciatic nerve insult. If
readily record, thus being absent not because of pathology, but there are findings of membrane instability in the short head of the
more so owing to technical factors. The superficial peroneal nerve biceps femoris muscle, one must consider a sciatic nerve lesion
SNAP should be normal in pure anterior tarsal tunnel syndromes. affecting not only the tibial, but also the peroneal nerve division.
Recording a CMAP from the EDB is a useful motor study to Detecting abnormalities only in the gastrocnemius muscle and
perform.402719 A reduced amplitude or prolonged latency is sug- distal tibial-innervated muscles is highly suggestive of a lesion in
gestive of a lesion affecting the deep peroneal nerve. Obviously, the popliteal fossa or just proximal to this area. Finding mem-
it is crucial to document the absence of a peripheral neuropathy. brane instability in only the toe flexors with sparing of the sural
If the patient has a peripheral neuropathy, the response may be SNAP, but abnormal medial and lateral plantar nerve responses,
absent secondary to the more generalized neural process and implies a lesion in the mid-leg. These are all possibilities to con-
definitive statements regarding the presence or absence of an sider because tibial nerve lesions in isolation proximal to the
anterior tarsal tunnel syndrome cannot be made. Needle elec- ankle are so atypical. In short, one must consider a more common
tromyographic examination of the foot intrinsic muscles can be insult to the peripheral nervous system prior to concluding that a
fraught with interpretive hazards. This is because 16-87% of focal tibial nerve compromise is present.
asymptomatic persons may have low grades of positive sharp
waves and fibrillation potentials present in the EDB as well as ANKLE AND FOOT REGION
tibial-innervated foot intrinsic muscles.,95-234-649-821 Even an
asymmetric finding requires a cautious interpretation. Tibial Nerve: Medial and Lateral Plantar
Although not strictly an anterior tarsal tunnel syndrome, it is and Calcaneal Nerves
possible for the superficial and deep peroneal nerves to become
compromised from wearing tight fitting shoes.426 One can antic- Anatomy
ipate symptoms consistent with an injury to both nerves. The In the ankle region, the tibial nerve travels posterior to the
superficial and deep peroneal SNAPs should be abnormal as tibia's medial malleolus to enter the so-called tarsal tunnel
well as the CMAP to the EDB. The majority of patients respond (tibiotalocalcaneal tunnel). Compression of the neural struc-
to changing shoe wear. Occasionally, surgical exploration may tures in this area is referred to as the tarsal tunnel syndrome.
be required to provide symptomatic relief.621 The tarsal tunnel's roof is the flexor retinaculum (also called the
laciniate ligament), which is the fusion of the deep and superfi-
cial aponeuroses of the leg (Fig. 24-31). This structure is an-
TIBIAL NERVE A N D BRANCHES chored anteriorly on the anteromedial surface of the medial
malleolus, while posteriorly it attaches to the medial tuberosity
KNEE REGION of the calcaneus. The inferior border of the flexor retinaculum
abuts against the abductor hallucis muscle that is enveloped by
Clinical Features. Tibial nerve injuries about the distal the retinaculum. Distal to the abductor hallucis muscle, the two
thigh, knee, and leg region are quite rare. Patients' symptoms can layers again fuse to continue as the plantar fascia. The tarsal
be quite variable and depend upon the lesion's location and tunnel's floor consists of the talus' medial surface, sustentacu-
severity. In the distal thigh and knee, a tibial nerve compromise lum tali, and the calcaneus' medial wall. The tarsal tunnel's lon-
capable of generating significant axonal loss usually results in an gitudinal extent is somewhat variable, but in general the
inability to plantar flex the foot and toes with associated diminu- proximal border is the distal tibia, while the distal border ap-
tion of sensation in the sural nerve distribution. Also, reduced proximates the navicular bone's base. This region may be subdi-
sensation on the plantar aspect of the foot is detected. Injury to vided into an upper (tibiotalar) and lower (talocalcaneal)
the nerve distal to the innervation of the gastrocnemius muscle tunnel.583 Individual fibrous septa extend from the inner surface
continues to produce toe flexor weakness, but there is some spar- of the flexor retinaculum to the periosteum of the calcaneus.
ing of ankle plantar flexion strength. In these cases, there is usu- Contained within these septa from anterior to posterior are the
ally sparing of the sural nerve but the sole and medial heel of the tibialis posterior tendon, flexor digitorum longus tendon, poste-
foot continue to have altered sensation. Mechanisms of tibial rior tibial nerve, artery and vein, and located most posterior is
nerve injury include ganglia, entrapment between the heads of the flexor hallucis longus tendon. The tibial nerve branches into
the gastrocnemius muscle, Baker cyst, neurilemmoma, and vari- its four divisions: (1) medial plantar, (2) lateral plantar, (3)
ous forms of trauma including bullet and knife wounds, disloca- medial calcaneal (pure sensory nerve), and (4) inferior (cal-
tions, and blunt injury.135-358-367-462'605-763-804 An interesting caneal nerves), usually within the confines of the tarsal tunnel
mechanism occurs when the tibial nerve is injured at the aponeu- proper (Fig. 24-32). In approximately 90% of the population,
rotic arch of origin of the soleus muscle.311-480a-480b branching of the medial and lateral plantar nerves occur within
Electrophysiologic Evaluation and Findings. The electro- the tarsal tunnel.147-287 In only 7% of feet does the tibial nerve bi-
physiologic evaluation should include a complete assessment of furcate into these main divisions proximal to the upper limits of
not only the tibial nerve, but also the sciatic nerve. Both sural and the flexor retinaculum. The medial calcaneal nerve's branching
superficial peroneal SNAPs should be performed. An absent sural from the tibial nerve is highly variable and may occur as (1) a
SNAP is anticipated, but if the superficial peroneal SNAP is also single branch from the tibial nerve proximal to the tarsal tunnel;
absent, an injury to the peroneal nerve or peroneal portion of the (2) multiple branches from the tibial nerve proximal to, distal
sciatic nerve is a possibility. Motor nerve conductions for both to, or within the tarsal tunnel; (3) single branch from the lateral
the peroneal and tibial nerves are also important. Of particular plantar nerve in the tarsal tunnel; and (4) other combinations of
value is the needle electromyographic examination. Detecting ab- the above. When originating in the tarsal tunnel, the calcaneal
normalities in the lumbosacral or gluteal regions suggests a branch(es) must pierce the flexor retinaculum to supply the
radiculopathy or sacral plexopathy, respectively. Abnormalities in medial and plantar surfaces of the calcaneal region. Just distal
Figure 24-31. Tarsal tunnel region. The tibial nerve is

Flexor digitorum shown to branch into the calcaneal, and medial and lateral
longus
Posterior tibial
plantar nerves.The flexor retinaculum is shown as a somewhat
artery 8 vein Medial narrow structure, but it is more diffuse than depicted. Note
calcaneal that in this instance a single calcaneal nerve arises from the
branch of tibial nerve prior to this nerve dividing into the medial and lat-
posttiha
eral plantar nerves.The medial and lateral plantar nerves pass
through separate fibrous tunnels between the abductor hallu-
cis and flexor digitorum brevis muscles. (From Liveson JA:
Peripheral Neurology: Case Studies in Electrodiagnosis.
to the medial calcaneal nerve's origin, the inferior calcaneal

nerve originates directly from the tibial nerve proper, or it may
be the first branch of the lateral plantar nerve (Fig. 24-32). This
nerve can innervate the quadratus plantae and flexor digitorum
brevis muscles, as well as always provide motor innervation to
the abductor digiti minimi pedis muscle. Distal to the caudal
margin of the flexor retinaculum, a transverse interfascicular
septum exists that separates the medial and lateral plantar
nerves and their accompanying vasculature. This structure orig-
inates from the medial calcaneus and aponeurosis of the abduc-
tor hallucis muscles and fuses distally with the medial
intermuscular septum of the foot, which acts to separate the
medial plantar compartment from the more centrally located
compartment.
Because of the interfascicular septum, a superior and inferior
chamber are formed for the medial and lateral plantar nerves,
respectively. The medial plantar nerve thus passes between the
abductor hallucis and flexor digitorum brevis muscles in associ-
ation with the flexor hallucis longus tendon. Passing inferiorly,
Figure 24-32. Neural branching in the tarsal tunnel.The right the lateral plantar nerve traverses the region between the flexor
foot's medial region is depicted.The medial calcaneal nerve (MCN) is the digitorum brevis and quadratus plantae muscles. Each nerve,
first branch of the tibial nerve (TN) and pierces the flexor retinaculum therefore, travels through its own compartment to enter the
(FR) followed by the inferior calcaneal nerve (ICN).The tibial nerve then plantar aspect of the foot. Unfortunately, there is some confu-
divides into the medial plantar nerve (MPN) and lateral plantar nerve sion as to the extent of the tarsal tunnel with respect to designat-
(LPN).The abductor hallucis muscle (AH) is partially removed for clarity. ing lesions. A lesion of the tibial or medial and lateral plantar
(From ParkTA, DelToro DR: Electrodiagnostic evaluation of the foot. nerves at any location between the proximal extent of the flexor
Phys Med Rehabil Clin North Am 1998;9:871-896, with permission.) retinaculum to essentially the metatarsophalangeal joint region
Chapter 24 FOCAL PERIPHERAL NEUROPATHIES — II03
is considered by some to lie within the tarsal tunnel. This is not Table 24-7. Tarsal Tunnel Etiologies
universally accepted, because once the medial and lateral plan- Trauma
tar nerves enter the region between the abductor hallucis and Displaced fractures Flexor tenosynovitis
flexor digitorum brevis muscles, individual lesions affecting Distal tibia Tibialis posterior
these nerves may also be considered plantar neuropathies. A de- Tarsal bones Flexor digitorum longus
finitive classification does not yet exist. Calcaneus Flexor hallucis longus
Ankle sprains Post-hemorrhagic epineural scarring
Tarsal Tunnel Syndrome Deltoid ligament
Clinical Features. The diagnosis of tarsal tunnel syndrome is Compression
not particularly easy because there are no hallmarks of the disor- Varicosities Lipoma
der. Persons with accepted tarsal tunnel syndrome usually com- Ganglia Neurilemoma
plain of a dull aching type of pain on the plantar aspect of the foot Perineural fibrosis Bony exostosis
not localized to a particular region.114-181-254-352-355^ Medial talocalcaneal bar Hypertrophic flexor retinaculum
This pain may also be described as burning, tingling, cramping, Hypertrophic abductor Accessory abductor hallucis
tightness, and even numbness. It may occur at any time of day or hallucis muscle muscle
night, but is exacerbated by prolonged standing or walking and is Accessory flexor digitorum Rapid weight gain
especially worse at night as the disease progresses. Most patients muscle
do not complain of weakness because mild-to-moderate intrinsic Fluid retention
foot weakness does not significantly hinder ambulation. The Chronic thrombophlebitis
above complaints can be experienced in a number of intrinsic as Systemic disorders
well as extrinsic foot disorders. Generalized inflammatory arthropathies
Physical examination can be quite variable from one patient Rheumatoid arthritis
to the next. Percussion should be performed along the course Ankylosing spondylitis
of the tibial nerve from the distal one third of the leg onto the Biomechanical
plantar surface of the foot for the medial and lateral plantar Varus heel with pronated foot
nerves. A Tinel's sign may be detected at any location on the Valgus heel with abducted forefoot in pes planus
nerve(s) course across the ankle and plantar foot regions. Idiopathic
Occasionally, neural percussion results in not only reproduc- Modified from LauTC, Daniels TR:Tarsal tunnel syndrome: A review of the lit-
tion of symptoms, but also pain radiation proximally along the erature. Foot Ankle 1999;20:201 -209.
nerve's course, which is referred to as the Valleix phenome-
non. 1,4181 Decreased sensation to touch and pain may be docu-
mented in the distribution of any or all of the tibial nerve's such as venous insufficiency and varicosities, arterial vasospasm,
three branches. Recall that the calcaneal nerve can branch diabetes mellitus, hyperuricemia, alcoholism, and coagu-
proximal to the tarsal tunnel or pierce the flexor retinaculum lopathies.264 Biomechanical dysfunction includes tarsal joint im-
quite high, thus accounting for the finding of normal heel sen- paction secondary to hypermobility of the first ray, rigid joint
sation. Manual muscle testing of the foot intrinsic muscles is a structures, tarsal joint coalition, and rearfoot varus.217-264-773
challenge, and it may not be possible to appreciate subtle loss Based on the above rather nonspecific symptoms and signs, a
of muscle power because the foot extrinsic muscles usually number of persons have been operated on for presumptive tarsal
compensate quite well. Provocative maneuvers such as everting tunnel syndrome with subsequent symptom resolution. Those
the ankle or extending the great toe may result in symptom pro- persons were found to have no structural abnormalities either
duction. The patient should also be examined while ambulating prior to or during surgery; however, the ubiquitous "fibrous ad-
with shoes and socks removed, as biomechanical causes of dis- hesions" were released. As a result, these persons are placed in
torted foot relations may not be apparent otherwise. Any pa- the idiopathic category. It is also necessary to consider a lesion
tient with vague foot pain should be examined with the affecting the sciatic nerve mimicking symptoms and signs of a
possibility of tarsal tunnel kept in mind. tarsal tunnel lesion.253
Multiple etiologies of tarsal tunnel have been reported in the Electrophysiologic Evaluation and Findings. A number of
literature (Table 24-7).415 One classification system proposes five electrophysiologic techniques have been developed to evaluate
categories producing tarsal tunnel syndrome: (1) trauma, (2) neurophysiologic compromise of the neural structures travers-
compression, (3) systemic disorders, (4) biomechanical causes, ing the ankle and foot area.
and (5) idiopathic.264 Trauma, usually from vehicular accidents Sensory Techniques. It is agreed that the most sensitive ex-
and occupationally related overuse syndromes, is a major cause. amination for possible compromise of either the medial/lateral
The trauma can include fractures of the ankle, leg, or foot; ankle plantar or tibial nerves in the ankle and foot region is some form
sprains (acute or recurrent); and surgical procedures about the pf sensory nerve conduction technique.515-558-559 There are a
foot and ankle. Compression of the tibial nerve or its various in- number of ways to assess primarily neural conduction through
dividual branches can occur from various space-occupying le- the above nerves. The authors' choice is to perform a mixed-
sions in the tarsal tunnel proper or more distally in the foot nerve excitation of the medial and lateral plantar nerves.145199 318¬
affecting solely the medial or lateral plantar nerve.246-275-337-562-564¬ 607,664 Essentially the mixed motor/sensory medial and lateral
618.850 -Tftg various causes of neural compression include ganglia, plantar nerves are excited in the sole of the foot while the re-
anomalous or hypertrophied muscles, neurilemoma, schwan- sponse is recorded from the tibial nerve proximal to the flexor
noma, tenosynovitis in rheumatoid arthritis, "fibrous bands," and retinaculum. Normal peak latencies should be less than 3.6 ms
hyperlipidemia.26-68160-258'327-613'656-667 Numerous systemic causes for both the medial and lateral plantar nerves. Shortcomings of
have been attributed to or associated with the tarsal tunnel syn- this technique include (1) not a pure sensory response, thus po-
drome. These associated systemic disorders are cardiovascular, tentially having normal motor fibers mask an abnormality of
sensory fibers (at present, this is an unsubstantiated concern); be less than 4.8 ms and 4.9 ms, respectively. Although easy to
(2) difficult to excite the medial/lateral plantar nerve in some perform, the motor technique is not particularly sensitive. It is
persons with thick calluses on the plantar surface of the foot not unusual for the motor studies to be completely normal while
even with long pulse durations and high current intensities the mixed-nerve action potentials are clearly abnormal. The
(mild abrasion with pumice stone or sand paper can help); (3) motor response can be of assistance when the mixed-nerve or
ankle swelling can increase the distance between the tibial sensory responses cannot be obtained secondary to pathology.
nerve and recording electrode, thereby resulting in a small am- In this instance, it may be helpful to determine the CMAP onset
plitude response and thus occasionally requiring the placement latencies to evaluate if they are abnormal. Abnormal sensory or
of needle recording electrodes next to the tibial nerve; (4) stim- mixed-nerve responses do not require abnormalities of the
ulus artifact may be a considerable problem in some persons motor studies to confirm a case of tarsal tunnel syndrome. Also,
(remove perspiration and rotate anode); and (5) some patients one can stimulate above and below the tarsal tunnel in an at-
cannot tolerate a sufficiently intense electrical stimulation to tempt to assess motor conduction across this structure.207 This is
evoke a response. Despite these potential problems, it is ar- of value in that it may be possible, when the motor fibers are
guably the most easily performed, reproducible, and reliable significantly affected, to determine if a lesion is within the tarsal
technique available for evaluating the medial and lateral plan- tunnel or located more distally affecting preferentially the
tar nerve. medial or lateral plantar nerves.
Additional sensory responses can be attempted by the practi- Needle Electromyography. This exam is said to be of ques-
tioner with the understanding that these are much more techni- tionable utility in the diagnosis of tarsal tunnel syndrome. The
cally demanding and yield very small responses even in healthy reason is that a number of asymptomatic persons apparently
persons. Pure sensory potentials can be performed by stimulat- have membrane instability in their foot intrinsic muscles simply
ing the first and fifth toes and recording from the tibial nerve owing to normal "wear-and-tear" of the foot muscles following
proximal to the flexor retinaculum (orthodromic technique), or the repetitive trauma of ambulation, running, and in some cases
stimulating the tibial nerve proximal to the flexor retinaculum sporting activities.195-234-649-821 In these authors' opinion, it is
and recording from the first and fifth toes (antidromic tech- rather rare to find true positive sharp waves and fibrillation po-
nique).40-265-3 56559 Although both the antidromic and orthodromic tentials in normal persons in any muscle, including the foot in-
techniques have the theoretic advantage of evaluating only the trinsic muscles. It is likely that many practitioners mistake
sensory fibers, thereby increasing the sensitivity of the exami- end-plate spikes with triphasic and positive sharp wave-like
nation, the responses are extremely small and averaging multi- morphologies for true denervation. 174 If there is noted to be a
ple trials is mandatory. These responses usually cannot be significant increase in positive sharp waves and fibrillation po-
obtained in all normal persons unless a significant number of tentials in the foot intrinsic muscles of the affected compared
averages are generated. It is the authors' experience that averag- with asymptomatic foot, this is likely of significance. On the
ing does not always result in a response in normal people, thus other hand, finding membrane instability in both feet of similar
limiting the clinical utility of this technique. A variation on the degree can be quite hard to interpret and may suggest a more
above orthodromic technique is the so-called near-nerve record- diffuse peripheral nerve problem. It is valuable to perform a
ing in which the first and fifth toes are stimulated while a needle needle electromyographic examination of three foot intrinsic
electrode is placed close to the tibial nerve above the flexor reti- muscles: (1) abductor hallucis, (2) abductor digiti minimi pedis,
naculum.561562-563 The necessity of near-nerve electrode location and (3) fourth dorsal interosseous.583 Needle examination of the
and averaging is certainly not an undue burden, but these re- abductor hallucis muscles provides information regarding the
quirements nevertheless limit the "ease of use" criteria required medial plantar nerve, while examination of the abductor digiti
for a technique to gain popularity. As a result, although quite minimi pedis assesses the inferior calcaneal nerve. Finally, ex-
valid, this method of assessing a patient for tarsal tunnel syn- ploring the fourth dorsal interosseous muscle provides informa-
drome is less frequently used than is the mixed-nerve action po- tion about the lateral plantar nerve. Finding membrane
tential technique. It is possible to stimulate the first and fifth instability in the foot intrinsic muscles should be considered j
toes while recording below and above the flexor retinaculum suspicious for an axonal lesion affecting the medial and/or lat- j
with near-nerve electrodes and record a trans-tarsal tunnel sen- eral plantar nerves.
sory response.139 Further work in this area is required. Somatosensory Evoked Potentials. Rarely, it may be nec-
It is possible to examine the sensory conduction of the essary to perform somatosensory evoked potentials of the
medial calcaneal nerve by stimulating the tibial nerve proximal medial and lateral plantar nerves while recording from the stan-
to the flexor retinaculum and recording from the medial aspect dard cortical position for lower limb studies.172 In persons who
of the calcaneus.144-580-581 If the calcaneal nerve is involved, it present with a clinical history highly suspicious of tarsal tunnel
may indeed be abnormal; however, it is entirely possible for yet have normal mixed nerve and motor studies, abnormalities
this nerve to escape injury by exiting proximal to the tarsal may be documented with the SEP. This technique requires spe-
tunnel's commencement. When heel pain is a significant com- cial expertise and should be performed only after more routine
ponent of the patient's complaint, it is worth pursuing this studies have failed to document an abnormality.
nerve's SNAP. Putting It Together. The electrophysiologic assessment of
Motor Techniques. One can also perform motor conduction a patient with suspected tarsal tunnel syndrome should begin
studies to the abductor hallucis and abductor digiti minimi pedis with a routine screen of the lower limb for a peripheral neuropa-
muscles in order to assess the medial and lateral plantar nerves, thy. The sural and superficial peroneal nerves are important
respectively.225-332 In this relatively easy technique, the CMAPs nerves to evaluate. In pure tarsal tunnel syndromes, the SNAPs
from the two muscles are recorded and latency parameters used for these two nerves are anticipated to be normal. If they are ab-
to assess if either of the nerves are conducting inappropriately. normal, the contralateral side must be examined. A bilateral ab-
At an ankle temperature of 32°C and a stimulus distance of 8 normality suggests a peripheral neuropathy provided more
cm, the medial and lateral plantar CMAP onset latencies should proximal peripheral lesions are not anticipated by history and
Chapter 24 FOCAL PERIPHERAL NEUROPATHIES — I 105
physical examination. In the presence of a peripheral neuropa- and surrounding structures. Appropriately performed and se-
thy, the medial and lateral plantar sensory/mixed nerve re- lected electrophysiologic tests define the physiologic status of
sponses will be abnormal. Studying the H reflexes to the the nerves as they pass from the foot into the leg, while the
gastrocsoleus muscles is worthwhile because these reflect the imaging studies help to localize a lesion when present. Correct
integrity of the proximal pathways of the tibial nerve. It is also anatomic localization of a lesion is critical prior to attempting to
possible that the distal motor latencies of the medial and lateral treat the patient. When there is a lack of structural abnormality,
plantar nerve motor responses are prolonged. When a periph- it is most appropriate to begin with a conservative approach of
eral neuropathy is documented, it is extremely difficult to diag- removing any aggravating factors such as poorly fitting shoes or
nose, by electrophysiologic means, the presence or absence of applying corrective foot orthoses. Nonsteroidal anti-inflamma-
medial/lateral plantar nerve compromise. The needle elec- tory medication may also be quite helpful. A local injection of a
tromyographic examination is of little help in differentiating steroidal preparation into a site of localized tenderness may be
between these two conditions if both are suspected. In the final helpful in some patients. When the conservative approach fails,
analysis, this is simply a limitation of the electrophysiologic a surgical exploration of the tibial nerve and the ankle, and
evaluation. A unilateral abnormality of either the medial and when necessary the medial and lateral plantar nerves in the foot,
lateral plantar or both nerves is suggestive of a tarsal tunnel may be necessary. Approximately a 10-20% surgical failure
syndrome in the absence of abnormalities from the sural and rate can be observed.848 Surgery may have failed because the pa-
superficial peroneal nerves. When this finding is present, motor tient did not have tarsal tunnel syndrome, did have tarsal tunnel
studies should still be performed, but they are likely to be syndrome but the nerve was decompressed at an inappropriate
normal. Across tarsal tunnel motor conductions are also a good location, or the patient was incompletely decompressed. MRI is
idea to consider in the hope of locating the lesion proximal or recommended for patients with failed surgery to assess the
distal to the inferior margin of the flexor retinaculum. Needle neural and surrounding structures as well as ensuring a com-
electromyographic examination of the muscles innervated by plete patient evaluation was initially performed and a correct di-
the medial and lateral plantar nerves, as well as the fourth agnosis made.
dorsal interosseous muscle, completes the examination.
In a patient complaining of solely anterior heel pain, consid- Sural Nerve
eration should be given to a possible isolated compromise of the Anatomy. The sural nerve is composed of a branch each
inferior calcaneal nerve.582 Recall that this nerve provides motor from the tibial and common peroneal nerves that fuse to form
innervation to the abductor digiti minimi pedis muscle as well the sural nerve proper in the proximal calf region. It continues
as innervates the periosteum of the calcaneus. A prolonged la- distally in approximately the midline of the calf until just proxi-
tency to the abductor digiti minimi pedis as well as membrane mal to the ankle region, where it courses posterior to the lateral
instability on needle electromyography solely to this muscle is malleolus. The cutaneous distribution of the sural nerve is along
suggestive of an isolated lesion of the inferior calcaneal nerve. the lateral margin of the calcaneus and foot.
Differential Diagnoses. The electrodiagnostic medicine Clinical Features. An injury to the sural nerve at or proxi-
consultation is very important in defining not only the presence mal to the ankle region results in decreased sensation along the
or absence of neural compromise, but also the presence of a lateral aspect of the heel and foot. Paresthesias and dysesthesias
lesion at some other level of the nervous system that may are usually associated with the decreased sensation. Oc-
mimic tarsal tunnel syndrome. A herniated lumbar disk with casionally, pain may be localized to a well-described region.
associated pain to the heel region is usually diagnosed by his- Physical examination demonstrates a diminution of sensation in
tory and physical examination. A needle examination is quite the cutaneous distribution of the nerve. There may be a Tinel's
revealing in these cases in that abnormalities proximal to the sign at some point along the course of the nerve possibly indi-
ankle region are detected. Sciatic or proximal tibial nerve cating a focal lesion. Strength in the foot intrinsic and extrinsic
tumors can present as a tarsal tunnel compression, 835 yet an ab- muscles is preserved. There should be normal sensation along
normal sural nerve SNAP and needle electromyographic ab- the foot's dorsum and sole.
normalities in the tibial-innervated muscles proximal to the Focal sural neuropathies are extremely rare, with the vast ma-
ankle are noted. The usual diagnostic challenge are the multi- jority resulting from some form of trauma (Table 24-8). This
ple musculoskeletal syndromes versus a neural compression in nerve may be compromised in the calf, ankle, or lateral margin of
the tarsal tunnel or foot region.140-619 Simple musculoskeletal the foot regions. In the calf, the nerve is vulnerable to lacerations,
derangements causing foot pain are not expected to generate circumferential constriction from the superior margin of tight
abnormal conduction of the medial or lateral plantar nerves socks, resting the calf against a hard surface, Baker's cyst, and
either through the foot or across the tarsal tunnel. Foot pain neuroma from sural nerve harvesting procedures.262*537-567-612,690 At
with completely normal electrophysiologic studies is certainly the ankle and foot, the sural nerve can be compromised by ankle
a good indication that there is no significant compression of the sprains with secondary neural entrapment by fibrotic bands,
medial or lateral plantar nerves. It is certainly possible, how- metatarsal fractures, and ganglia.117163177-257-624
ever, for the patient to still have a mild degree of compression Electrophysiologic Evaluation and Findings. The electro-
generating pain, yet the electrophysiologic tests are not sensi- physiologic evaluation of potential sural nerve compromise is
tive enough to pick up an alteration in neural conduction. relatively straightforward. Either orthodromic or antidromic
Peripheral neuropathy from diabetes mellitus is a common studies of this nerve can be easily performed.38-90-277-304'677'788
cause for foot discomfort, and fortunately this is quite easily Antidromic responses usually yield larger amplitude responses
demonstrated on routine electrodiagnostic testing. and are clinically preferred over near-nerve needle techniques. In
MRI of the tarsal tunnel region can be of significant help in focal sural neuropathies, only this nerve's response should be
diagnosing a tarsal tunnel syndrome provided there is an absent. The superficial peroneal nerve is also of importance to
anatomic abnormality present.I87-847-848 In idiopathic causes, test in addition to the sural nerve. Needle electromyographic ex-
there is likely to be a normal configuration to the tarsal tunnel amination is anticipated to be normal in a focal sural neuropathy.
Table 24-8. Isolated Sural Neuropathies
Reports (Ref#) Number of Cases Etiology
Trauma Bakers Cyst Ganglion Idiopathic
Acciarri et al.3 1 0 0 I 0
Bruyn74 I 1 ' 0 0 0
Chang et al.102 1 I 0 0 0
Colbert, et al.117 I 1 0 0 0
Docks et al.163 I 1 0 0 0
Dyro et al.176 1 I 0 0 0
Ferkel et al.209 6 6 0 0 0
Gould et al.257 3 3 0 0 0
Gross et al.262 2 2 0 0 0
Mondelli et al.514 2 2 0 0 0
Nakano 538 I 0 1 0 0
Pasternack et al.S86 I 0 0 0 1
Perlman594 1 1 0 0 0
Pringle et al.612 4 1 0 2 1
Raynor et al.624 2 1 0 1 0
Reisin et al.632 3 3 0 0 0
Schon et al.673 2 2 0 0 0
Schottland 674 1 1 0 0 0
Schuchmann 678 2 2 0 0 0
Seddon 682 5 5 0 0 0
Shaffrey et al.690 1 I 0 0 0
Total/Percent 42/100 35/83.3 1/2.4 4/9.5 2/4.8
Interdigital Neuropathy (Morton distribution of the medial and lateral plantar nerves as well as
Neuroma/Morton Metatarsalgia) the calcaneal nerve should be normal.
Clinical Features. The common plantar interdigital nerves can A large review of one series demonstrates that the majority of
be compromised about the heads of the metatarsal bones. Patients patients with an interdigital neuropathy are women (96%). 384
with profound disease usually complain of a constant pain, often Either one or both feet can be affected, with a slight preponder-
described as a throbbing dull ache.47-266-384*502-526-628 An associated ance for the left foot to be symptomatic. Most persons suffering
intermittent pain can also occur, which is noted to be stabbing, from this disorder are between the ages of 30 and 60 years.
shooting, piercing, or like an electric shock. The pain is often char- There is a suggestion that axial Tl-weighted spin-echo MR
acterized as involving the entire foot, but on careful and persistent imaging is very useful in the diagnosis of interdigital neuropa-
questioning, there is a preferential localization to the interdigital thy.777-846 Sonography has also demonstrated promising results
distal metatarsal region between the third and fourth and occasion- in detecting this disorder. 1,6626
ally second and third toes. The pain is observed to begin in the Electrophysiologic Evaluation and Findings. There is es-
region of the ball of the foot or interdigital area and radiate to the sentially only one electrophysiologic technique to assist in the
dorsum of the foot, proximally to the ankle, and rarely to the hip. clinical evaluation of this disease.196-560 The individual digital
There is also a radiation of pain into the distal aspects of the af- nerves are directly excited, and the response is recorded from
fected toes. The pain is exacerbated by walking or running, wear- the tibial nerve at the ankle. This is a pure sensory response with
ing tight shoes, or prolonged standing. As the pain increases in potential ranging from 0.4 pV to about 9 pV. The method re-
intensity, most patients describe a desire to remove the shoes. quires the adjacent sides of the toes representing a single inter-
Physical examination demonstrates a patient who is often space to be stimulated while a near-nerve needle is located next
anxious about having his or her foot examined for fear of in- to the tibial nerve. Multiple averages are required to improve
creasing the pain. The patient's complaints can frequently be re- the signal-to-noise ratio, as the responses are so small. The
produced by palpating the interdigital space about the neural stimulation described has been shown to be diagnosti-
metatarsophalangeal joint region or just a few centimeters more cally efficacious. Unfortunately, the small size of the potentials,
anterior or posterior. Medial/lateral compression of the foot in necessity of near-nerve needle placement, and multiple averages
the examiner's hand is another way of eliciting the patient's have not lead to widespread use of the technique. Because of
symptoms. Sensation is typically spared, although a careful sen- these relative technical limitations, diagnosing an interdigital
sory examination in some patients can demonstrate a diminu- neuropathy remains largely a clinical diagnosis.
tion to touch and pain in the interdigital space and adjacent Treatment for an interdigital neuropathy is conservative upon
aspects between the toes of the affected area. Sensation in the initial presentation for most patients and consists of avoiding
high heel shoes, metatarsal padding, shoe orthoses, and occa- membrane instability should not be found in the ulnar hand in-
sionally injections. For severe pain, operative removal of the intrinsic muscles; however, the median-innervated APB and OP
terdigital nerve is considered definitive. At operation, a swelling are completely denervated. On the other hand, if the ulnar nerve
of the division point of the interdigital nerves is frequently is completely sectioned at the elbow region or proximally (prox-
found, hence leading to the designation Morton's neuroma. In imal to the median-ulnar cross-over), one can anticipate some
reality, histopathologic evaluation reveals this is a misnomer in preservation of the ulnar-innervated hand intrinsic muscles.
that there are primarily fibrosis and fibrinoid degeneration in This is because there is sparing of some of the "ulnar fibers" ini-
the soft tissues surrounding the interdigital nerve resembling the tially traveling with the median nerve that bridged to the median
histology of neural entrapment.502-628 nerve in the forearm. It is possible for all of the ulnar-innervated
hand intrinsic muscles to demonstrate membrane instability, but
Joplin's Neuroma some may continue to display significant numbers of voluntary
A neuroma affecting the medial plantar proper digital nerve, motor units because of dual innervation through the cross-over
which supplies cutaneous innervation to the great toe's medial and non-cross-over fibers. In cases where a patient sustains a
aspect, is referred to a Joplin's neuroma. Clinically, a small neu- high ulnar nerve lesion in the presence of a Martin-Gruber anas-
roma may be palpated at the base of the first hallux. Palpation tomosis with significant innervation to the ulnar-innervated
usually, though not always, reproduces the patient's symptoms. muscles conveyed through this route, a clinical impression of an
A reduction to sensation is detected along the medial aspect of "all median" hand can be arrived at. This is really not an "all
the first hallux. Near-nerve and surface stimulation of the first median" hand in the sense that the median nerve in the hand
hallux while recorded with a near-nerve electrode located next sends branches to the normally ulnar-innervated muscles.
to the tibial nerve at the ankle has documented a lesion affecting Instead, there is sparing of "ulnar nerve" fibers because of a
this nerve.113-474 In patients with this disorder, it is likely that the temporary confluence with the median nerve. Stimulation of the
above technique is most likely to reveal an electrophysiologic ulnar nerve at the wrist continues to result in CMAPs from the
abnormality. ulnar-innervated hand intrinsic muscles, while stimulation of
the median nerve at the wrist only yields volume-conducted re-
sponses from these same muscles. Elbow median nerve stimula-
ELECTRODIAGNOSTIC MEDICINE tion, however, generates responses in the ulnar-innervated
CONSULTATION PITFALLS intrinsic hand muscles. In short, this is not a true median-inner-
vated hand. These potential variations should be kept in mind to
A number of potential pitfalls can result in erroneous data avoid unnecessary confusion.
collection and faulty diagnostic interpretations with respect to The Martin-Gruber anastomosis can also result in several
focal peripheral nerve compromise. The practitioner must be electrophysiologic anomalies. In a patient with median nerve
thoroughly familiar with these potential sources of error in conduction slowing at the wrist, an extremely fast median nerve
order to obtain reliable data upon which to formulate an accu- conduction velocity of greater than 70 m/s can observed. This is
rate diagnosis. This is an extremely important issue, as a techni- because the CMAP is recorded at low amplifier sensitivities and
cal error can result in a patient receiving inappropriate operative a prolonged distal motor latency is subtracted from a perceived
intervention. The described pitfalls can result in false-positive relatively normal proximal motor latency leading to a short
or false-negative studies and should be considered as potentially forearm conduction time. The short forearm time is arrived at
present in all patients examined. One cannot be too critical in because the proximal stimulation traverses the ulnar nerve with
assessing all of the factors discussed below. impulses arriving at the adductor pollicis and first dorsal in-
terosseous as well as the deep head of the flexor pollicis brevis
ANATOMIC VARIATIONS muscles prior to the median nerve impulses reaching the APB
and OP because of the above-noted slowing at the wrist.
Upper Limb. As previously stated, it is crucial for any prac- Increasing the amplifier sensitivity demonstrates an initial
titioner of electrodiagnostic medicine to be thoroughly familiar CMAP positive deflection only with elbow stimulation, sug-
with both normal anatomy and its many possible variations. gesting that the initial aspect of the CMAP originated from
One of the more commonly encountered anatomic variations in muscle fibers whose motor points were not directly under the
the upper limb is the Martin-Gruber anastomosis. In this situa- recording electrode, i.e., a volume-conducted response from the
tion, it is important to recall that a number of C8/T1 motor ulnar-innervated muscles. This is not always observed. From
fibers travel with the median nerve until reaching the upper time to time the motor point of the ulnar-innervated thenar mus-
forearm, at which time they commonly cross into the anterior cles may align with those of the APB and OP. In this instance,
interosseous nerve and from this nerve form a bridge with the an initial negative deflection is generated with both elbow and
ulnar nerve. These fibers then continue into the hand. After join- wrist median nerve stimulation despite the presence of a
ing the ulnar nerve, the cross-over fibers are now considered Martin-Gruber anastomosis combined with conduction slowing
ulnar nerve fibers and innervate ulnar intrinsic hand muscles. at the wrist. There are hints to the presence of a Martin-Gruber
They do not innervate the APB or OP muscles. In this anomaly, anastomosis in this case. First, the conduction velocity may still
a selective and complete section of the median nerve in the an- be erroneously high. Second, the CMAP amplitude with elbow
tecubital fossa or arm region can result in paresis and positive stimulation is significantly larger than with wrist stimulation.
sharp waves and fibrillation potentials in a number of intrinsic This larger CMAP amplitude proximally does not happen nor-
hand muscles innervated by the ulnar nerve depending upon the mally, and when it is observed with or without a CTS (normal
particular distribution of the cross-over fibers. This is one persons), again a Martin-Gruber anastomosis should be sus-
manner in which a high median nerve injury can result in mem- pected (see Fig. 24-12).
brane instability in ulnar hand intrinsic muscles. If, in this same Another relatively common anomalous innervation involves
patient, the median nerve is completely lacerated at the wrist, the median and ulnar nerves in the hand, i.e., the Riche-Cannieu
anastomosis, which is a neural communication between the this instance, the EDB can be expected to generate membrane
deep branch of the ulnar nerve and the recurrent branch of the instability with little in the way of voluntary motor units when
median nerve.89-282-638 This is an anatomic variation in which the indeed it may be only minimally affected because of its aberrant
typically median-innervated APB and OP can receive either par- innervation pathway. When a typical pattern of a deep peroneal
tial or nearly total innervation from the ulnar nerve. It is this nerve injury is noted with the exception of EDB sparing, an ac-
anastomosis and not the Martin-Gruber that accounts for the cessory peroneal nerve should be suspected.
true "all ulnar" hand. Severance of the median nerve at any lo-
cation except the recurrent branch in the hand results in sparing REFERENCE VALUES
of the APB and OP as they are innervated at least in part by the
ulnar nerve fibers traversing the above noted anatomic bridge. It is always imperative to use only published reference values
On needle electromyographic examination, membrane instabil- if the exact technique including instrumentation parameters are
ity may be noted in the APB and OP as well as numerous volun- reproduced. Despite this attention to detail, there can still be
tary motor units despite the median nerve lesion. In this problems. Comparing median and ulnar SNAP amplitudes is
instance, the median thenar muscles are dually innervated by one method recommended to identify abnormalities between
both the median and ulnar nerve. It may be possible for the these two nerves.437 Unfortunately, 30% of normal persons can
bridge to also convey median fibers to some of the ulnar intrin- have abnormal values using this technique. 627 The difficulty in
sic muscles. This may be one manner of achieving a true all using SNAP amplitudes is their dependence on several factors.
median innervated hand, although it is likely that the Martin- One of the critical parameters directly influencing SNAP mag-
Gruber anastomosis more commonly yields what appears to be nitude is the interelectrode separation between the active and
an all median-innervated hand, which is in fact a pseudome- reference electrodes. Unless this is specified in the original
dian-innervated hand. study and strictly adhered to, amplitude criteria cannot be used.
Of particular interest is the relatively common minor varia- Unfortunately, most persons do not pay much attention to this
tions in cutaneous hand innervation particularly affecting those important detail. A second important factor is the distance be-
digits sharing dual innervation. For example, the fourth digit tween the recording and cathode electrodes. The SNAP ampli-
may be wholly innervated by the ulnar or median nerve, al- tude is very dependent upon the time of travel between the site
though a recent study in 2047 hands found no evidence for a of neural activation and where the impulse is eventually
mononeural innervation of digit 4. 4,4 Similarly, the first digit recorded. As the distance between these two sites increases, the
may be completely or significantly innervated by the radial or SNAP magnitude declines quite dramatically. This is a result of
lateral antebrachial cutaneous nerve with little contribution temporal dispersion leading to phase cancellation of the individ-
from the median. This is of particular importance, as a number ual positive and negative phases of the single fiber action poten-
of nerve conduction techniques utilize recordings from these tials. The longer the distance of travel, the more dramatic is the
digits while attempting to simultaneously activate both nerves effect. Also, during the course of the study, the patient's digital
through a volume-conducted spread of the current. The pur- temperature can change resulting in an increase in SNAP ampli-
ported sign of abnormality is the detection of two SNAP peaks tude with a decline in temperature (see below).
instead of one or looking for an absolute time difference be- Some techniques simply are not as sensitive as originally
tween two resolvable peak latencies. There are several difficul- claimed. The residual latency can be abnormal in up to 14% of
ties with these techniques. If there is anomalous innervation of normal persons.627 Nerve conduction variability and anomalous
the fourth or first digits solely by the ulnar and radial nerves, reinnervation can result in false-positive and -negative results
spectively, only a single SNAP is detected and the study is con- with respect to this method. Also, since motor studies are inher-
cluded to reveal no evidence of median compromise even if a ently less sensitive than sensory studies, it is doubtful whether
profound CTS is present. Similarly, if the median nerve is so this method is of significant diagnostic value.
profoundly affected that it cannot generate a SNAP, again only Comparing normal latencies between the median and ulnar,
one response is detected and a normal study is concluded. Both and median and radial nerves is considered helpful in diagnos-
instances may lead to an erroneous conclusion. This is the diffi- ing CTS. Again, using described reference differences can result
culty with attempting to take shortcuts. When using these tech- in 8% of normal persons having positive tests.627 It may be nec-
niques, it is always a good idea to stimulate both nerves essary to increase the time discrepancy between these two
independently so as to verify that indeed they are either present nerves to produce less false-positive tests upon which rather in-
or absent so as to separate out the above-noted false impression. vasive procedures can be based. Further critical work needs to
Individually activating the ulnar and median nerve while record- be done comparing published values for normality in both
ing from the fourth digit is a very good technique; fortunately, normal and patient populations.
anomalous innervation to this digit is very rare.
Lower Limb. There is only one anomalous innervation pat- TEMPERATURE
tern in the lower limb that may be commonly encountered with
the possibility of generating diagnostic confusion. This is the One of the single most important and no doubt most preva-
accessory peroneal nerve, which originates from the superficial lent errors encountered in electrodiagnostic medicine evalua-
peroneal nerve and traverses posterior to the lateral malleolus to tions is a result of temperature effects. Specifically, the
provide variable innervation to the EDB. This anomaly is examiner may fail to record the patient's temperature over the
quickly identified when a response recorded from the EDB to segment of nerve being studied. A reduction in temperature re-
peroneal stimulation is smaller with ankle stimulation than with sults in two important effects relevant to focal peripheral nerve
neural excitation at the fibular head. Of course, this presupposes insults. The first is a slowing in neural conduction, while the
a supramaximal stimulus at the ankle. It may pose difficulties second is an increase in the amplitude of both the SNAP and
when an anterior tarsal tunnel syndrome is suspected or a deep CMAP, especially the former. These are two very relevant para-
peroneal nerve insult has occurred in the distal leg or ankle. In meters, as conduction velocity/latency and waveform magnitude
II
are always recorded and compared with reference values in be warranted. For example, performing a needle examination of
order to determine the presence or absence of pathology. the pronator teres and biceps brachii muscles may provide addi-
Performing a median nerve sensory conduction in a cold hand tional information regarding the possibility of a concomitant cer-
will certainly result in a prolonged latency, which may be mis- vical radiculopathy. A conduction time assessment across the
taken as pathology. Failure to recognize this error can end up carpal tunnel on the contralateral hand can be very quickly per-
with the patient receiving unnecessary surgery. Similarly, rely- formed. It could be certainly argued that these added studies in-
ing on amplitude comparisons in a cold limb can also yield crease the cost of health care. Consider, however, the added cost
larger responses than would be recorded at more physiologic and patient suffering if a cervical radiculopathy is missed and the
temperatures. It is most likely not a good idea to resort to tem- patient continues to have attention focused on a possible failed
perature correction factors, as they are based on normal nerves CTS release instead. Also, once the symptomatic CTS is treated,
and not pathologic nerves. One can safely conclude that ab- the less symptomatic hand may now become more apparent to
normal nerves may not correct to temperature in the same the patient and the patient is referred for a complete study of the
manner as normal nerves. The best course of action in any pa- contralateral limb. This same argument basically applies to the
tient is to first record the temperature. If it is low, the limb majority of focal neuropathies. Attention must be directed not
should be warmed to the desired temperature for that particu- only at the affected area, but also the entire patient, keeping in
lar laboratory. mind the differential diagnosis consistent with the symptomatic
complaints.
STIMULATION
As noted above, one of the critical parameters used is the ILLUSTRATIVE CASES
waveform's latency. It is not uncommon for pathologic nerves
to require significantly more stimulus intensity for supramaxi- CASE I:HAND NUMBNESS/ARM PAIN
mal activation compared with normal nerves. When increasing
either the stimulus intensity or duration, there is always the pos- Reason for Referral. Right upper limb hand numbness and
sibility that the site of initial neural stimulation may exceed the arm pain.
visualized cathode location. Measuring from the cathode is then History. A 46-year-old right hand dominant woman is em-
not an accurate representation of where the impulse is initiated. ployed as a domestic and complains of right hand numbness
Only enough current should be used to achieve the desired re- with associated right wrist, elbow, and shoulder pain with occa-
sponse. Excessively increasing the current output can generate a sional neck pain for a period of 3 months. She notes intermittent
shorter than anticipated latency divided into an erroneously long symptoms of numbness only in the left hand for a similar period
distance, resulting in a potentially normal velocity in a patho- of time. There is no history of illness, and no medications are
logic nerve. Too strong a stimulus can also generate current consumed at this time. The patient also states that she is having
spread an excessive longitudinal distance not only along the de- trouble buttoning the clothes when finished washing and iron-
sired nerve, but also to neighboring nerves. A number of nerves ing them. Sewing is extremely difficult because of the fine hand
are relatively close together, and inadvertent activation of a dexterity required to complete the task.
nearby nerve can occur. Also, it is rather obvious but bears stat- Physical Examination. The patient is alert and very cooper-
ing that the desired nerve must be excited. This can be ensured ative. Deep tendon reflexes of the left biceps brachii, triceps, and
only if the practitioner is thoroughly familiar with the body's pronator teres are 2+/2+, while the right biceps brachii and
surface anatomy with respect to the proper location of neural pronator teres are 1+/2+ but the triceps reflex on this side is
tissue. 2+/2+. There is noted to be decreased touch and pin prick in the
median nerve distribution bilaterally, but worse on the right.
INADEQUATE STUDY Proprioception is grossly intact in the hands bilaterally. Manual
muscle testing reveals a normal grade of strength in the left
Arguably, the most frequently recognized or unrecognized upper limb, while the deltoid, biceps brachii, forearm pronators,
error is the performance of an inadequate study. A number of and shoulder external rotators are 4/5. The remaining muscles in
reasons can be found for lack of obtaining a sufficient data base, the right upper limb are 5/5. The lower limb reflexes, strength,
but short of the patient requesting termination of the examina- and sensation are normal. Cervical range of motion is somewhat
tion, there are few acceptable excuses for this shortcoming. limited with respect to lateral bending to the right and left/right
Perhaps a worse folly is to then formulate a diagnosis predicated rotation. Compression of the head produces a generalized aching
upon the minimal information gained. Simply answering the rein the cervical region without radiation into either upper limb.
ferring physician's question is not fulfilling the responsibility of Nerve Conduction Studies. Nerve conduction studies are
the practitioner to evaluate the patient's complaints fully. This is performed in the upper limbs bilaterally. The mid-palm temper-
the necessity of performing a directed history and physical ex- ature is 33.5°C on the right and 32.7°C on the left.
amination so as to formulate an appropriately tailored consulta- Nerve DSL S Amp DML M Amp NCV
tion. A common request is to "rule out CTS." This is a rather (ms) (pV) (ms) (mV) (m/s)
straightforward request and can be answered relatively quickly R median 5.5 19.0 6.2 4.5 51.0
by performing a few simple nerve conductions to the affected R median 1.9 25.0
hand. However, a number of these patients have bilateral disease (7.0 cm)
and can certainly have a more proximal lesion that will continue R ulnar 3.1 35.0 3.2 5.5 58.0
to generate the patient's complaints despite appropriate thera- L median 3.9 30.0 4.6 5.0 54.0
peutic intervention directed to the CTS. Depending upon the his- L median 1.9 33
tory and physical examination combined with the practitioner's (7.0 cm)
index of suspicion, a few limited additional investigations may L ulnar 3.0 38.0
DSL, distal sensory latency; S Amp, sensory amplitude; impression. Note that a split time is measured so as to calculate
DML, distal motor latency; M Amp, motor amplitude; NCV, the latency across the carpal tunnel. Equally effective would
nerve conduction velocity; ms, milliseconds; pV, microvolts; have been to stimulate the median nerve in the hand and record
mV, millivolts; m/s, meter/second. Motor and sensory ampli- orthodromically at the wrist. The important point when examin-
tudes are measured baseline to peak. Sensory latencies are ing a patient for CTS is to calculate a latency across the carpal
measured to peak, while motor latencies are measured to ini- tunnel, as this is where the problem is believed to occur. Simply
tial negative onset. Ulnar and median motor studies are to the recording a 14-cm SNAP latency alone constitutes an incom-
abductor digiti minimi and abductor pollicis brevis, respec- plete median nerve evaluation even if combined with an ulnar
tively. Median sensory studies were performed to digit III, SNAP unless one is recording from the fourth digit (ring finger)
ulnar to digit V. following median and ulnar stimulation. In this patient, there is
Needle Electromyography. A needle electromyographic in- also noted to be a prolonged distal motor latency suggestive of
vestigation is performed on the right upper limb using a dispos- compromise of the motor fibers in addition to the sensory
able monopolar needle. nerves. Needle electromyographic examination of the APB fails
Muscle Rest Activity Recruitment to reveal membrane instability; however, this does not mean that
Supraspinatus 1+Fibs/PS W Normal axonal loss has not occurred in the carpal tunnel region. The rel-
Deltoid 1+ Fibs/PS W Normal ative rate of axonal loss may be so slow as to be difficult to
Biceps brachii 1+Fibs/PS W Normal detect secondary to the compensatory process of collateral
Triceps Silent Normal sprouting reinnervating the denervated muscle fibers at a rate
Pronator teres 1+Fibs/PS W Normal commensurate with axonal loss.
Extensor carpi radialis 1+Fibs/PS W Normal The needle electromyographic examination demonstrates
Flexor carpi radialis Silent Normal membrane instability in the C6 myotome (a C5 radiculopathy is
Extensor digitorum Normal Normal less probable in view of pronator teres involvement). A careful
communis physical examination directed by the history suggests a possible
Abductor pollicis brevis Silent Normal cervical lesion. Exploring only the APB or hand intrinsic mus-
First dorsal interosseous Silent Normal cles would have resulted in the misdiagnosis of this patient with
Abductor digiti minimi Silent Normal respect to her C6 radicular lesion. If this diagnosis had been
Pronator quadratus Silent Normal missed, the CTS may well have been treated appropriately, but
Rhomboid major Silent Normal the symptoms would fail to completely resolve because the cer-
Paraspinal C4-T1 Silent Normal vical lesion would persist. As the C6 sensory fibers converge on
(except C6 bony level) Increased insertion Normal the same region innervated in the hand by part of the median
Comment. The pronator teres, biceps brachii, and APB nerve, a failed CTS release may have been entertained with re-
muscles were also examined in the left upper limb, but no ab- exploration of the carpal tunnel to no avail. Properly treating not
normalities were detected. The amplitude of the fibrillation only the CTS, but also the cervical radiculopathy, should result
potentials and positive sharp waves were between 200 and in complete symptom resolution with time.
400 uV. Note that the patient's median and ulnar nerves were also ex-
amined on the contralateral limb. In this person, there exists a
Summary of Findings mild CTS on the left. A brief needle examination of the left
1. Increased insertional activity noted in C6 paraspinal mus- hand failed to reveal evidence suggestive of a C6 radicular
cles. There is also noted to be isolated membrane instability in lesion on this side. The relatively high incidence of bilateral
the right supraspinatus, deltoid, biceps brachii, pronator teres, CTS warrants at least a limited electrophysiologic evaluation of
and extensor carpi radialis. the less symptomatic hand. Also, the temperature is documented
2. Slowing of conduction across right carpal tunnel region bilaterally for this study. If the hands were less than 32°C, they
for both motor and sensory fibers of the right median nerve is would have been warmed to at least 32°C. Temperature correc-
observed. Similar but less severe findings are noted for the left tion factors are of questionable value in pathologic nerves.
median nerve.
CASE 2: HAND NUMBNESS/ELBOW PAIN
Electrodiagnostic Medicine Impression
1. Right and left sensorimotor compromise of the median Reason for Referral. Right upper limb hand numbness and
nerve about the carpal tunnel region more severe on the right elbow pain.
with mild slowing noted on the left. History. A 56-year-old man who is employed as a carpet
2. There is noted to be a form of membrane instability at the layer complains of progressive hand numbness and weakness
C6 paraspinal level and muscles innervated by the C6 nerve over the past 4 months. This lack of hand function began about
root. These findings are consistent with a C6 radiculopathy on 2 days after a particularly large job where he had to lay carpet in
the right. an office complex. His specific job is to take a special instru-
ment and stretch the carpet under the molding along the edges
Comment of the room. It entails the forceful banging of the palm of his
The patient has a history and physical examination consistent hand against the instrument. Unfortunately, he had to continue
with a clinical diagnosis of CTS. There is also a suspicious his- to work and so has been performing similar jobs. Prior to this
tory and correlative physical findings for a concomitant C6 particular incident, he noted some numbness of his right hand
radiculopathy. The electrodiagnostic medicine examination is but no significant weakness. He takes no medication, denies
constructed to explore these two possibilities. Finding a pro- smoking, but drinks approximately 3-^1- beers per night.
longed right median sensory latency with preferential slowing Physical Examination. The patient is alert and cooperative.
across the carpal tunnel region is consistent with the clinical Deep tendon reflexes of the left biceps brachii, triceps, and
1
Chapter 24 FOCAL PERIPHERAL NEUROPATHIES — I III
pronator teres are 2+/2+ bilaterally. There is noted to be asym- 2. The distal motor latency comparison between the abduc-
metric wasting of the right first dorsal interosseous muscle. tor digiti minimi and first dorsal interosseous muscles is abnor-
Wasting of at least a mild degree is also noted of the remaining mally prolonged on the right.
interossei muscles. Questionable wasting of the hypothenar 3. Neural conduction of the ulnar nerve across the right
muscles of the right hand may also be present. Manual muscle elbow region is markedly slow without an amplitude drop.
testing of the both limbs reveals a grade of strength of 5/5
throughout except for the right hand. The hypothenar muscles Electrodiagnostic Medicine Impression
are graded as 4-/5, while the palmar and dorsal interossei are 1. The slowed neural conduction of the right ulnar nerve
3-/5. The abductor pollicis brevis and opponens pollicis are across the elbow region combined with an absent dorsal ulnar
4+/5. Decreased sensation to light touch and pin prick are noted cutaneous nerve SNAP suggests there is a lesion, most likely
along the volar aspect of the fifth and medial half of the fourth demyelinative with a component of axonal loss (absent SNAPs)
digits. There is also a mild decrease to these two modalities in nature, across the right elbow either in the postcondylar
along the dorsum of the right hand as well. Sensation in the left groove or cubital tunnel regions. An absent dorsal ulnar cuta-
upper limb is normal. A Tinel's sign is present at the right post- neous nerve combined with denervation in the hypothenar emi-
condylar groove as well as in the mid-palm region. nence muscle implies there is a component of axonal loss as
Nerve Conduction Studies. Nerve conduction studies are well involved at the elbow.
performed in the upper limbs bilaterally. The mid-palm temper- 2. The observation of significant denervation potentials in
ature is 32.5°C on the right and 32.0°C on the left. the dorsal interossei out of proportion to those found in the ab-
Nerve DSL S Amp DML M Amp NCV ductor digiti minimi muscle plus a prolonged latency to the first
(ms) (pV) (ms) (mV) (m/s) dorsal interosseous muscle supports the conclusion that an
R median 3.5 39.0 3.2 7.5 58.0 axonal lesion with concomitant Wallerian degeneration of the
R median 1.9 44.0 deep branch of the ulnar nerve in the hand is also likely present.
(7.0 cm) This lesion is likely a result of the acute and subsequent chronic
R ulnar Absent 4.7 5.5 49.0 trauma to the palm of the hand secondary to this patient's em-
(across elbow fully flexed) 5.2 42.2 ployment as a carpet layer.
R ulnar (FDI) 7.1 Comment
RDUC Absent
L median 3.5 40.0 3.6 6.4 56.0 This patient's history and employment are certainly suspi-
L median 2.0 45.0 cious for a lesion of the ulnar nerve, most likely in the hand. The
(7.0 cm) clinical finding of diminished sensation along the medial aspect
L ulnar 3.0 28.0 3.4 5.9 62.2 of the hand's dorsum suggests a lesion proximal to the dorsal
(across elbow fully flexed) 5.6 64.5 ulnar cutaneous nerve's branching from the main trunk of the
L ulnar (FDI) 3.6 ulnar nerve. The most likely location for this injury is about the
LDUCdistal sensory2.4 latency;
19.4 S Amp, sensory amplitude; DML, elbow region. Electrophysiologically, both the digital and dorsal
DSL, ulnar cutaneous nerves' SNAPs are absent. Performing neural
distal motor latency; M Amp, motor amplitude; NCV, nerve con- conduction to both the abductor digiti minimi and FDI reveals a
duction velocity; ms, milliseconds; pV, microvolts; mV, milli- significantly prolonged latency difference. This suggests there
volts; m/s, meter/second. DUC, dorsal ulnar cutaneous; FDI, is an insult to the deep branch of the ulnar nerve distal to the in-
first dorsal interosseous. Motor and sensory amplitudes are mea- nervation of the abductor digiti minimi. Needle electromyo-
sured baseline to peak. Sensory latencies are measured to peak, graphic examination supports this contention by finding
while motor latencies are measured to initial negative onset. membrane instability in the dorsal interossei muscles out of pro-
Needle Electromyography. A needle electromyographic in- portion to those found in the abductor digiti minimi. These find-
vestigation is performed on the right upper limb using a dispos- ings, combined with the clinical impression, strongly favor an
able monopolar needle. axonal insult to the deep branch of the ulnar nerve in the palm
Muscle Rest Activity Recruitment of the right hand.
Abductor pollicis brevis Silent Normal Because the absent SNAPs noted above are not consistent
First dorsal interosseous 3-4+ Fibs/PSW Markedly reduced with a lesion of the deep branch of the ulnar nerve, an additional
Abductor digiti minimi 1-2+ Fibs/PSW Mildly reduced ulnar nerve lesion is sought. The most common location for an
2nd/3rd dorsal 3-4+ Fibs/PSW Markedly reduced ulnar nerve injury is about the elbow region. Neural conduction
interosseous across the elbow segment reveals a markedly abnormal conduc-
Pronator quadratus Silent Normal tion. The absence of a SNAP precludes examining sensory con-
Extensor digitorum Silent Normal duction across this area, but the slowed motor conduction is
communis sufficient to localize a problem to the elbow. The absence of
Flexor carpi uinaris Silent Normal membrane instability in the two forearm ulnar-innervated mus-
Flexor digitorum Silent Normal cles is not unusual, as they are typically affected only with pro-
profundus found lesions at the elbow. A combination of slowed motor
Paraspinal C7-T1 conduction across the elbow, absent dorsal ulnar cutaneous
Comment. Membrane Silent Normala magnitude
instability demonstrates SNAP, and denervation in the abductor digiti minimi less than
of 400-600 pV. that detected in the dorsal interossei point to an ulnar nerve
injury at the elbow. This individual demonstrates electrodiag-
Summary of Findings nostic medicine evidence consistent with two distinct ulnar
1. Ulnar sensory potentials to the palmar digital and dorsal nerve injuries, one at the elbow and one involving the deep
ulnar cutaneous nerves are absent on the right. branch of the ulnar nerve in the hand.
It is certainly possible to further pursue the exact site of loca- Extensor carpi uinaris 3+ Fibs/PSW Markedly reduced
tion of the elbow lesion. One could stimulate the ulnar nerve in Extensor pollicis pongus 3+ Fibs/PSW Markedly reduced
centimeter segments looking for a "jump" in the latency sug- Extensor indicis proprius 3+ Fibs/PSW Markedly reduced
gesting a preferential delay. As there is no significant amplitude Biceps brachii Silent Normal
drop across the elbow, an abrupt amplitude drop cannot be used Deltoid Silent Normal
to localize the lesion. Note that additional muscles other than Pronator teres Silent Normal
those innervated by the ulnar nerve were examined by needle Flexor carpi radialis Silent Normal
electromyography. All of these muscles contained innervation First dorsal interosseous Silent Normal
from the C8 or Tl myotome. This evaluation is performed to Abductor pollicis brevis Silent Normal
ensure that a radicular lesion is not present, as similar clinical Comment. Membrane instability demonstrates a magnitude
findings may be present with a C8/T1 radiculopathy. of 500-1500 pV.
CASE 3: FINGER EXTENSOR WEAKNESS Summary of Findings
1. The superficial radial and median/ulnar nerve conduction;
Reason for Referral. Inability to extend left fingers. were normal.
History. A 56-year-old woman employed as a CEO of a 2. Radial motor conduction using intramuscular needlq
major corporation in the area presents with a history of progres- recordings in the extensor indicis proprius demonstrated a pro'
sive inability to completely extend the digits of the left hand. longed latency and slowed forearm conduction.
She has an associated complaint of a dull but intense aching 3. Needle electromyographic examination demonstrated pro-
pain in the right proximal forearm just distal to the lateral epi- found denervation with minimal sparing of motor units in the
condyle. This pain occasionally radiates distally to the wrist and posterior interosseous nerve distribution beginning with the
proximally to the elbow region. She has no significant medical supinator muscle.
problems and only takes vitamins on a regular basis. The patient
cannot think any incident that may have precipitated this com- Electrodiagnostic Medicine Impression
plaint of weakness. 1. The abnormal radial motor conduction combined with the
Physical Examination. The patient is alert and cooperative. pattern of denervation in the radial innervated forearm muscles
Deep tendon reflexes of the biceps brachii, triceps, and pronator is consistent with a posterior interosseous nerve insult between
teres are 2+/2+ bilaterally. Sensation in the left upper limb is the innervation to the extensor carpi radialis and the supinatoi
intact throughout to all sensory modalities. There is noted to be muscles. The most likely location for such a lesion is just proxi-
obvious muscle wasting of the extensor muscles of the left fore- mal to the supinator muscle or as the posterior interosseous
arm distal to the extensor carpi radialis group. Attempted finger nerve passes beneath the arcade of Frohse, or in the substance
extension results in only a trace grade of strength. The extensor of the supinator muscle.
carpi radialis and proximally located radial innervated muscles
are 5/5. Wrist extension results in marked radial deviation of the Comment
hand. There are no associated joint deformities. Because of the Clinically, the patient presents with symptoms suggestive of a
patient's inability to extend the fingers, it is difficult to accu- posterior interosseous nerve injury or rupture of the extensor
rately test the median and ulnar innervated hand intrinsic mus- tendons. The lack of a history for rheumatoid arthritis or trauma
cles but there is no gross wasting of these muscles noted. favors the former diagnosis. The only abnormality on nerve
Nerve Conduction Studies. Nerve conduction studies are conduction is a slow conduction of the radial nerve through the
performed in the upper limbs bilaterally. The mid-palm temper- forearm segment. A superficial radial SNAP on the left is
ature is 32.2°C bilaterally. normal, as would be anticipated because this nerve divides from
Nerve DSL S Amp DML M Amp NCV the main trunk of the radial nerve proximal to the suspected site
(ms) (pV) (ms) (mV) (m/s) of the lesion, i.e., distal to the innervation of the extensor carpi
L median 3.2 60.0 3.2 8.4 59.0 radialis muscle as evidenced by the above-described pattern oi
L ulnar 3.1 38.0 3.1 5.5 64.0 muscle wasting. The most revealing aspect of the electrodiagJ
L radial 2.9 29.0 4.3 — 48.0 nostic medicine evaluation is the needle electromyographic as-
R radial 2.8 33.0 3.0 — 64.0 sessment. The presence of membrane instability in all of the
DSL, distal sensory latency; S Amp, sensory amplitude; DML, muscles innervated by the posterior interosseous nerve from the
distal motor latency; M Amp, motor amplitude; NCV, nerve con- supinator to the extensor indicis proprius muscles suggests a
duction velocity; ms, milliseconds; pV, microvolts; mV, milli- lesion proximal to the supinator muscle. The radial nerve is par-
volts; m/s, meter/second. Motor and sensory amplitudes are ticularly vulnerable proximal to the supinator, as it is in direct
measured baseline to peak. Sensory latencies are measured to contact with the radius and susceptible to insult by being com-
peak, while motor latencies are measured to initial negative onset. pressed against this bone. Similarly, the radial nerve can also be
Needle Electromyography. A needle electromyographic in- compressed as it travels beneath the tough fibrous arcade of
vestigation is performed on the left upper limb using a dispos- Frohse. It is also conceivable that the posterior interosseous
able monopolar needle. nerve could be compromised within the substance of the supina-
Muscle Rest Activity Recruitment tor muscle with some of the neural fibers arising within the
Triceps Silent Normal muscle and thus also be injured, leading to the detected mem-
Brachioradialis Silent Normal brane instability. It is not possible to localize the lesion site ex-
Extensor carpi radialis Silent Normal actly. As noted, the insult to the posterior interosseous nerve is
Supinator 3+ Fibs/PSW Markedly reduced documented as being incomplete but profound and located be-
Extensor digitorum 3+ Fibs/PSW Markedly reduced tween the innervation to the extensor carpi radialis and about or
communis within the supinator muscle. A number of muscles sharing the
same root levels as those radial innervated muscles are also inves- Muscle Rest Activity Recruitment
tigated by needle electromyography. This procedure is performed Gluteus medius Silent Normal
to ensure that a more proximal lesion such as a radicular insult is Gluteus maximus Silent Normal
not present. Simply assessing the radial nerve is insufficient. In the Vastus medialis Silent Normal
described case above, the findings are fairly straightforward; how- Short head biceps Silent Normal
ever, additional possibilities must be considered and subsequendy femoris
pursued on at least an investigatory level. Should membrane insta- Semitendinosus Silent Normal
bility have been detected in muscles outside of the radial nerve Medial/lateral Silent Normal
distribution, further study would be necessary to investigate other gastrocnemius
possibilities. If there had been a normal radial nerve conduction Abuctor hallucis Silent Normal
velocity and a completely lack of membrane instability with con- Flexor digitorum longus Silent Normal
comitant normal findings in all of the other nerves tested, one Tibialis anterior 3+ Fibs/PSW Markedly reduced
would have to conclude that an extensor tendon rupture occurred. Extensor digitorum 3+ Fibs/PSW Markedly reduced
Extensor hallucis 3+ Fibs/PSW Markedly reduced
CASE 4: FOOTDROP Extensor digitorum 4+ Fibs/PSW Absent
brevis
Reason for Referral. Inability to dorsiflex right foot. Peroneuslongus 2+ Fibs/PSW Reduced
History. A 28-year-old male graduate student celebrated re- Comment. Membrane instability demonstrates a magnitude
ceiving his Ph.D. in physics by drinking alcohol to excess and of 600-1500 pV.
passed out. Upon awaking the following afternoon, he noted he
could not ambulate properly secondary to a footdrop on the left. Summary of Findings
This occurred 3 weeks prior to this investigation. Since the orig- 1. The superficial peroneal SNAP is absent on the left.
inal incident, he has noted some return of function; however, he 2. A significant drop in amplitude to the TA is noted on the
cannot ambulate normally. He also complains of numbness on left across the fibular head.
the superior aspect of his left foot. 3. Needle electromyographic examination reveals significant
Physical Examination. The patient is alert and cooperative. denervation in the muscles innervated by the deep and superfi-
Deep tendon knee and ankle reflexes are 2+/2+ bilaterally. cial peroneal nerves with less severe findings in the superficial
Manual muscle testing reveals a grade 5/5 strength in all lower peroneal nerve distribution.
limb muscles except for the left peroneal nerve distribution. In
the left leg the ankle dorsiflexors are 3-/5; foot everters 4-/5; Electrodiagnostic Medicine Impression
and toe extensors 3-/5. There is noted to be significantly dimin- 1. The patient demonstrates evidence consistent with a
ished sensation to all modalities along the entire dorsum of the common peroneal nerve injury about the fibular head on the left.
left foot. There is also decreased sensation about the lateral There is noted to be a component of conduction block still pre-
aspect of the leg just proximal to the ankle area. sent as well as axonal loss. The superficial peroneal nerve divi-
Nerve Conduction Studies. Nerve conduction studies are sion is less affected than the deep peroneal nerve division. The
performed in the lower limbs bilaterally. The temperature ante- lesion is in continuity as evidenced by voluntary motor units
rior to the ankle and posterior to the lateral malleolus is 31.5°C present in all muscles innervated by the peroneal nerve except
on the left and 30.9°C on the right. for the EDB. The patient should demonstrate continued recov-
Nerve DSL S Amp DML M Amp NCV ery as the conduction block resolves and a second recovery
(ms) (pV) (ms) (mV) (m/s) phase as collateral sprouting and reinnervation occurs.
L peroneal Absent Absent Recommendations
(EDB)
L peroneal 3.1 4.0/(2.0)* 43.0 1. Will prescribe the patient an ankle-foot orthosis to assist
(TA) with gait abnormality until foot function returns.
R peroneal 2.9 25.0 3.9 5.0/(4.9)' 48.0 Comment
(EDB)
R peroneal 3.1 8.0/(7.9)* 49.0 This patient presented with a classic history and physical find-
(TA) ings for compression of the common peroneal nerve about the
L sural 3.5 40.0 fibular head region following excessive drinking and deep sleep
R sural 3.6 37.0 with minimal movement. No doubt the patient laid on the affected
L tibial 4.0 10.2 48.0 limb, compressing it against a hard floor, or crossed one leg over
R tibial 3.9 8.9 51.0 the other. The superificial peroneal sensory response is com-
DSL, distal sensory latency; S Amp, sensory amplitude; DML, pletely absent, suggesting the lesion causing the footdrop is distal
distal motor latency; M Amp, motor amplitude; NCV, nerve to the dorsal root ganglion level and of a profound nature.
conduction velocity; ms, milliseconds; pV, microvolts; mV, mil- Because the lesions causing the footdrop is presumed to be at the
livolts; m/s, meter/second; EDB, extensor digitorum brevis; TA, fibular head region at least initially and the sensory nerve is stim-
tibialis anterior. Motor and sensory amplitudes are measured ulated quite a distance below this site, an absent response implies
baseline to peak. Sensory latencies are measured to peak, while significant Wallerian degeneration. Any component of conduc-
motor latencies are measured to initial negative onset. *: tion block would be discovered, as the stimulus is distal to the
Amplitude above fibular head. pathology affecting the nerve. Motor studies to the EDB and TA
Needle Electromyography. A needle electromyographic in- suggest that the deep peroneal fibers to the EDB are more pro-
vestigation is performed on the left lower limb using a dispos- foundly affected than those to the TA. It is always a good idea to
able monopolar needle. perform a CMAP study to both the EDB and TA. Just examining
the EDB in a patient with footdrop is inappropriate because the by firm palpation over the course of the medial and lateral plan-
patient's complaint is that of a drop foot, which results from a tar nerves just distal and inferior to the navicular tubercle.
weak TA, not EDB. This individual reveals a TA CMAP with Nerve Conduction Studies. Nerve conduction studies are
50% drop across the fibular head with a smaller response proxi- performed in the lower limbs bilaterally. The anterior ankle and
mal than distal to this site. A finding such as this implies there is a posterior malleolus temperature is 31.7°C on the left and 30.9°C
conduction block affecting a portion of the fibers innervating the on the right.
TA. This is an important finding because one can anticipate a rel- Nerve DSL S A m p DML M Amp NCV
atively rapid return of function to at least a portion of the nerve (ms) (pV) (ms) (mV) (m/s)
fibers traversing the affected region. The patient's history sug- L sural 3.8 35.0
gests that the insult resulted from a single compressive episode as R sural 3.7 30.0
opposed to a progressive lesion such as a tumor and that the tem- L MP 3.5 28.5
porary blockage of neural fibers should resolve shortly with a sig- LLP 3.5 18.0
nificant return of function. Comparing the TA CMAP amplitude R MP 5.1 8.0
to the contralateral side suggests that there are also significant R LP Absent
numbers of neural fibers that have undergone axonal loss with L tibial
Wallerian degeneration. Fortunately, chances are the endoneurial AH 4.7 6.8
tubes to these fibers are still intact and once the nerve begins to ADP 4.9 5.5
regenerate, there should be little in the way of obstruction to the R tibial
regrowth of the axons along their respective endoneurial paths. AH 4.6 5.8
Needle electromyographic examination confirms the clinical ADP 4.8 5.5
and motor/sensory conduction impression. Specifically, there is L peroneal 2.9 19.0 4.2 4.8 47.5
significant denervation and reduction in voluntary motor units R peroneal 3.1 22.0 4.4 5.7 49.5
with the EDB most profoundly affected. There is, however, rel- DSL, distal sensory latency; S Amp, sensory amplitude; DML,
ative sparing of the muscles innervated by the superficial per- distal motor latency; M Amp, motor amplitude; NCV, nerve
oneal nerve. A needle investigation of the proximal muscles was conduction velocity; ms, milliseconds; pV, microvolts; mV, mil-
also performed as well as to the tibial-innervated muscle just to livolts; m/s, meter/second; AH, abductor hallucis; ADP, abduc-
confirm the absence of membrane instability in muscles sharing tor digit pedis; MP, medial plantar nerve; LP, lateral plantar
a similar myotome as the peroneal-innervated muscles, thereby nerve. Motor and sensory amplitudes are measured baseline to
eliminating the possibility of a radicular lesion coexisting with peak. Sensory latencies are measured to peak, while motor la-
the peroneal nerve injury. Continued detection of voluntary tencies are measured to initial negative onset.
motor units confirms the impression that the lesion is one in Needle Electromyography. A needle electromyographic in-
continuity with a good prognosis for regrowth along the previ- vestigation is performed on the left and right lower limb using a
ous endoneurial tubes. The patient should demonstrate a Dipha- disposable monopolar needle.
sic return of function in the near future with resolution of the Muscle Rest Activity Recruitment
conduction block first, followed by reinnervation of muscle R tibialis anterior Silent Normal
fibers through collateral sprouting and axon regrowth across the R medial/lateral Silent Normal
lesion site. In the interim, the patient should be prescribed an gastrocnemius
ankle-foot orthosis to assist with the footdrop and prevent R abductor hallucis 2+ Fibs/PSW Normal
overuse of the remaining muscles. R abductor digiti minimi 2+ Fibs/PSW Normal
pedis
CASE 5: FOOT PAIN/NUMBNESS L abductor hallucis Silent Normal
L abductor digiti minimi Silent Normal
Reason for Referral. Left foot pain/numbness. pedis
History. A 45-year-old woman presents with a 6-week history Comment. Membrane instability demonstrates a magnitude
of right foot pain with burning along the sole of the foot. She of 450-900 pV.
denies any traumatic incidents that may have precipitated the
complaint. The patient states that she is in a good state of health, Summary of Findings
has no known medical conditions, and does not take any medica- 1. Medial and lateral plantar mixed nerve responses are ab-
tion. She is an active person and likes to bicycle for recreation normal on the right.
purposes. The complaint of foot pain is now constant and worse 2. Needle electromyographic examination of the affected
at night. It is of a burning character with occasional twinges of foot intrinsic muscles reveal evidence of denervation.
sharp pain about the medial and midportion of the foot.
Physical Examination. The patient is alert and cooperative. Electrodiagnostic Medicine Impression
Deep tendon reflexes at the knees and ankles are 2+/2+. Manual 1. There is electrophysiologic evidence consistent with a
muscle testing reveals a 5/5 in the lower limbs bilaterally. medial and lateral plantar neuropathy in the right foot. The
Sensation to all modalities is intact in the lower limbs bilaterally exact site of this lesion cannot be accurately pinpointed; how-
except for the sole of the right foot. There is noted to be de- ever, the reproduction of pain in the midfoot suggests that the
creased sensation to pin prick, temperature, vibration, and touch nerves are compromised distal to the tarsal tunnel region.
along the entire sole of the foot except for the heel region,
which appears spared. There is also noted to be some compara- Comment
tive sparing of sensation along the lateral aspect of the foot, al- This patient presents with a history highly suggestive of a
though this is not normal. Compression of the forefoot does not plantar neuropathy. The reproduction of symptoms with com-
reproduce the patient's complaints. Of note, the pain is reproduced pression of the plantar surface of the foot supports the initial
clinical impression. The electrodiagnostic medicine examina- 7. Aiken BM, Moritz MJ: Atypical electromyographic findings in pronator teres
tion is directed at assessing neural conduction in the medial and syndrome. Arch Phys Med Rehabil 1987;68:173-175.
8. Al-Qattan MM, Thomson HG, Clarke HM: Carpal tunnel syndrome in children
lateral plantar nerves in addition to exploring the possibility of a and adolescents with no history of trauma. J Hand Surg 1996;21B: 108-111.
peripheral neuropathy. The procedure of choice in this patient is 9. Albers JW, Brown MB, Sima AAF, Greene DA for the Tolrestat study group for
the mixed-nerve action potentials of the medial and lateral plan- EDIT (Early Diabetes Intervention Trial): Frequency of median mononeuropa-
thy in patients with mild diabetic neuropathy in the Early Diabetes Intervention
tar nerves. These responses are completely normal on the Trial (EDIT). Muscle Nerve 1996;19:140-146.
asymptomatic foot, while a distinct abnormality is found for 10. Almekinders LC, Logan TC: Results following treatment of traumatic disloca-
both of these nerves in the right foot. An absent response is tions of the knee joint. Clin Orthop 1992;284:203-207.
noted for the lateral plantar nerve, while the medial plantar 11. Amadio PC, Beckenbaugh RD: Entrapment of the ulnar nerve by the deep
flexor-pronator aponeurosis. J Hand Surg 1986; 11 A:83-87.
nerve's waveform is reduced in magnitude and delayed. Needle 12. American Association of Electrodiagnostic Medicine: Practice parameter for
electromyographic examination of the foot muscles reveals evi- electrodiagnostic studies in carpal tunnel syndrome: Summary statement.
dence of denervation only in the affected limb in the distribu- Muscle Nerve 1993;16:1390-1391.
tion of the medial and lateral plantar nerve. If abnormalities had 12a. American Association of Electrodiagnostic Medicine: Practice parameter for
electrodiagnostic studies in ulnar neuropathy at the elbow: Summary state-
been observed in both feet, little in the way of conclusions can ment. Muscle Nerve 1999,22:408^12.
be drawn. It is not unusual to find normal motor latencies and 13. Anastasopoulos D, Chroni E: Effect of carpal tunnel syndrome on median nerve
amplitudes of the medial and lateral plantar nerves despite find- proximal conduction estimated by F-waves. J Clin Neurophysiol 1997;14:63-67.
14. Andary MT, Fankhauser MJ, Ritson JL, et al: Comparison of sensory mid-palm
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proximal muscles were also examined on needle electromyog- Neurophysiol 1996;36:279-285.
raphy in the symptomatic limb to ensure there were no abnor- 15. Anderson MH, Fullerton PM, Gilliat RW, Hern JEC: Changes in the forearm
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Neurol Neurosurg Psychiatry 1970;33:70-79.
person did not have electrophysiologic evidience suggestive of 16. Andresen BL, Wertsch JJ, Stewart WA: Anterior tarsal tunnel syndrome. Arch
a peripheral neuropathy. If the sural nerve responses had been Phys Med Rehabil 1992;73:1112-1117.
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Plast Reconstr Surg 1973;51:76-81.
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Chapter 24 FOCAL PERIPHERAL NEUROPATHIES — I I 19
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Chapter 25
Neuromuscular Junction
Disorders
Daniel Dumitru, M.D., Ph.D.
Anthony A. Amato, M.D.
CHAPTER OUTLINE
Anatomy of the Neuromuscular Junction Congenital Myasthenic Syndromes
Presynaptic Region • Neurotransmitter Release
• Postsynaptic Region Presynaptic Disorders • Synaptic Space Disorders
• Postsynaptic Disorders * Partially Characterized Congenital
Physiology of Neuromuscular Junction Transmission Myasthenic Syndromes • Treatment
Presynaptic Region • Synaptic Region • Postsynaptic Region
Drugs and Toxins Modulating Neuromuscular Junction
Transmission
Pathophysiology of Neuromuscular Junction Disorders Presynaptic Disorders • Synaptic Space Disorders
Anticholinesterase Agents • Postsynaptic Disorders
Presynaptic Region • Synaptic Region • Postsynaptic Region
Electrophysiology Correlates of Neuromuscular Other Disorders That May Manifest with
Junction Disease Neuromuscular Junction Dysfunction
History and Physical Examination • Nerve Conduction Studies
• Technical Factors Electrodiagnostic Medicine Pitfalls
Acquired Neuromuscular Junction Disorders False-Positives • False-Negatives
Presynaptic Disorders • Postsynaptic Disorders Illustrative Cases
The electrodiagnostic medicine evaluation of neuromuscular ANATOMY O F THE NEUROMUSCULAR

junction (NMJ) disorders provides significant insight into the JUNCTION
manner in which the peripheral nervous system's propagated
action potential is converted into a muscle contraction. The The fundamental building block of the peripheral nervous
NMJ is the interface between the distal motor nerve and muscle system is the motor unit, which is composed of an anterior horn
and has the specific function of transducing and amplifying the cell (alpha motor neuron), its peripheral axonal extension^ and
peripheral nerve's relatively small electrical current into a cur- all of the muscle fibers innervated by the anterior horn cell. A
rent of sufficient intensity and proper location to induce action neuromuscular junction or end-plate may be defined as a
potential propagation along the muscle fiber. Alterations in the chemical synapse with the specific function of transmitting an
structure and subsequent function of the NMJ's various sub- electrical signal from the terminal portion of a nerve to a well-lo-
components can lead to disorders with characteristic clinical calized region of muscle.284-305 The actual morphologic appear-
and electrophysiologic findings. ance of NMJs varies with the species and the muscle under
The fundamentals of NMJ anatomy and physiology were de- investigation. Regardless of species or muscle, however, all
scribed in Chapter 1. This chapter explores the NMJ in more NMJs can be subdivided into three major areas: (1) presynaptic
detail, and the reader is encouraged to reread the pertinent sec- region, (2) synaptic space, and (3) postsynaptic region (Fig. 25¬
tion in Chapter 1. A brief review is included because it is neces- 1) 305 presynaptic region can be subdivided into (1) the ter-
sary to understand both the anatomic and physiologic details of minal Schwann cell process and (2) the unmyelinated nerve
how neural impulses normally induce muscle action potentials terminal, whereas the synaptic region is composed of the synap-
through a chemical intermediate step to appreciate fully NMJ tic space and its constituents. The postsynaptic region consists of
disorders. the (1) postsynaptic membrane and (2) junctional sarcoplasm.
I 127
I 128 — PART IV CLINICAL APPLICATIONS
Figure 25-/. A mammalian NMJ. A.The presynaptic por-

tion of the NMJ consists of the terminal Schwann cell
processes and a terminal bulbous nerve ending.The postsy-
naptic region is composed of the postsynaptic membrane and
the junctional sarcoplasm. Between these two areas of the
NMJ is the synaptic space or synaptic cleft. B,A superior view
of the NMJ revealing its "circular" appearance with individual
finger-like projections. C, Close-up view of a NMJ demon-
strating its cellular components. (From Fawcett DW: Bloom
and Fawcett: A Textbook of Histology. Philadelphia, W.B.
Saunders, 1986, with permission.)
PRESYNAPTIC REGION
Terminal Schwann Cell Process. A peripheral motor nerve
branches into a myriad of terminal axons, each of which forms a
NMJ with a single extrafusal muscle fiber. Thus, each muscle
fiber is innervated by one motor neuron; however, a single
motor neuron innervates multiple muscle fibers. The terminal
motor nerve is myelinated along its entire length except for the
bulbous axon termination (Fig. 25-2). 284 The last node of
Ranvier is located a few micrometers proximal to the terminal
bulb, thus demarcating the last myelinated segment. This last
remaining neural region is not completely bare but covered by
several tissue layers. A Schwann cell envelops the unmyelinated
aspect of the terminal bulb. Superficial to the Schwann cell is a
collection of epithelial cells, Henle's sheath, which lie just
proximal to the last node of Ranvier and extends to the terminal
bulb.823 The basement membrane of Henle's sheath extends dis-
tally over the last Schwann cell and is continuous with the base-
ment membrane, covering the related muscle fiber.284 Therefore,
the basement membrane is the only barrier, albeit incomplete,
between the synaptic and extracellular spaces.
Nerve Terminal. The bulbous nerve terminal contains a
number of subcellular components. About 15% of the nerve ter-
minal's volume is composed of mitochondria, usually located in
the center of the structure (Fig. 25 -3 ).268-270-284 Multiple smooth
synaptic vesicles containing acetylcholine (ACh), adenosine
triphosphate (ATP), and proteoglycans are also present. These
vesicles have a mean diameter of 50-60 nanometers (nm) and a
density of 50-70 vesicles per |im 2 of nerve terminal. 195J96-9S7 The
Figure 25-2. Electron micrograph showing three NMJs from synaptic vesicles tend to cluster close to the presynaptic mem-
slightly different perspectives.The last node of Ranvier forms the brane in small groups opposite membrane dense regions called
paranodal loops of myelin (asterisk). Henle's sheath ends just proximal active zones. 73176199 238 Giant synaptic vesicles occasionally
to the nerve's terminal bulb (arrows).That portion of the terminal bulb can be seen and may represent the membranous binding of mul-
not facing the postsynaptic aspect of the NMJ is observed to be cov- tiple smooth vesicles. 736 Coated vesicles also can be detected
ered by a Schwann cell (S). External to Henle's sheath and the terminal and are believed to represent the endocytotic precursors of
Schwann cell, multiple layers of an amorphous matrix constitutes the smooth vesicles.700-852-,0°2 Specifically, the terminal membrane
basement membrane. A few fibroblasts (F) can be seen external to the undergoes endocytosis, forming an empty vesicle surrounded
basement membrane. (From Engel AG:The neuromuscular junction. In by remnants from the extracellular membrane surface. This outer
Engel AG, Banker BQ (eds): Myology: Basic and Clinical. N e w York, coating is later removed, thus forming a smooth vesicle. Dense-
McGraw-Hill, 1986, pp 209-253, with permission.) core vesicles may represent vesicles containing a cholinergic
Chapter 25 NEUROMUSCULAR JUNCTION DISORDERS — I 129
type of transmitter but their true nature remains obscure.197-402
Microtubules and microfilaments not only contribute to the cy-
toskeletal structure of the nerve terminal but also participate in
the transport and direction of the vesicles toward the active
zones.73-801
The active zone is an intriguing structure of the nerve termi-
nal membrane. 73J76J99 - 238 Active zones are recognized in elec-
tronmicrography (EM) of the presynaptic membrane because of
an increased filamentous density to the membranous region and
an accumulation of smooth synaptic vesicles. Close inspection
of these active zones in the frog demonstrates a regularly recur-
ring raised ridge with a convexity facing the nerve terminal pro-
toplasm aligned perpendicular to the long axis of the nerve
terminal (Fig. 25 -4).73-399-400-402-544 Imbedded within this ridge is a
double row of parallel intramembranous, 10-12 nm parti-
cles.131238-400 In mammals, the terminal nerve is not tubular but
more bulbous. The active zones continue to be directly opposite
the postsynaptic junctional folds; however, they are consider-
ably shorter, and there is no convexity between the two rows of
intramembranous particles.318-786-788 In human intercostal muscle
there is an average of 2.6 active zones per Jim2 for the presynap-
tic membrane with about 51 intramembranous particles per Jim2
and approximately 19 particles per active zone.277-318-319
NEUROTRANSMITTER RELEASE
Release of the neurotransmitter ACh, like most complex Figure 25-3. Electronmicrograph of a normal rat NMJ.The
processes in the body, is truly a remarkable sequence of nerve's terminal region contains mitochondria (large irregularly
665.85o,850a. 55.965.ioo4a T h e detailed molecular aspects of ACh
s t e p s 8
release is only partially understood, and considerable work re- shaped objects in the center), multiple synaptic vesicles, conglomera-
mains to more fully define all of the steps involved. This section of vesicles surrounded by a membrane (asterisk), dense core vesi-
tion provides an admittedly incomplete overview. Briefly, cle (arrowheads), and active zones opposite secondary synaptic clefts
synaptic vesicles filled with ACh are initially attached to a fine, (arrows). Note the continuous nature of the basement membrane as it
.filamentous actin cytoskeletal network in the presynaptic por- flows over the nerve's terminal and postsynaptic muscle region and
'tion of the terminal nerve, which transports the vesicles close into the synaptic space.The highly convoluted postsynaptic membrane
to the presynaptic plasma membrane (Fig. 25-5). The vesicle is is quite obvious as are the mitochondria beneath the membranous
then bound to an active target zone in the plasma membrane convolutions. (From Engel AG:The neuromuscular junction. In Engel
near a calcium channel through a process called tethering. The AG, Banker BQ (eds): Myology: Basic and Clinical. New York, McGraw-
vesicle then docks with a molecular complex in the membrane Hill, 1986, pp 209-253, with permission.)
immediately adjacent to a calcium channel (see Fig. 25-5). 3I5a
After docking, an ATPase-dependent process facilitates a re- proteins (PEPs) have been identified. Two function as phos-
versible process known as priming of the synaptic vesicle. phatidylinositol transfer proteins (Table 25-1), and the third
Once primed, the synaptic vesicle can proceed to a step termed serves as phosphatidylinositol-4-phosphate 5-kinase. These
fusion, whereby its contents are released within 200-300 ms if substances are believed to be important in the process of lipid
the nerve terminal's calcium concentration reaches a critical kinase-mediated phosphorylation in the ATP-dependent vesicle-
level (see Fig. 25-5). After fusion, the empty vesicle undergoes priming step. A fourth type of cytosolic protein, identified as
reuptake (endocytosis) and is recycled for the next vesicle for- calcium-dependent activator protein for secretion (CAPS), in-
mation and packaging. Hence, there are four main processes teracts with several cytoskeletal proteins, as regulated by cal-
involved in ACh release: (1) tethering, (2) docking, (3) prim- cium ions. Its full role remains to be clarified.
ing, and (4) fusion. A slightly more detailed appreciation of the In addition to cytosolic proteins, there are a number of vesi-
molecular aspects of these four processes is appropriate. The cle-associated proteins (VAMPs or also called synaptobrevin)
molecular process of neurotransmitter release detailed below is (Fig. 25-6). A number of VAMPs have been identified as SNAP
presented in general terms with the understanding that some receptors and are referred to as SNAREs. SNAREs associated
specifics may change for different neurotransmitters, depend- with the synaptic vesicle are known as vesicle-associated
ing on the specific body site (i.e., central or peripheral nervous SNAREs or v-SNAREs (Table 25-1 ). 3,5a Another vesicle pro-
system). tein, known as synaptotagmin, binds calcium as well as a target
Initially, investigations into the general aspects of neurotrans- protein SNARE (t-SNARE) known as syntaxin (see below).
mitter release identified a number of cytosolic proteins con- Synaptophysin is also an integral vesicle membrane protein that
tained within the terminal nerve associated with this process (Table binds with VAMP and may act as a kind of "molecular clamp"
25-1). Proteins confirmed to be involved in the process are N- to prevent vesicle docking until all of the necessary proteins are
ethylmaleimide-sensitive fusion protein (NSF) and a soluable aligned and ready to function. Synapsin is a vesicle protein pro-
protein that attaches to NSF, called soluable NSF attachment jecting into nerve terminal cytoplasm and is believed to cross-
proteins (SNAPs) (Fig. 25-6). Three priming-in-exocitosis link the vesicle with the actin cytoskeleton. It also may have a
Figure 25-4. Sequential magnifications of the frog

NMJ. A,The terminal axon collaterals form the tubular axon
terminal interfacing with the skeletal muscle fibers, which
form the NMJs. Note that the nerve terminals are not cov-
ered by myelin but only by a single Schwann cell and its cyto-
plasmic extensions. B, Close-up view of the synaptic region
demonstrates the orientation of the raised active regions
with synaptic vesicle clustering. Opposite the active zones are
the synaptic folds of the convoluted postsynaptic membrane.
C, Extreme close-up view of an active zone shows the some-
what raised dual membranous region with a double row of
intramembranous particles on the ridges. Smooth synaptic
vesicles are in close proximity to this active zone. In the
synaptic cleft is located the basement membrane's fibrous
matrix containing acetylcholinesterase. Finally, the postsynap-
tic membrane has multiple ACh receptors imbedded primar-
ily in the summits of the membrane surface facing the cleft In
mammals, the primary difference is a disk-like instead of
tubular nerve terminal and less organization to the active
zones. (From Lester HA:The response to acetylcholine. Sci
Am 1977;1236:107-118, with permission.)
postdocking function, which remains to be fully clarified. The

protein Rab3 assists in the transport of the vesicle and facilitates
vesicle docking and fusion. Rabphillin 3A interacts with Rab3
Mobilization from the Synaptic cytoplasm to help regulate Rab3; it also may play some role in sensing cal-
reserve pool and new cium ions.
|x SSV synthesis Recycling A final set of five proteins involved with neurotransmitter re-
lease is integral to the nerve terminal's plasma membrane (see
Table 25-1, Fig. 25-6). The first group of proteins are known as
syntaxins. These proteins are designated as t-SNAREs and are re-
sponsible for vesicle docking with the membrane as well as mem-
brane fusion and possibly calcium channel regulation. Another
important plasma membrane protein, known as SNAP-25, joins
with syntaxin and VAMP to form a stable complex. This protein
is also a target for botulinum toxins A and E. Unc-18 (also known
Figure 25-5. Neurotransmitter release. Mobilization of the ACh as Munc-18) is a protein that binds tightly with syntaxin and pre-
vesicle occurs through an interaction with an intracellular actin cy- vents syntaxin from binding with SNAP-25, thus serving as a reg-
toskeleton. A series of protein-protein interactions then binds the ulator or molecular clamp. The protein Hrs-2 preferentially binds
vesicle to the synaptic plasma membrane.The vesicle is first tethered, to SNAP-25, but this binding is inhibited by the influxing calcium
then it docks with the membrane after which it is primed for re- during synaptic transmission. Hrs-2 also may serve as a molecu-
lease. Then it releases its contents through fusion after calcium ion lar clamp (similar to VAMP-synaptophysin and syntaxin-Unc-
entry into the terminal nerve. (From Schiavo G, Sternbeck G: 18), preventing SNAP-25 from joining with other SNAREs until
Molecular analysis of neurotransmitter release. Essays Biochem sufficient calcium is present. Finally, Rab3 interacting protein
1997;32:29-41,with permission.) (RIM) is believed to regulate vesicle fusion.
Chapter 25 NEUROMUSCULAR JUNCTION DISORDERS — 1 131
TABLE 25-1. Neurotransmitter-Associated Proteins
Name Properties Functions
Cytoplasmic proteins
NSF Low ATPase activity Primes synaptic vesciles
ATP-binding domains Recruits NSF to docking
SNAPs Three isoforms complex
(a,b,g)
Vesicle priming in some
PEP proteins Pin transfer protein cells
Pln-4-phosphate kinase Calcium-dependent step
CAPS Interacts with cyto-
skeleton proteins
Moderate affinity for
calcium
Synaptic vesicle-associated proteins v-SNARE; vesicle docking;
VAMP (synap- Target of BoNT membrane fusion
(tobrevin) B, D, F, G
Synaptotagmin N-terminal Calcium sensor; vesicle
transmembrane docking; vesicle
domain recycling
Synaptophysin Four transmembrane Molecular clamp;
domain membrane fusion
Sy naps in Interacts with synaptic Tethers synaptic vesicle
vesicle and actin to cytoskeleton; helps
cytoskeleton regulate synaptic vesicle Ca2+
exocytosis channel
Rab3 Associated with synap- Vesicle targeting, docking,
tic vesicle; cycles and membrane fusion Figure 25-6. Synaptic vesicle-associated proteins.A number of
between cytoplasm the primary proteins associated with neurotransmitter release are de-
and vesicle membrane. picted in relationship to their presumed positions. (From Zheng X,
Calcium sensor; regulates Bobich JA:A sequential view of neurotransmitter release. Brain Res
Rabphillin 3A Zinc domain Bui 1998;47:1 17-128, with permission.)
Rab3 cycling
Plasma membrane proteins t-SNARE; vesicle docking; t-SNAREs (syntaxin and SNAP-25) to form a stable docking
Syntaxin Transmembrane
protein; target membrane fusion; protein complex (Figs. 25-6 and 25-7). Furthermore, synapto-
for BoNT CI. calcium channel physin, Unc-18 (Munc-18) and Hrs-2 also are involved in this
regulation complex and may act as regulators or clamps to ensure the
SNAP-25 t-SNARE; membrane
proper sequence of docking events and prevent premature re-
Integral membrane lease of the vesicle's contents. RIM (plasma protein) interacts
protein; target for fusion with Rab3 (vesicle protein) to assist in the specificity of the
BoNT A & E docking process. Synaptotagmin also is believed to be involved
Unc-18 Interacts with Possible molecular clamp; in this process. It may be involved not only in vesicle docking
syntaxin vesicle docking but also in linking the calcium sensory to the protein complex as
Hrs-2 Interacts with Vesicle docking/possible a whole. Once the complex is formed, a high-affinity binding
SNAP-25 membrane fusion site is created for the binding of SNAPs to this complex. The
RIM Zinc binding Vesicle docking/possible binding of SNAPs causes NSF and PEPs to fuse with this pro-
membrane fusion tein complex and subsequently hydrolyze ATP, thereby priming
the vesicle as a necessary step for vesicle fusion if the calcium
BoNT, botulinum toxin. concentration reaches a necessary threshold (see Fig. 25-7). So
(Modified from Zheng X, Bobich JA:A sequential view of neurotransmitter re- far the vesicle has been docked and primed, but it has not yet
lease. Brain Res Bui 1998:47:1 17-128.)
fused with the plasma membrane and awaits a rise in intracellu-
lar calcium ion concentration. Neurotransmitter can be released
To explain neurotransmitter release, the above information is in as short a time as 150 us following presynaptic excitation,
combined in the so-called SNARE hypothesis, according to and the interval between calcium entry and exocytosis is less
which a v-SNARE binds with a t-SNARE to form a specific than 60 us.8,9A Hence, it is reasonable to assume that the binding
union. As noted above, the synaptic vesicles are attached to an complex occurs adjacent to P/Q-type calcium channels.
actin cytoskeleton and mobilized toward the terminal nerve's Calcium ion entry results in ion triggering and binding with
plasma membrane. After the synaptic vesicle has been brought synaptotagmin (calcium sensor), which, in conjunction with
into close proximity with the plasma membrane, the first step in synaptophysin, may induce the close approximation of the vesi-
the release process is docking. The vesicle docking process is cle and plasma membranes from the SNARE complex to fuse
initiated by binding of the v-SNARE known as VAMP to the with a resultant channel or pore production (see Fig. 25-7). The
A
major or primary gap (cleft) between the nerve terminal and
muscle and multiple secondary clefts, thus forming postjunc-
DOCKING • PRIMING tional folds extending into the postsynaptic region (see Figs. 25¬
1 and 25-2).284 On average, the distance between the presynaptic
membrane and summits of the postsynaptic folds is about 70
nm. There is direct communication between the primary synap-
tic space and all of the secondary synaptic clefts. The only lat-
eral boundary to the synaptic space is the porous basement
membrane, thereby permitting communication between the
synaptic space and hence synaptic clefts with the extracellular
region. Communication also exists between the muscle fiber's
transverse tubules and the secondary synaptic clefts.1003
The synaptic cleft is not empty but filled with an extension of
the basement membrane covering the external surface of both
the terminal nerve and muscle fiber. A relatively dense basal
layer extends across the center of the synaptic space with small
filamentous extension projecting from the central region and
FUSION -* CO-TRIGGER forming bridges between the presynaptic and postsynaptic
membranes. This aspect of the basement membrane is believed
to serve multiple important functions. It may have a directional
role in the guiding of regenerating nerve terminals to the previ-
ous site of NMJs as well as maturation of this struc-
ture.117-342*638-839 Of particular importance in mature NMJs is
acetylcholinesterase (AChE), the enzyme responsible for de-
grading ACh into acetate and choline. AChE is attached to the
basement membrane through a collagen tail and is present only
in the synaptic region.840
POSTSYNAPTIC REGION
Postsynaptic Membrane. The postsynaptic membrane is
B highly convoluted and consists of multiple folds of junctional
sarcoplasm. The major consequence of the junctional folds is a
significant increase in surface area compared with the presynap-
tic membrane. It is estimated that the postsynaptic membrane
has a surface area 8-10 times greater than the presynaptic mem-
brane. 268.270.843 Qf interest, the junctional folds are not well
formed at birth but develop with age. 459 The summits of these
folds assume a perpendicular arrangement to the longitudinal
extent of the primary synaptic cleft opposite the presynaptic ter-
minal. Generally, fast-twitch muscle fibers have more pro-
VAMP % Munc-18 nounced and extensive junctional folds than slow-twitch muscle
fibers.244-740
9* •m Calcium ions The junctional folds contain numerous intracellular organelles
such as microtubules, ribosomes, and different types of tubular
Figure 25-7. Neurotransmitter release sequence.The synaptic and vesicular structures (see Fig. 25-3). Of particular note is the
vesicle is docked to the plasma membrane through the formation of a thicker and denser appearance of the junctional fold summit.
stable docking complex consisting ofVAMP binding to SNAP-25 and Special imaging studies have demonstrated that this region's
syntaxin.Vesicular priming is followed by calcium entry and fusion of membrane contains small particles, 6-12 nm in diameter, with a
the vesicle, which expels its contents. (From Zheng X, Bobich JA:A se- spatial density reaching 10,000 particles per jim2.809 The density
quential view of neurotransmitter release. Brain Res Bull I998;47: of these membrane structures decreases by more than 95% as
I 17-128, with permission.) one proceeds into the recesses of the secondary synaptic clefts.311
Toxins (e.g., alpha bungarotoxin, a snake poison from the
banded krait Bungarus multicinctus, a cobra relative) that specif-
net result of this process is release of the neurotransmitter. The ically and irreversibly bind to the ACh receptor (AChR) can be
membranous portion of the vesicle is then recycled. radiolabeled and exposed to NMJs. There is a very good correla-
tion between the location of the toxin and the small intramem-
SYNAPTIC SPACE branous particles, and it is generally accepted that the AChR and
above-noted particles are one and the same structure. These re-
As the name implies, the synaptic space or synaptic cleft is ceptors are maintained in compact arrangements by the filaments
the region located between the presynaptic and postsynaptic within the basement membrane.310-628-629
membranes of the nerve terminal and muscle, respectively. The There are two types of AChRs: nicotinic and muscarinic recep-
morphology of the synaptic space may be subdivided into the tors. Nicotinic receptors respond to nicotine but not muscarine
Chapter 25 NEUROMUSCULAR JUNCTION DISORDERS — 1133
(poison derived from the mushroom Amanita muscaria).
Conversely, muscarinic receptors bind muscarine but not nico-
tine. In addition to the NMJs, nicotinic receptors are found at
the synapses between pre- and postganglionic neurons of both
the sympathetic and parasympathetic nervous systems.
Muscarinic receptors are located in all of the organs innervated
by the postganglionic neurons of the parasympathetic system as
well as organs innervated by postganglionic cholinergic sympa-
thetic nerves.
Junctional Sarcoplasm. A small region of the muscle fiber
sarcoplasm, the junctional sarcoplasm, overlies the myofibrils
and extends into the junctional folds.297 Contained within the
junctional sarcoplasm are multiple cellular organelles such as
mitochondria, Golgi complexes, smooth and rough endoplasmic
reticulum, vesicles, lysosomes, and various types of filaments.
Cluster of 5-10 myonuclei are also found here and code mes-
senger RNA for the construction of AChRs.316'644-880 The junc-
tional sarcoplasm's function is to manufacture and degrade
AChRs, maintain an appropriate ionic balance for the sacroplas-
mic constituents, and synthesize AChE for the synaptic space.
ACh Receptor. The AChR is a transmembrane complex
consisting of four different types of glycoprotein subunits des-
ignated a, (3, 8, and £. There are two a subunits (Fig. 25¬
8 ) 394.5oi.56i.78i.79! I n f e t a l AChR, there is a y subunit instead of the
£ subunit. These glycoproteins are believed to fit together in a
manner similar to the staves of a barrel with a central channel.
An ACh binding site is thought to be located on the extracellular
surface of each a subunit.26139171-918 The central channel is hy-
drophilic and has a narrow middle portion that expands toward
the extracellular and intracellular regions similar to that of an
hourglass configuration. In the resting state the central narrow
regions of al! five subunits meet in opposition, preventing any
substances from passing through. Physically, the entire AChR is
approximately 11 nm long with a central diameter of 8 nm.501
The long axis of the receptor is perpendicular to the junctional
fold's membrane surface, with about 5.5 nm protruding from
the extracellular surface to face the synaptic space and 1.5 nm
extending into the intracellular junctional sarcoplasm. The
AChRs are connected in clusters by rapsyn, a 43-kD protein.28
Rapsyn also serves to anchor the AChRs to the utrophin-glyco-
protein complex. 28 463 This complex is similar to the dystrophy-
glycoprotein complex except that utrophin (dystrophin-related
protein) replaces dystrophin (see discussion of the dystrophin- Figure 25-fi. Acetylcholine receptor (AChR).The AChR is be-
glycoprotein complex in Chapter 27). In addition, the AChR- lieved to be a composite of five glycoprotein subunits (a, a, (3,8 and 7; in
utrophin-glycoprotein complex is connected to the extracellular adults, the y subunit is replaced with an £ subunit) surrounding a central
matrix by agrin, a basement membrane protein. passage that is closed by opposition of the subunits in the resting state.
AChR subunits are synthesized by ribosomes and then trans- Two ACh receptors are located on the alpha subunits, as is the main im-
ported to the membrane surface by way of the Golgi cister- munogenic region (MIR). A,Acetylcholine is assumed to have been re-
nae.562 The half-life of an AChR in the junctional membrane is leased into the synaptic space. It is going to bind with the two ACh
about 8-10 days. 826 The "old" receptors are internalized by the receptor sites on the AChR. B, Once ACh binding has occurred, the
process of endocytosis and transported to lysosomes for degra- AChR undergoes a conformational change and its central pore opens,
dation through an intricate network of intracellular tubules. The allowing sodium (Na + ) and calcium (Ca2+) ions to enter the postsynaptic
AChRs are not recycled but replaced by newly synthesized re- region of the muscle cell while potassium ions (K+) attempt to exit the
ceptors. The cross-linking of the AChR by antibodies in patients muscle cell. C.This ionic movement results in a depolarization of the
with myasthenia gravis accelerates the internalization of the re- postsynaptic membrane, which in turn induces the AChR to expel the
ceptors and shortens their half-life (see below). ACh and close its central pore, stopping ionic current flows.
Also located on the postsynaptic muscle membrane are volt-
age-gated sodium channels, which are concentrated in the
depths of the secondary folds. The density of these sodium Interactions between the distal motor nerve terminal and
channels is 5-10-fold higher in the endplate region than in more muscle involve more that just the release of ACh and the bind-
distant regions.463 The increased density of the sodium channels ing to its receptor. Neuregulins and calcitonin gene-related pro-
at the endplate increases the probability of an endplate potential tein are synthesized by nerves and are capable of inducing
to trigger an action potential. AChR gene transcription in nearby muscle fibers.463 Nitric
action potential depolarization of the axon terminal. Because
the myelin sheath ends before the formation of the nerve's ter-
minal enlargement, it is questionable whether the action poten-
tial actually traverses the terminal nerve membrane and
depolarizes it or stops at the last node of Ranvier with a result-
ing electrotonic spread of current. Evidence indicates that the
action potential propagates into and directly depolarizes the ter-
minal bulb, although the electrotonic spread of current also may
play some role.110-472 The concept of electrotonic current spread
is simply that the negative sink at the last node of Ranvier, prox-
imal to the terminal bulb, creates a large enough current that it
"attracts" sodium ions on the surface of the nerve terminal, cre-
ating an ionic current flow. The further the ions are from the
current sink, the less the attraction. The voltage change associ-
ated with this declining current flow over distance is also less. If
the current sink is large enough, a sufficient voltage change can
be created at a distance to alter the transmembrane voltage and
result in nerve terminal depolarization.
The propagation of neural depolarization into the terminal
axon results in the release of ACh. As the wave of depolarization
traverses the terminal axon bulb, voltage-gated calcium channels
open for approximately 1 ms and allow calcium ions (Ca 2+ ) to
Figure 25-9. Calcium ion transport. After free calcium ions enter
enter the terminal bulb down their concentration gradient from
the active region (DP = dense projections), they rapidly diffuse away
about 2-30 millimolar outside to 0.1 micromolar inside the nerve
once synaptic vesicles (SV) have been induced to release their con-
terminal.41 Removing calcium ions from the extracellular
tents.The calcium ions are then actively bound by calcium-binding pro-
medium results in failure of ACh release; however, experimental
teins (CaBrPr) and sequestered in the smooth endoplasmic reticulum
injection of these ions into the nerve terminal causes ACh re-
(SER) and mitochondria (Mito). After the free calcium ions have been
lease .474.476.477.478 Calcium channels are located at the active sites
either bound or sequestered, they are finally eliminated from the ter-
near the synaptic vesicles. The voltage-gated calcium channels
minal by a sodium/calcium exchange mechanism (Na + /Ca 2+ circle in
open in response to depolarization of the terminal nerve by un-
the terminal membrane). (From Blaustein MP, Ratzlaff RF, Schweitzer
dergoing a conformational change. Intracellular calcium ions
ES: Calcium buffering in presynaptic nerve terminal. II: Kinetic proper-
bind to synaptogamin and facilitate the fusion of synaptic vesicles
ties of the non-mitochondriai calcium sequestration mechanism. J Gen
with the terminal membrane. Evidence in the frog suggests that
Physiol 1978;72:43-66, with permission.)
four calcium ions are required to bind or interact in some fashion
for the synaptic vesicle to extrude its contents. Similar relation-
ships may hold in mammals.25-225 " 5 This process of voltage-de-
oxide synthetases is bound to syntrophin in the utrophin-glyco- pendent calcium ion entry into the nerve terminal and subsequent
protein complex and may serve to increase nitric oxide. Nitric ACh release (time from action potential arrival at the nerve termi-
oxide, in turn, may diffuse from its point of synthesis and serve nal to ACh release) accounts for the greatest proportion of synap-
as a second messenger influencing cell-signaling functions.463 tic delay. Specifically, the time from action potential arrival at the
nerve terminal to action potential observation at the postsynaptic
membrane is about 75-100 |is. Approximately 50 |is are required
PHYSIOLOGY O F NEUROMUSCULAR for calcium ions to enter the nerve terminal and facilitate ACh re-
lease.110-463-477-568 The calcium channels do not open until the peak
JUNCTION TRANSMISSION of the nerve terminal's action potential is achieved, and calcium
The actual mechanism whereby the above-described conductance peaks about the time the neural action potential has
anatomic structures participate in the conversion of an electrical dissipated, thus suggesting that a large portion of the delay can be
impulse into a chemical one, which in turn generates a muscular attributed to calcium activation.567
action potential, is fascinating. Although every step in the elec- The exact fate of calcium after the release of ACh is rather
trochemical transduction of neural impulses is not known, con- obscure. Free calcium ions are present for only a few millisec-
siderable information is available to gain an overall appreciation onds, after which time the ions most likely freely diffuse away
of the complexity involved in the process of NMJ transmission. from the active sites. Intracellular calcium is removed from the
Once the normal process of NMJ transmission is appreciated, terminal by both a coupled sodium/calcium exchange mecha-
considerable insight can be gained into various pathologic nism and an uncoupled extrusion process.42-76-77-222-783 Addi-
processes affecting the NMJ. The actual manner in which neural tionally, energy-dependent, high-affinity calcium-binding
impulses result in a muscle action potential is similar to that de- proteins are present in the nerve terminal and constitute an
scribed for the anatomic aspects of the NMJ (i.e., presynaptic, uptake mechanism of reducing calcium ion concentration (Fig.
synaptic space, and postsynaptic regions). 25-9).43-78-79 Calcium ions also may be sequestered in the smooth
endoplasmic reticulum64 and mitochondria.' 01
PRESYNAPTIC REGION The calcium ions enter the nerve terminal and facilitate the
release of ACh. After calcium entry into the presynaptic termi-
The initiating event in NMJ transmission leading to action nal, there is fusion of synaptic vesicles with the termi-
potential induction in the associated single muscle fiber is nal 129.i3o.i31.399.400.404.948 The vesicle membrane is actually added
to the axon terminal membrane and increases its overall length
(Fig. 25-10).399-403-404-405-655 This fusion of the vesicle membrane
and the nerve terminal membrane leads to the release of the
vesicle's contents through exocytosis. Within several minutes of
vesicular collapse into the terminal membrane, there is an in-
creased number of coated vesicles in the more superior margins
of the terminal bulb near the Schwann cell margins. These
coated vesicles are then incorporated into vesicular cisternae
with removal of their cellular coats, thus forming new vesicles.
It is unclear how and at what point in the cycle of vesicular for-
mation the vesicles are filled with ACh.
Approximately 200,000-400,000 individual synaptic vesicles
are contained in most nerve terminals, with 1,000-30,000 lo-
cated in the immediate vicinity of the active zones.50 905 A single
synaptic vesicle contains approximately 5,000-10,000 ACh
molecules.49-202-3,4-5,3-6°9-652 When an action potential excites the
terminal axon, the amount of calcium that enters is sufficient to
facilitate the release of approximately 50-100 synaptic vesicles Figure 25-/0. Synaptic vesicles.The synaptic vesicles are believed
in mammalian NMJs and 100-200 vesicles in frogs.521 At each to be recycled vesicular membrane after neurotransmitter exocytosis.
nerve terminal, a number of synaptic vesicles, abbreviated as Initially, the synaptic vesicle collapses into the terminal axon's membrane
n, are positioned near active zones and ready to be released. at the active sites.This added membrane serves to lengthen the total
These vesicles are assumed to have a probability of release amount of terminal membrane.The additional membrane most likely
(p). The contents of each synaptic vesicle is called a quantum gains the extracellular proteinacious coat and moves toward the mar-
of ACh, and the total number of quanta released per action po- gins of the terminal axon. An equal amount of membrane to that added
tential is known as the quantal content and abbreviated m. The at the active zone undergoes endocytosis at the margins of the Schwann
amount of ACh or number of quanta (m) extruded during an cell region to coalesce into noncoated cisternae. Synaptic vesicles are
action potential is the result of the total number of vesicle avail- then reformed from the cisternae to complete the vesicular cycling of
able (n) multiplied by the probability of release: m = np. In the membrane. (From Heuser JE, Reese TS: Evidence for recycling of synap-
resting state, p is very small; consequently m is minimal. On the tic vesicle membrane during transmitter release at the frog neuromus-
other hand, after an action potential, p is dramatically increased cular junction. J Cell Biol 1973;57:315-344, with permission.)
secondary to calcium entry, resulting in a large m.
Once the vesicles in close proximity to the membrane have rates. Approximately 1,000 vesicles or quanta are located along
released their ACh content, it stands to reason that there are the active zone region constituting the immediately available
fewer vesicles than prior to the action potential. As a result, ACh store, and about 300,000 vesicles are present within the
there needs to be a mechanism whereby the collapsed vesicles mobilization or depot store.439-496 A transition "compartment" of
are replaced from the group of vesicles in the immediate vicin-
ity of the active zones. As noted above, the membrane is recy-
cled, but the neurotransmitter ACh contained in the vesicles also Stationary
must be replaced. It is possible to measure directly the amount
of ACh contained in the nerve terminal before and after nerve
stimulation at rates comparable with physiologic muscle con-
tractions. 777 The amount of ACh in the nerve terminal remains Together =
relatively constant despite its continuous release; therefore, ACh Releasable
synthesis can apparently keep pace with physiologic nerve ter-
minal discharge rates. Bathing the NMJ with hemicholinium-3, Depot
which blocks the reuptake of choline across cell membranes, re- Surplus
sults in a significant decline in the total amount of ACh released
during repetitive activation of the nerve. It is not possible to de- Available
plete the nerve terminal of all ACh, because about 20% of the
prestimulation total always remains. Similar observations are
noted in sympathetic preganglionic nerve terminals.74 Figure 25-11.Model of ACh depletion at NMJs under various
An immediately available store of ACh in the region of active stimulation conditions. The two boxes contained in the larger
zone is readily released during neural activation (Fig. 25-ll). 438 dotted square represent ACh stores available for release during NMJ
The ACh released during the first several stimulations is greater activation.After the immediately available store is quickly depleted.ACh
than that released during the ensuing stimulations, which levels release declines during initial stimulation but then reaches a stable
off to a relatively constant amount. Transport from the larger re- amount-This stable amount can keep pace with stimulation, suggesting a
serve depot of ACh to the active zone region reaches a steady- larger depot store that interacts (arrows) with the immediately available
state value during repetitive activation of the nerve terminal at store. A reserve 20% store (stationary box) can interchange ACh with
physiologic rates. The immediately available and depot store the depot store but cannot be eliminated, regardless of stimulation
constitute the releasable ACh store. During physiologic condi- time or rate. Finally, a surplus store of ACh or its constituents in the
tions, the depot store is obviously replaced from sources outside plasma is available to replenish the depot compartment. (From
the nerve terminal because the ACh released continues essen- Hubbard Jl: Microphysiology of vertebrate neuromuscular junction
tially indefinitely during prolonged stimulation at physiologic transmission. Physiol Rev 1973;53:674-723, with permission.)
roughly 10,000 vesicles is readily available to replace the im- catalyzing another ACh molecule. This process of ACh cataly-
mediately available vesicles upon release. Compartmental- sis is one of the fastest enzymatic process known and occurs at a
ization of ACh is simply a method of "visualizing" ACh release, rate of 5 ACh molecules per millisecond.810-969
because no defining anatomic boundaries form identifiable After liberation of ACh through synaptic vesicle fusion with
NMJ partitions. the presynaptic membrane, the ACh diffuses across the 50-70
nm synaptic space in about 50 jis.204-254-473 There are approxi-
SYNAPTIC SPACE mately 2 x 107 molecules of AChE per NMJ, and each molecule
of AChE has two receptor sites. There are similar amounts of
Once a quantum of ACh is released, it diffuses into the synap- AChR on the postsynaptic membrane. 6 - 48138438 However, the
tic space. Recall that the synaptic space is filled wifh the base- AChRs are concentrated primarily on the summits of the
ment membrane material. This matrix has bound to it three postjunctional folds at a density of 15-30 x 103/p.m2, while the
different types of cholinesterase enzymes: (1) acetylcholin- AChE is uniformly distributed throughout the basal lamina at a
esterase (AChE), (2) butyryl cholinesterase (pseudocholin- density of 2-3 x 103/(im2. Thus, the comparative density of the
esterase), and (3) eserine-resistant carboxylic esterase.152-210-290-439-810 AChRs is 5-10 times greater than that of AChE and promotes a
Only AChE is important in the process of neuromuscular trans- rather efficient capture of ACh compared with AChE. On re-
mission; blocking the other two enzymes has little, if any, effect lease from the nerve terminal, 25-50% of the ACh is immedi-
on neuromuscular transmission. AChE is a serine esterase; thus, ately bound to AChE and hydrolyzed.110-758 The remaining
serine is the site where ACh is catalyzed. This catalytic site is 50-75% of ACh binds to the postsynaptic membrane AChRs.
anionic (negatively charged) and attracts the positive quater- After ACh is released from the AChR, it may be hydrolyzed by
nary ammonium ACh group by means of electrostatic forces. the AChE in the synaptic cleft. As noted above, the two prod-
When ACh and AChE combine, ACh is broken down into ucts of ACh breakdown are acetic acid and choline. The acetic
choline and acetate. The acetate in turn combines with water to acid presumably diffuses away and is ultimately removed. Of
from acetic acid, while the reconstituted AChE is capable of importance to our present discussion is the fate of the choline
generated through ACh breakdown.
The nerve terminal takes up approximately one-half of the
choline, and the remaining choline most likely ends up in the
plasma (Fig. 25-12).438-545-637-777 The choline enters the nerve ter-
minal by means of a carrier mechanism that is inhibited by the
drug hemicholinium-3. Once in the nerve terminal, choline
combines with acetyl coenzyme A (acetyl-CoA) in a reaction
catalyzed by the cytoplasmic enzyme, choline-o-acetyltrans-
ferase (ChAc). Mitochondrina may be the source of acetyl-
CoA, but it cannot directly penetrate the mitochondrial
waU j ^ e intramitochondrial acetyl-CoA may translo-
248,506,956.957
cate to the nerve terminal's cytoplasm by first combining with

oxaloacetate. Subsequent reaction with citrate synthase yields
diffusable citrate that may be converted to acetyl-CoA through
ATP citrate lyase. An alternative method of translocating acetyl-
CoA across mitochondria is hydrolyzing it to acetate by acetyl-
CoA hydrolase. Acetate crosses the mitochondrial membrane
and then is converted back to acetyl-CoA via acetyl-CoA syn-
thetase. Regardless of the actual pathway, ACh formation is
both efficient and rapid, as evidenced by continued NMJ trans-
mission even at rapid rates of neural activation. In fact, the
process of ACh formation is accelerated by elevated rates of
neural stimulation.777
Once the ACh is formed, it is unclear exactly how it is pack-
Figure 25-12. A C h synthesis and vesicular storage. Choline is aged into the synaptic vesicles, i.e., during or after vesicular for-
absorbed into the nerve terminal after vesicular content release and mation. The synaptic vesicle membrane probably contains an
actively absorbed from the plasma space (not shown). Choline then ATP-dependent carrier mechanism that actively pumps in posi-
combines with acetyl-CoA (AcCoA) by means of the enzyme choline- tively charged hydrogen ions (H+).608-885 Subsequently, an ion-
o-acetytransferase (CAT).The formed ACh is then packaged in an un- exchange transmembrane protein may import the positively
clear fashion into synaptic vesicles and readied for release.A proposed charged ACh molecule in exchange for the hydrogen ions. This
mechanism is an energy-dependent pump acting to increase the intrav- allows the vesicle to achieve an ACh concentration of about 300
esicular concentration of positively charged hydrogen ions and nega- millimoles compared with the nerve terminal's cytoplasmic
tively charged ATP. A transmembrane protein most likely then concentration of 30 millimoles. Additional substances, such as
exchanges hydrogen ions for the positively charged ACh.The enzyme ATP and proteins, also are located within the vesicles to main-
acetyl cholinesterase (AChE), which is responsible for ACh hydrolysis tain both an ionic and osmotic equilibrium and to prevent the
into choline (Ch) plus acetate (Ac), is located in the synaptic space vesicle from either collapsing or bursting because of osmotic
bound to the basement membrane. (From Jones SW: Presynaptic pressures.
mechanisms at verterbrate neuromuscular junctions. In Salpeter MM There are four methods of ACh secretion from the motor nerve
(ed):The Vertebrate Neuromuscular Junction. New York, Alan R. Liss, terminal. The nerve impulse propagation into the axon terminal,
1987, pp 187-245, with permission.) with entry of calcium ions facilitating the fusion of approximately
C h a p t e r 25 NEUROMUSCULAR JUNCTION DISORDERS — 1137
50-200 vesicles, is one manner of ACh release.50110-437-488 A negative interior of the cell. At the cell's negative equilibrium
second type of ACh release consists of spontaneous fusion of potential (-80 mV), the high extracellular Na + concentration re-
synaptic vesicles with the presynaptic membrane extruding the sults in the summated electrical and concentration forces gener-
contents of only one vesicle at a rate approximating ating a large infusion of Na + into the cell (i.e., a large positively
0.2-0.03/second.20-271 The source of nerve terminal calcium for direct intracellular current). It takes about 200-300 JIS for the in-
this type of spontaneous release is probably the mitochondria. wardly directed Na + current to peak, and the current flow lasts
There are also two calcium-independent methods of ACh secre- about 1 ms with a net transfer of roughly 5 x 104 positive
tion. One is associated with large amounts of ACh release and is ions.323-524 The inward-flowing, positively charged sodium ions
insensitive to the concentration of calcium either inside or out- result in an elevation of the resting membrane potential toward
side the nerve terminal but increases in frequency proportional the equilibrium potential of sodium (+55 mV). As the resting
to temperature, vinblastine, and 4-inoquinoline.493-555-583-936-937 membrane potential becomes less negative, the electrical gradi-
This increased amount of ACh release may be related to the so- ent maintaining K+ in the cell decreases, and the concentration
called giant synaptic vesicles, which are more abundant after gradient of K+ causes an extracellular flow of K+. This mecha-
tetanic stimulation.309-401-756 The remaining mechanism of ACh nism, in part, attempts to restore the resting membrane potential,
release from the nerve terminal occurs in a continuous nonquan- but the gate closes too quickly. Gate closure reduces membrane
tal manner, while the nerve terminal is at rest.482-520-658-939-975 conductance to Na + —probably enough to restore the resting
membrane potential, according to the Goldman-Hodgkin-Katz
POSTSYNAPTIC REGION equation (see Chapter 1). The relatively small amount of Na +
entry can be handled by the cell through diffusion, passive potas-
For discussion puiposes, it is most illustrative first to consider sium leak currents, and a sodium/potassium energy-dependent
the action of one synaptic vesicle release, as may occur in the exchange mechanism. All serve to discharge any capacitance
spontaneous fusion of a synaptic vesicle with the presynaptic built up on the membrane and to restore ionic equilibrium. The
membrane. As previously noted, about 0.2-0.03 times per most important factor in depolarization/repolarization is not the
second a synaptic vesicle in the nerve terminal spontaneously total amount of ion transfer, but alterations in ionic conductance
liberates its roughly 10,000 molecules of ACh, thus generating (see Chapter 1).
one quantum of ACh. The molecules of ACh cross the synaptic The AChR stays open for only about 1 ms, after which time it
space in approximately 50 JLIS with about 25-50% of the ACh closes, blocking further ions from either entering or escaping
immediately hydrolyzed by AChE.758 Let us assume that 75% of the postsynaptic region. The major mechanism responsible for
the ACh escaped hydrolysis on the first pass. Recall that the closing the gate is believed to be the membrane potential. In
region of vesicle release typically spans a postjunctional sec- other words, the AChR is responsive to both a chemical and
ondary cleft with roughly 6,000-10,000 AChR/fim2 on the sum- electrical stimulus; it is chemical- and voltage-gated. At the
mits of the postjunctional folds. The ACh is then free to bind in resting membrane potential, the AChR responds to the ACh
a 2:1 ratio with AChRs within a region with a radius of about chemical stimulus by undergoing a conformational change and
0.3 |J.m from the release site.91-524 Beyond this somewhat circular permitting Na+ to enter the muscle cell's NMJ (endplate region)
region, few ACh molecules are bound by AChRs. Thus, small (see Fig. 25-8). An elevation in Na+ conductance depolarizes or
regions of postsynaptic membrane containing AChRs opposite increases the local membrane potential by making it less nega-
the ACh release site become saturated with ACh and generate tive. At some undefined, less negative potential close to
focal regions of activated AChRs. sodium's equilibrium potential, the voltage-gated properties of
After the binding of two ACh molecules with each AChR, the AChR result in a conformational return to the resting state,
there is a conformational change in the AChR (see Fig. 25- ejecting the two ACh molecules, which are hydrolyzed by
g) i83.i84.205.359.435.589.785 T h i s change results in the opening of a cen- AChE. The net result is a closing of the central channel and an
tral pore with cross-sectional dimensions approaching 0.65 nm x immediate decline in the membrane's conductance to Na+ and
0.65 nm in under 10 jis.374-598 The open AChR channel is perme- K+. The AChR is now ready to combine with two additional
able primarily to positively charged ions (cations) and is large ACh molecules to repeat the process.
enough to permit passage of the three cations physiologically Evidence indicates that the above explanation of how ACh
present in the area (i.e., relatively high extracellular concentra- binds to AChR and results in a single time of opening may be a
tions of Na+ and Ca 2+ and high intracellular concentrations of bit too simple. Micropipette recordings of single AChRs sug-
K+). The direction and degree of ion flow depend on the intracel- gest that the AChR channel opens when two ACh molecules
lular electric potential and the specific ionic concentrations become attached. As the intracellular membrane potential be-
across the postsynaptic membrane. The muscle cell has a resting comes less negative,.the channel may close for a very brief
membrane potential approximating -80 mV, which is quite close period and open again without unbinding ACh in a process
to the equilibrium potential for potassium ions.410-411 When the called bursting. 23 163 164 165-166-221-704-907 The 1 ms of open channel
ACh receptor channel opens, there is a high concentration of K+ time is most likely composed of multiple openings and closings
within the cell. However, K+ does not readily leave the cell upon that cannot be observed with crude measuring techniques. In
receptor opening because the resting membrane potential is es- short, the open channel time is in reality the summation of all of
sentially at the equilibrium potential for K+ (i.e., the concentra- the individual burst times.
tion gradient "pushing" K+ out is balanced by the electrical In human intercostal muscle, a single spontaneous release of
gradient "pulling" K+ into the cell). Calcium ions enter the one vesicle results in the opening of approximately 1500 AChRs
muscle cell to some degree because the electrical and concentra- for a total period approaching 1.5 ms when all channels are con-
tion gradients favor an intracellular movement. The most impor- sidered. Micropipette recording techniques within the endplate
tant ion capable of traversing the water-filled electrically neutral zone reveal that the activation of the above-noted number of
ion pore is Na + because of its small size, relative abundance 9 51 AChRs results in a current flow of 2.6 nanoamperes. This small
outside compared with inside the cell, and attraction toward the amount of current flow is associated with a depolarization voltage
Figure 25-13. Amplitudes of EPPs resulting

from increasing extracellular concentrations
of magnesium. Note how the EPPs form distinct
peaks that are multiples of the mean MEPP ampli-
tude (insert) supporting the concept that the EPP is
composed of summated MEPPs. (From Boyd IA,
Martin AR: Spontaneous subthreshold activity at
mammalian neuromuscular junctions. J Physiol
1956; 132:61 -73, with permission.)
Amplitude of end-plate potentials (mV)
of about 0.5-1.0 mV when recorded with intracellular elec- amount of calcium ions entering the nerve terminal, which in
trodes in the postsynaptic region of the endplate. The sponta- turn reduces the probability that any one synaptic vesicle will
neous 0.5-1.0-mV endplate region potential occurring at about fuse with the presynaptic membrane. Thus the total number of
0.2 Hz is called a miniature endplate potential (MEPP). One vesicles that fuse with the presynaptic membrane is reduced.
quantum or synaptic vesicle of ACh, therefore, results in the ac- The same effect can be achieved by increasing the extraterminal
tivation of 1,000-2,000 AChR channels with a depolarization of concentration of magnesium, which competitively binds with
0.5-1.0 mV.23-479 Because two molecules of ACh are required to the calcium sites, significantly above that of calcium or simply
bind to the AChR before it is activated, at least 4,000 molecules by replacing calcium with magnesium. The net result is less cal-
or 40% of the 10,000 total molecules of ACh contained in one cium entry into the nerve terminal and less synaptic vesicle
vesicle are necessary to generate a typical MEPP. fusion. If calcium ions are removed while the nerve-muscle
The MEPPs are recorded with conventional monopolar or preparation is bathed in a high magnesium ion concentration, an
concentric needle EMG needle electrodes when they are located action potential propagating into the nerve terminal results in no
in the muscle's endplate zone. Multiple MEPPs from a large synaptic vesicle release. Therefore, a microelectrode located in
number of endplates appear to fire at rapid rates, giving rise to the postsynaptic muscle region records no electrical activity.
endplate noise. These MEPPs are much more abundant and fire Elevating the calcium concentration by small increments even-
at greater than 0.2 Hz because the large needle electrode records tually results in the generation of a small electrical current in
from multiple endplates simultaneously and may irritate the the postsynaptic membrane, indicating the release of ACh. A
nerve terminal, generating a greater release of vesicles than a further increase in calcium at small increments continues to
nerve terminal in the resting state. The small amount of current generate the potential until a level is reached when a potential
or voltage change produced at the site of open AChRs is insuffi- with twice the previous value is recorded. Repeating this
cient to generate a current sink large enough to depolarize the process eventually results in a third potential with three times
membrane of the surrounding skeletal muscle fiber. The voltage the original potential's magnitude. Experiments similar to these
change simply diminishes with distance from the region of de- and experiments using slightly different methods documented
polarization, and this reduction is called an electrotonic volt- that the generated potential and the spontaneously observed
age/current decline; i.e., it is nonpropagated. The frequency of MEPP are quite similar. It is proposed that the MEPP of about
MEPPs also can be increased by increasing the extracellular 0.5-1.0-mV amplitude in humans results from the release of
concentration of calcium or potassium ions in the nerve termi- one quantum (synaptic vesicle) and that it is the fundamental
nal or by electrically stimulating the nerve terminal directly building block of voltage changes in response to nerve terminal
with subthreshold currents.430-431-432-433-434-353-534 Calcium facili- depolarizations.
tates fusion of the synaptic vesicles, and increasing extracellular Continuing the experiment with increasing amounts of extra-
potassium concentration decreases the resting membrane poten- cellular calcium about the nerve terminal generates a voltage
tial, which in turn may help extracellular calcium to cross the change in the endplate terminal that is some multiple of quanta
nerve terminal membrane. After minimal neural excitation, the or MEPPs (Fig. 25-13). The potential generated at the NMJ re-
frequency of MEPPs increases, perhaps as a result of increased sulting from summation of more than one MEPP is called an
numbers of synaptic vesicles opposite the active sites. endplate potential (EPP). The amplitude of the EPP depends
MEPPs can be studied in more detail by either decreasing the on both presynaptic factors (number of vesicles released and
calcium concentration external to the nerve terminal or increas- their content), postsynaptic factors (status of the AChRs), and
ing the magnesium concentration.49-20,-5,a5n-609 Curare usually is synaptic space factors (AChE). When the external calcium con-
applied to the muscle to prevent action potential-induced mus- centration is normalized to physiologic levels in humans, a de-
cle contraction, which would dislodge the recording electrode. polarizing neural impulse results in the release of 50 or more
An externally diminished calcium ion concentration reduces the synaptic vesicles (quantal content), each with 10,000 molecules
of ACh. The summated electrical activity generated by this re- mV.
lease produces a localized depolarization of the postsynaptic
membrane, i.e., an EPP (Fig. 25-14). The magnitude of the EPP
Time of spike |peak

8
can approach 50-60 mV or greater.93-94-521 Given these numbers
(msec.)
and the assumption that a single vesicle generates a MEPP with
roughly 1 mV in amplitude, about 50-60 synaptic vesicles are <56
3
released for one depolarization of the nerve terminal. In frogs, 1 1 1

the MEPP is about 0.5 mV, suggesting that 100-200 vesicles \ Distance along fibre (mm.)
are released with nerve terminal depolarization. Mammalian

EPPs decay or lose 80% of their magnitude over a distance of
0.8 mm, which represents the electrotonic decline or extent of 5.6/?// //
their depolarization. 8
Skeletal muscle has a resting membrane potential between " u r 1 I
-70 and -80 mV; the threshold of depolarization for action po-
tential initiation is 10-15 mV less negative. 475 If the threshold
potential is reached, a self-perpetuating/propagating action po- 0 1
1
2 3
1
4
1
5 msec.
tential is induced. Let us consider how the EPP generates a
single muscle fiber action potential. A single MEPP results in Figure 25-14. Intracellular microelectrode recording of a
the localized depolarization of the postsynaptic membrane with frog muscle near the endplate region of a single muscle fiber.
a change of 1 mV (i.e., -80 mV to -79 mV). A neural impulse, The endplate is represented by numbers 5 and 6; numbers 1-4 and
however, allows sufficient calcium to enter the nerve terminal for 7—8 designate measurements made on either side of the NMJ (insert).
a duration of 1 ms to result in the liberation of 50-60 or more Note that potentials recorded in the immediate vicinity of the end-
synaptic vesicles. This single nerve impulse generates the open- plate reveal an initial "hump" followed by a rapid elevation in potential
ing of multiple AChRs, thus generating a 50-60-mV endplate to a peak amplitude.The inflection point between the two curves rep-
region depolarization or depolarizing the postsynaptic mem- resents the membrane depolarization threshold for the surrounding
brane from -80 mV to -30 or -20 mV. This focal region of depo- muscle membrane. Once this level is reached, there is a rapid elevation
larization does not propagate but is localized only to the region in the measured potential.The initial "hump" represents the EPP, which
of the AChRs. Unlike excitable membrane, depolarizing one is hidden by the muscle fiber depolarization potential.This initial por-
small region of the postsynaptic membrane with open AChRs tion of the curve is absent or difficult to detect at recording locations
does not result in the depolarization of neighboring regions. This away from the endplate zone because the EPP is a nonpropagated po-
is what is meant by an electrotonic spread: the generated electric tential and declines with distance. (From Fatt P, Katz B:An analysis of
field exerts an influence over distance but does not leave the end- the endplate potential recorded with an intracellular electrode. J
plate region or affect neighboring AChRs because AChRs are not Physiol I95i;l 15:320-370.)
voltage-gated but ligand-gated. In other words, the AChR does
not respond to depolarization by opening with depolarization but threshold. Blocking about 90% of the AChRs continues to gen-
instead closes and ejects the ACh from its receptor sites. erate an EPP that has been reduced to about 70% of
Creating a larger negative current sink into which positive ions normal.598-635-758 It is a graded response in that the EPP magni-
can flow, however, influences the surrounding region and attracts tude depends directly on the number of MEPPs that reach the
positive sodium ions from the extracellular surface of the adja- postsynaptic membrane and is the net summation of single
cent muscle membrane. The large current sink is of sufficient synaptic vesicles. Studies have revealed a safety factor at
magnitude that a neural impulse activating the nerve terminal normal NMJs of 1.7-3.3. Of course, this safety factor is nor-
always generates an action potential. Pulling enough sodium mally reduced with repetitive activation of the nerve terminal
ions from the extracellular surface of the adjacent muscle mem- (e.g., with exercise) because of the reduced number of ACh
brane creates a positive intracellular charge in the adjacent vesicles during repetitive activations (see below).437 Because we
muscle region. Thus the potential across the muscle membrane do not experience complete inability to use muscles after even
surrounding the endplate site exceeds the 10-15-mV change strenuous exercise, the normal safety factor may be reduced but
necessary to induce a self-propagating single muscle fiber action is still quite capable of sustained neuromuscular transmission.
potential (see Fig. 25-14). The nearby muscle membrane thresh- At this point it is important to clarify several terms. The
old of 10-15 mV for action potential generation is thereby MEPP is the result of a single quantum of ACh and can be de-
exceed by a factor of 3-4. Excessive depolarization above that tected with routine needle EMG electrodes when the electrode
required to reach threshold is known as the safety factor. is placed in the muscle endplate zone. This activity results in so-
It is also possible to define the neuromuscular transmission called endplate noise or "sea shell murmur" and is one type of
safety factor from the perspective of the minimal amount of endplate potential or waveform. In this sense, the term "end-
AChRs necessary to generate an EPP large enough to result in plate potential" refers to potentials or waveforms capable of
muscle membrane action potential induction. 598 The safety being recorded with a standard concentric or monopolar record-
factor, therefore, is the total number of open AChRs following a ing electrode and is not the same as the EPP discussed before. A
neural action potential divided by the number of AChRs that second type of endplate potential or waveform is the "endplate
must be opened to generate an EPP capable of depolarizing the spike," which is a single muscle fiber depolarization recorded
surrounding muscle membrane. This value can be derived by about the endplate zone. In short, the EPP is a nonpropagated
blocking increasing numbers of AChRs, measuring the ensuing potential generated by AChRs and can be recorded only with
EPP and comparing it with normal values. Investigations have microelectrodes placed in the subsynaptic sarcoplasm, while
documented a large excess of receptors at the postsynaptic MEPPs and endplate spikes are extracellular recordings, as de-
membrane compared with the amount necessary to achieve tected with routine needle electrodes.
H40 — PART IV CLINICAL APPLICATIONS
By positioning a microelectrode in the perisynaptic region on that a microelectrode is located in the endplate region so that an
the boundary zone between the distal motor nerve terminal and EPP can be recorded after a nerve terminal depolarization. A
muscle tissues and then moving the electrode away from the single nerve depolarization leads to the above-noted findings.
synaptic region, interesting findings can be observed (see Fig. However, if one stimulates the nerve terminal at a slow rate
25-14).303-831 In the immediate vicinity of the NMJ is noted a po- (e.g., once every 5 seconds) to establish a baseline EPP ampli-
tential with an initial prominence and short rise time that tude and then increases the stimulus rate to 20 Hz, the EPP am-
abruptly changes to a significantly greater rise time. This inflec- plitudes are characteristically affected (Fig. 25-15A). The EPP
tion point demarcates the relatively slow-rising EPP (AChR acti- dramatically increases in magnitude during the initial 300 im-
vation) that induces the all-or-none response in the surrounding pulses of 20-Hz stimulation and can reach a magnitude 14 times
excitable muscle membrane. Once the muscle membrane's that of the baseline EPP. Stimulating the nerve terminal at set
threshold level is achieved, a rapidly rising voltage associated intervals with single stimuli after cessation of the repetitive
with muscle fiber depolarization (sodium channel activation) is neural activation reveals a decline in EPP magnitude to baseline
recorded and superimposed over the still present, but now level within about 100 seconds. This initial elevation in EPP
hidden, EPP. Moving further from the NMJ results in a pro- amplitude is called facilitation or post-tetanic facilitation. The
longed time to peak depolarization The initial "hump" is no two major phases of facilitation are based on the rate of decline
longer appreciated because of the distance that must be traversed of the EPP. Within the first 30-50 ms, the EPP obtained after a
by the propagating muscle action potential before it reaches the single stimulus is quite large (first phase of facilitation). From
recording electrode and the electrotonic decline of the EPP, 50 to 500 ms the evoked EPP is still larger than the baseline
which is confined to the endplate region. Although these find- value (second phase of facilitation). This period is followed by
ings originally were noted in frog sartorius muscles, 303 similar augmentation, roughly 7 seconds of response that is elevated
observations apply to human muscle tissue.831 but considerably less than that recorded during the facilitatory
The above description applies to the induction of one muscle phase.104-593-594 The mechanism is similar to that of facilitation
action potential following a single nerve impulse. Rather dif- but has different calcium removal kinetics. The clinical signifi-
ferent findings are noted for multiple and sequential nerve ter- cance of this physiologic finding is similar to facilitation; it may
minal activations.50-68-140-203-292-432'590-591-592-597'601 Let us suppose assist in the elevation of sequential EPPs during disorders that
Figure 25-/5. Endplate potential (EPP) magnitude

after repetitive endplate activation. A,After the estab-
lishment of a baseline EPP value, the terminal nerve is acti-
vated at a rate of 20 Hz for a total of 300 impulses
• Decoy of foci m o t i o n (horizontal bar). Each point represents the recorded EPP am-
£ 8- plitude after repetitive stimulation divided by the control
EPP (EPPD) amplitude. N o t e the significant increase in EPP
during repetitive stimulation and the decline of this effect
over the next 200 ms. Results are obtained under condi-
Decoy of augmentation tions promoting reduced quantal content (i.e., elevated
Decay of potentiation magnesium and reduced calcium). B,A nerve is stimulated at
100 Hz for 90 seconds after a baseline stimulus.The vertical
axis is the same as for A. Note the initial facilitation phase, j
as in A, followed by a minute of depression with several min-
utes of potentiation. The depression occurs because of a
50 100 prolonged stimulation (horizontal bar superimposed over
Time <s) the horizontal time axis) and significantly depletes the avail-
able ACh, thus overriding any facilitation during this period.
Results were obtained under normal extracellular ionic
Potentiation conditions. (From Barrett EF, Magleby KL: Physiology of
cholinergic transmission. In Goldberg AM, Hahn P (eds):
Biology of Cholinergic Function. N e w York, Raven Press,
1976, pp 29-100, with permission; Magleby KL: Neuro-
muscular transmission. In Engel AG, Banker BQ (eds):
Myology: Basic and Clinical. New York, McGraw-Hill, 1986,
• I
pp 393-418; and Zengel JE, Magleby KL: Augmentation of fa-
cilitation of transmitter release. J Gen Physiol 1982;80:
583—61 I, with permission.)
10 20 30
T i m <m)
produce low quantal content. A fourth period of a slightly ele- These observations have significant implications. The mecha-
vated EPP compared with baseline lasts considerably longer nism generating the facilitatory phenomenon in situations of re-
than the previous periods (about 50 seconds or more) and is duced quantal content is incompletely understood, but it is
called potentiation. Facilitation, augmentation, and potentia- speculated to depend in part on residual calcium. Following a
tion are considered separate periods primarily because of the single neural impulse, calcium ions enter the nerve terminal
rate at which they decay. Under conditions of low quantal con- about the active zones for about a millisecond through the volt-
tent, the evoked EPP is larger than a baseline value after rapid age-sensitive calcium channels. The calcium ions somehow fa-
repetitive stimulation. In other words, two or more stimuli de- cilitate synaptic vesicle exocytosis of ACh, after which they
livered at intervals of less than approximately 100 seconds rapidly diffuse away from the active zone to be bound and se-
result in facilitation of the EPP. These conditions provide in- questered (see above). This diffusion, regardless of how rapid
sight into pathologic disorders producing low quantal content the process, is nevertheless finite, defined by the time required
(see below). to leave the active zone. Diffusion and removal of free calcium
The dramatic increase in EPP amplitude results from the ini- ions require some time to achieve a concentration below an ill-
tially small number of quanta released by the altered terminal defined critical value required to potentiate synaptic vesicle ex-
nerve during the baseline recordings secondary to the external ocytosis. Even more time is required for significant removal of
environment. Specifically, reducing the extracellular calcium calcium ions from the active zone. If a second impulse occurs
and elevating the magnesium concentrations ensure that only before the free calcium ion concentration reaches the critical
small amounts of calcium ions enter with each depolarization. low concentration, the residual amount is added to the newly
Thus, only a few vesicles fuse with the postsynaptic membrane, entering calcium ion to reach a concentration higher than usual
and the ensuing EPP is dramatically smaller than normal. The with one stimulus. The residual calcium is insufficient to acti-
baseline value of recorded EPPs is considerably smaller in ab- vate synaptic vesicle exocytosis by itself, but when it is com-
solute magnitude compared with the normal situation of rela- bined with the calcium from a second impulse, there are
tively high extraterminal calcium and low magnesium ions. The sufficient calcium ions not only to release the anticipated
above-described facilitation, therefore, is not equivalent with amount but also to liberate an additional amount of synaptic
normal nerve terminal reactions to repetitive stimulations at vesicles. As long as the second impulse arrives before the re-
high rates but provides insight into basic physiologic processes, moval of all residual calcium, an EPP larger than the preceding
i.e., some mechanism of facilitating ACh release during patho- one is produced. Multiple stimuli in rapid succession (time in-
logic states producing defective calcium entry. At high rates of terval less than 200 ms; e.g., 5 Hz or greater) thus should lead to
stimulation, there is apparently some mechanism whereby the progressively larger EPPs. The residual free calcium continues
EPP can be dramatically facilitated to reach threshold values. to build up because diffusion and binding/sequestering cannot
In normal nerve terminals subjected to high rates of repetitive keep pace with the increasingly higher concentrations of cal-
stimulation for relatively long periods, a number of interesting cium. The above scenario is particularly dramatic during situa-
findings are noted. The initial facilitation of the response is sim- tions creating low quantal content, such as low extracellular
ilar to that noted in the setting of reduced calcium ion entry into calcium, high magnesium ion concentrations, or diseases caus-
the nerve terminal. However, the magnitude of EPP increment ing decreased ACh release (see Fig. 25-15A). These "patho-
during the rapid stimulation phase is considerably less, ap- logic" ion conditions result in the release of only a few vesicles
proaching twice as opposed to 14 times the baseline value (Figs. with each stimulus. Thus, a large number of vesicles are spared
25-15 A and B),338,609 because in the normal situation the ab- so that each sequential stimulus releases more vesicles than the
solute magnitude of the baseline EPP is considerably larger than previous stimulus because of the larger than "normal" amounts
the baseline value in the abnormal situation. Because a physio- of calcium. The longer the interval between successive stimuli,
logic amount of calcium may enter the nerve terminal, a 40-50 the lower the EPP compared with the preceding one because
mV EPP may be produced as opposed to a 3-mV EPP ampli- less free residual calcium is available as it moves into the differ-
tude, for example. In the pathologic setting, the initial 3-mV ent phases of facilitation, augmentation, and potentiation. The
EPP approached the more normal value of 50 mV, hence in- same process is no doubt operative in normal endplates, but the
creasing its relative magnitude 14 times. On the other hand, the large amount of ACh released precludes as dramatic an increase
normal 40-mV EPP increased only to about 70 mV, or 1.8 times as in situations of low quanta! content. With continuous high-
its baseline value. Facilitation, therefore, is a normal phenome- rate stimulation approaching 1 minute or more, this effect is not
non at high rates of stimulation and has the capability to in- observed. Instead, the EPP declines with sequential stimuli after
crease the EPP amplitude under both normal and possibly the initial increment. This finding most likely results from de-
pathologic situations. The clinical implication is that under pletion of the immediate store of synaptic vesicles, because sig-
normal physiologic conditions, the added amount of calcium re- nificant numbers have been released by the previously applied
sulting from the brief interstimulus intervals (and hence facilita- tetanus. It may take several minutes for facilitation to be ob-
tion) is inconsequential, because all EPPs are suprathreshold served again (see Fig 25-15B).
and generate a single muscle action potential. As previously noted, under normal extracellular ionic condi-
Continuing to stimulate the nerve terminal in the normal ex- tions, high-rate stimulation results in an initial facilitation with
tracellular ion environment results in several other findings. a subsequently declining EPP that is reduced below the initial
Depending on the number of stimuli, the EPP amplitude EPP amplitude, given sufficient numbers of stimuli. This EPP
demonstrates a dramatic return to baseline and subsequent de- magnitude decline depends on the total number of stimuli deliv-
pression to the point that the EPP may be nearly absent. ered, not necessarily the rate of delivery, once more than about
Cessation of the high-rate stimuli train results in the return of 2 stimuli per second are delivered. If low rates of stimulation
the EPP to its previous facilitated state of about twice the base- approaching 1-4 Hz are applied to the nerve terminal, the EPPs
line value. Over the next 10 minutes the EPP declines to its rest- demonstrate a sequential decline in magnitude for the first 5-10
ing state. stimuli to a minimal amplitude roughly one-half the first EPP
2nd 3rd 4ih 5th and constitutes the mobilization process. Although significant
Depletion amounts of residual calcium may be present, attempting to fa-
cilitate release of larger numbers of vesicles, the relatively de-
100 creased numbers of vesicles due to depletion offset the
400 facilitatory effect of the residual calcium, producing depression.
Again, under normal conditions, the decreased magnitude of the
EPPs is still sufficient to generate a muscle action potential be-
Output
cause of the safety factor effect. Additional factors may be in-
volved in post-tetanic depression, but further work is required to
500 explain the process more fully.
B 315 When nerve terminal calcium entry is normal and the nerve
terminal is continually excited at a high rate (e.g., 20 Hz), the
first several EPPs are likely to approach a value that is larger
than that observed at low rates of stimuli (e.g., 1 Hz). This facil-
• 10D 20
0- itation, however, is short-lived because the EPP declines from
the increased amplitude with each successive excitation after
the first several stimuli as more and more vesicles are released.
Figure 25-/6. The immediately available ACh store at a NMJ. The decline in EPP magnitude reaches a new baseline at some
A, Five sequential stimuli are delivered with about 20% (probability re- point when mobilization compensates for the ACh released.
lease factor) of the available ACh released with each stimulation.This This facilitation is not detected clinically if the muscle response
results in a decline in the amount of ACh available for release with each is recorded because all of the EPPs are suprathreshold and the
stimulus as well as trie amount of ACh actually released. In the absence same number of muscle fibers is activated with each stimulus.
of replacement ACh, the nerye terminal eventually delivers insufficient An example may clarify the consequences of ACh mobiliza-
amounts of ACh to generate a suprathreshold EPP. B, After the second tion. Let us assume that the immediately available store of
stimulus ACh is mobilized in increasing amounts from the various stor- quanta contains 500 synaptic vesicles (Fig. 25-16). 19 If one
age compartments to replace the excreted ACh. Mobilization is maxi- stimulus is delivered to the nerve terminal, the amount of ACh
mized in this example by about the fifth response so that the amount of released is equivalent to 100 quanta (m), thus generating a "re-
ACh released from the nerve terminal is balanced by the amount mobi- lease probability" (p) of 0.2 (recall that m = n x p; therefore,
lized. Thus a new EPP baseline is reached with no further decline. 100 = 500 x p, and p = 0.2). At relatively low rates of stimula-
Occasionally the mobilization process delivers slightly more ACh than tion, below the 5-Hz level at which any type of facilitation is
that released by the fifth response, causing a slight increase in the EPP initiated, the probability of release is essentially constant at 0.2.
above the fifth response. Altering the rate of stimulation and number of The second stimulus, delivered at a rate of 1-4 Hz, results in the
stimuli delivered can result in ACh depletion that far outstrips the rate release of about 20% of the remaining ACh quanta (80 synaptic
of mobilization. Postactivation exhaustion then becomes manifest. vesicles), which is reduced by the 100 quanta released by the
(From Ali HH, Savarese JJ: Monitoring of neuromuscular function. previous stimulus (m = 0.2 x [500 - 100] = 80. If each quantum
Anesthesiology 1976;45:216-249, with permission.) of ACh generates a MEPP of 1 mV, the first five stimuli gener-
ate EPPs of 100, 80, 64, 51, and 41 mV (see Fig. 25-16). These
and then increase slightly to a new baseline level.933 This decline EPPs are of sufficient magnitude to reach threshold because
is not preceded by an initial facilitatory response in pathologic only about 15 mV of depolarization is typically required to de-
situations because an interval of at least 200 ms (5 Hz or higher polarize the resting membrane potential from - 8 0 mV to -65
rates) between stimuli is typically necessary to demonstrate a mV. This run-down of EPP magnitude for the first five stimuli is
readily apparent effect above normal amplitude variations (see inconsequential with respect to muscle contraction because
Fig. 25-15). The decreased EPPs persist for as long as the stim- each of the suprathreshold EPPs generates an identical all-or-
uli are applied and can be observed for variable periods after none single muscle fiber action potential.94104-263'552 Obviously, if
stimulus cessation. The time course of this post-tetanic depres- some process did not intervene, the number of quanta in the im-
sion depends on the duration of rapid stimulation applied to the mediately available store would decline to a level at which it
nerve terminal (see Fig. 25-15B). The longer the duration of could no longer generate an EPP sufficiently large to trigger an
repetitive stimulation, the more persistent the duration of de- action potential.
pression. Post-tetanic depression is not completely understood The process of mobilizing ACh vesicles from the main stor-
but is believed to result from the utilization of neurotransmitter. age "compartment" of the nerve terminal can offset the continu-
The delivery of large numbers of stimuli at high rates no doubt ous reduction in neurotransmitter. After the initial stimulus is
depletes in short order the 1,000 synaptic vesicles contained in delivered, some form of communication occurs within the nerve
the immediately available vesicle store. Increased numbers of terminal to facilitate the replacement of extruded synaptic vesi-
stimuli use more and more vesicles. Because the EPP is directly cles. Intracellular recordings of EPPs document that by about
dependent on the number of ACh molecules released under the fifth or sixth consecutive stimulus the EPP amplitude no
normal conditions, as the number of immediately available vesi- longer declines but remains stable and may even increase
cles falls, so does the EPP. The depression persists until a suffi- slightly.'w-203-253-434-437-48"-574-575 This finding implies that by the
cient number of additional ACh vesicles can be mobilized from fifth response, mobilization of ACh stores is sufficiently large to
surplus stores. The actual mechanism of mobilization is un- compensate for the quantity of ACh released (see Fig. 25-16).
known but may involve calcium cleavage of the attachments of The time required for mobilization to compensate for the ACh
storage vesicle to neurofilaments in the nerve terminal. The released is about 500-2,000 ms. After cessation of stimuli,
vesicles must then be guided to the active zones and prepared about 20-30 seconds are required for the mobilization process
for release. This mechanism requires a finite amount of time to restore the amount of ACh released from the immediately
available store to its resting level of 100 quanta. Mobilization Table 25-2. Effect of Reducing Temperature
depends on the amount of neurotransmitter released, which in from 30°C to 20°C
turn depends on the rate and duration of stimulation. The greater Increased Decreased
the amount of ACh released, particularly at higher frequencies,
the more responsive the mobilization process. Under physio- Nerve action potential
logic rates of stimulation (20-30 Hz), mobilization can main- Duration
tain EPP magnitude above threshold, otherwise we would Amplitude
deplete nerve terminals of ACh and be unable to function. In Rise time
pathologic conditions affecting either the nerve terminal or Conduction velocity
postsynaptic membrane, mobilization may not be able to com- Compound muscle action potential
pensate for the normal run-down of the EPP and achieve the Duration
amount required to activate diseased NMJs. Amplitude
After the post-tetanic potentiation phase, if sufficient avail- Rise time
able stores of ACh have been depleted by the initial high-rate Conduction velocity
stimulation and subsequent calcium-mediated elevated EPP Single muscle fiber action potential
phase, a further decline in EPP amplitude may occur. The find- Duration
ing of reduced EPP amplitude after the facilitatory phase is Amplitude *
known as post-tetanic or postexercise exhaustion. 211212 Rise time *
Although the EPP may be depressed below baseline levels, in Conduction velocity *
the normal NMJ the safety factor allows continued generation MUAP
of a muscle fiber action potential. This phenomenon cannot be Duration *
observed in normal people under physiologic conditions, but Amplitude *
only in people with disorders affecting the NMJ or in specially Rise time *
treated animal preparations. The depressed EPP amplitude may
persist for several minutes. Although the mechanism is not fully MEPP
understood, it may be related to full replenishment of the imme- Duration *
diately available ACh store, given the totally buffered excess of Amplitude *
calcium. The combination of baseline levels of calcium with Rise time *
some depletion of ACh stores may result in lower-than-expected Frequency of occurrence *
EPP magnitudes. Of course, this is speculation, and the true EPP
mechanism may be exceedingly more complex and subtle. Duration *
During successive depolarization of the nerve terminal, each Amplitude *
EPP occurs at a slightly different time from the onset of stimu- Rise time *
lation.49472-478 In frog muscle at 20°C, slightly more than 50% of Time to occurrence *
the stimuli vary within a range of 0.5 ms about a mean value, Quantal content per depolarization *
with a few varying from 1-4 ms.473 A number of potentials with- AChR
out identical arrival times may approach 100 \is or less. Human Open time *
muscle at physiologic temperatures may have variations consid- Conductance N o change
erably less than those noted above. Most of this time delay is
thought to arise from the presynaptic portion of NMJ transmis-
sion. This is certainly likely, because the postsynaptic aspect of AChE ability to hydrolyze ACh *
NMJ delay is only about 250 JLLS leaving at least 500 |is at the Resting membrane potential *
presynaptic terminal. As previously stated, a significant proba- and threshold level voltage
bility function (p) is associated with calcium facilitated ACh ex- difference
ocytosis. The probability that calcium requires exactly the same
amount of time for the necessary interaction with slightly differ- Decrement at 2-3 Hz in NMJ disorders *
ent ACh vesicle locations from one stimulus to the next is ex- Postactivation exhaustion in NMJ disorders *
tremely small. Furthermore, synaptic diffusion is quite fast at MEPP, miniature end-plate potential; EPP, end-plate potential; AChR, acetyl-
about 50 |is or less, leaving little room for large variations in choline receptor;AChE, acetylcholinesterase; MUAP, motor unit action potential.
time. Similarly, the 100-200 jis required for AChR opening and
peak current flow is also rather short to generate such large vari- in generation of an EPP from the time of nerve impulse arrival at
ations. There is little doubt that the majority of successive EPP the nerve terminal from about 0.5-0.75 ms at 20°C to 3.5-7.0 ms
variation arises in the presynaptic aspect of NMJ transmission. at 2.5°C. This increased delay may result from a prolongation in
Temperature Effects. Temperature has a number of interest- the time required to release ACh from the nerve terminal after ar-
ing effects on the physiologic processes involved in NMJ trans- rival of the nerve action potential, decreased rate of diffusion
mission (Table 25-2). Action potential conduction velocity along across the synaptic space, delayed AChR reaction to the pres-
the nerve terminal in frogs at 20°C is approximately 0.3-0.4 m/s ence of ACh, or a combination of these factors. The direct appli-
and decreases to 0.12-0.16 m/s at 4°C.471 The reduction in tem- cation of ACh through a micropipette at 2.5°C results in endplate
perature to this degree results in a halving of the terminal nerve current flows beginning within 200 (is, which is quite similar to
conduction velocity. Reducing the temperature surrounding a current flows at 20°C. Thus diffusion and AChR conformational
nerve produces a longer-duration, larger-amplitude potential, changes are eliminated as the major factor in synaptic delay of
most likely as a result of the delay in the sodium inactivation EPP generation at lower temperatures. The most important
mechanism.85-572*582 Lowering the temperature increases the delay factor in the delay appears to be the release of ACh from the
nerve terminal (i.e., the calcium-facilitated release of the ACh- at lower temperatures less current is necessary to depolarize the
containing synaptic vesicles). muscle membrane.
The relationship of temperature and MEPP (spontaneous All of the effects are for normal NMJs studied in both rats
ACh) release is rather complex.85-304-436-481-553 At temperature and frogs under specialized conditions of presynaptic or postsy-
ranges of 30^0°C, the frequency of spontaneous MEPP release naptic blocking agents. Findings under normal extracellular ion
increases from 5 Hz to 25 Hz. A peak of 5 Hz is present at 20°C, conditions are assumed to be the same. Although tempting, it
which decreases to about 2.5 Hz at 10°C and 30°C. There is also may be incorrect to generalize all of these findings to pathologic
a slight increase in the MEPP amplitude of about 0.06 mV as conditions, although no doubt some do apply. The above find-
the temperature decreases from 40°C to 10°C. ings are discussed below in relation to the commonly noted
The EPP also is profoundly affected by alterations in temper- clinical conditions of NMJ disease.
ature.436 Recall that EPP generation is directly dependent on the Desensitization. As stated above, the presence of ACh in the
number of ACh vesicles in the immediately available store (n), synaptic space results in the activation of the AChRs with an in-
number of ACh vesicles released per nerve terminal depolariza- crease in postsynaptic membrane permeability to sodium, cal-
tion (m = quantal content), and the probability of ACh release cium, and potassium through AChR opening. Normally, the
(p). The peak of quanta released and hence the probability of re- ACh is hydrolyzed after release from the AChR. If high concen-
lease occurs at about 20°C. From 20°C to 30°C and from 20°C trations of ACh are maintained under experimental or therapeu-
to 10°C the decrease in the quanta released for a given neural tic conditions, the postsynaptic membrane AChRs no longer
stimulus is dramatic. A second small peak in the quantal release respond to the presence of ACh because of failure of EPP gener-
is present from 30°C to 40°C, but this rise is quite small com- ation. The process of AChR inactivation to the neurotransmitter
pared with the 20°C peak. The total number of quanta available is called desensitization.37-59-470-520,785-825 Desensitization also
for release is reduced by approximately one-half from 40°C to may result not only from high ACh concentrations but also from
10°C. Over the same temperature range, facilitation increases to the sustained application of low depolarizing doses of ACh or
a 30% maximum at 10°C compared with 40°C. The quantal other AChR agonists. Inhibition of AChE results in persistence
content, probability factors, and facilitation effects are believed of more ACh in the synaptic space and is another method of pro-
to be based in the poorly understood effect of temperature on ducing desensitization. Removal of the high ACh concentration
calcium ion entry, interaction with synaptic vesicles, and subse- in the synaptic space results in activation of the desensitized
quent binding/sequestration processes. The rate of replenish- AChR so that it is again responsive to ACh.
ment or mobilization of synaptic vesicles is increased at The exact mechanism of desensitization is not known. How-
physiologic compared with lower temperatures.46,413,436 ever, desensitization can be produced by as few as two stimuli,
Lowering the temperature also can reduce the rate at which if the second follows the first within 5-25 ms (i.e., equivalent to
AChE is capable of hydrolyzing ACh. Specifically, a reduction a stimulation of 200 and 40 Hz, respectively).596 The initial ex-
from 39°C to 27°C reduces the rate of ACh hydrolysis by posure of the AChR to the ACh somehow produces an alteration
83%. 315 Temperature reductions also produce EPPs at 20°C with in the AChR to a "desensitizable" state with a time course of
a total duration that is twice that of EPPs recorded at a 37°C.759 about 30 ms or less. If ACh is presented again to the same AChR
Additionally, the response of the endplate to ACh is enhanced at within the 30-ms critical period, the AChR is converted to a new
lower temperatures. 380 Investigations have confirmed that the state in which it can no longer respond to the AChR for a short
AChR maintains the same conductance at decreased tempera- period or until the ACh concentration in the synaptic space is re-
tures, but the channel remains open for significantly longer duced. The AChR then is desensitized and remains in its "closed
times.530,996 The increased responsiveness of the postsynaptic state," regardless of the presence of ACh. In other words, even if
membrane to ACh, combined with slightly larger and longer- the ACh molecules have been displaced from the two AChR
duration EPPs, suggests that the AChRs remain open for longer alpha receptor sites and ACh rebinds with the AChR within the
periods at comparatively reduced temperatures, allowing more 30 ms time frame, the AChR does not respond by undergoing a
sodium ions to enter the muscle cell. Although the amplitude of conformational change with opening of its internal ion chan-
the EPPs does not change dramatically, the open-channel effect nel.759 Once the ACh concentration is reduced or if it is low and
results in flow of a depolarizing current for considerably longer the roughly 30 ms elapses, the AChR can again produce an end-
duration. The actual amplitude of the EPP is not expected to plate current if exposed to two ACh molecules. It also has been
change much, given the similar conductance at the various tem- suggested that during the open phase of the AChR, calcium ions
peratures. As you may recall from the Goldman-Hodgkin-Katz enter the subsynaptic portion of the muscle membrane and bind
equation (Chapter 1), the major determinant in membrane volt- to the AChR receptor for the above-noted time period.588-606,687
age is the permeability of the various ion species under consid- During this period, the calcium somehow inhibits the AChR
eration. If the permeability to sodium and potassium is from responding to ACh if it is attached, thereby either solely
essentially the same at all temperatures, the resting membrane producing or contributing to the desensitization process. ATP
and peak depolarization voltages also should change little. If also is believed to be involved in the process of desensitization
sodium conductance increased dramatically at lower tempera- with respect to the phosphorylation of the desensitized AChR
tures, which it does not, only then could an EPP also increase, and re-conversion to its active form.95 During the period of de-
because it would most likely move closer to the equilibrium po- sensitization, the AChR continues to have a very high affinity
tential of sodium. for ACh; it simply cannot respond to ACh by channel opening.
The resting membrane potential assumes a less negative value The process of desensitization is believed not to occur under
as the temperature is lowered from 30°C to 5°C.8 An opposite normal physiologic conditions in vivo because of the normal
trend is found for the threshold level, which increases in nega- maximal firing rate of motor neurons. This principle is demon-
tivity with a temperature reduction. These two opposing effects strated by stimulating the frog NMJ at 33 Hz for 1000 impulses
tend to bring the resting membrane and threshold potentials with no failure of transmission despite the effective opening and
closer together as the temperature declines. It is anticipated that closing of 400 million channel responses.596 Additionally, maximal
voluntary effort in humans usually produces motor unit firing in Sequential depolarizations of the nerve terminal cause different
the 20-30-Hz range, which is insufficient to generate desensiti- active zones, and hence different regions of the presynaptic
zation either clinically or experimentally.350 On the other hand, nerve terminal, to release ACh. Thus, previously activated
inactivation of AChE by pharmacologic means typically results AChRs have a chance to extrude ACh molecules and be reset
in desensitization even at stimulation rates of 5 Hz. In this case, for the next vesicle from the newly filled active zone overlying
the desensitization process most likely occurs because the ACh them. This scheme of "cycling" different regions of the postsy-
is present in high concentrations in the synaptic cleft as the naptic membrane from one depolarization to the next prevents
AChE is inactivated and, therefore, incapable of eliminating desensitization. If the same AChRs were continually exposed to
ACh. The large quantities of ACh result in rapid rebinding within ACh, the AChRs would soon become desensitized and the pa-
the critical 30 ms because so much of the ACh is still present. tient would be unable to activate muscles.
Even though the AChR gives up the ACh molecule secondary to NMJ disorders are quite complex. Only recently have we
depolarization of the postsynaptic membrane, the empty binding begun to understand them at the molecular level. The fine de-
sites continue to have a high affinity for ACh and will bind ACh, tails of molecular interactions require tedious and exacting in-
if diffusion or AChE does not remove it. This process then leads vestigatory techniques. Despite this complexity, one can attempt
to desensitization until the ACh concentration is sufficiently low to appreciate the pathophysiology of NMJ disorders from the
to allow reconversion of the AChR to its resting state. general viewpoint of where the pathology is located. NMJ dis-
orders may be considered from the perspective of the sequence
of events that begin with action potential invasion of the nerve
PATHOPHYSIOLOGY OF NEURO- terminal and ends with muscle action potential induction by
MUSCULAR JUNCTION DISORDERS way of suprathreshold EPP generation (Fig. 25-17).110 The mol-
ecular interactions arising from and producing an electrical
The basic problem common to all disorders affecting the event can be further partitioned. All of the electrical and molec-
NMJ is a reduced safety factor. When the EPP generated by vol- ular events occur in or about three general locations: (1) nerve
untary activation of a nerve terminal innervating one of the mul- terminal (presynaptic region), (2) synaptic space, and (3) post-
titude of motor units in a muscle fails to reach the muscle fiber's synaptic membrane (postsynaptic region).
threshold, an action potential is not produced. Failure to pro-
duce an action potential results in failure of the muscle fiber to PRESYNAPTIC REGION
contract. If enough muscle fibers fail to contract, the patient ex-
periences weakness and fatigues with effort. Three major areas of metabolic/anatomic failure may affect
The underlying mechanism of NMJ failure and its inability to the presynaptic region, resulting in possible symptoms: (1) di-
generate threshold or larger EPPs can best be appreciated if the minished calcium ion entry, (2) defective ACh synthesis or
saturating disc model is considered.311524-628 The normal verte- vesicular packaging, and (3) decreased probability of ACh re-
brate NMJ is composed of a nerve terminal in close approxima- lease. Any one of the disorders can lead to profound weakness.
tion to a highly convoluted postsynaptic membrane. The Sophisticated microphysiologic techniques may make it possi-
terminal's active zones are positioned opposite the secondary ble to explore further the existence of some or all of these possi-
synaptic clefts. When the nerve terminal spontaneously releases ble neurophysiologic defects.
the contents of one synaptic terminal, there is sufficient ACh to Diminished Calcium Ion Entry. A number of important
overwhelm the comparatively diffuse distribution of AChE. events occur at the presynaptic portion of the NMJ. After inva-
Enough ACh remains to interact with the densely packed sion of the motor nerve terminal by an action potential, voltage-
AChRs. The ACh can be viewed as diffusing out from the focal dependent calcium gates must open for calcium ions to enter.
region of synaptic release into the synaptic space to interact Failure of gate opening results in the lack of calcium ion entry,
with the AChE. The residual first-pass ACh then combines with which may have several important consequences. The most im-
the AChRs. ACh diffusion spreads out and contacts the postsy- mediate result is failure of fusion between the synaptic vesicles
naptic membrane. A circular region with a radius approximating and the active zones. Furthermore, it is believed that calcium
0.3 (im on the synaptic fold containing AChRs is the only re- ions are required to break the bonds holding the reserve synap-
quirement to produce a typically measured MEPP. Specifically, tic vesicles (storage zones) to the network of various types of
flattening out this amount of membrane appears to produce a neural filaments and supporting structures. The calcium gates
small circular region in which the AChRs are completely satu- may fail to open or open only in reduced numbers. Calcium ions
rated by the released ACh that is not hydrolyzed by the AChE; may be unable to bind with the active zone to facilitate the re-
hence the term saturating disc model. The current produced by lease of synaptic vesicles.
the opening of AChRs over this focal region of membrane then Defective ACh Synthesis or Vesicle Packaging. The nerve
generates the voltage measured as the MEPP. terminal must take up choline from the extracellular environ-
As previously noted, depolarization of the nerve terminal re- ment and convert it to ACh, which then must be packaged into
sults in the random fusion and release of 50-100 presynaptic the synaptic vesicles. A pathologic disorder may arise in which
vesicles.96-98 Each vesicle's ACh content then diffuses toward the nerve terminal has difficulty in incorporating sufficient
the postsynaptic membrane, and the quantity that is not hy- quantities of choline. This disorder may lead to synaptic vesi-
drolyzed results in multiple "saturated discs" of depolarization. cles with insufficient amounts of neurotransmitter. Similarly,
The small size of the depolarized postsynaptic membrane and the process whereby synaptic vesicles are filled with ACh may
random distribution of vesicle release result in minimal, if any, break down leading to vesicles with reduced quantities of trans-
overlap of saturated discs during any one terminal depolariza- mitter. The enzymatic processes producing the substrate for
tion. Thus, activation of AChRs is carried out in a highly effi- ACh or one of the intermediary steps in converting acetylCoA
cient manner in which little ACh is wasted by two or more and choline into ACh also may fail. The saturating disc model
vesicles attempting to activate the same region of membrane. can explore the net result of these potential disorders.
Nonquantal
Quantal release release
Stimulus-evoked Spontaneous
Presynaptic impulse
Entry of CA** into

terminals
Near synchronous Release occasional

ACh Figure 25-/7. Sequence of events generating either a
release of 50-60 asynchronous quanta
quanta ACh
MEPP or EPP.A defect conceivably may occur at any one of
these varied steps to result in a reduced safety factor and
hence a NMJ transmission disorder. Keeping this scheme in 1
mind permits ready classification of any disease process af-
Single quantum (1,000-10,000 molecules ACh)
equivalent to 1 vesicle fecting the neuromuscular junction. (From Brown WF:The
binding to ACh-R Physiological and Technical Basis of Electromyography. Boston,
Butterworth, 1984, with permission.)
Choline
and acetylCoA AChE
Activation and opening of
ion channels
(1,000-1,500 channels/quantum)
Dissociation ACh-R and Miniature EPC x 50-60

ACh = EPC
Inactivation channel
EPP
Let us suppose a defect in uptake of choline, synthesis of Decreased Probability of ACh Release. If a particular dis-
ACh, or packaging of ACh into synaptic vesicles. The longer order affects the probability of synaptic vesicle fusion with the
the vesicles remain in the nerve terminal, the closer their con- presynaptic membrane, somewhat different findings are ob-
tent of ACh approaches normal. In this case, the MEPP is essen- served with intracellular recordings of electrical events associ-
tially normal because it arises from vesicles that are in close ated with neural and spontaneous muscular depolarizations.
contact with the presynaptic membrane and most likely has This situation may arise from reduced calcium ion entry or an
been in the vesicle longer than newly synthesized MEPPs head- inability to facilitate ACh vesicle fusion with the nerve terminal.
ing for one of the storage zones. The size of the saturated disc We may speculate about a situation in which the entry of cal-
arising from one vesicle is relatively normal (i.e., normal cium secondary to terminal depolarization is normal, but its
MEPP). Depolarization of the nerve terminal leads to the antici- ability to facilitate the release of ACh vesicles is impaired. The
pated release of normal numbers of vesicles with a suprathresh- detection of spontaneous MEPPs would be reduced because
old EPP because it arises from the summated normal MEPPs. their probability decreases secondary to the reduced ability of
Continued neural activation at physiologic rates, however, re- calcium ions to facilitate their occurrence. When observed,
quires mobilization of more newly synthesized synaptic vesi- however, each MEPP should be normal because the number of
cles with less than normal ACh content. The size of each ACh molecules per vesicle is normal, as is the size of its satu-
saturated disc decreases because the ACh per quantum is insuf- rated disc. Nerve terminal depolarization secondary to volun-
ficient both to overwhelm the AChE and to produce a com- tary activity should result in the release of significantly fewer
pletely saturated region of the postsynaptic membrane. Each ACh vesicle than normal. The ensuing EPP at multiple NMJs
subsequent neural activation produces the release of fewer ACh would be anticipated to be subthreshold. In this instance, signif-
vesicles, as would happen normally, but each vesicle contains icant numbers of muscle fibers fail to contract, and the patient
fewer ACh molecules than normal. As a result, each MEPP gen- experences significant weakness. Further exertion by the pa-
erated from the many less than completely saturated discs pro- tient, however, results in elevated firing rates with multiple de-
duces sequential EPPs with a declining magnitude. At some polarizations of nerve terminals produced at short intervals of
point individual NMJs generate an EPP that no longer reaches about 30-50 ms (firing rate of 33-20 Hz). Under conditions of
or exceeds threshold. When this occurs, individual muscle fibers reduced quantal content and interstimulus intervals less than
no longer respond by action potential induction; hence clinical about 200 ms, significant amounts of residual calcium accumu-
weakness ensues. Rest results in return of strength, but activity late in the nerve terminal. The elevated concentration of calcium
initiates the same cycle. ions has the effect of facilitating the release of more and more
C h a p t e r 25 NEUROMUSCULAR JUNCTION DISORDERS — M 4 7
vesicles with each ensuing stimulation. The net result is an in- the muscle in response to only one neural impulse. Furthermore,
creasing number of NMJs with EPPs meeting or exceeding the if the nerve terminal is activated sequentially, desensitization
muscle membrane's threshold level. Increasing amounts of may occur because of the large quantities of ACh quickly re-
force are produced with each attempted motor unit firing as binding with the same AChR. Patient survival depends on com-
newly acquired suprathreshold muscle fibers are produced. An pensatory mechanisms: a decreased number of vesicles per
improvement in clinical strength is the net result. With rest, the impulse or fewer AChRs capable of responding to nerve termi-
residual calcium is removed, and the patient's improved nal depolarization. These compensatory alterations in the NMJ
strength slowly diminishes with time to the originally measured are necessary to restore the EPP to the "normal" level and pre-
weakness. vent continuous saturation of large AChR discs.
In the above patient, each saturated disc arising from the
spontaneous release of one ACh vesicle is normal. The rate at POSTSYNAPTIC REGION
which these vesicles are released, either spontaneously or in re-
sponse to neural activation, is decreased. Although each satu- A number of abnormalities can be anticipated in the postsy-
rated disc is normal, there are insufficient numbers at any one naptic region (see Fig. 25-17). The number of AChRs may be
time to summate to an EPP above threshold after one neural reduced or normal, but each receptor has a diminished ability to
stimulus at many, but not all, NMJs. Sufficient number of NMJs react to ACh. In either case, the patient experiences progressive
must be spared within all muscles; otherwise patients would be weakness as NMJ transmission fails.
completely paralyzed. Low-grade activities can be expected to Decreased Numbers of AChRs. A rather obvious cause of
result in further weakness because the immediately available potential failures about the postsynaptic region is a reduction in
store of ACh vesicles is exhausted and the EPP amplitude nor- total number or malfunction of the AChRs. A decreased number
mally declines with each nerve terminal depolarization. An at- of AChRs for whatever reason requires a larger saturated disc to
tempt at vigorous exercise with neural firing rates of 20-30 Hz, encompass more AChRs per synaptic vesicle release to generate
for example, generates increased quantities of residual calcium. an MEPP of normal size. If the AChE is completely functional,
Thus, by the time the next impulse arrives, the relatively large there is actually an increase in the ratio of AChE to AChR with
quantities of spared ACh combine with increased facilitation of an assumed reduction in numbers of AChRs. A larger propor-
ACh release. As a result, multiple saturated discs of normal size tion of ACh binds to AChE than normal because there are no
summate to yield EPPs above threshold. This process is associ- AChRs to bind with. This scenario is unfavorable to the devel-
ated with increased numbers of muscle fibers contracting (i.e., opment of the required saturated disc. Hence, a reduction in the
improved strength). number of AChRs leads to small MEPPs. In response to nerve
terminal depolarization, a normal number of synaptic vesicles is
SYNAPTIC SPACE released. The reduced quantity of AChRs generates the expected
number of MEPPs (or possibly fewer), but their smaller magni-
The primary substance associated with the synaptic space is tude produces an EPP that may be suprathreshold—but just
AChE. A reduction in AChE essentially results in a diminution barely.
in the rate of ACh hydrolysis with "excess" amounts of neuro- Minimal voluntary activity results in a reduction in strength
transmitter for relatively prolonged periods. In this instance, and fatigue. This response can be anticipated because normally
ACh is eliminated from the NMJ by simple diffusion as op- the number of synaptic vesicles released is depleted with each
posed to a process of hydrolysis combined with diffusion. If sequential activation. Fewer of the smaller MEPPs are gener-
there were no compensatory mechanisms, patients with this ated with each stimulus until the summated voltage is insuffi-
type of disorder obviously would not survive for long because cient to produce an EPP capable of exceeding the muscle's
of a massive cholinergic crisis. The release of one spontaneous threshold level. This scenario results in failure of contraction,
synaptic vesicle should result in the generation of a saturated and the force from the muscle fiber is no longer additive to the
disc that is roughly 20% larger than normal, given the added motor unit. Continued activity results in a progressive decline in
amount of ACh not initially hydrolyzed.279 This larger saturation strength as more NMJs fail.
disc activates more AChRs than normal with a MEPP of 20% An attempt at maximal effort may lead to some increase in
greater amplitude. Expulsion of ACh from the activated AChRs strength, but this effect is fleeting and can be followed by in-
does not lead to hydrolysis. Thus, the ACh is free to rebind with creased weakness. In this case, the quantal content is normal,
the same or neighboring receptors and generates MEPPs not but the attempt at maximal exertion creates motor units that fire
only with larger amplitude but also of longer duration. With at rather rapid rates with short interpotential intervals. For a
time, the released ACh eventually diffuses to a disc that is rather brief period, the residual calcium is able to facilitate the release
spread out, leading to a less than optimally saturated disc with a of slightly increased number of ACh vesicles above baseline
current flow distributed over a considerable area and hence very values. This added ACh can produce saturated discs in suffi-
low density (i.e., a very small MEPP). Diffusion and small cient numbers to approach the patient's resting level. Of
amounts of AChE decrease the ACh concentration below levels course, rapid depletion of immediately available stores eventu-
capable of creating a MEPP and hence result in subthreshold ally results in a significant decrease in the quantal content. This
EPPs. situation produces a decreased number of saturated discs capa-
In response to nerve stimulation, however, the normal num- ble of generating EPPs that exceed threshold with associated
bers of synaptic vesicles result in considerable concentration of complaints of increased weakness. In short, postexercise po-
ACh about the postsynaptic membrane because of the lack of tentiation is followed by postexercise exhaustion. Reducing the
AChE. The larger saturated discs now generate rather large activity of AChE with medication can result in sufficient num-
EPPs of relatively long duration. The duration may be so long bers of saturated discs that generate suprathreshold EPPs by
that it exceeds the refractory period of the muscle membrane, creating a favorable AChE to AChR ratio (i.e., improving the
resulting in reactivation and hence multiple depolarizations of safety factor).
Abnormal AChR Response to Depolarization. Consid- from the single muscle fiber no longer summates with its neigh-
eration also should be given to the possibility of an abnormal boring single muscle fibers belonging to the same motor unit.
AChR with respect to its ability to alter the conformational state As a result, the net summated electrical activity from the af-
in response to a change in the postsynaptic transmembrane po- fected motor unit is reduced. This "blocking" can be intermit-
tential. As the postsynaptic membrane depolarizes in response tent and dependent on the amount of calcium, synaptic vesicles,
to the opening of AChRs through ACh binding, a voltage level and AChRs functioning at any one time as well as previous
is reached at which the ACh molecules are released. Some NMJ activity and, no doubt, other ill-defined factors. If the first
AChRs may have a delayed response to this elevated voltage of neural stimulus that activates the nerve terminal results in an
depolarization; i.e., the time of opening is prolonged (delayed EPP of sufficient magnitude to reach muscle membrane thresh-
closure). In affected patients, muscle weakness and fatigue can old, the electrical activity from this muscle fiber contributes to
be anticipated. the motor unit action potential (MUAP). Subsequent neural ac-
The spontaneous release of a synaptic vesicle with normal tivations eventually can result in release of insufficient quanta
number of ACh molecules results in a saturated disc of normal with subthreshold EPP generation. If the ACh vesicles are better
size. The total duration of the generated MEPP, however, is pro- mobilized with continued stimulation, the EPP may reach
longed by the inability of the AChR to assume its resting con- threshold, allowing the muscle fiber's electrical activity to con-
figuration with a closed internal ion pore in the anticipated tribute to the MUAP. Furthermore, the time necessary to reach
amount of time. Neural activation of the NMJ produces threshold normally varies somewhat from impulse to impulse
suprathreshold EPPs that persist for a longer time than because of the probability factors involved in synaptic vesicle
normal—potentially longer than the refractory period of the release. The variability depends on the amount of extracellular
muscle membrane. In such a scenario, repetitive firing of the calcium, how fast it diffuses into the nerve terminal, the neces-
muscle membrane and hence multiple contractions can be ex- sary interaction between calcium and the synaptic vesicles, how
pected to follow a single nerve impulse. many synaptic vesicles are released with any given impulse, dif-
The AChR contains a nonselective cation pore and permits fusion time across the synaptic space, opening of the AChR
the entrance of both sodium and calcium as well as the egress of channel, number of AChRs present and subsequently activated
potassium ions. An elevated intracellular concentration of cal- with each stimulus, time to peak MEPP current, resting mem-
cium has been shown to have detrimental effects on the subsy- brane potential, and possibly other factors. The slightly differ-
naptic region of the muscle fiber.279 Focal degeneration of the ent amounts of time required for each of these processes are not
junctional folds may ensue with a net reduction in the number constant. With each neural stimulus, the individual variabilities
of AChRs at multiple NMJs. These secondary effects create add up to a different time interval to reach threshold. If an ab-
electrical and associated clinical findings quite similar to the normality involves any one of these steps because of anatomic
disease state of reduced AChRs (see above). The resulting or physiologic pathology, the EPP may take longer to reach
MEPPs and EPPs are similar in that they are of reduced magni- threshold. Because a slightly different portion of the postsynap-
tude, but the duration is considerably prolonged because of the tic membrane is activated with each neural depolarization (see
slow relaxation time. discussion of saturating disc model), at times the EPP may fail
The above mechanisms provide a brief overview of potential to reach threshold (i.e., it blocks). The above description of EPP
sites of pathologic involvement in the various steps required to generation at pathologic endplates essentially accounts for all of
transduce a neural impulse into a muscle action potential. To be the findings during the electrodiagnostic medicine consultation,
sure, other disorders are possible. However, this overview sets including historical complaints, physical findings, and electro-
the stage for a more thorough discussion of the electrodiagnos- physiologic testing observations.
tic medicine evaluation of the known disorders affecting human
NMJs. Additional details of proposed disease mechanisms are HISTORY AND PHYSICAL EXAMINATION
presented during the discussions of specific NMJ disorders.
The history and physical examination in patients suspected of
NMJ disorders are no different from those routinely performed.
ELECTROPHYSIOLOGIC CORRELATES OF Patients usually complain of weakness and easy fatigability.
NEUROMUSCULAR J U N C T I O N DISORDERS Initial symptoms are often blurred vision or diplopia, ptosis,
slurring of speech, or chewing or swallowing difficulties. Other
The focal area of neurophysiologic dysfunction in NMJ dis- patients may note a more diffuse weakness worse in the upper
orders is obviously the neuromuscular junction. Peripheral (shoulder) or lower (pelvic girdle) muscles. Clinicians should
nerve and muscle tissue are unaffected aside from the nerve ter- inquire about difficulties in performing activities of daily living.
minal and postsynaptic membrane. As a result, neural and To be sure, such complaints are rather vague and can result from
muscle tissue conduct action potentials without difficulty. The a host of benign or more serious disorders. Therefore, the phys-
interface or transducing region converts the electrical neural im- ical examination can be of significant help in defining the cause
pulse into a chemical neurotransmitter, which, in turn, is con- of the patient's complaints (Table 25-3).
verted into an electrical muscle impulse. The pathophysiologic Observation of the patient at rest and during activity can help
mechanisms responsible for various NMJ diseases are founded to determine the territory and extent of clinical involvement.
in the failure to generate an EPP that exceeds the muscle mem- Alterations in speech patterns with sustained talking may be
brane's threshold level. heard during the course of the history. Facial appearance may
The failure of suprathreshold EPP generation results in the be asymmetric with smiling or after tight closure of the eyelids.
absence of the all-or-none muscle action potential. The inability After several minutes the patient may have difficulty in main-
to generate a muscle action potential resulting from safety factor taining eye closure against resistance, which improves with rest.
failure is referred to as neuromuscular blocking. Not only does Similarly, asking the patient to smile may result in what appears
the muscle fail to contract, but also the electrical activity arising to be a snarl because of weakness of the risorius muscle. Ptosis
is also an important sign in patients with suspected NMJ disor- Table 25-3. Differential Diagnosis of Weakness and Fatigue
ders, especially after sustained periods of upward gaze. During Emotional Neurological
testing of external ocular muscles, some patients have limited Hysteria Stroke
range of movement, which can give the appearance of pseudoin- Depression Motor neuron disease
ternuclear ophthalmoplegia. Depending on the degree of gener- Exhaustion Myelitis
alized weakness, the examiner may or may not be able to Malingering Other central disorders
"break" the limb muscles on manual muscle testing. It is useful Endocrine Peripheral neuropathies
to try to fatigue the proximal muscles by holding the arms ab- Thyrotoxicosis Myopathies
ducted at the shoulder for 1-2 minutes. Asking the patient to Hypothyroidism Neuromuscular junction disorders
arise from the floor or hop on one foot also can bring out mild Hyperparathyroidism Poisons/toxins
forms of weakness and fatigue. The differential diagnosis of Osteomalacia Botulism
weakness, even in a proximal distribution, is large (see Table Addison's disease Venomous bites
25-3). The various electrophysiologic procedures of the electro- Cushing's syndrome Tetanus
diagnostic medicine examination can be quite helpful in ascer- Organophosphate poisoning
taining the presence or absence of a NMJ disease. Electrolyte
Medications
Hypo- and hyperkalemia
NERVE CONDUCTION STUDIES Hypophosphatemia
Hypermagnesemia
Sensory Nerve Conduction Studies. In patients with NMJ
disorders only, sensory nerve action potentials (SNAPs) and
sensory nerve conduction velocities (NCVs) are normal. occurs with fast (> 10 Hz) stimulation. The previously dis-
Motor Nerve Conduction Studies. There are two major as- cussed information allows one to design a protocol applicable to
pects of the motor nerve conduction study. The first concerns all patients suspected of having a NMJ disorder with minor
the velocity with which the peripheral motor nerve conducts an modifications in specific disease states.
electrical impulse. In patients with NMJ disorders, the lack of Repetitive Stimulation Assessment of NMJ Disorders.
pathology affecting the nerve proximal to the nerve terminal re- Essentially any skeletal muscle with an accessible nerve supply
sults in normal nerve conduction velocity. can be studied, including the phrenic nerve. The active electrode
The second aspect of motor nerve conduction studies is com- is secured to the muscle's motor point while a reference elec-
pound muscle action potential (CMAP) analysis. Motor units trode is located over the distal tendonous region (i.e., electri-
are composed of multiple single muscle fibers, each contribut- cally "silent" region). Either surface or needle electrodes can be
ing a finite amount of voltage to the summated MUAP. When a used to excite the peripheral nerve. Some investigators prefer
peripheral motor or mixed nerve is activated by a supramaximal needle electrodes because they can be placed subcutaneously in
electrical stimulus, all of the nerve fibers are simultaneously de- close approximation to the nerve, thus requiring less current to
polarized. The ensuing electrical impulses that traverse each activate the nerve thereby minimizing patient discomfort.
motor axon in turn activate all of the motor units. The summated The current/voltage intensity delivered to the nerve is incre-
electrical activity of all of the motor units forms the CMAP. If mentally increased until a supramaximal level is reached (Table
the depolarization of all the nerve terminals subserving the ex- 25-4). The initial test stimuli are delivered at slow rates of less
cited peripheral nerve produces EPPs at individual muscle than 1 Hz in order not to fatigue the NMJ. Once a supramaximal
fibers that are above the muscle fibers' threshold, the surface- level is achieved, the patient is prepared for the delivery of mul-
recorded CMAP is representative of the electrical activity from tiple repetitive stimuli by a full explanation of the procedure. It
the entire muscle under study. However, a variable and tenuous is desirable to have an instrument capable not only of delivering
safety factor at different NMJs contained in the muscle may multiple stimuli at variable rates but also of storing each succes-
result in random failure of different individual NMJs with each sive trace on the screen for later analysis. A train of about 5-10
stimulation. Additionally, the EPP normally declines in ampli- stimuli is delivered at a rate of 2-3 Hz. This stimulus rate is
tude with each successive stimulation at slow rates (1-5 Hz) of chosen because it normally results in the sequential delivery of
activation. Failure of tenuous NMJ transmission can be antici- fewer and fewer ACh vesicles with each stimulus until about
pated with repetitive nerve activation as the quanta per stimuli 5-10 stimuli are delivered, at which time mobilization of stor-
decline, thus reducing the safety factor for each NMJ. In NMJs age ACh vesicles can keep pace with exocytosis (Fig. 25-18). 780
with a tenuous safety factor, more and more NMJ blocking can Furthermore, the 2-3-Hz rate has too long an interstimulus in-
be anticipated with continued activation. Because the individual terval to result in residual calcium in the nerve terminal, poten-
single muscle fibers fail to generate a muscle action potential, tially causing facilitation. The delivery of 2-3-Hz stimuli results
the MUAP and hence CMAP demonstrate a sequential decline in immediate depression of quantal release. In other words, the
in magnitude until a new steady state is reached in which mobi- safety factor at all excited nerve terminals undergoes a normal
lization of quantal stores can keep pace with the ACh vesicle re- physiologic reduction. The neuromuscular junctions with tenu-
lease and prevent further NMJ failure. ous safety factors are induced to undergo neuromuscular trans-
It is possible to take advantage of what is known about mission block when the EPP drops below threshold. As more
normal endplate physiology to explore the pathologic NMJ and more NMJs fail at single muscle fibers, the resulting
through repetitive activation of peripheral nerves. Stimulating a MUAPs and hence CMAP demonstrate a sequential reduction
nerve terminal at intervals less than about 200 ms (5 Hz) results in amplitude over the course of the first 5-8 stimuli. Clinically,
in residual calcium in the terminal, which increases the proba- the reduction of each EPP with successive stimuli, as mani-
bility of ACh vesicle release. Similarly, activating the nerve ter- fested by a similar decline in the CMAP amplitude, is represen-
minal at slow (2-3 Hz) rates results in immediate depression, tative of the phenomenon of depression or exhaustion. The
whereas facilitation followed by depression of ACh release utilization of immediately available ACh stores with sequential
Table 25-4. Electrodiagnostic Medicine Evaluation of Suspected NMJ Disorders

History. Attempt to elicit a history consistent with some form of emotional, endocrine, electrolyte, neurologic, or poison/toxin disorder.
Consider age at symptom onset and progression of complaints. Pursue family history and work environment. Define social aspects of the pa-
tient's home situation and any reasons for secondary gain.
Physical examination. Direct examination to differentiate one of the general categories noted above and specific disorders noted in Table 25¬
3. Manual muscle testing is aimed at defining weakness or fatigue with sustained maximal voluntary contraction or other maneuvers designed to
exacerbate subtle weakness, particularly of facial and external ocular muscles'and/or limb musculature. Sensation should be normal in pure NMJ
disorders.
Electrophysiologic tests
I. Sensory nerve conduction studies. Perform at least two sensory studies in one upper and one lower limb.This is necessary to eval-
uate the possibility of a peripheral neuropathy, which may cause weakness, particularly in a distal limb distribution.
IIA. Motor nerve conduction studies. Perform at least two motor studies in one upper and one lower limb.As with sensory studies, an
attempt is made to define the physiologic status of peripheral nerve conduction.
I IB. Repetitive stimulation: CMAP assessment
1. Establish supramaximal CMAP.
2. Stimulate nerve at 3 Hz for 5-10 responses.
3. Repeat step B after several minutes of rest to ensure reproducibility.
4. Exercise muscle under investigation.
• 10-15 seconds: If > 10% decrement is present before exercise, look for facilitation and repair of decrement as well as
postactivation exhaustion.
• 60 seconds: If no decrement is present at rest, look for postactivation exhaustion.
5. Immediately after exercise, stimulate nerve at 3 Hz for 5-10 responses.
6. Repeat stimulation at 3 Hz for 5-10 stimuli every minute for about 5-6 minutes.
7. If the CMAP is small (several hundred microvolts), exercise the muscle for 10—15 seconds to look for an incrementing response. If the
patient cannot cooperate, stimulate the nerve at about 20-50 Hz for a few seconds to demonstrate facilitation of response after 5-10
minutes of rest from procedures.
8. Perform the above test sequence in distal and proximal muscles in the affected limb (e.g., ulnar nerve to ADM or median nerve to
APB, musculocutaneous nerve to biceps brachii muscle, spinal accessory nerve to trapezius muscle, and facial nerve to nasalis or or-
bicularis oculi).
III. Needle electromyography
1. Examine at least one upper and one lower limb.
2. Evaluate patient for either neurogenic or myopathic cause for weakness.
3. Consider quantitative MUAP analysis if myopathy is suspected.
4. In affected muscles reduce sweep speed and record single MUAP, looking for variability of amplitude.
IV. Single-fiber electromyography (SFEMG). If repetitive stimulation testing, especially of facial and trapezius muscles, is normal, con-
sider SFEMG of the EDC or a facial muscle.
NMJ, neuromuscular junction; CMAP, compound muscle action potential,ADM, abductor digiti minimi;APB, abductor pollicis brevis.
nerve terminal activation in a sense "runs down" the NMJ. and then multiplying the result by 100: {(Rl - R5) -r R l ) x 100
Therefore, any decrement of the EPP with repetitive nerve ter- = percent increment/decrement. Generally, people with normal
minal activation is said to constitute the run-down phase of NMJs do not demonstrate an alteration in the fifth compared
NMJ stimulation. Similarly, a running down of the EPP below with first response in excess of a few percent. An abnormal re-
threshold at diseased NMJs produces a reduction in CMAP am- sponse is defined as a decrement in excess of 10%. A decrement
plitude. In short, depression, exhaustion, and run-down denote a exceeding 5-8 % is suspicious and should lead the practitioner
decline in the EPP magnitude, which is reflected in CMAP am- to ensure a technically satisfactory set-up and then pursue an in-
plitude decrement only in pathologic situations. vestigation of additional muscles.
For measuring CMAP amplitude, it is acceptable to use peak- Patients with a decrementing response at baseline to repeti-
to-peak or baseline-to-peak amplitudes or area under the tive stimulation at 2-3 Hz are instructed to contract maximally
CMAP's negative phase. The use of area gives a more accurate the muscle under investigation for 10 seconds. This muscular
indication of decrement and better defines artifactual alterations contraction typically results in motor units firing at 20-30 Hz,
in amplitude secondary to movement, but this technique re- which implies that individual nerve terminals composing the
quires more sophisticated equipment than is routinely available. motor units are also excited at this frequency. Interstimulus in-
Negative peak CMAP magnitude is a physiologic measure of tervals of less than about 200 ms result in a temporary over-
amplitude because it reflects more accurately the total number whelming of the nerve terminal's ability to buffer or sequester
of muscle fibers depolarized. Regardless of the method used, it all of the entering free calcium ions, thus producing a period of
is typical to measure the amplitude of the first CMAP and com- increased facilitated release of ACh vesicles. This increased
pare it with the fourth or fifth CMAP amplitude. A percentage amount of vesicular release produces sufficient MEPPs, which
change, increment or decrement, is calculated by subtracting the summate to an EPP that exceeds threshold; i.e., the safety factor
fourth or fifth response (R4 or R5) from the first response (R,), is increased. The patient's nerve is again activated at 2-3 Hz im-
and dividing the remainder by the first response's magnitude, mediately after maximal muscle contraction.
Safety factor restoration results in two possible electrodiag-
nostic medicine findings. The magnitude of the CMAP may
exceed that recorded in the resting state at supramaximal stimu-
lation with or without an ensuing decrement. Additionally, a 50
previous decrement between the first and fourth or fifth re- Quantal
sponse may be repaired or eliminated completely. It is also pos- 1 3 5 1 3 5

sible to stimulate the nerve at 20-50 Hz for -If) seconds, but this
technique can be quite uncomfortable for the patient, particu-
larly if performed with surface stimulation. The application of
high rates of electrical stimulation are necessary only if the pa-
tient is physically unable to cooperate or cannot comply with
the request (altered mental status, profound paresis, or pediatric
patients).
Clinically, exercise or high-rate pulses of electrical current
for brief periods are capable of facilitating quantal release and
thus can produce facilitation, augmentation, and potentiation of
the EPP. This phenomenon is manifest as a repair in the previ-
ous CMAP decremental response. When this repair effect is
noted during the electrodiagnostic medicine examination it is
known as postactivation (exercise) potentiation, although the
term postactivation facilitation is also used.
In people with little or no CMAP decrement at rest, a maxi-
mal exercise period of about 60 seconds may be necessary.
Since no decrement was initially present, one should not expect
to detect any change in the CMAP responses immediately after
exercise. The patient's nerve is then activated at 2-3 Hz once
every minute for 5-6 minutes. Even though a decrement is
absent at rest during 2-3-Hz stimulation, the 1 -minute period of
muscle exercise may be sufficient to deplete a number of nerve
terminals of ACh vesicles below a value capable of producing
subthreshold EPPs once the excessive calcium is removed (i.e., 1 3 5 3 5 3 5
postactivation exhaustion phase). Failure of sufficient numbers Normal MG LES
of EPPs may result in a significant decremental response sev-
eral minutes after a relatively long period of exercise. In this in- Figure 25-18. Repetitive stimulation findings. Under normal
stance, the initial facilitation is not observed because the safety conditions the quantal content resulting from depolarization of the
factor is of a sufficient magnitude to exceed threshold. The nerve terminal at about 2-3 Hz sequentially declines to about 50% of
combination of EPPs greater than threshold and an all-or-none that arising from the initial stimulus.There is an associated decline in
muscle response results in no incremental CMAP, even though the magnitude of the EPP as one would expect, given the ACh reduc-
the absolute magnitude of EPPs may increase immediately after tion. However, all of the EPPs are suprathreshold for the muscle fiber's
exercise. However, continually activating the motor units with action potential. Because the single-fiber action potential's (SFAP's)
sustained exercise over the course of 1 minute sufficiently taxes electrical response is an all-or-none phenomenon, as long as the EPP is
the nerve terminals to reduce significantly the immediately suprathreshold, each muscle depolarization is essentially identical.The
available stores of ACh vesicles. ensuing CMAP is simply the electrical summation of all activated SFAPs
Immediately after the prolonged exercise, the residual calcium and hence is the same with each peripheral nerve trunk depolarization.
is removed over the course of the next 1 or 2 minutes. With the In a postsynaptic disorder such as myasthenia gravis (MG), the EPPs fall
calcium back to normal levels and reduced amounts of ACh vesi- below threshold in response to the reduction in normal quantal con-
cle adjacent to the nerve terminal's presynaptic membrane, a tent secondary to reduced safety factor.There is blocking of the SFAP
stimulus of 2-3 Hz may now produce sequential EPPs that fail to once this occurs at some NMJs; hence the CMAP also declines. With a
reach threshold in multiple muscle fibers. The result is a decre- prejunctional disorder of significantly reduced quantal content, multiple
menting CMAP response. Over the course of the next 5-20 min- muscle fibers' EPPs are reduced on initiation of stimulation. Only a few
utes, depending on the severity of the disease, the CMAP SFAP occur because of the markedly reduced number of EPPs.The cor-
decrement declines. If a patient with significant disease (CMAP responding CMAP is also significantly reduced, and additional NMJs are
decrement > 10-20%) is exercised for 1 minute, the initial facili- induced to fail with slow rates of repetitive stimulation. (From Radecki
tation may be very short-lived or of minimal magnitude so that PL: Electrodiagnostic evaluation of neuromuscular junction disorders. In
prolonged exercise simply results in a more profound decrement. Dumitru D (ed): Clinical Electrophysiology. Philadelphia, Hanley &
By convention, it is part of the NMJ protocol to attempt to repair Belfus, I989,pp 757-778, with permission.)
the decrement. The decrement in excess of that possibly
recorded at rest after exercise is known as postactivation exhaus- phenomenon is essentially equivalent to depression, as defined
tion. As previously noted, postactivation exhaustion may repre- for the run-down phase. Desensitization, or the inability of the
sent the end result of a complex interaction between the decline postsynaptic membrane to respond to ACh, is probably not a
of immediately available ACh stores and the influence of previ- factor in postactivation exhaustion.
ous stimuli on the kinetics of ACh mobilization from the storage The clinical application of postexercise exhaustion is useful for
zones as well as other less understood mechanisms.62-63-64 This documenting severe as well as mild NMJ disorders and deserves
25 min
Figure 25-19. Postactivation exhaustion in a patient with myasthenia gravis. A, Results of repetitive stimulation at 3 Hz of the ulnar
nerve while recording from the adductor pollicis. Note the 40% decrement between the first and fourth response. B,A decrement with stabiliza-
tion of a new baseline CMAP is noted during the second period of 50-Hz stimulation. C, About 10—15 seconds after the high rate stimulation, the
decrement between the first and last response is now only 9%. D, Four minutes after the tetanic stimulation a decrement of 54% is obvious. E,
Twenty-five minutes after high-rate stimulation the decrement is 37% and approaches the resting state. F, Diagrammatic representation of facilita-
tion and exhaustion as competitive factors generating the net CMAP response.The solid black line prior to time zero represents the baseline
amount of neuromuscular block. Several seconds after high-rate stimulation the amount of NMJ block decreases to some degree and offsets the
exhaustion effect.This facilitatory effect is rather short-lived, allowing the CMAP to succumb to the exhaustion or ACh depletion effect. Over the
next 15-30 minutes the resting state is slowly approached as replenishment of ACh stores through mobilization is complete. (From Desmedt JE:
Presynaptic mechanisms in myathenia gravis. Ann NY Acad Sci 1966;135:209-246, with permission.)
further discussion. The mechanism observed under microelec- and decrement again approach resting levels during the recov-
trode recording techniques in animal preparations is the founda- ery phase.
tion for what is observed clinically in pathologic situations. Unlike presynaptic deficiency of ACh release, decreased ex-
Specifically, in patients with postsynaptic disorders, such as tracellular calcium, or elevated extracellular magnesium, pro-
myasthenia gravis, repetitive stimulation at high rates for a brief longed rapid rates of stimulation in patients with defective
interval (40-50 Hz for 2 seconds) results in a small initial facili- AChRs do not generate a continuously larger CMAP response
tation, followed by a more prominent decline in CMAP ampli- approaching several hundred-fold, but instead a CMAP decre-
tude (Fig. 25-19). After stopping the stimulation for 1-2 ment is noted. This decrement results from rapid depletion of
seconds, activating the nerve again at 3 Hz produces a response the immediately available ACh vesicle store. Although increas-
that may be larger and display less decrement—i.e., postactiva- ing amounts of residual calcium act to facilitate greater vesicle
tion facilitation, which lasts about 20-30 seconds. This period of release, the high rates of stimulation deplete so much on ACh
"facilitation" consists of the two phases of facilitation, augmen- that the attempt at facilitation is overwhelmed by the greater de-
tation, and potentiation: a maximal effect within the first 200 ms pressant effect of neurotransmitter depletion. After the pro-
and decreases over the next 50-100 or so seconds (see Fig. 25¬ longed high-rate stimulation or brief period of maximal
15). The phenomenon of clinically observed facilitation appears exercise, only a few seconds of rest between cessation of the
to be more dependent on the frequency of stimuli (optimal at high-rate and low-rate stimulation is required for the process of
50-200 Hz) than the number of delivered impulses during high mobilization to replenish to a small degree the immediately
rates of stimulation. 215 It is certainly possible to observe this available stores of ACh. NMJs that could not respond to the ini-
effect after exercise with motor unit firing at 20-30 Hz. High tial stimuli as well as those that failed secondary to ACh deple-
rates of repetitive stimulation for more than a few seconds or tion during high rates of stimulation can now respond because
maximal exercise in excess of 30-60 seconds runs the risk of of the combined effect of residual calcium and replenishment,
overwhelming facilitation so that only exhaustion is observed. to some degree, of the immediately available ACh store. This
Over the next 3-4 minutes this facilitatory effect is overcome combined effect results in the postexercise facilitation, generat-
by postactivation exhaustion. The CMAP amplitude declines, ing a possibly larger than initial CMAP amplitude as well as a
and the percent decrement increases over that of resting decremental repair. Unfortunately, this facilitation effect is
levels.215 The postactivation exhaustion is more dependent on short-lived because the more powerful depletion effect causes
the total number of stimuli than on the rate at which the nerve the NMJ to succumb to the removal of residual calcium and rel-
terminal is excited. For any given motor unit firing frequency, atively depleted store of immediately available ACh. It takes
the degree of exhaustion increases with higher numbers of dis- quite some time (15-20 minutes) for the process of mobiliza-
charges. Within the next 15-20 minutes the CMAP amplitude tion to restore ACh to levels at which the safety factor, in as
many severely affected NMJs as possible, is brought to mini- is produced. As a result, only a small proportion of muscle
mally functional levels. Some NMJs may not be capable of gen- fibers generate an electrical response, and the associated CMAP
erating an EPP of sufficient magnitude to reach muscle is correspondingly low. If the nerve is stimulated at 2-3 Hz, the
membrane threshold unless increased calcium levels facilitate normal sequential reduction in EPPs results in failure of addi-
ACh release. These NMJs account for the increased magnitude tional NMJs to generate a suprathreshold EPP, and a decrement-
of facilitation for the CMAP 1-2 seconds after exercise or high ing CMAP similar to a postsynaptic NMJ defect is observed.
rates of stimulation. Stimulation at 2-3 Hz immediately after a 30-second maximal
In presynaptic disorders consisting of decreased vesicle re- muscle contraction in which motor units fire at 20-30 Hz now
lease, the initial CMAP is only a small fraction of normal because demonstrates a relatively larger CMAP that may display only a
multiple NMJs fail to reach threshold. This failure may result small decrement between the first and fourth or fifth response.
from decreased calcium entry, thus producing a low probability Within several minutes the residual calcium ions accumulated
of ACh release. Low rates of stimulation result in a decrementing during the exercise are buffered or sequestered, and the quantal
response similar to that noted above, but the decrement begins release is again significantly reduced so that a very small
with the initial small CMAP and subsequently declines. Brief ex- CMAP is obtained as well as a decrementing response to low
ercise or rapid rates of stimulation result in a several hundred-fold rates of repetitive stimulation.
increase in the CMAP because residual calcium activates all of Needle Electromyography. The needle EMG examination
the failed NMJs. The residual calcium temporarily increases the in patients with NMJ disorders serves several purposes.
probability of ACh release, thus dramatically potentiating the Because of the wide variety of disease states that may mimic
CMAP amplitude. This same effect repairs any decrement, as de- NMJ dysfunction and cause weakness and fatigue, the presence
scribed for postsynaptic disorders. Over the next several minutes, of both neuropathies and myopathies must be explored.
the residual calcium is sequestered and the CMAP declines pre- Evidence of positive sharp waves and fibrillation potentials is
cipitously. In addition, the same mechanism of ACh depletion, relatively rare in the majority of commonly encountered NMJ
combined with the attempt to catch up with depleted ACh through disorders unless the disease is severe. The observation of signif-
mobilization, generates postactivation exhaustion which lasts icant degrees of membrane instability and reduced numbers of
until the resting equilibrium is again reached. large MUAPs firing at rapid rates suggests a neurogenic disease
This protocol is useful for disorders affecting either the presy- affecting some portion of the motor unit other than the NMJ. In
naptic (nerve terminal) or postsynaptic (AChR and supporting addition, small-amplitude, short-duration motor units firing
membrane) portion of the NMJ. In patients with postsynaptic dis- rapidly in abundant numbers at low levels of muscular effort can
ease, the usual finding is an initial CMAP with a magnitude quite be found in NMJ disorders but are more commonly observed in
similar to that in normal people. When a nerve terminal disorder primary myopathic processes.
results in reduced quantal content, release of decreased numbers The characteristic abnormality observed during routine
of ACh vesicles, or a normal number of vesicles with reduced ACh needle EMG in patients with NMJ disorders is variability in
molecules, quite a different finding is noted. The initial CMAP to MUAP morphology and amplitude (Fig. 25-20). Normally,
supramaximal stimulation is quite small (e.g., several hundred mi- MUAP variability from one discharge to the next is minimal. In
crovolts) compared with a normal response of several thousand NMJ disorders, each firing of the MUAP under consideration
microvolts. Stimulation at 2-3 Hz produces a decrement similar to may be somewhat different from the preceding MUAP because
that found in postsynaptic disorders. Immediately after brief peri-
ods of exercise, however, the magnitude of the CMAP approaches
normal, resulting in an increment of several hundred percent.
Occasionally it may be possible to observe an incrementing re-
sponse in normal people during rapid rates of repetitive stimula-
tion, but this increment does not exceed 30-50% and is clearly
distinguishable from several hundred percent. The normal incre-
ment is believed to be due to more synchronous firing of motor A
fibers (termed pseudofacilitation). The actual basis of this phe-
nomenon is poorly understood, but it has been attributed to be due
1t
to an increase in the conduction velocity of the stimulated muscle
fibers.215 713 898 Apparently the slow muscle fibers increase their
conduction velocities more than the fast fibers. The electrical ac-
11 1
tivity then summates to a greater degree because less temporal dis-
persion results in a larger-amplitude, shorter-duration CMAP (i.e.,
the area remains the same). This observation distinguishes true fa-
cilitation due to added muscle fibers (reversal of neuromuscular
block) from better synchronization.900 Further work is required to B
elucidate more fully the mechanism of pseudofacilitation. Figure 25-20. Concentric needle recording of a single motor
When a presynaptic disorder causing a reduction in quantal unit action potential. A, A patient with no known pathology affect-
content is suspected, the repetitive activation of a peripheral ing the motor unit demonstrates little variation from one MUAP t o
nerve with CMAP analysis can be quite helpful. The initial re- the next. B, In a patient with myasthenia gravis, amplitude variation is
sponse should be quite small, as previously noted, because the easily identified with continuous MUAP firing.This observation is a
number of ACh vesicles induced to undergo exocytosis is suffi- result of random neuromuscular blocking of individual single muscle
ciently low at a significant number of muscle fibers composing fiber action potentials composing the motor unit action potential. At
most, if not all, of the motor units constituting a muscle. In a any one time there is a different number of active single muscle fibers
large proportion of the muscle fibers' NMJs, a subthreshold EPP because of the variability in EPPs that achieve threshold.
I 154 — P A R T IV CLINICAL APPLICATIONS
the total number of single muscle fibers activated at any one explore the physiologic properties of single muscle fibers. Of im-
time varies as individual EPPs at the NMJs contained in the portance to NMJ disorders is the ability to record from two single
motor unit fail to generate a suprathreshold EPP in a random muscle fibers belonging to the same motor unit. Locating the
manner. Each discharge of the motor unit results in a different active recording surface of the needle next to these two muscle
number of single muscle fiber action potentials that contribute fibers permits one to measure the time variation between neuro-
electrical activity to the MUAP at any given time. The best muscular transmission of the two muscle fibers (i.e., jitter.)
manner in which to observe this phenomenon is to decrease the s The interpotential interval between two single muscle
sweep speed to about 30-50 ms/div and have the patient fire fibers is measured when the anterior horn cell is voluntarily ac-
only one motor unit. One also may note a rather rapid decline in tivated. The time between the two single muscle fiber action
the absolute magnitude of the MUAP, which then reaches a new potentials is not constant with each depolarization of the pe-
lower amplitude that subsequently varies in amplitude. An in- ripheral nerve. The time required to facilitate the release of
creased instrument sensitivity may be required to observe the ACh through synaptic vesicle fusion with the presynaptic
variability in the smaller MUAPs. In profound disease in which membrane is a probabilistic event that varies from one nerve
NMJs have completely disintegrated, the muscle fibers are ef- terminal depolarization to the next. The threshold level from
fectively denervated. In such muscles, variable amounts of one depolarization to the next at the same single muscle fiber is
single muscle fibers can be devoid of NMJs; hence, both posi- believed to vary slightly. As a result, it takes a different amount
tive sharp waves and fibrillation potentials may be documented. of time for the EPP to reach threshold each time the nerve ter-
Astute observers, particularly when performing quantitative minal is activated because of the variable delay in calcium-fa-
EMG with appropriate instrument parameters, may note cilitated ACh release combined with a changing muscle
MUAPs of reduced amplitude and duration.219 7033 A reduction in membrane threshold. This variability is normally on the order
MUAP duration and amplitude may suggest a myopathic dis- of 35-55 jis.335-898
ease, particularly in a patient complaining of weakness and easy In disorders of the neuromuscular junction, the reduced safety
fatigue (see above). This finding may be especially prominent margin secondary to either presynaptic or postsynaptic factors ex-
in proximal muscles, which are less likely to be subject to tem- aggerates the amount of time and hence the variability required to
perature alterations and approach core body temperature more reach threshold (Fig. 25-22). This increased variability is referred
closely than distal muscles. 445 Cooling the muscle with a cold to as an increase in neuromuscular jitter. The jitter at a normal
pack may alter the MUAPs by increasing both the duration and endplate is relatively small, whereas that at a diseased NMJ can
amplitude (Fig. 25-21 ).219 This finding suggests a NMJ disorder be quite long (Fig. 25-22). Reduction of the safety factor below
rather than a myopathy. A myopathy should not respond in such threshold levels also produces failure of muscle fiber activation
a fashion, aside from a minimal alteration in duration and am- (i.e., neuromuscular blocking). Jitter determination is a rather
plitude. However, a single study suggests a concomitant autoim- sensitive parameter in NMJ disease. Unfortunately, it is also non-
mune myopathy with antibodies to titin in late-onset myasthenia specific because immature NMJs from denervation or some my-
gravis should be considered.8893 opathies also can result in a prolongation of jitter.
Single-fiber Electromyography (SFEMG). SFEMG is an In attempting to record jitter, it is necessary to attempt to
extremely important technique because it permits investigators to record 20 potential pairs and at least 10 potential pairs with a
Figure 25-21. Concentric needle recording in a pa-

tient with NMJ disease. A-D, Motor unit action poten-
tials of reduced amplitude and duration approximating 5 - 7
ms or less recorded in the deltoid muscle at 36°C. E—G,
Similar MUAPs from the same muscle after the muscle had
been cooled to 30°C. Note the increase in both amplitude
and duration. H,A scattergram of the MUAPs amplitude
(abscissa) plotted against duration (ordinate) at 30°C (dots)
and 36°C (circles).The MUAPs at the lower temperature
display normal amplitudes and durations, whereas those at
higher temperatures are highly suggestive of myopathic
MUAPs secondary to short durations and small amplitudes.
(From Desmedt JE: How to validate myasthenia gravis in the
patient with a diagnostic problem. Ann N Y Acad Sci
1981 ;377:583-605, with permission.)
% o <?
0.5 0.6 0.7 m V 08

minimum of 50 consecutive discharges per pair. In patients less Normal Myasthenia Gravis
than 60 years of age, three criteria are proposed for defining the Membrane
presence of abnormalities: (1) the mean jitter (jitter of individual
pairs for a single muscle summated and then divided by the
number of pairs) for a muscle exceeds the normal limit (Table 25¬
5); (2) more than 10% of the potential pairs recorded demonstrate
jitter larger than the upper limit for individual jitter pair values
(see Table 25-5); and (3) potential pairs with frequent blocking
are observed, but jitter is not calculated.827-832 When blocking is
marked, it may be biased toward NMJs that are capable of gener-
ating a muscle impulse for each neural depolarization. In this in- 5 ms . blocking
stance, the mean jitter for the muscle is lower than the actual
value because potential pairs with profound blocking and hence Figure 25-22. A schematic explanation of the phenomena of
jitter in excess of 80-100 jis are discounted. Blocking is fre- jitter in both a normal and myasthenic NMJ. A,A normal NMJ
quently seen with jitter in excess of 80-100 p.s; hence the third demonstrating a small amount (< 50 |is) of variability in achieving
criterion. For people over 60 years of age, criteria 2 and 3 are threshold from one depolarization to the next. Each EPP is of sufficient
used. Although it is ideal to record as many potential pairs as pos- magnitude to reach threshold and generate a single muscle fiber action
sible (up to 20), this goal may not be practical because of patient potential. B, Endplate potentials recorded from a patient with myas-
intolerance, inability to maintain a steady contraction, time con- thenia gravis. Note the increased time and variability from one depo-
straints, or profound disease with significant blocking.895-898-899-952 larization to the next, which results from the different number of
Axonal-stimulated SFEMG is another method of assessing AChRs activated with each depolarization that are just barely able t o
I jitter and blocking and requires minimal patient coopera- reach threshold because of the borderline number of AChRs.As each
tion j12.447.m950.952.954.%3a j h e technique can be performed on young depolarization has a different rise time because of a variable safety
children, comatose patients, extremely weak patients, or patients factor, there is significant variability and even blocking of individual
with pyschosomatic illness who do not give a good effort. It is also EPPs (solid lines below the wavy threshold value approximating - 6 0
particularly useful in patients with ocular myasthenia gravis.739b-963a mV). (From Stalberg E.Trontelj JV, Schwartz MS: Single fiber recording
A single-fiber EMG needle is inserted into the muscle near the of the jitter phenomena in patients with MG and in members of their
motor endplate. The anode can be a surface electrode placed families. Ann NY Acad Sci 1976;274:189-202, with permission.)
nearby. The stimulation frequency can range from 2-10 Hz; dura-
tion of the stimulus should be 0.05 ms. The initial intensity of the
current should be low but increased gradually until a visible twitch mean for 20 potentials. Normal MCDs during axonal stimula-
in the muscle is apparent. However, current should never exceed tion of the orbicularis oculi are 30 jis for individual potentials
20 mA—if large currents are necessary, the stimulating electrode and less than 20 jis for 20 potentials.950
is too far from the axon branch. The single-fiber needle is placed It is possible to measure jitter with a standard monopolar or
at the site where the muscle twitching is apparent. The needle is concentric needle electrode and to obtain jitter values compa-
adjusted so that recorded potentials have a rise time less than 200 rable to those obtained with a commercially available
jis and amplitudes of at least 200 p.V. The jitter of the recorded po- SFEMG electrode. 1 ".113.157.291.989 The utility and diagnostic ap-
tentials is measured in relation to the triggered stimulus. plicability of this technique require further study. The obvi-
Stimulated SFEMG does not depend on fiber density or pa- ous benefits are electrode cost and patient comfort, but
tient cooperation. With axonal stimulation, it is often possible to sophisticated equipment is still required to analyze the data
record two or more potentials at any given position of the efficiently. At present, it is perhaps best to perform jitter and
recording single-fiber needle. Therefore, stimulated single-fiber fiber density analysis using only an appropriately manufac-
EMG is much faster that volitional SFEMG. A major pitfall of tured single-fiber electrode.
the procedure is direct stimulation of the muscle fiber itself
rather than the innervating axon. Because direct stimulation of TECHNICAL FACTORS
the muscle fiber bypasses the NMJ, the measured "jitter" is ab-
normally short (i.e., 5 JIS or less). Data obtained from these A number of important technical issues must be considered in
recordings should be discounted and the stimulating monopolar performing an electrodiagnostic medicine evaluation of patients
needle repositioned. Another important pitfall is that stimulat-
ing the axon near the threshold for excitation also induces extra
jitter (and possibly blocking at subthreshold values) because of Table 25-5. Upper Limit of Normal Jitter Values (ps)333 898
uncertainty as to the node at which the response starts.949 Muscle Largest Single Jitter Measurement Mean
The recorded MCD is less with the stimulated technique than EDC 55 34
with volitional SFEMG, because the jitter is measured about Biceps brachii 35 30
one potentially stimulated single fiber as opposed to two end-
plates with the voluntary technique. 950 The theoretical relation- Deltoid 35 30
ship between jitter recorded from axonal stimulation and Frontalis 45 30
volitional responses is expressed by the formula: Mean MCD ADQ 60 49
(axonal stimulation) = mean MCD (volitional activity) -r V2.950
The predicted MCDs based on the above formula are close to TA 60 32.1
the MCDs obtained for normal control populations. Normal Rectus femoris 60 31
values for mean MCD during axonal stimulation of the EDC are EDC, extensor digitorum communis; ADM, abductor digiti minimi;TA, tibialis
less than 40 jis for individual potentials and less than 25 jis anterior
1156 — P A R T IV CLINICAL APPLICATIONS
suspected of having a disease affecting the NMJ. Impeccable (secondary to increased quantal content) and a longer open time
technique and attention to detail are crucial. Each of the factors has a synergistic effect on the EPP. In short, more open AChRs
discussed below can be used to advantage in attempting to assess increase the magnitude of the EPP, whereas a longer open time
whether a particular patient has an NMJ junction defect. increases the EPP's duration. Both effects create a relatively
Particular consideration should be directed to each of these large negative sink (compared with a higher temperature) into
issues to achieve the highest yield possible, even in patients with which positive sodium ions about the surrounding muscle mem-
mild disease. brane can flow. This sodium ion current flow decreases the pos-
Temperature. The role of temperature is extremely impor- itive charge on the outside of the muscle membrane and
tant. Temperature must be measured before beginning the elec- increases the amount of positive charge on the inside of the
trophysiologic assessment and continuously , monitored muscle membrane. In other words, there is a change in the
throughout the examination, particularly when repetitive stimu- transmembrane potential across the muscle membrane sur-
lation studies are performed. Clinically, patients with NMJ dis- rounding the endplate zone. Additionally, a slightly reduced
orders may prefer cool to warm baths because heat causes them (more negative) threshold value at comparatively lower temper-
to feel weak and produces fatigue.87 Similarly, drinking hot as atures means that less transmembrane depolarization of poten-
opposed to cool drinks results in swallowing difficulties. From tial is required. All of these effects increase the safety factor,
the above information about the normal physiologic response of depolarize the muscle membrane to threshold level, and create a
the NMJ to temperature and the findings in NMJ disorders, we propagating muscle action potential. In patients with borderline
may hypothesize a rationale for these findings. or lower EPP magnitudes, a reduction in temperature may facil-
In patients with myasthenia gravis, a reduction in muscle itate all or some of the above factors and increase the number of
temperature results in a number of well-documented find¬ single muscle fibers, previously blocked by a reduced safety
i n g s86,87.88.364.365.796.797.833,902.979 T h e magnitude of a decremental factor, that respond to a neural impulse. Depolarization of more
response during repetitive stimulation at a muscle temperature muscle fibers per neural impulse not only improves fatigue but
of 34°C can be significantly reduced or repaired by muscle also results in a commensurate reduction in the percent decre-
cooling of only a few degrees. Similarly, both the absolute mag- ment to repetitive stimulation.
nitude of the CMAP and the decrement after exercise (postacti- This effect of NMJ repair continues into the postactivation
vation exhaustion) can be increased and decreased, respectively. exhaustion phase after maximal exercise. The same factors—in-
Furthermore, the decrement at rest and several minutes after ex- creased facilitated release of ACh, decreased AChE activity,
ercise can be significantly increased by warming the muscle to more AChRs open for longer times, and less potential difference
34-35°C. Although the exact mechanism of the diseased NMJ's between threshold and resting membrane potentials—may be
response to alterations in temperature is only partially under- operational. The net result is less decrement after exercise at
stood, one can speculate about various known reactions of the lower compared with higher muscle temperatures. The mobi-
NMJ to conceptualize more clearly and thus remember what ef- lization of ACh is reduced in relatively cool muscle tissue, as is
fects are observed. the total number of ACh molecules available with each subse-
The conduction velocity of the nerve impulse traversing the quent stimulus secondary to a larger than "normal" quantal con-
peripheral nerve trunk and nerve terminal is significantly tent. Because the decremental repair at lower temperatures is a
slowed.471 Additionally, the duration, rise time, and amplitude of consistent physiologic finding in diseased NMJs, the reduced
the response are increased (see Table 25 - 2).85-528-572-582 Of partic- mobilization and smaller number of synaptic vesicles, both
ular importance to NMJ transmission is the prolonged duration. which tend to reduce the safety factor, are more than compen-
Specifically, a longer-duration, greater-magnitude neural im- sated by facilitated release of the available synaptic vesicles.
pulse may prolonge the open time of calcium channels because Several other findings can be noted in patients with NMJ dis-
of a larger and longer depolarization of the nerve terminal. If orders when their muscles are cooled during an electrodiagnos-
the calcium channels are open for a longer time, a larger cal- tic medicine evaluation. The amplitude, duration, and rise time
cium ion flow should ensue and increase the probability of ACh of individual single muscle fiber action potentials are in-
release to each nerve impulse at a lower temperature. Indeed, creased, 219299 probably as a result of altered sodium kinetics
both the net amount of ACh released and the probability of ACh (e.g., delay in sodium inactivation at reduced temperatures).
release are increased as the muscle's temperature is lowered When sodium channels are open for an increased period, more
from 34°C to 20°C.94-304-436-481-553 The increased amount of ACh current flows for a longer time. Furthermore, it takes slightly
per neural volley diffuses across the synaptic space in about the longer to open the sodium channels at lower temperatures be-
same (or insignificantly longer) time at cooler compared with cause of their proteinaceous nature; protein-based reactions
warmer temperatures. During its passage across the synaptic occur more slowly at reduced temperatures compared with rela-
space, the ACh must encounter AChE. The hydrolytic capability tively higher temperatures. Each sodium channel no doubt re-
of AChE is significantly reduced at temperatures below 34°C.315 sponds slightly differently. When multiple sodium channels
The net result at this point is that larger amounts of ACh reach respond more slowly, a longer time is required to reach the peak
the AChRs because the quantal content per neural impulse is in- current flow; i.e., the rise time increases. An increase in the pa-
creased and less ACh is hydrolyzed during the first pass of ACh rameters of the single muscle fibers composing a motor unit can
across the synaptic cleft. be expected to result in the same changes in the corresponding
When an increased net amount of ACh reaches the postsynap- MUAP. Thus, recording either single muscle fibers or MUAPs
tic membrane, more AChRs should be activated, thus increasing with needle EMG results in the same parameter changes in both
the size of the saturated disc. Furthermore, reducing the affected types of potentials. Similarly, if the muscle's MUAPs display
muscle's temperature is known to increase the AChR's open increases in rise time, duration, and amplitude, the same find-
time.539 An increased period of AChR opening allows more cur- ings are observed in the resultant CMAP. Indeed, there is an in-
rent to flow into the muscle membrane at lower compared with crease in the CMAP amplitude with muscle cooling in normal
higher temperatures. The combination of more open AChRs people as well as patients with NMJ disorders (Fig. 25-23).
Temperature-dependent changes in jitter also can be seen in A _„
people with normal or abnormal NMJs.88-901 When single-fiber Abductor fl i —57%
EMG analysis is performed in normal people at both warm and Po.Hcis Jl_X_X_ J\
relatively cool intramuscular temperatures, characteristic findings
are noted. Normally, jitter is less than 50 JIS in persons without
neuromuscular disease. Lowering the intramuscular temperature Flexor >T V" " " V25%
several degrees below 35°C increases jitter about 2-3 JIS per
degree, while further decreases in temperature toward 30°C in- R X i i s - / ^ - i | ^ ^ L - ^ - ' ' | / < - ] 4 mv
crease jitter to 6-8 p,s per degree of change. In other words, the
jitter increases from 50 (is to 60-70 jis and may even reach 100 2 msec
JIS at temperatures of 25°C.898 The EPP's increased rise time and
the variability of all factors necessary to facilitate ACh release
may explain this rinding. However, in patients with NMJ disor-
ders, particularly of the postsynaptic membrane, the jitter may ac-
tually improve with a reduction in muscle temperature.
Additionally, neuromuscular block present at 34°C may no longer
occur at an intramuscular temperature of 30°C. At reduced tem-
peratures in patients with markedly abnormal jitter (> 80-100
(is), the increased quantal content results in an EPP of larger mag-
nitude, which subsequently results in a faster rise time that ap-
proaches, but does not reach, normal values, with less inherent Figure 25-23. Repetitive stimulation of a 20-day-old infant
variability arid an increased safety factor. Thus, jitter is reduced. with neonatal myasthenia gravis. A, Recordings from the abduc-
I Normal people display an increase in jitter because the rise time tor pollicis brevis and flexor carpi radialis performed with an intra-
' is somewhat prolonged by mild reductions in temperature. muscular temperature of 35°C. Note the large percent decrements
Patients with abnormal NMJs and profoundly abnormal jitter ap- documented between the first and fifth response. B, Same patient and
proach, but do not reach, the normal values of the cold muscles muscles examined with only the hand cooled to 29°C.There is no
because of a modest improvement in the safety factor. At abnor- change in the forearm muscle since the temperature was not altered.
mal NMJs, the increased ACh release offsets the prolongation In the hand, however, there is a significant repair in the percent decre-
effect of temperature on rise time and variability. ment as well as a marked increase in the CMAP magnitude for all re-
The above processes are equally applicable in presynaptic sponses. (From Borenstein S, Desmedt JE: Local cooling in myasthenia:
and postsynaptic disorders. In a presynaptic disease process in Improvement on neuromuscular failure. Arch Neurol 1975;32:
which fewer quanta are released per nerve impulse at slow rates 152—157, with permission.)
of stimulation, a reduction in temperature leads to release of
more quanta, more ACh reaches the postsynaptic membrane be- with the stimulating electrodes and peripheral nerve can result
cause of the reduced hydrolytic action of AChE. This effect is in a false decrement (Fig. 25-24). If the cathode and anode are
probably sufficient to correct the reduced quantal content at minimally displaced during delivery of multiple stimuli, a less
warmer muscle temperatures. Similarly, a defect in the postsy- than supramaximal current is applied to the nerve. As a result,
naptic membrane in which reduced numbers or ineffective less than all of the motor nerves may be activated during each
AChRs are found also can be improved by cooling the muscle. stimulus. Additionally, it is possible for each successive muscle
The size of the saturated disc increases because of an increase contraction to displace the cathode slightly more. The end result
in the quantal content of ACh per impulse. Larger EPPs ensue, is a declining current intensity with an associated decrementing
and current flows longer because the AChRs are open for a CMAP. A similar situation may result if the recording elec-
longer time. Both factors assist the muscle in reaching the trodes inadequately record the electrical activity from the
slightly lowered threshold level. The net effect is an improve- muscle. Again, a decrementing response may be recorded.
ment in the safety factor that reduces the amount of neuromus- One can determine whether a recorded decrement is the result
cular block and hence improves both clinical strength and of disease or an artifact secondary to inadequate electrode stabi-
fatigue as well as reduces decrement during repetitive stimula- lization by recognizing the characteristics of a CMAP decre-
tion at rest and after exercise. ment due to a true NMJ disorder when it is investigated at a
Stabilization. It is important to ensure that the recording stimulation rate of 2-3 Hz. Specifically, a pathologic decrement
electrodes are securely attached to the patient to obtain a techni- should exceed 8-10% with the greatest sequential interpotential
cally satisfactory study. During repetitive stimulation, the decrement between the first and second response.87-215-711-738-739
muscle under study is activated several times per second at a The actual percent decrement that is considered normal varies
supramaximal level. Significant forces are generated between somewhat from person to person and muscle to muscle. Thus,
the skin and recording electrode surfaces. As a result, poorly se- most practitioners should develop reference decremental data
cured electrodes tend to become dislodged or to slip slightly for specific muscles. Smaller interpotential decrements occur
with each muscle contraction. Additionally, slippage may occur with each subsequent response until an unchanging amplitude is
between the skin surface and stimulating electrodes. Either or noted for 2-3 potentials. Continued stimulation can result in a
both of the above situations can result unless precautions are small increment with each succeeding response until a new
taken to ensure that the electrodes are properly attached to the baseline is achieved, which continues to be smaller than the
patient. original response in the train. During continuous low-rate stim-
Attention must be paid to this detail because movement of the ulation for several minutes, a smooth pattern of CMAP ampli-
electrodes off the muscle's motor point, insufficient contact be- tude decline usually is followed by a leveling off, then a slight
tween the skin and recording electrodes, or similar problems increase, and a final leveling off of the CMAP amplitude.738-739
as the cathode and anode can be taped to the wrist or forearm.
An arm board is a convenient device to ensure adequate stabi-
lization during muscular contraction. Unfortunately, it is
mandatory to explore more than just the distal muscles. In ex-
amining the shoulder girdle, facial, and knee extensor muscles,
stabilization becomes quite difficult, if not impossible. In these
cases, it is imperative to scrutinize carefully each train of repet-
itive responses to ensure that the decrement, if present, appears
physiologic as opposed to artifactual. Additionally, it is a good
idea to repeat the repetitive stimulation several times to ensure
reproducibility after resting the patient for several minutes be-
tween stimuli. A physiologic decrement should appear quite
similar between trials, whereas an artifactual decrement is usu-
ally slightly different with each train of stimuli.
Muscle Sensitivity. In performing NMJ testing through
repetitive stimulation, it is important to sample a sufficient
number of muscles to maximize the potential for documenting
an abnormality. As with most diseases, in NMJ disorders a spec-
trum of pathology can be present at any one time, and the
degree of pathology affecting neuromuscular junctions typically
varies from one muscle to the next as well as from one muscle
fiber to another. In postjunctional disorders, proximal muscles
about the shoulder and hips as well as bulbar muscles tend to be
more severely affected than distal muscles.90-91213-384'508-738-872-899
Figure 25-24. Artifactual decrements resulting from im- This predisposition to proximal muscle involvement may result
proper electrode stabilization. A, Cathode displaced from optimal from higher temperatures, which potentiate a reduced safety
location of the nerve during the initial stimulus. Note the larger decre- factor, as one approaches the axial aspect of the body. 445 As
ment initially with no further decrement or increment observed. A noted previously, the more proximal muscles are more difficult
stable baseline suggests that the recording electrodes are well secured to stabilize. Nevertheless, it is important to investigate both
to the patient. B, Repositioning the cathode described in A results in a proximal and distal muscles.
normal train of CMAPs with no decrement. C, An apparent decre- One may wish to begin with stimulation of either the ulnar or
ment is recorded, but note how the second through fourth CMAPs median nerve while recording from the hypothenar or thenar
not only decline in amplitude above the baseline but also increase in muscles respectively (Table 25-6). These muscles can be easily
amplitude below the baseline. The last three responses again decline stabilized; unfortunately, they may demonstrate little if any
after an apparent increment for the fifth through seventh CMAPs.This decrement in 50-68% patients with moderately severe myasthe-
type of alternating decrementing/incrementing series of responses is nia gravis.739-900 The accessory nerve is perhaps the best nerve to
suggestive of recording electrode movement. (From Sanders DB: examine in NMJ disorders because it innervates a proximal
Electrophysiologic study of disorders of neuromuscular transmission. muscle and is likely to demonstrate a decrement. In addition,
In Aminoff MJ: Electrodiagnosis in Clinical Neurology, 2nd ed. New the nerve is easily accessible for stimulation behind the stern-
York, Churchill Livingstone, 1986, pp 307-332, with permission.) ocleidomastoid muscle. In about 90% of patients with general-
ized myasthenia gravis, repetitive stimulation of the spinal
accessory stimulation demonstrates a decrementing response.858
A smooth decline to a new baseline, with no further increases, is Erb's point stimulation with recording from the deltoid muscle
also possible. An artifactual decrement, however, may demon- can yield rather high percentages of abnormality (80-90%) in
strate an abrupt decline with no further decrement, suggesting patients with disease.397-739 The difficulty with excitation at Erb's
that either the recording or stimulating electrode is displaced point is that the brachial plexus is activated, resulting in con-
with the initial muscle contraction. A loose recording electrode traction of the entire arm with significant potential for contami-
can result in a response that declines rather precipitously or a nation by movement artifact (Table 25-6).
response that is barely visible. Another common artifactual Stimulation of the femoral nerve with recording from the
decrement secondary to recording electrode movement is a quadriceps muscles or stimulation of the peroneal nerve while
series of responses that alternate between decrement and incre- recording from the tibialis anterior or extensor digitorum brevis
ment over the train of stimuli (i.e., a CMAP of variable ampli- muscles also can be performed. As expected, at times it can be
tude). It is helpful to align the baseline of the CMAPs as well as rather difficult to stabilize the lower limb, regardless of the
the maximum positive and negative peaks. An apparent decre- muscle used, because of the strength of contraction and associ-
ment that results from electrode movement usually reveals an ir- ated movement (see Table 25-6).
regular baseline or a maximum positive peak that wavers about Facial nerve activation with recordings from the orbicularis
the baseline as opposed to a smooth decline or no change. oculi or nasalis muscles has a higher yield than limb muscles,
Movement artifact is best avoided by making sure that both but movement can be a significant problem in some patients.
the recording and stimulating electrodes are firmly fastened to Exercise of the facial muscles also may result in dislodgement
the patient. In stimulating the distal median and ulnar nerves of the recording electrodes. The potential for movement of the
and recording from the hand intrinsic muscles, stabilization is stimulating electrodes is significant, particularly if a hand-
relatively easy. Sufficient tape should be applied to separate hand stimulator is used. The authors prefer to use electrodes
discs or a bar type of electrode. Similarly, a bar electrode serving securely taped to the angle of the jaw over the facial nerve. A
Table 25-6. Comparison of Muscles Used for Repetitive Stimulation

Nerve Muscle Stimulation Advantage Disadvantage
Median APB Wrist Well tolerated by May not demonstrate decrement; somewhat difficult
patient to stabilize
Ulnar ADM Wrist Same as median nerve May not demonstrate decrement
Musculocutaneous Biceps brachii Axilla Proximal muscle May be difficult to stabilize in all patients; can have move-
ment of cathode; some patients find stimulus painful
Brachial plexus Deltoid Erb's point Proximal muscle Very difficult to stabilize; can be very uncomfortable;
cannot ensure identical stimuli to plexus
Spinal accessory Trapezius Posterior Proximal muscle Difficult to stabilize; may be painful in some persons;
triangle of neck cathode may move with contractions
Facial Nasalis; orbicu- Angle of jaw Proximal muscle Same as spinal accessory nerve
laris oculi
Peroneal TA; EDB Fibular head Lower limb May not demonstrate decrement; can be immobilized
well in some persons
Femoral Quadriceps Inguinal region Relatively proximal Hard to stabilize; painful

(RF orVM) muscle
APB, abductor pollicis brevis;ADM, abductor digiti minimi;TA, tibialis anterior; EDB, extensor digitorum brevis; RF, rectus femoris;VM, vastus medialis.
plastic pen or pencil is then applied to the middle of the bar ischemia tends to result in limb cooling, which can repair subtle
electrode to exert a counter pressure, thus ensuring that facial decrements. Either an infrared warmer coupled to the thermistor
muscle contraction does not result in significant movement of or hot packs located over the muscles should be in place. A re-
the cathode. duction in muscle temperature below about 33°C warrants ad-
Ischemia. Repetitive stimulation is relatively easy to per- justment of the heating element or replacement of hot packs.
form, and a number of muscle can be examined rather efficiently. Three or four sets of neural stimuli at 3 Hz, roughly separated
Unfortunately, the muscle that can be readily immobilized for by 30 seconds, establishes a baseline set of CMAPs with a per-
testing purposes may not be the most sensitive muscles for cent decrement calculated between the first and fourth or fifth
demonstrating a decrement in NMJ disorders (Table 25-6). As a response (Fig. 25-25). The nerve under investigation is then
result, various aspects of the repetitive stimulation procedure stimulated continuously at 3 Hz for 4 minutes. Upon comple-
have been modified in an attempt to increase its sensitivity. tion of the 4 minutes of stimulation, three sets of 5-10 stimuli
Ensuring that muscle temperature is 32-33°C or higher and in- are delivered immediately upon completing the 4 minutes, with
cluding maximal exercise in an attempt to demonstrate postacti- 2 additional times at 30-second intervals. The blood pressure
vation exhaustion are recommended for all muscles to increase cuff is then inflated about 50 mmHg above the patient's systolic
the yield of repetitive stimulation. If repetitive stimulation is pressure. Two trials of 5-10 stimuli at 3 Hz are performed. A
normal in both proximal and distal muscles, some investigators second train of 3-Hz stimulation for a period of 4 minutes is
recommend that the muscle be reexamined with repetitive stimu- performed. On completing this second "exercise" period, but
lation under ischemic conditions, particularly if single-fiber now under ischemic conditions, the nerve is excited at 3 Hz for
EMG analysis is not available. 5-10 stimuli at 30-second intervals for 2 minutes. The blood
A less common method of evaluating patients during an is- pressure cuff is deflated, and 4-5 more trains of 5-10 stimuli at
chemic period is the double-step test.216-217-219-333 Usually the 3 Hz are delivered.
median and ulnar nerves are stimulated at either the wrist or In normal people, the baseline stimuli result in a CMAP
elbow. Elbow stimulation allows examination of the forearm voltage percent difference of 92-104% (98.1 ± 2.4 %). 217 After
flexor muscles (flexor carpi radialis and flexor carpi uinaris) as completion of both 4-minute periods of continuous 3-Hz stim-
well as the hand intrinsic muscles (abductor pollicis brevis, first ulation (with and without ischemia), there is no significant per-
dorsal interosseous, and abductor digiti minimi muscles). Either cent decrement of the first compared with fourth or fifth
surface or subcutaneous needle electrodes can used for both response. However, the absolute CMAP amplitude may be
neural activation and recording. If subcutaneous needles are quite similar to that obtained during the rest period, or it may
used for recording the CMAP, it is important to ensure that they decline progressively over the ischemic period (Fig. 25-26).
are noninsulated and located subcutaneously over the motor The difference between the first and 720th response during is-
point rather than placed into muscle tissue. A blood pressure chemia may be as much as 50%. This amplitude decline is be-
cuff is placed around the arm, and the hand and forearm are se- lieved to result from anoxic nerve block of some of the axons
cured to an arm-board and immobilized to minimize movement composing the peripheral nerve as the absolute CMAP ampli-
artifact. Of particular importance is the placement of a thermis- tude declines, suggesting that fewer axons are activated. The
tor either on the skin or, preferably, intramuscularly into a hand lack of a decrement despite an absolute amplitude drop argues
intrinsic muscle. This aspect of the examination is crucial, because against a NMJ etiology.
FIRST STEP SECOND STEP
• ISCHEMIA
I II I
/ EXERCISE 4mm EXERCISE 4 mm
I I
{ stim at 3/s N
TITRATIONS sum. at 3/s illZJ
(6 shocks-3/s)
Figure 25-25. The double-step test. Four trains of 5-10 stimuli delivered at 3 Hz are performed at 30-second intervals to establish a base-
line. The investigated nerve is then activated at 3 Hz for 4 minutes, followed by several trains of 5-10 stimuli at 3 Hz performed at 30-second in-
tervals. A blood pressure cuff is then inflated roughly 50 mmHg above the patient's systolic pressure.Three trains of 5-10 stimuli at 3 Hz are again
delivered. A second period of 3-Hz stimulation is delivered for 4 minutes, after which 5-10 stimuli are delivered at 3 Hz at 30-second intervals for
3-4 minutes.Two minutes after the 4-minute period, the blood pressure cuff is deflated. (From Desmedt JE: How to validate myathenia gravis in
the patient with a diagnostic problem. Ann N Y Acad Sci 1981;377:583-605, with permission.)
In patients with NMJ disorders of the postsynaptic membrane it means only that ischemia could not document a decrementing
(e.g., myasthenia gravis), quite a different set of results can be response in the distal limb muscles. Several muscles should be
observed (Fig. 25-27). An insignificant or borderline decrement examined simultaneously because a patient may demonstrate a
may be present initially. After 4 minutes of continuous stimula- decrement under ischemic conditions in one intrinsic hand
tion, some patients may demonstrate a significant decrement. If muscle but not another. For example, the ulnar nerve at the wrist
this is the case, then there is no need to continue the test; the can be stimulated while recording simultaneously from both the
decrement confirms that a NMJ disorder is present through abductor digiti minimi and first dorsal interosseous muscles
postactivation exhaustion. An absent or continued borderline with a two-channel recording technique.
decrement suggests that one should proceed with inflating the Curare Testing. In the 1950s and 1960s, intravenous doses
blood pressure cuff above systolic pressure. After cessation of 4 of d-tubocurarine (curare) were administered to patients with
minutes of continuous stimulation but before deflating the cuff, suspected NMJ disorders in whom all repetitive nerve stimula-
trials of 3-Hz stimuli at 30-second intervals for 2 minutes may tion studies were normal. This procedure was recommended be-
reveal an unquestionable decrement between the first and fourth cause of the anecdotal observation of patients with myasthenia
or fifth responses. The cuff is then deflated, and recovery of the gravis who demonstrated a dangerous sensitivity to various
exhaustion phase can be serially followed for several minutes. If forms of curare when it was administered during surgical proce-
there is no evidence of a decrement, the test is considered nega- dures.812 This technique is rarely used today.
tive. A negative test, however, does not exclude a NMJ disorder; The patient is first placed supine in a comfortable position.
An intravenous line is started, and anesthesia personnel should
be present. The presence of an anesthesiologist is a precaution
f • 3/sec-5min in case the patient requires ventilatory support. One-tenth (0.3
mg/18.2 kg body weight) of a normal curarizing dose is diluted
t
- 8
80fl9« in 4.0 ml of normal saline.812 From this dilute solution, 0.5 ml
80
L Add dig I
are administered intravenously into a continuous infusion of
normal saline every 2 minutes. The 0.5-ml bolus represents 1/80
of the normal curarizing dose. After the administration of each
B too fl 8 t
dose the patient is carefully examined for any objective signs of
9
e
- O
80
9 9 A
weakness. The injection of the curare solution continues until
L Abd dig V weakness is documented or all eight of the 0.5 ml dosages are
injected. The test is terminated by administering 0.5 mg of at-
G wo - 0 ropine and 15-20 mg of Tensilon.
80
, i . ' !
' '
The theoretical basis of curare administration is relatively
L Interosseus 1 9
8 easy to understand. D-tubocurarine competitively blocks the
...J
0
1 L-.
2
L J
4
1 1
6
1
8
1 1
10
I 1
12min AChR and thus prevents ACh from generating postsynaptic
membrane depolarization from the blocked receptor region. In
Figure 25-26. Double-step test in healthy subjects. A-C,The normal people and patients with a NMJ defect capable of gener-
adductor pollicis (Add Dig I), abductor digit minimi (Abd digV), and first ating a suprathreshold EPP at all activity levels of NMJ activity,
dorsal interosseous (interosseous I) are examined. Note the amplitude a muscle action potential is always generated with no loss in
of the first (open circle), and fifth response (dot) expressed as a percent- strength. Suppose that the EPP is barely suprathreshold in a
age of the first response prior to the ischemic period of exercise. All number of NMJs in multiple muscles, regardless of the muscu-
muscles demonstrate an absolute decline in amplitude as ischemia pro- lar activity required. When a sufficient amount of curare is de-
gresses, particularly near the end of 4 minutes, but there is minimal per- livered in small aliquots, a dosage is reached at which the barely
cent decrement between the first and fifth response at any time during suprathreshold EPPs begin to fail because the safety factor is no
or after ischemia. (From Desmedt JE, Borensein S: Double-step nerve longer suprathreshold. The declining EPP amplitude results in
stimulation test for myasthenic block: Sensitization of postactivation muscle weakness and a decrement on repetitive stimulation
exhaustion by ischemia. Ann Neurol 1977; 1:55-64, with permission.) when none was previously present.
Stim 3/sec - 4 min - 20 min later

g Test after 3 0 sec ^
]5mV 20msec ~~
2 mm later
Ischemia
Ischemia
o o o o o o
- I V °o o
80 -
40
» I « 1 I I I I L J I L.
24 26 28 30 32 34
H ioo 9 9 9 9 9 9 9 9
80 -
3/s - 4 mm 3 / s - 4 min
60 - H
I I I 1 1 L 10 J I I L
Figure 25-27. Double-step test (abductor digiti minimi) in a patient with moderately severe generalized myasthenia gravis.The
patient was deprived of an anticholinesterase for 5 hours. A,The top row of traces represents the first five stimuli delivered at rest as well as the
last three stimuli during the 4-minute period of stimuli without ischemia.There is approximately a 12% decrement between stimuli I and 5. B,An
increased decrement is observed 30 seconds after the 4-minute "exercise" period.This decrement recovers somewhat 20 minutes after the long
train of stimuli. D, During the 4-minute exercise under ischemic conditions, both a decrement during the first several stimuli and a dramatic de-
cline in the absolute CMAP amplitude are noted. E,A profound decrement between stimuli I and 5 is noted 30 seconds after the 4-minute train
while the blood pressure cuff is still inflated. F, Some recovery is present two minutes after relief of ischemia. G, Graphic representation of first
(open circle) and fifth (dot) response in a train during the time preceding and during the 4 minutes of continuous stimulation without ischemia as
well as a similar period during and after ischemia. Note the significant decrement after exercise but still during ischemia. H, Same patient and con-
ditions after anticholinesterase medication. (From Desmedt JE, Borensein S: Double-step nerve stimulation test for myasthenic block: Sensitization
of postactivation exhaustion by ischemia. Ann Neurol 1977; 1:55-64, with permission.)
Unfortunately, the systemic administration of curare pro- either a median or ulnar nerve CMAP from the hand intrinsic
duces results that are highly subjective and extremely depen- muscles. A blood pressure cuff is then inflated approximately
dent on the cooperation of the patient. No attempts have been 30-50 mmHg above the patient's maximal systolic blood pres-
made to objectify fully the systemic administration of curare sure. Between 0.2 mg and 0.5 mg of d-tubocurarine is diluted in
with repetitive stimulation in a controlled investigation. The 20-30 ml of normal saline and injected into the angiocatheter,
systemic curare test has been used infrequently because of both followed by about 6 ml of normal saline. Ischemia is maintained
the subjective nature of the test and the potential danger of sub- for 6 minutes. A 3-Hz train of nine stimuli is delivered to the
jecting a particularly sensitive patient to curare with potentially ulnar or median nerve after 5 minutes of ischemia and continued
disastrous complications. 566 Given the multiple diagnostic op- at 1-minute intervals for 15-20 minutes. A decrement in excess
tions currently available, the systemic curare test should not be of 10% constitutes an abnormal response. In patients suspected
performed for diagnostic purposes in any patient suspected of of having myasthenia gravis who demonstrate a normal repeti-
having a NMJ disease. tive stimulation test in multiple muscles, an increase in about
Because of the potential problems with systemic administration 15% sensitivity is obtained with a regional curare test.419-420'421-422
of curare, a regional technique has been advocated.'07-,08-4,9-420-42U22 Other investigators have not duplicated these results.83-396 Even
The regional administration of curare is essentially a modifica- normal people can demonstrate decrements to repetitive stimula-
tion of a regional anesthetic blockade technique. A small intra- tion with equivalent dosages of d-tubocurarine. The regional
venous angiocatheter, such as a butterfly needle, is inserted into curare test is of limited benefit.
a small vein about the wrist and flushed with normal saline to Similar comments can be made about the utility of regional
maintain patency. Surface recording and stimulating electrodes and systemic curare testing. In short, the increased yield of curare
are fastened to the patient in the routine manner for recording in people with normal repetitive stimulation does not justify the
potential risk in patients who may be particularly sensitive to no change. At 5 Hz, most full-term infants should demonstrate
curare or its analogs. From an electrophysiologic testing stand- no alteration in the sequentially recorded CMAPs; however, a
point, if multiple muscles, including those innervated by the few may demonstrate a mild increment (11-17%) with an occa-
spinal accessory and facial nerves do not demonstrate a decre- sional decrement noted. If a 10-Hz train of stimuli is applied for
ment during repetitive stimulation at 32-33°C with exercise and 15 seconds, about one-half of children examined at 39 weeks or
possibly a double-step test, single-fiber EMG should be done. older may reveal an increment approaching 14%. When a 15-
Unlike several years ago, single-fiber analysis is capable of second, 20-Hz stimulation train is applied, most children reveal a
being performed in most large medical centers serving metro- decrement of about 24%, whereas premature infants (< 38
politan areas. Given all of the electrophysiologic and laboratory weeks) have a larger decrement (about 32%). A few full-term in-
testing available, combined with the potential risk to the patient, fants may demonstrate an initial increment for several responses,
curare testing should not be used. followed by the anticipated decrement. If repetitive stimulation
Age. A systematic study specifically addressing the effects is delivered at 50 Hz for 15 seconds, all full-term as well as pre-
of various rates of stimulation on NMJ transmission in various mature infants demonstrate a decrementing CMAP response of
age groups has not been performed. Most adults and children approximately 50%; premature infants have larger decrements of
above the age of about 3-5 years behave in essentially the same about 77%. At these high rates of stimulation, roughly one-half
manner. Specifically, at all rates of stimulation between 1 Hz of children tested reveal postactivation exhaustion for 10 seconds
and 50 Hz, they show no decrement to repetitive stimulation; to 10 minutes, with permature infants clustering in the 10-minute
occasionally pseudofacilitation, not exceeding 50%, may be group. These findings suggest that full-term infants and espe-
present. In neonates and premature infants, however, few stud- cially premature infants have a reduced NMJ reserve capacity
ies have been performed to investigate the response of the NMJ especially at higher rates of stimulation. It is certainly possible to
to various repetitive stimulation rates. examine infants with repetitive stimulation techniques as long as
The limited data suggest that at 1-2 Hz there is no alteration those findings are kept in mind. They are particularly relevant to
in the CMAP to repetitive stimulation, i.e., no increment, decre- 50-Hz stimulation in attempts to define the presence of postacti-
ment, or postactivation facilitation or exhaustion. 153328503 vation exhaustion.
Repetitive stimulation at rates of 2-5 Hz yield variable results.
Some normal infants demonstrate a decrement, and others reveal
ACQUIRED NEUROMUSCULAR JUNCTION
DISORDERS
Table 25-7. Neuromuscular Junction Disorder
Presynaptic Presynaptic and postsynaptic One way to classify acquired NMJ disorders is based on the
Lambert-Eaton myasthenic syndrome Anticonvulsants pathogenic site of involvement: presynaptic, synaptic space,
Some congenital myasthenic Antibiotics postsynaptic, and pathologic states affecting simultaneously
syndromes (i.e., deficient ACh Polymyxins both presynaptic and postsynaptic regions (Table 25-7). This
synthesis) Aminoglycosides classification is based in part on previous discussions of the
Toxins/venoms Streptomycin anatomy and physiology of the NMJ. By keeping the basic
Botulism Neomycin normal NMJ anatomy and physiology in mind, it is relatively
Tick Kanamycin easy to identify any structure or process and to consider not
Tetanus Amino acid derivative only its location but also the clinical and electrophysiologic
Black widow spider Li neomycin consequences of the derangement. The most common and best-
Scorpion Clindamycin studied NMJ transmission disorder is myasthenia gravis. As a
Cation-induced Procainamide result, it is appropriate to discuss this disease before addressing
Magnesium Quinidine other forms of NMJ transmission diseases. To be consistent,
Calcium Lithium postsynaptic disorders are discussed before presynaptic NMJ
Primary nerve/muscle disorder P-Adrenergic blockers problems.
Peripheral neuropathies
Motor neuron disorders POSTSYNAPTIC DISORDERS
Synaptic space
AChE deficiency The most common NMJ disorder is myasthenia gravis. Other
disorders that result from varied causes, such as drugs and
Postsynaptic toxins, are in the large sense, "postsynaptic"; a number of pri-
Myasthenia gravis mary muscle diseases also are included.
Some congenital myasthenic syndromes
(i.e., Primary AChR deficiency, slow-channel, and fast-channel Myasthenia Gravis
syndromes)
Primary myopathies Epidemiology. The incidence of myasthenia gravis ranges
Medication-related between 1 to 9 per million, and the prevalence ranges between
Antibiotics 25 and 142 per million.21 •' 62.284.327.416.514.734.764.765,889.909.910 Jfo
i _
n c i
Tetracycline dence of myasthenia gravis is slightly greater in women than in

Oxytetracycline men. The age of onset is bimodal for both genders. Women have
D-penicillamine peak incidences at ages 20-24 years and 70-75 years, whereas
Anticholinesterase men have peak rates at 30-34 years and 70-74 years. In the
Neuromuscular blocking agents (e.g.,d-tubocurarine pavulon) early-onset group, the female-to-male ratio is roughly 7:3,
Modified after Brown."0 whereas in the late-onset group the gender ratio is 1:1. In the
age group of 6-19 years, female patients predominate with a 7:3
ratio. The mean mortality rate per million population approxi- important to assess for weakness of the masseter muscles by
mates 1.7 (0.9-3.1) for all patients with a diagnosis of myas- having the patient resist forceful jaw closure. Palatal and pha-
thenia gravis, whereas the mortality rate directly attributable to ryngeal muscle weakness eventually manifests in roughly 40%
the disease itself is 0.8 (0.0-2.2). These figures reflect the im- of patients. Nasal regurgitation of liquids and solid food may
proved emergency medical techniques applicable to all persons result from palatal and pharyngeal muscle involvement. A slug-
with cardiopulmonary distress. Before the implementation of gish gag reflex may be noted as well as poor elevation of the
emergency medical services, improved therapeutic interven- palate. The tongue can be tested by having the patient push
tions, and a higher index of suspicion for respiratory distress, against the examiner's hand placed on the cheek or by pushing
the mortality rate of patients with myasthenia gravis was sig- the tongue straight outward against a tongue blade.
nificantly higher. Additionally, palatal, pharyngeal, and tongue weakness leads to
Clinical Features. The clinical hallmarks of myasthenia dysarthric or nasal speech.
gravis are fluctuating weakness characterized by abnormal fati- Facial weakness can be detected by having the patient close
gability that improves with rest. 57 - 234 - 28 ^ Weakness the eyelids tightly. Affected patients may be unable to bury the
may be limited to specific muscle groups, particularly the eyelashes or maintain eye closure against resistance. An inabil-
ocular, bulbar, and proximal limb muscles. In profound disease, ity to whistle or puff the cheeks against resistance can be noted.
weakness is generalized. Patients may complain of various fac- From time-to-time the "myasthenic snarl" may be noted by
tors other than exercese that exacerbate the feeling of weakness asking the patient to smile. Failure of the corners of the mouth
or fatigue, such as warm weather, systemic infections, menses, to be withdrawn in association with lip retraction causes the
anxiety, emotional stress, and pregnancy.87'125-308,364-365-659-728-734 facial appearance to resemble a snarl because the frontal and
Unfortunately, such complaints may be seen with a host of psy- canine teeth are revealed but not the premolars.
chological and physical disorders affecting the neuromuscular Proximal limb and neck weakness is a presenting symptom
system (see Table 25-3). A detailed history is required to ascer- in approximately 20-30% of patients. Of importance, approx-
tain all of the potential problems that may present with the imately 3% of patients manifest with predominantly distal
rather vague complaints of weakness and fatigue. It is particu- weakness.449-688 Head drop secondary to neck extensor weak-
larly important to question the patient about disease progres- ness is not uncommon and may be the presenting feature.
sion. Symptoms usually affect the ocular muscles initially, but There may be a gradual but definite onset of fatigue after
they tend to become more generalized by about 2-3 years after repetitive activities. The neck and limb muscles should be
onset. tested with patients placed in positions that force the exam-
Patients often complain of drooping eyelids, blurred vision, ined muscles to move against gravity (i.e., neck extensors are
or„frank diplopia, particularly after prolonged reading or at the assessed with the patient lying prone). In addition to routine
end of the day. Ptosis is the presenting symptom in 50-90% of manual muscle testing, repeated movements such as arising
patients, whereas 15% complain of blurred vision or frank from the floor several times or climbing steps can be as-
diplopia. 1872953 If not a presenting symptom, external ocular sessed. We also assess upper arm strength after the arm has
muscle involvement is present at some point in about 90-95% been abducted at the shoulder for 1 minute. The examiner
of patients. One should assess for ptosis at rest or determine also can measure the amount of time that the arms can be ab-
whether ptosis can be induced with fatigue. The patient is asked ducted without resting.
to perform a sustained upward gaze or repeated eye opening and Occasionally, patients can present in respiratory failure due to
closure. Ptosis may be unilateral or worse in one eye than the weakness of the diaphragm and assessory muscles of respira-
other. If the patient is asked to refixate to primary position after tion.600-648 Patients with diaphragmatic weakness complain of or-
sustained downgaze, quick lid retraction, followed by resump- thopnea and have paradoxical inward movements of the
tion of the ptosis, may be demonstrated in patients with myas- abdomen on inspiration when they lie supine. Respiratory insuf-
thenia gravis (Cogan's sign). Weakness of external ocular ficiency also may manifest as drowsiness, agitation, tachycardia,
muscles may vary with respect to degree of involvement and or decreased mental alertness and difficulty in concentrating.
side affected. One may observe partial ophthalmoparesis or Pulmonary function tests (forced vital capacity and negative in-
complete ophthalmoplegia.3-566 Having the patient perform hori- spiratory force) are important to assess in patients with respira-
zontal gaze for a sustained period may result in progressively tory symptoms. A crude way of assessing respiratory function at
rapid movements of the eye, resembling nystagmus.3-892 the bedside is to have the patient count to 20. If the patient is
Furthermore, pseudointranuclear ophthalmoplegia can be noted unable to count to 20 without taking a breath, forced vital capac-
during ocular pursuits and saccades. This form of "nystagmus" ity probably is less than 1 liter. It goes without saying that respi-
is differentiated from central causes by the observation of in- ratory failure is a medical emergency and elective intubation is
creasing velocity and magnitude with maintained extremes of preferable to emergent intubation. Thus, clinicians need to moni-
gaze. The reason for preferential involvement of the external tor closely the respiratory status of patients with myasthenia
ocular muscles is unclear, but it may be related to the elevated gravis.
temperature of the head compared with limbs, specific anatomic Sensory testing should reveal normal sensation to all modali-
and physiologic aspects of these muscles, different antigenic ties throughout. Deep tendon reflexes are usually quite normal
AChR subtypes, firing rates, and/or other poorly understood during the initial presentation but occasionally may be increas-
factors.462-587 ingly difficult to obtain on repeated attempts, especially in prox-
As many as one-third of patients present with difficulty in imal muscles.
chewing or swallowing food that worsens during the course of a Classification Schemes. Patients with myasthenia gravis
particularly long meal. Some patients suffer significant weight can be classified according to the Osserman criteria.734 737 Adult
loss secondary to diminished food intake. Patients usually have myasthenia gravis is subdivided into group 1 (ocular: 15-20%);
no difficulty in opening the mouth (ptergoid weakness), although group 2A (mild generalized: 30%); group 2B (moderately
jaw closure (e.g., the masseter muscle) may be weak. It is severe generalized: 20%); group 3 (acute fulminating: 11%);
Table 25-8. Myasthenia Gravis Clinical Classification (MGFA) (see Table 25-8).450a Patients are categorized based on clinical find-
CLASS I Any ocular muscle weakness.
ings into one of five major classes with several subclassifica-
May have weakness of eye closure.
tions. It is recommended that "the most severely affected
All other muscle strength is normal.
muscles be employed to define the patient's Class and that the
'maximum severity' designation be used to identify the most
CLASS II Mild weakness affecting other than ocular muscles. severe pretreatment clinical classification status. The 'maxi-
Also may have ocular muscle weakness of any severity. mum severity' designation may be made historically and is em-
Ila Predominantly affecting limb, axial muscles, or both. ployed as a point of reference." Future clinical trials will most
Also may have lesser involvement of oropharyngeal likely be using this clinical classification system.450a
muscles Associated Systemic Disorders. Autoimmune diseases that
lib Predominantly affecting oropharyngeal, respiratory can coincide with myasthenia gravis include rheumatoid arthritis,
muscles, or both. systemic lupus erythematosus, Sjogren's syndrome, red blood
Also may have lesser or equal involvement of limb, axial cell aplasia, ulcerative colitis, sarcoidosis, Addison's disease, and
muscle, or both. hyperthyroid/hypothyroid disease.36-230-736-757-994 Other neuromus-
cular disorders that can be seen concurrently in patients with
CLASS III Moderate weakness affecting other than ocular muscles. myasthenia gravis and thymoma.992 Both acute and chronic in-
Also may have ocular muscle weakness of any severity. flammatory demyelinating polyneuropathy have been reported
Ilia Predominantly affecting limb, axial muscles, or both. in patients with concurrent myasthenia gravis.82-789-981 Sensory
Also may have lesser involvement of oropharyngeal signs and symptoms and appropriate nerve conduction studies
muscles. should alert the clinician to a superimposed demyelinating
Illb Predominantly affecting oropharyngeal, respiratory polyneuropathy. In addition, some patients develop a severe au-
muscles, or both. tonomic neuropathy (e.g., intestinal pseudo-obstruction), with
Also may have lesser or equal involvement of limb, axial or without encephalopathy, along with myasthenia gravis and
muscles, or both. thymoma.24-82-744
CLASS IV Severe weakness affecting other than ocular muscles. Various autoimmune channelopathies occur in patients with
myasthenia gravis. Rare patients have a combination of myas-
Also may have ocular muscle weakness of any severity. thenia gravis and LEMS serologically and electrophysiologi-
IVa Predominantly affecting limb and/or axial muscles. cal |y 483.695.712.928 LEMS is caused by antibodies directed against
the voltage-gated calcium channel on the distal motor nerve ter-
Also may have lesser involvement of oropharyngeal minals. Approximately, 5% of patients also have an inflamma-
muscles. tory myopathy.118«453-683-685-750 Most of these patients also have a
IVb Predominantly affecting oropharyngeal, respiratory thymoma and a few have myocarditis. The histopathology often
muscles, or both. reveals a giant cell or granulomatous myositis (Fig. 25-28).
Also may have lesser or equal involvement of limb, axial Serum CK levels are usually elevated. A recent report noted an
muscles, or both. increased frequency of antibodies directed against the skeletal
CLASS V Defined by intubation, with or without mechanical muscle calcium release channel of the sarcoplasmic reticulum
ventilation, except when used during routine (e.g., the ryanodine receptor). Acquired neuromyotonia or
postoperative management.The use of a feeding tube Isaacs' syndrome may occur in patients with myasthenia
without intubation places the patient in class IVb. gravis and thymoma. 1-389-534-6,a683-696-761 Patients with Isaacs' syn-
MGFA, Myasthenia Gravis Foundation of America. drome have a constellation of symptoms, including continuous
(From Jaretzki A, Barohn RJ, Ernstoff RM, et al, for the Task Force of the Medical
Scientific Advisory Board of the Myasthenia Gravis Foundation of America: muscle fiber activity (myokymia), muscle pain and stiffness ex-
Myasthenia gravis: Recommendations for clinical research standards. Neurology acerbated by activity, and excessive diaphoresis (see the discus-
2000;55:16-23, with permission.) sion of Isaacs' syndrome in Chapter 16). Some patients also
may have an encephalopathy. Antibodies directed against the
and group 4 (late severe: 9%). Patients in group 1 primarily voltage-gated potassium channels on peripheral nerves cause
have complaints related to external ocular movements. At least this syndrome. An interesting entity called rippling muscle dis-
50% of patients initially presenting as group 1 eventually de- ease also can occur in the setting of myasthenia gravis and thy-
velop a more generalized form of the disease. Patients in group moma (discussed in greater detail in Chapter 27).26a-675-683-966
2A demonstrate not only involvement of the bulbar muscles but This rare disorder is characterized by peculiar rippling move-
also weakness and fatigue affecting the limb and truncal mus- ments of the muscle induced by percussion or activation of
cles, particularly those located proximally. Respiratory weak- muscle. Unlike myotonia, the rippling muscle movements are
ness is not a prominent aspect of this group, and patients electrically silent. Rippling muscle disease can be hereditary or
respond to anticholinesterase medications. Patients in group 2B acquired. The pathogenic basis is unknown, but it is probably
have similar complaints as those in group 2A but to a greater caused by a muscle channelopathy. Stiff-persons' syndrome
degree. They have marked ptosis, diplopia, dysarthria, dyspha- also can occur in patient with myasthenia gravis and thy-
gia, and difficulty with activities requiring physical exertion. moma.696-769 This syndrome is caused by antibodies directed
Patients in group 3 have severe generalized weakness that pro- against glutamic acid decarboxylase (GAD) or amphiphysin
gresses relatively quickly over the course of 6-8 months to res- (see Chapter 16).
piratory compromise. Patients in group 4 usually begin with a As many as 70% of patients with myasthenia gravis have
relatively mild form of disease, maintain a plateau for 2 or more thymic hyperplasia, and approximately 10% have a thy-
years, and then progress to severe disease. moma.415371 Thymomas are much more common in patients be-
A new alternative classification system has been developed tween the ages of 50 and 70 years. Most patients with thymomas
by a task force of the Myasthenia Gravis Foundation of America have circulating serum antistriatal antibodies in addition to
Chapter 25 NEUROMUSCULAR JUNCTION DISORDERS — II65
increase in ACh in the NMJ and theoretically improves strength.
Unfortunately, some patients are overly sensitive to the anti-
cholinergic side effects of edrophonium and develop fascicula-
tions, bradycardia, nausea, vomiting, increased tearing, and
lacrimation. Clinicians should monitor pulse and blood pressure
and be prepared to administer atropine to counteract the anti-
cholinergic effects of edrophonium. For this reason, some 731
prefer the atropine-neostigmine test, which causes few unpleas-
ant cholinergic side effects and provides more time for the tests
because of the longer-lasting effect of neostigmine. To perform
the edrophonium test, we place a butterfly needle in an antecu-
bial vein, keeping the catheter open with saline. A 2 mg (0.2¬
ml) test dose of edrophonium 10 mg/1 ml is administered
because some patients are extremely sensitive to low doses. If
there is no response after 30 seconds, the remaining 8 mg are
administered in increments (2 mg every 15 seconds). If the pa-
tient shows objective improvement or severe side effects, the
rest of the injection may be halted. It is most important to assess
an objective sign of weakness rather than the patient's subjec-
tive response. In this regard, evaluating improvement in mea-
sured ptosis or ophthalmoparesis is most useful. A test is not
considered positive if patients state that they feel stronger.
Unfortunately, the edrophonium test is not always positive in
patients with myasthenia gravis. Furthermore, a modest re-
sponse to edrophonium may be seen in other disorders, such as
LEMS, 727 combined or overlap myasthenia gravis/LEMS, 84
amyotrophic lateral sclerosis (ALS), 674 congenital myasthenic
syndromes (CMS),802 botulism,145 and Guillain-Barre syndrome
(GBS). 220 As a result, improved clinical function secondary to
the administration of edrophonium is not diagnostic of myas-
thenia gravis but rather indicative of a potential NMJ transmis-
sion failure that can occur in a number of quite diverse diseases.
Laboratory Features. AChR antibodies are detected in
most but not all patients with myasthenia gravis (Table 25-9).
There are three types of detectable AChR antibodies: (1)
AChR-binding antibodies, (2) AChR-modulating anti-
Figure 25-28. Giant cell myositis. A biceps brachii muscle biopsy bodies, and (3) AChR-blocking antibodies. 425 543 Elevation of
in a patient with malignant thymoma, myasthenia gravis, and myositis any of the three antibody levels is detected in about 80-90% of
demonstrates endomysial inflammatory infiltrate (arrow) that includes patients with all grades of myasthenia gravis, with a slightly
giant cells (H&E stain). lower value in the ocular form (70-80%). The test is abnormal
in over 90% of patients with more severe generalized forms of
the disease. There does not appear to be significant clinical or
anti-AChR antibodies. The thymomas may be malignant and in- electrophysiologic differences between seropositive and
vasive. The role of the thymus in myasthenia gravis is unclear seronegative patients with myasthenia gravis, including progno-
and is discussed in greater detail in the Pathogenesis section. sis and response to treatment. AChR-binding antibodies are the
Pharmacologic Testing. The edrophonium (Tensilon) test most frequent antibody subtype, followed closely by modulat-
can be helpful in diagnosing myasthenia gravis.733-735 Edro- ing antibodies (see Table 25-9). Most patients have both binding
phonium is an anticholinesterase agent that results in transient and modulating antibodies, but in approximately 8% only one of
Table 25-9. Comparison of Myasthenia Gravis Testing Methods and Percentage of Patients with Abnormal Tests
AChR Antibodies Distal Proximal
MG Subtype Binding Blocking Modulating Rep Stim Rep Stim SFEMG
Remission 81 19 75
Ocular 71 30 72 0-35 45-50 59-63 (80-94*)
Mild generalized 88 52 89 55 76 91
Mod-severe generalized 93 66 91 86-99 96-99 99*
Total 86 52 86 37-62 62-77 86-92 (99*)
All numbers are expressed in percentages and are composites of multiple studies.
* = addition of a facial muscle.
Data gathered from references 177, 333,425,486,504,543,551,710,717,739,811,827, and 832.
without detectable binding or modulating antibodies. AChR-
binding antibodies are relatively specific for myasthenia gravis,
but they also can be detected in patients with autoimmune liver
disorders, approximately 13% of patients with LEMS, and
about 3% of patients with lung cancer without an apparent neu-
rologic disorder.543
In addition, antistriatal muscle antibodies (synonymous
with antititan antibodies) are evident in approximately 30% of
adults with myasthenia gravis and 80% of patients with thymo-
mas.543-683 Jhese antibodies also are detected in around 24% of
patients with thymoma but no signs of myasthenia gravis. They
also have been detected in patients without thymoma or thymic
hyperplasia. Therefore, we obtain a chest CT in all patients with
myasthenia gravis to look for evidence of thymic enlargement,
regardless of antibody status. As discussed above, antibodies di-
rected against the voltage-gated calcium channel, antiryanodine
receptor, and peripheral nerve potassium channel can be seen in
patients that also have LEMS, myositis, or Isaacs' syndrome, re-
spectively. Anti-GAD or amphiphysin antibodies may be noted
in patients with concurrent stiff persons' syndrome.
There is also a known association between myasthenia gravis
and certain HLA genotypes. 167 Some studies have noted a pre-
dilection for HLA types A1, A3, B7, B8, and DRw3 in patients
with myasthenia gravis.167 These HLA subtypes may somehow
predispose patients to autoimmune diseases. Antinuclear anti-
bodies and thyroid function tests may be abnormal in patients
with other associated autoimmune conditions. The serum CK
level may be elevated in the few patients (approximately 5%)
who have both myasthenia gravis and an inflammatory myopa-
thy. In such cases, we obtain an EKG and echocardiogram be-
cause of the predilection for involvement of cardiac muscle as
well.
Histopathology. Routine light microscopy may reveal mild,
nonspecific abnormalities on muscle biopsies. 617 Type 1 fiber
predominance, mild fiber type grouping, or type 2 fiber atrophy
may be noted. Focal interstitial inflammatory infiltrates, so-
called lymphorrhages, are not uncommon, particularly at the
Figure 25-29. Lymphorrhage. Muscle biopsy in a patient with endplates (Fig. 25-29).615-751 Structural abnormalities are much
myasthenia gravis demonstrates a large focal lymphocytic infiltrate more apparent on electron microscopy than on light microscopy.
(i.e., a lymphorrhage). Immunoelectronmicroscopy of the postsynaptic membrane
region in myasthenic patients demonstrates IgG and complement
the antibodies is detected.423-543 AChR-blocking antibodies are pre- precipitation on the membrane, increased synaptic space, re-
sent in slightly over 50% of patients with generalized myasthenia duced postsynaptic membrane complexity associated with fewer \
gravis and only about 30% of patients with ocular myasthe- postjunctional folds, and decreased numbers of AChRs (Table j
nia.425-343 Less than 1 % of patients have AChR-blocking antibodies 25-10 and Fig. 25-3).73-268-272-273-560-842 Many of the remaining
AChRs are bound with IgG. In contrast, the presynaptic portion
of the NMJ appears completely normal (Fig. 25-30).
Table 25-10. Neuromuscular Junction Parameters Pathogenesis and Pathophysiology. Myasthenia gravis is an
in Health and Disease acquired autoimmune disorder of neuromuscular transmission
MEPP Mean Area Vesicles resulting from antibodies directed against AChR. The autoim-
Condition (mV) QC (Mm2) (Mm2) Post/PM mune nature of myasthenia gravis was initially suggested be-
cause of the observations that the disease is associated with (1)
Normal 1 56 3.9 50 10 abnormalities of the thymus gland, (2) other known autoimmune
MG 0.15 (l) 56 2.3 (i) 46 8(i) diseases. (3) a fluctuating course, and (4) transient neonatal
LES 1 8(4) 4.1 53 17 (T) myasthenia gravis.686-872 As noted above, various autoimmune
MG, myasthenia gravis; LES, Lambert Eaton syndrome; N, normal; t , increased diseases and specific HLA antigens are associated with myasthe-
compared with normal; I, decreased compared with normal; MEPP, miniature nia gravis 56,167.230,736.757.994
endplate potential; mean QC, mean quantal content; area, area occupied by The initiating factor in patients who develop autoimmune
NMJiVesicle/iJm2, the number of synaptic vesicles per unit area in the nerve ter- myasthenia gravis is unknown. There are suggestions of a genetic
minal; post/PM, postsynaptic membrane length * presynaptic membrane length. predisposition in at least some patients,393-773 an infectious agent
(From Engel AG, Santa T: Motor end-plate fine structure: Quantitative analysis in may precipitate the disease in others,505 and the thymus may play
disorders of neuromuscular transmission and prostigmine induced alterations.
In Desmedt JE (ed): New Developments in Electromyography and Clinical a role in some patients. The role of the thymus gland is particu-
Neurophysiology, vol I. Basel, Karger, 1973, pp 196-228, with permission). larly intriguing. About 40-70% of patients with autoimmune
Control A \ B
Figure 25-30. Schematic representation of NMJ in normal

controls compared with NMJs found in patients with myas-
thenia gravis and myasthenic syndrome. In myasthenia gravis the
postsynaptic membrane demonstrates a reduction in the number of
postsynaptic junctional folds with an overall simplification. Myasthenic
syndrome NMJs, however, demonstrate an increase in the complexity
, of the postsynaptic membrane architecture. (From Engel AG, Santa T:
Histometric analysis of the ultrastructure of the neuromuscular junc-
tion in myathenia gravis and the myasthenic syndrome. Ann N Y Acad
Sci 1971; 183:46-63,with permission.)
myasthenia gravis have evidence consistent with thymic hyper-

plasia, and about 10-15% of patients have a documented thy-
moma.330-743-799-968 Some patients also respond clinically to the
removal of the thymus gland. The thymus contains myoid cells
and other types of stem cells that may serve as autoantigens by
expressing AChRs or AChR protein subcomponents on their
surface.984 Furthermore, within the thymus are AChR-specific B
lymphocytes, which generate antibodies to AChR in culture.
Finally, T lymphocytes specific to AChRs are found in patients
with myasthenia gravis.565-691-692-846
A proposed sequence of events whereby myasthenia gravis is
initiated and maintained begins with an antigen-presenting cell
such as a macrophage (Fig. 25 - 31).234-570*615-617-794 This macro-
phage may phagocytize AChRs and degrade them into peptide
subcomponents, which are then linked with a class II MHC
(e.g., HLA-B8, DR3, and DQw2) molecule required for reactiv-
ity to "self-antigens." 906 This AChR antigenic fragment and
MHC complex are transported to the macrophage's surface.
Once they are on the cell's surface, specific helper T cells Figure 25-31. Proposed mechanism of initiation and mainte-
through the CD3 complex and CD4 molecular T-cell receptor nance of autoimmune myasthenia gravis. A, Macrophage ingests
site recognize the antigenic complex.17a653J02 ' 821879 Additionally, an AChR. B,The AChR is broken down into peptide subcomponents
specific receptor sites recognize cytokines secreted by the that are combined with a molecule (class II MHC) and transported to
macrophage on the T cell for these substances. The activated the surface. C.This molecular complex interacts with a helper T cell
helper T cells begin to secrete substances that stimulate specific and activates it to secrete B-cell growth and differentiation factors. D,
B lymphocytes. The activated B lymphocytes undergo growth B cells with AChR fragments attached are stimulated to differentiate
and differentiation into plasma cells. The differentiated plasma into a plasma cell. E.The differentiated plasma cell manufactures anti-
cells manufacture IgG anti-AChR antibodies that bind to NMJ AChR antibodies. (From Lopate G, Pestronk A: Autoimmune myasthe-
AChRs. These anti-AChR antibodies are polyclonal because nia gravis. Hosp Pract 1993;28:109-131, with permission.)
they include multiple IgG subclasses directed at different but
specific sites on the AChR.536-879-960-970
A number of antibodies belonging to the IgG class are di- may indirectly block the ACh-binding site by steric hindrance
rected against the main immunogenic receptor (MIR) as well as when it binds to a nearby site.857 It is also possible for the anti-
other sites on the AChR and other regions of the MIR (see Fig. 25- bodies to bind directly to the ACh site or at some specific loca-
g) Q n ce they are bound to the AChR a number of irre-
98.354.959.988 tion on the AChR and somehow prevent the necessary
versible processes are induced. These processes are directed at the conformational change required to open the ion pore. These an-
AChR and postsynaptic membrane (Fig. 25-32). The antibodies tibodies have been detected in 10-88 percent of patients with
Figure 25-32. Antibody mediated reduc-

tion of AChRs at the postsynaptic mem-
brane. A, Antibody bound to AChR may block the
ACh-binding site. B, Cross-linking of AChRs
through a bond with anti-AChR antibodies in-
creases endocytosis of AChRs and subsequent de-
struction by lysosomes. C, Complement-mediated
destruction of the postsynaptic membrane in-
creases the synaptic space, reduces the complex-
ity of the postsynaptic membrane, and assists in
the destruction of AChRs. (From Lopate G,
Pestronk A: Autoimmune myasthenia gravis. Hosp
Pract 1993;28:109-131, with permission.)
myasthenia gravis but account for less than 1 % of all recognized localized to the postsynaptic membrane in patients with myas-
forms of anti-AChR antibodies.233-343'539-660-972 Blockade of the thenia gravis.272-560 Additionally, circulating IgG antibodies are
AChR prevents ACh binding, which in turn renders the blocked found in over 90% of patients with myasthenia gravis. 559
AChRs unable to contribute to the generation of an EPF The Patients with myasthenia gravis also demonstrate an approxi-
MEPP magnitude generated by a spontaneous release of a mately 70-90% reduction in the total numbers of AChRs identi-
single synaptic vesicle is reduced because of the reduced fiable at the postsynaptic membrane. 300 In normal muscle tissue,
number of AChRs per unit region of postsynaptic membrane it is possible to block approximately 75% of functioning AChRs
(see Table 25-10). This reduction in the single MEPP's ampli- (with 25% of AChRs remaining), thus reducing EPP currents to
tude results in the decreased EPP. There is some doubt as to 60% of normal amplitude and still maintain essentially normal
whether this is a significant effect in vivo because MEPPs cor- NMJ transmission.598-733-752 In myasthenia gravis, however,
relate with the total amount of AChR in affected NMJs suggest- blocking only a small number of the remaining AChRs can
ing that all of those remaining are functional and not transform a marginally function NMJ into one that can no
significantly blocked.273-444-560 Of note, purified immunoglobu- longer generate a muscle contraction. For this reason, myas-
lins from both seropositive and seronegative patients with myasthenic patients are particularly prone to curare (see above).
thenia gravis reversibly block currents through nicotinic AChR Anti-AChR antibody IgG and complement deposition on the
in patch-clamp experiments.114 In addition, there is a reduction postsynaptic membrane results in a decreased number of
in endplate voltage-gated sodium channels in clinical and ex- AChRs, increased synaptic space, and a diminished postsynap-
perimental myasthenia gravis.815 tic membrane area associated with fewer postjunctional folds
The antibodies not only bind to the AChR but also cross-link (see Fig. 25 - 30).73-268-273-560-842 These findings readily produce the
with other antibodies.320-643-904 When the AChRs are cross-linked 33% reduction in MEPP amplitude observed in patients with
in this manner, they are reabsorbed by the postsynaptic mem- myasthenia gravis. 181 Decreased numbers of receptors effec-
brane and degraded up to 3 times faster than unlinked AChRs, tively diminish the size of the saturated disc. Fewer AChRs acti-
thus decreasing the number of available AChRs.231-468 The normal vated per unit area of membrane result in less current flowing
NMJ AChR half-life of 5-10 days is dramatically reduced.232-301 through the remaining AChRs, thus creating smaller MEPPs
Synthesis of new AChRs remains unchanged, thus resulting in the and hence EPPs that may be subthreshold.
net reduction of total AChRs per NMJ. Finally, the antibodies are Electrophysiologic Findings. A careful consideration of the
believed to result in activation of the complement cascade that is pathophysiologic findings in myasthenia gravis provides con-
directed at the postsynaptic membrane.272-275-278-302-787-822 siderable information pertinent to the electrophysiologic evalu-
Destruction of the postsynaptic membrane has several conse- ation. The general electrodiagnostic medicine approach to
quences for neuromuscular transmission. Simplification of the patients with suspected neuromuscular junction disorders is rel-
postsynaptic membrane reduces the surface area available for atively straightforward (see Table 25-4). Additionally, the elec-
AChRs. Widening of the synaptic cleft increases the diffusion trophysiologic protocol and anticipated findings are firmly
time of ACh from the presynaptic to postsynaptic membranes, based on the pathophysiology of this autoimmune postsynaptic
thus increasing the exposure of ACh to AChE. All of these factors disorder of AChRs.
act in concert to reduce the NMJ's safety factor through reduced Sensory Nerve Conduction Studies. Sensory nerve amplitude
quantities of ACh (longer diffusion times, increased exposure to and conduction velocity are normal in myasthenia gravis (Table
AChE, greater chance to diffuse out of the synaptic space) and 25-11). Despite these anticipated findings, it is important to eval-
decreased number of AChRs (direct binding and allosteric block- uate sensory conduction to ensure that no pathologic process af-
ade, increased turnover and internalization of AChRs). fects the peripheral nervous system (see Table 25-4). An
Support for the above hypotheses is found in the documenta- abnormal conduction velocity or amplitude suggests that a dis-
tion of IgG complexed with AChRs and identification of IgG ease affecting the peripheral nervous system is present and must
Table 25-11. Electrophysiologic Finding in LEMS, Botulism, and Myasthenia Gravis
LEMS Botulism MG
RNS
Resting CMAP Decreased Normal/decreased Usually normal
% patients with decreased CMAP 95 45 Small
PTA Present Present Present
Degree CMAP increase (PTA) Marked Mild/moderate Variable
LRS Decrement Variable Decrement
HRS Marked increment Moderate increment Variable
PAE Present Absent Present
Distribution of abnormality Any muscle Affected muscle Affected muscle
Changes with time Minimal Significant Mild/moderate
Sensory NCV Normal Normal Normal
Motor NCV Normal Normal Normal
Routine needle EMG N o fibrillations or PSWs; may May or may not see fibrillations or N o fibrillations or PSW; may
see a myopathic pattern PSWs; usually see myopathic pattern see myopathic pattern
SFEMG
Increased; decreases with Increased; decreases with elevated Increased; increases with
Jitter elevated firing rate firing rate elevated firing rate
Present even at less than Present even at less than markedly Present at markedly
Blocking markedly elevated jitter elevated jitter elevated jitter
Slightly increased Slightly decreased Slightly increased
Fiber
This tabledensity
is a reference for most patients with the above diseases. It is important to realize that individual patients may differ in presentation, given the degree of dis-
ease and distribution of weakness. RNS, repetitive nerve stimulation; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; CMAP, compound muscle
action potential; PTA, post-tetanic activation; LRS, low rates of stimulation; HRS, high rates of stimulation; PAE, postactivation exhaustion. Modified from Oh.713
be investigated as a possible cause for the patient's complaints. medications should be discontinued at least 12 hours before
A concomitant NMJ defect, however, also may be present. repetitive stimulation studies are performed. Adequate immobi-
Motor Nerve Conduction Studies. Evaluation of motor con- lization and temperature must be ensured before beginning the
duction tby evoking proximal and distal CMAPs is important in test. Keeping the room at a specified temperature is inadequate
patients suspected of having NMJ disorders. As with the sen- to ensure a proper study because limb temperatures can vary
sory system, the neural conduction of impulses along the pe- considerably despite a constant room temperature. Of note,
ripheral aspects of the motor fibers should be normal. Motor warming the limb in a hot water bath of 44° enhances the decre-
nerve conduction velocities in the upper and lower limbs are ex- ment on repetitive nerve stimulation and can improve the sensi-
pected to be within normal limits (see Table 25-11). Similar to tivity of the study.818 Repetitive stimulation typically is
sensory studies, abnormal motor conduction velocities or am- performed on an intrinsic hand muscle such as the abductor
plitude reductions require complete assessment and may be the digiti minimi first (see Table 25-4 for protocol). In patients with
reason for complaints of weakness and fatigue. only proximal weakness, however, the trapezius, biceps brachii,
In addition to the conduction velocity of motor nerves, or quadriceps muscles can be assessed. In patients with only
CMAP amplitude is also an important parameter. Patients with ocular or bulbar weakness, a facial muscle (orbicularis oculi,
myasthenia gravis may have a variable amount of NMJ dys- nasalis, or orbicularis oris) should be studied. If a distal limb
function from one muscle to the next as well as from one single muscle is examined and found to be normal, a proximal limb or
muscle fiber to the next, even within the same motor unit. The facial muscle should be evaluated. Repetitive stimulation of the
ability of any one NMJ to transmit an impulse successfully de- facial and more proximal muscles is more sensitive but techni-
pends not only on the number of functional AChRs but also on cally difficult and occasionally painful.
the amount of ACh released per neural impulse. When a muscle The complete repetitive stimulation protocol, including at-
is sufficiently rested, the total number of ACh vesicles available tempted exercise facilitation and exhaustion, is performed on
for release is greater than that for each subsequent impulse. In the muscle and any decrement is documented (Fig. 25-33). First
mild disease, therefore, it can be anticipated that a single or rel- we perform a slow repetitive stimulation with the patient at rest;
atively few stimuli delivered at intervals of several seconds may 3 Hz seems to be optimal.215 If a decrement is noted at any time
release a sufficient amount of ACh for most, if not all, of the during the procedure, it can be expected to be greatest between
EPPs to reach threshold. In this instance, the supramaximally the first and second response. A smaller-than-rest amplitude is
elicited CMAP from a limb muscle may well fall within normal usually observed for several stimuli, and then the amplitude of
limits for amplitude. On the other hand, if several stimuli are the CMAP typically stabilizes or increases slightly. Typically, a
delivered in succession in a patient with profound disease, an progressive decrement is seen until the fourth or fifth response,
increasingly stronger stimulus applied at short intervals may with some increase in the following responses. Normally, there
result in a small CMAP. This CMAP may be at the low end of should be less than a 10% decrement with the 3-Hz repetitive
normal or clearly fall below the anticipated level. stimulation. If an abnormal decrement is demonstrated, the pa-
Repetitive Stimulation. Repetitive stimulation is the electro- tient is instructed to exercise the muscle for 10 seconds to assess
diagnostic medicine procedure of choice for evaluating patients the response for postexercise facilitation and the resulting im-
with potential NMJ dysfunction.710-738-739 All anticholinesterase provement in the decrement on 3-Hz stimulation immediately
PRE EXERCISE EXERCISE clear on clinical grounds, needle EMG may be useful because
some patients have a superimposed inflammatory myopathy or
peripheral neuropathy (e.g., chronic inflammatory demyelinat-
ing polyneuropathy, Isaacs' syndrome). A sample of proximal
and distal muscles of an upper and lower limb should be studied.
In patients with significant NMJ disease, a number of single
muscle fibers composing a motor unit in particularly affected
muscles may be rendered functionally denervated. It is possible,
therefore, to detect positive sharp waves and fibrillation poten-
tials in some patients with myasthenia gravis, especially during
examination of the paraspinal, bulbar, and proximal limb mus-
cles.47 This is not a common finding (< 15% of patients) and is
limited primarily to patients with generalized disease, probably
of a profound and chronic nature.177 If membrane instability is
noted in patients with myasthenia gravis, especially with normal
or only mildly abnormal repetitive stimulation studies, another
cause should be considered before these abnormalities are attrib-
uted to a primary NMJ disorder.440-729-772
Loss of muscle fibers belonging to a motor unit can be ex-
pected to produce characteristic changes in the MUAP (Table
25 -11).ioo.44o.558.729.77i.772.893 Because the defect affecting specific
Figure 25-33. Typical observation in a patient with moder- NMJs is essentially random with respect to severity of dysfunc-
ately severe generalized myasthenia gravis when a repetitive tion, a pattern of loss approximating a myopathy as opposed to a
stimulation protocol is performed on a hand intrinsic muscle. neurogenic process may be seen. Furthermore, the functional
Before exercise there is approximately a 68% decrement between the status of NMJs in myasthenia gravis is dynamic and directly de-
first and fifth response. Note that the largest sequential percentage in- pendent on the severity of involvement as well as the level to
terpotential decrement is between the first and second potential in any which they are stressed in terms of firing frequency and dura-
one train of stimuli.Within a few seconds of exercise the decrement tion. Asking a patient to contract maximally for prolonged peri-
decreases to about 50%, and the first response increases by about 35% ods stresses the NMJs more than a brief submaximal contraction.
compared with the preexercise potential.This implies blocking of multi- A long-duration maximal muscle contraction can be expected to
ple single muscle fibers, even at rest. By 2 minutes after exercise the deplete the immediately available ACh stores to a greater degree
decrement is larger than that at rest (76%), and the first response is sig- than a brief contraction, by decreasing the safety factor at in-
nificantly smaller compared with immediately after exercise. At 6 min- creasingly more NMJs. Depending on the severity of the disease
utes the CMAPs are approaching the resting level obtained before process and safety factors of various motor units, the MUAP
exercise. (From Brown WF: The Physiological and Technical Basis of may begin to fire with a particular duration and amplitude but
Electromyography. Boston, Butterworth, 1984, with permission.) decline in amplitude and duration with continued firing. The
degree to which this phenomenon is detected depends on the
severity of disease and diligence of the practitioner. In addition
after exercise. If no decrement is appreciated at rest, the muscle to an observable decline in these two parameters, one may
is exercised for 1 minute to see whether postexercise exhaustion simply observe MUAPs that are shorter in duration than antici-
will produce an abnormal decrement. Repetitive stimulation at pated. If the practitioner does not have a high index of suspicion
3 Hz is performed immediately after exercise and once per and does not use a trigger and delay line, such abnormalities may
minute for the next 5-6 minutes after 1 minute of exercise. be overlooked. In moderately severe or severe myasthenia
In patients with normal-appearing amplitudes, the application gravis, MUAPs may appear somewhat shorter in duration and
of high rates of stimulation is usually not necessary because the smaller in amplitude primarily because of the drop-out of single
exercise portion of the test assesses the NMJ at 20-30 Hz. If co- muscle fibers whose NMJ have failed during excitation. It is un-
operation is lacking, consideration may be given to high-rate clear exactly how many patients with myasthenia gravis demon-
stimulation. Specific recommendations have been suggested for strate decreased MUAP duration, but one limited study
postactivation facilitation of the CMAP: 95-115% in normal documented this finding in 55% of patients.177,279 In one study of
people, 96-194% in patients with myasthenia gravis; and 32 patients with myasthenia gravis, quantitative motor unit
220-1900% in patients with LEMS. 713 These recommendations analysis was consistent with a myopathy in 12/32 patients, while
should be taken as rough approximations because at stimulation turns amplitude analysis demonstrated a myopathic appearance
rates of 20-50 Hz, it is possible to detect an increase in ampli- in 4/32 patients.703a Such patients do not have a myopathic dis-
tude approaching 50% secondary to pseudofacilitation in nor- ease but instead have a profound NMJ disorder. It is important
mals. Keep in mind the disadvantage of significant discomfort not to be confused by these findings and not to misdiagnose a
due to the high rates of stimulation. Stimulating patients with myopathy. The keys to differentiation are several. Increasing the
myasthenia gravis at rates approaching 25 Hz may continue to muscle's temperature (applying a hot pack) shortens the duration
result in a decrementing response. This is usually the case in and lowers the MUAP amplitude, whereas decreasing the
persons with moderately severe to severe disease. muscle's temperature (applying a cold pack) results in an in-
Needle Electromyography. Routine needle EMG using either crease in MUAP amplitude and increases duration. Myopathies
standard concentric or monopolar needle electrodes should be typically do not display variability in MUAP amplitude of the
performed on patients complaining of muscle weakness and fa- same motor unit with continuous firing. Membrane instability
tigue. Even when the diagnosis of myasthenia gravis is quite may be present but is certainly not a prominent feature, as it may
be in some myopathies. Having the patient display a maximal in-
terference pattern in myasthenia gravis can reveal a gradual reduc-
tion in the number of MUAPs with sustained contraction, whereas
myopathies usually do not demonstrate this feature. Also, admin-
istering edrophonium results in longer-duration, larger amplitude
MUAPs in myasthenia gravis but not in myopathies.
It is also possible to observe "unstable" MUAPs with varying
morphologies secondary to random and intermittent neuromus-
cular blocking of single muscle fibers. This is best observed
with a slow sweep speed using a free-running trace, or a trigger
and delay line can be used to maintain the potential in the same
location for observation. Initially, MUAPs fire with little alter-
ation in amplitude but then demonstrate considerable variability
with prolonged and continuous activation. As NMJ transmission Figure 25-34. SFEMG recording from the EDC of a patient
fails, the EPP falls below threshold. Blockage of activation of with myasthenia gravis. A,The jitter in this potential pair is normal
individual muscle fibers contributing to the MUAP results in the at 29 u.s. B, Abnormal jitter of 65 |xs but no blocking. C.Three poten-
variability of the MUAP morphology. The more severe the dis- tials are shown with the second and third having jitter values of 81 us
ease, the more prominent the MUAP variability and alterations. and 49 JIS. Note the second potential demonstrates intermittent
Single-fiber Electromyography. SFEMG (volitional or stim- blocking.The upper trace in each panel represents a superimposition
ulated) has been applied to myasthenia gravis more extensively of 20 consecutive sweeps, and the lower traces are rastered for indi-
than to any other disease. Of all the electrophysiologic methods vidual display. In C the third and seventh traces from the top demon-
applicable to NMJ disorders, SFEMG is the most sensitive, ca- strate blocking of the second potential. (From Stalberg E: Clinical
pable of documenting abnormalities of jitter in 77-100% of patients, electrophysiology in myasthenia gravis. J Neurol Neurosurg Psychiatry
depending On disease Severity. 'n8.179.5O4.624.827.832.893-895.897.899.9O0.963a
80 1980;43:622-633, with permission.)
Patients with myasthenia gravis demonstrate increased jitter and
blocking during continuous contraction of weak muscle fibers. myasthenia gravis the weakest muscles should be tested first.
SFEMG is abnormal if mean jitter is increased for the muscle The EDC is usually examined before other muscles in patients
under investigation; at least two potential pairs have jitter values with generalized disease, however, because of the significant col-
greater than the accepted maximum for the muscle. In more lective experience with reference data. It is also relatively easy
severe cases, blocking also is noted (Table 25-11). Fiber density for most patients to sustain a minimal contraction of the finger
is usually normal, but in rare cases, slightly increased.898-899 extensors. If the EDC is found to be normal or if the patient has
When a patient is examined with SFEMG, it is not unusual to only ocular or bulbar symptoms, the frontalis or orbicularis
find variable NMJ dysfunction at different endplates within the oculi should be studied, thereby increasing the yield of the study
same muscle (Fig. 25-34). Indeed, quite varied findings can be from about 87% to 99%. 829 Before examining a more proximal
obtained from NMJs of the same motor unit. Some of the NMJs muscle, consider having the patient contract the EDC muscle
may have normal jitter, others may be moderately abnormal, and continuously, possibly against mild resistance, taking care not
still others may demonstrate not only excessive jitter but also neu- to induce pain or dislodge the electrode. This maneuver may
romuscular blocking. The degree of variability in 433 potential result in postexercise exhaustion and an increase in jitter.895 Of
pairs from 32 patients demonstrated normal jitter in 9%, in- particular concern is the patient with primarily ocular myasthe-
creased jitter in 38%, and abnormal jitter with blocking in 53% of nia gravis. Performing SFEMG of the frontalis muscle increases
the potentials.895-899 Blocking in potential pairs is usually observed the diagnostic yield from 26-66% to 54-100%.,78-739b-827-900-963a
when the jitter exceeds values of 80-100 JIS. SFEMG may be able Although it is recommended that at least 10 potential pairs be
to demonstrate abnormal jitter in patients with myasthenia gravis obtained, once two clearly abnormal potential pairs are docu-
who did not stop taking anticholinesterase medications before the mented, the diagnosis of impaired neuromuscular transmission
electrodiagnostic study.898-899 Nevertheless, it is wise to have the is at hand, especially if blocking is present. If the patient experi-
patient cease taking the drug for 12 to 24 hours prior to SFEMG. ences significant discomfort or becomes uncooperative, con-
It is possible to demonstrate an improvement in jitter and block- sider terminating the study.
ing in patients with myasthenia gravis by administering edropho- Jitter values appear to correlate with the severity of weakness of
nium.80-895-898 This improvement can be quite dramatic but is the studied muscle. After thymectomy, immunosuppressive treat-
short-lived (i.e., several minutes). In patients taking high-dose an- ment, or plasma exchange, improvements in jitter may be demon-
ticholinesterase medication, the administration of edrophonium strated.178-504832 Nevertheless, jitter is still abnormal in 69-85% of
may actually worsen the jitter. This finding suggests that some of patients with clinical improvement, including those in apparent
the NMJs are "overtreated" and the edrophonium may have preclinical remission.178-265-832 In contrast, patients in clinical remis-
cipitated a desensitization effect by decreasing, as opposed to in- sion usually have normal repetitive stimulation studies. Of interest
creasing, the safety factor. is the finding of abnormal jitter in patients with asymptomatic thy-
Jitter abnormalities usually correlate with the severity of dis- moma,832 who may have subclinical myasthenia gravis.
ease and muscle involvement. Patients with profound general- As with repetitive stimulation, temperature also has a signifi-
ized myasthenia gravis tend to have significantly increased jitter cant effect on jitter values. It is a good idea to maintain skin
values and easily identifiable blocking. Patients with less severe temperatures above 32-33°C, thus ensuring a warm muscle.
disease have less marked jitter abnormalities and comparatively Elevation of tissue temperatures increases the degree of jitter
less blocking. In any given patient, weaker muscles usually dis- abnormality.895 As anticipated, there is a correlation between the
play more elevations in jitter than muscles that are clinically number of potential pairs demonstrating blocking and the
strong. This finding suggests that in patients suspected of
degree of decrement on repetitive stimulation. Some studies sug- by roughly 10%. SFEMG of the EDC reveals abnormalities in
gest that at least 20-25% of potential pairs must experience block- 86-92% of patients. When the EDC yields normal results,
ing before an abnormal decrement is manifest.178 Patients with SFEMG of a second muscle, such as the frontalis, can increase
abnormalities on repetitive stimulation should have abnormal jitter the abnormal results to 99%.
findings on SFEMG. Of interest, some SFEMG studies demon- Patients with only ocular symptoms can be quite a challenge
strate abnormal jitter values in 33% of asymptomatic relatives of from the perspective of documenting a NMJ defect. Of patients
patients with myasthenia gravis.417 877 This finding supports the with ocular myasthenia gravis, repetitive stimulation of a distal
suggestion that genetic factors play a role in the development of at upper limb nerve yields positive results in only up to 35%, even
least some forms of autoimmune myasthenia gravis. with provocative maneuvers such as exercise and ischemia (see
SFEMG is highly sensitive for myasthenia gravis. Un- Table 25-9). Adding a proximal nerve increases the yield
fortunately, increased jitter is not specific for myasthenia gravis slightly to 45%. SFEMG of the EDC alone may demonstrate
and can be found in both neurogenic as well as myopathic dis- positive results in 59-63% of patients, and including a facial
eases.827.894.898.899 Nerve conduction studies and routine needle muscles, such as the orbicularis oculi or frontalis, can improve
EMG examinations are of value in defining electrophysiologic the yield to 80-94% or higher.
compromise of some portion of the motor unit other than the In general, the more severe and widespread the disease, the
NMJ. If a patient presents with weakness and fatigue but clini- greater the chance that repetitive stimulation will document an
cally weak muscles reveal normal jitter, it is highly unlikely that abnormal decrement. Almost all patients with profound general-
the patient has myasthenia gravis. ized disease, have repetitive stimulation and SFEMG abnormal-
Comparison of Different Techniques. The two major "diag- ities. Of patients with mild or moderate generalized myasthenia
nostic" electrophysiologic tests available for myasthenia gravis gravis, stimulation deficits may be found in 76% and 94% and i
are repetitive stimulation and SFEMG. A number of adjunctive abnormal SFEMG results in approximately 91% and 100%, re- I
procedures are applicable to repetitive stimulation to improve spectively. These results can be obtained only if meticulous
the number of abnormal results in patients with known myas- technique and patience are exercised in performing the studies.
thenia gravis: (1) postexercise facilitation, (2) postexercise ex- The most sensitive tests in myasthenia gravis is SFEMG
haustion, (3) double-step ischemic challenge, and (4) curare (92-100%), followed by repetitive nerve stimulation of distal
challenge. Although not an electrophysiologic test, AChR anti- and proximal nerves (77-100%). ACh antibody testing is
bodies are rather specific for myasthenia gravis but are not slightly less sensitive (73-90%). In patients suspected of having
100% sensitive. The complexity of clinical presentation in myasthenia gravis based on history and physical examination,
myasthenia gravis requires the further breakdown of test utility the electrodiagnostic medicine evaluation should begin with
in terms of type and severity of disease (e.g., ocular myasthenia routine nerve conduction and needle EMG studies, followed by
gravis vs. mild generalized myasthenia gravis). repetitive stimulation of a distal upper limb nerve (Fig. 25-35).
The electrophysiologic test most commonly used to diagnose Concurrently, anti-AChR antibody levels should be evaluated. If
myasthenia gravis is repetitive nerve stimulation of either the the repetitive stimulation of the distal arm nerve does not
ulnar or median nerve with recording from the respective hand demonstrate a decrement at rest or facilitation/decrement after
intrinsic muscles. Of patients with some form of myasthenia exercise, proximal nerves, such as the spinal accessory and
gravis, ocular and/or generalized disease of variable severity, musculocutaneous nerves, should be evaluated. Consideration
repetitive stimulation is abnormal in 37-62% (see Table 25- also should be given to facial nerve stimulation. An abnormal
9)i77.333.486.504,551.71o.717.8u Stimulation of a proximal muscle in- result on any of these tests obviates the need to pursue further
creases the percentage of abnormal responses to 62-77%. investigation. If repetitive nerve stimulation is normal,
Adding the double-step procedure may increase the sensitivity SFEMG should be performed. If the practitioner is expert in
the performance of this test, it may be considered an option Acetylcholinesterase Inhibitors. The acetylcholinesterase in-
before the performance of repetitive stimulation. A normal hibitor, pyridostigmine bromide (Mestinon), usually improves
SFEMG study on the EDC warrants exploration of a facial weakness in patients with myasthenia gravis. Transient inhibi-
muscle, such as the frontalis. Axonal-stimulated SFEMG also tion of ACh catabolising by acetylcholinesterase increases the
should be considered as a viable alternative to voluntary con- amount and duration of ACh action at the NMJ, permitting ACh
traction methods. If both the EDC and one of the facial muscles to interact with sufficient numbers of AChRs to generate
are completely normal on SFEMG evaluation, serious consider- suprathreshold EPPs at the NMJs. Elevation of subthreshold
ation should be given to a diagnosis other than myasthenia EPPs results in an increased safety factor and hence at least
gravis. The diagnosis of myasthenia gravis should be observed some amelioration of muscle weakness and fatigue. Of impor-
only when the antibody levels are clearly positive but SFEMG tance, pyridostigmine does not affect the underlying im-
is negative. Continued electrophysiologic testing may be re- munopathology of the disease process. In our experience,
peated at a later time, and, if there is any doubt about the valid- patients with severe generalized weakness, particularly those
ity to the antibody test, it too should be repeated. with bulbar and respiratory involvement, require treatment with
Treatment. Four strategies commonly used for treatment of more than just pyridostigmine.
myasthenia gravis are (1) acetylcholinesterase inhibitors, (2) We initiate pyridostigmine in adults at a dose of 30-60 mg
immunosuppressive/immunomodulating medications, (3) every 6 hours. In children, we start pyridostigmine at a dose of
plasma exchange, and (4) thymectomy.232-427-547-563-564-566-645-731-1006 1.0 mg/kg. The dosage is gradually titrated, as necessary, to
The regimen used in patients with myasthenia gravis is individ- control myasthenic symptoms and reduce side effects. Most
ualized and depends on the severity of the myasthenia (e.g., adults require pyridostigmine dosages at 60-120 mg every 4-6
Osserman classification), age of the patient, presence of ab- hours. A time-released form of pyridostigmine (Mestinon
sence of an enlarged thymus, and concurrent medical problems. Timespan, 180 mg) is available, but we do not use it routinely,
Use of immunosuppressive agents to treat patients with purely unless the patient has severe weakness on awakening. In such
ocular symptoms is controversial.13-464 Some authorities suggest cases, a Mestinon Timespan tablet can be given at night. In pa-
that patients with an abnormal repetitive nerve stimulation or tients with only mild or moderate weakness, it is equally effica-
SFEMG of a limb muscle should be considered to have general- cious to have the patient set the alarm 30 minutes before they
ized disease (despite lack of generalized symptoms or signs) and need to arise from bed and take a regular pyridostigmine dose at
treated aggressively with immunosuppressive agents. However, that time.
no prospective trials have randomized such patients with ocular Patients can develop cholinergic side effects secondary to the
myasthenia to receive Mestinon alone or Mestinon plus im- build-up of ACh at muscarinic and nicotinic receptors.
munosuppressive agents. One can try to manage patients with Muscarinic side effects include nausea, vomiting, abdominal
ocular myasthenia only with Mestinon. If patients are still symp- cramping, diarrhea, increased oral and bronchial secretions,
tomatic, eye crutches can be used to treat ptosis or patches/prism bradycardia, and, in rare cases, confusion or psychosis. In pa-
lenses to prevent diplopia. Some patients do not like this ap- tients with significant side effects, we pretreat with anticholin-
proach for cosmetic reasons or still feel quite debilitated by the ergic medications (e.g., Anaspaz, propantheline, glycopyrrolate,
ocular disease. In such cases, we treat with a short course (2-3 or diphenoxylate with atropine) 30 minutes before the pyri-
months) of prednisone in a slowly incrementing fashion (see dostigmine doses.
below). Nevertheless, most patients require long-term immuno- Very rarely, too high a dose of pyridostigmine may result in a
suppressive therapy to control their symptoms. The goal is to cholinergic crisis in which build-up of ACh at the nicotinic
maintain these patients on the lowest possible dose. AChR "desensitizes" or blocks receptors, leading to increased
Patients in myasthenic crisis (severe respiratory distress or weakness. This type of crisis needs to be distinguished from the
bulbar weakness) represent the opposite end of the spec- myasthenic crisis secondary to inadequate anticholinesterase
trum.66-940 They should be admitted to an ICU and followed medication 749 by performing an edrophonium test. If intra-
closely, particularly in regard to pulmonary function. When the venous edrophonium results in clinical worsening, the increased
forced vital capacity declines to less than 15 ml/kg or negative weakness is most likely the result of overdosing of the anti-
inspiratory pressure is less than 30 cm H 2 0, we intubate the pa- cholinesterase medication. If weakness improves, it is due to the
tient to protect the airway and begin mechanical ventilation. Of underlying myasthenia gravis. In our experience, cholinergic
importance, these pulmonary function parameters decline crisis is quite rare in the doses that we prescribe.
before diminished Pa0 2 or increased PaC0 2 on routine blood Corticosteroids. The most commonly used immunosuppres-
gases. We initiate plasma exchange (PE) and continue ex- sive agents are corticosteroids. Various trials have demonstrated
changes until the patients has had significant return of strength the efficacy of corticosteroids in the treatment of myasthenia
and can be weaned off the ventilator. IVIG may be an alterna- gravis.35-324-424-556-604-742-980 Corticosteroid treatment results in marked
tive treatment, although in our opinion its effect in myasthenic improvement (45%) or remission (30%) in the majority of
crisis is more variable and slower in onset than PE. While the myasthenic patients. We start most of our patients with moder-
patient is intubated, we usually do not treat with antiacetyK ate-to-severe generalized myasthenia gravis on prednisone. Two
cholinesterase medications, which can increase saliva production. strategies generally are used for prednisone treatment in patients
In addition to starting PE, we usually begin corticosteroids at with myasthenia gravis: (1) aggressive high-dose daily steroids
or around the same time. If thymectomy is considered, some at the onset of treatment and (2) "a start low and go slow ap-
surgeons prefer to withhold the corticosteroid until after the proach." In our experience, the high-dose daily regimen leads to
thymectomy because of the increased risk of infection and a much quicker improvement of weakness. We initiate treatment
slower wound healing. However, most patients whom we with prednisone, 1.5 mg/kg/day (up to 100 mg) for 2 weeks, and
have treated with high doses of corticosteroid prior to then switch to alternate-day prednisone (e.g., 100 mg every
thymectomy have done well without significant postoperative other day). We maintain the patients on this high dose until
complications. strength has normalized or there is a clear plateau in improvement.
Subsequently, we slowly taper the prednisone by 5 mg every We do not prophylactically treat with histamine-H 2 receptor
2-3 weeks, down to 20 mg qod. At this point we taper even blockers, unless the patient develops gastrointestinal discomfort
more slowly by 2 mg per 4 weeks. At these low doses patients or has a history of peptic ulcer disease. Patients are instructed to
may have a relapse. Most patients require some amount of im- start a low-sodium, low-carbohydrate, high-protein diet to pre-
munosuppressive medication, but we try to find the lowest vent excessive weight gain. Patients also are given physical
doses necessary to maintain strength. The addition of other im- therapy and encouraged to begin slowly an aerobic exercise pro-
munosuppressive agents (e.g., azathioprine, cyclosporine, or gram. Blood pressure is measured with each visit, along with
mycophenolate) may have a prednisone-sparing-effect and periodic eye examinations for cataracts and glaucoma. Fasting
allow lower doses. blood glucose and serum potassium levels are periodically
Of importance, as many as 30% of patients experience vary- checked. Potassium supplementation may be required, if the pa-
ing degrees of initial worsening (within the first 1-3 weeks), tient becomes hypokalemic.
which lasts about 1 week after initiation of high doses of Steroid Myopathy vs. Relapse of Myasthenia Gravis. High-
steroids.745-836 In our experience, significant weakness occurs in dose, long term steroids and lack of physical activity can cause
less than 10% of patients. Nevertheless, we usually hospitalize type 2 muscle fiber atrophy with proximal muscle weakness.
patients for the first week after initiating treatment with high- This.disorder needs to be distinguished from relapse of the
dose corticosteroids. The mechanism of the exacerbation of myasthenia. Patients who become weaker during a prednisone
myasthenic symptoms is not clear. It may represent a milder taper, with worsening of decrement on repetitive stimulation or
form of acute quadriplegic myopathy (see Chapter 28). Further increasing jitter and blocking on SFEMG, are probably experi-
research is necessary in this area. encing a flare of the myasthenia. In contrast, patients with con-
Because of the risk of exacerbation with high-dose corticos- tinued high doses of corticosteroids, normal repetitive
teroids some clinicians advocate the "start low and go slow ap- stimulation and SFEMG, and other evidence of steroid toxicity
proach."234 Patients are started at a dose of 15-20 mg/day, and (e.g., Cushingoid appearance) may have type 2 muscle fiber at-
the dose is slowly increased by 5 mg every 2-4 days or so until rophy and may benefit from physical therapy and reducing the
definite improvement is noted. Unfortunately, improvement dose of steroids.
takes much longer with this approach and is thus not very useful Azathioprine. Azathioprine is probably the second most fre-
in patient with severe weakness. We reserve this approach for quently used immunosuppressive agent in the treatment of
the patient with mild generalized disease not controlled with myasthenia gravis (after prednisone). Several treatment trials
mestinon or the occasional patient with ocular myasthenia have demonstrated the efficacy of azathioprine alone or in com-
whom we treat with immunosuppression. bination with prednisone.'02-324-414-682-742 Improvement is noted in
There are many potentially serious side-effects to the chronic ad- 70-90% of myasthenic patients treated with azathioprine, in-
ministration of corticosteroids (e.g., risk of infection, diabetes mel- cluding some patients who are steroid-resistant. 836 Patients
litus, hypertension, glaucoma, osteoporosis, aseptic necrosis of the treated with azathioprine also may be maintained on lower
joints). We obtain a chest x-ray and PPD skin test as controls for all doses of prednisone (i.e., azathioprine has a steroid-sparing
patients before initiating immunosuppressive medications. Patients effect).
with a history of tuberculosis or a positive PPD may need to be We start azathioprine in patients with moderate to severe gen-
treated prophylactically with isoniazid. In addition, we measure eralized myasthenia gravis whose disease is not well controlled
bone density with dual energy x-ray absorptiometry (DEXA) at by prednisone and Mestinon. We initiate azathioprine at a dose
baseline and every 6-12 months while patients are receiving corti- of 50 mg/day in adults and gradually increase over 1-2 months
costeroids. A bone density less than 2.5 standard deviations below to a total dose of 2-3 mg/kg/day. A systemic reaction, charac-
normal is considered positive for osteoporosis. Supplementation terized by fever, abdominal pain, nausea, vomiting, and
with calcium (1 gm/day) and vitamin D (400-800 IU/day) is anorexia, requires discontinuation of the drug in 12% of pa-
started for prophylaxis against steroid-induced osteoporosis. tients. This reaction generally occurs within the first few weeks
Postmenopausal women should be treated with estrogen, unless it of therapy and resolves within a few days of discontinuing aza-•
is contraindicated (e.g., breast cancer), because it is effective in thioprine. Rechallenge with azathioprine usually results in re- j
preventing and treating osteoporosis. Postmenopausal women currence of the systemic reaction. Other major complications of
who cannot or do not wish to take estrogen should be treated with azathioprine are bone marrow suppression, hepatic toxicity,
a bisphosphonate, i.e., alendronate. Bisphosphonates have recently pancreatitis, teratogenicity, oncogenicity, and risk of infection.
been demonstrated to be effective in the prevention and treatment Allopurinol should be avoided, because combination with aza-
of osteoporosis.5-819 Efficacy in preventing osteoporosis has been thioprine increases the risk of bone marrow and liver toxicity. A
reported in postmenopausal women with and without concurrent major drawback of azathioprine is that it often takes 6 months
estrogen therapy, premenopausal women, and men receiving corti- or longer to become effective.
costeroids.819 Thus, some authorities advocate alendronate (5-10 We monitor CBC and liver function tests (LFTs)—AST, ALT,
mg/day orally) as prophylaxis for osteoporosis in any patient bilirubins, and gamma-glutamyl transpeptidase (GGT)—every
placed on corticosteroids.819 However, the long-term side effects 2 weeks until the patient is on a stable dose of azathioprine, then
of bisphosphonates are not known, especially in men and young once a month. If the white blood count (WBC) falls below 4,000
premenopausal women. If DEXA scans demonstrate osteoporosis per mm 3 , we decrease the dose. Azathioprine is withheld if the
at baseline or during follow-up studies, we initiate alendronate, 10 WBC declines to 2,500 per mm 3 or the absolute neutrophil
mg/day. In patients with mild bone loss not yet diagnostic of os- count falls to 1000 per mm3. Leukopenia can develop as early as
teoporosis, we consider starting alendronate 5 mg/day. Alendro- 1 week or as late as 2 years after initiating azathioprine. The
nate can cause severe esophagitis, and absorption is impaired if it leukopenia usually reverses within 1 month, and it is possible to
is taken with meals. Therefore, patients must be instructed to rechallenge the patient with azathioprine without recurrence of
remain upright and not to eat for at least 30 minutes after taking a the severe leukopenia. In addition, we discontinue azathioprine
dose of alendronate. if the LFTs increase more than twice the baseline values. Liver
toxicity generally develops within the first several months of treat- gm/kg) slowly over 2-5 days and repeat infusions at monthly
ment and can take several months to resolve. Patients occasionally intervals for at least 3 months. Thereafter treatment is individu-
can be successfully rechallenged with azathioprine after LFTs alized. Some patients may need treatment (0.4-2 gm/kg) every
return to baseline without recurrence of hepatic dysfunction. week, whereas others may go several months between IVIG
Cyclosporine. Cyclosporine inhibits primarily T-cell-depen- courses. In all patients the IgA level should be checked before
dent immune responses and has been demonstrated to be effec- treatment, because those with low IgA levels may be at risk for
tive in treating patients with myasthenia gravis.838-945-946 Most anaphylaxis. Renal functions also should be checked, especially
patients notice improvement within 2-3 months of initiating in patients with diabetes mellitus, because of a risk of IVIG-in-
treatment; thus cyclosporine works much faster than azathio- duced renal failure. Flu-like symptoms—headaches, myalgias,
prine. Cyclosporine also appears to have a steroid-sparing fever, chills, nausea, and vomiting—are common (in as many as
effect. As many as 95% of patients are able to discontinue or de- one-half of the patients receiving IVIG). These symptoms can
crease their prednisone dose. ,54a However, approximately 25% be reduced by premedication with a corticosteroid and lowering
of patients develop renal toxicity, which has limited enthusiasm the rate of infusion. Rash, aseptic meningitis, and stroke also
for its uses. We tend to use cyclosporine mainly in patients who may complicate IVIG infusions.
are refractory to prednisone and azathioprine. We start cy- Plasma Exchange. PE is clearly effective in the treatment of
closporine at a dose of 3.0-4.0 mg/kg/day in two divided doses myasthenia gravis.,89-325'426'599-626-770-779-9,6-,0°1 We use PE in pa-
and gradually increase to 6.0 mg/kg/day, as necessary. The cy- tients with myasthenic crisis or moderate weakness prior to
closporine dose is initially titrated to maintain trough serum thymectomy to maximize perioperative strength. The typical
levels of 50-150 ng/ml. Blood pressure, electrolytes and renal course involves exchange of 2-3 liters of plasma 3 times/week
function, and trough cyclosporine levels need to be monitored until strength is significantly improved (at least 5-6 total ex-
periodically. We lower the dose as necessary to keep the trough changes). Improvement is noticeable after 2-4 exchanges. PE
less than 150 ng/ml and the creatinine level less than 150% of lowers the serum concentration of anti-AChR antibodies, but it
baseline. After patients achieve maximum improvement, we must be repeated at relatively regular intervals because of its lim-
lower the dose over several months to the minimum doses nec- ited duration of effect. Within 1 week after PE, the autoantibod-
essary to maintain the therapeutic response. ies begin to rebound. Patients need also to be started on an
Mycophenolate. Mycophenolate mofetil is a newer immuno- immunosuppressive agent. Because of cost and side effects
suppressive agent that inhibits the proliferation of T and B lym- (thrombosis, thrombophlebitis, infection, cardiovascular insta-
phocytes by blocking purine synthesis only in lymphocytes. bility), PE is limited to the above indications, although continued
Mycophenolate has been used in transplant patients to prevent periodic PE can be used in patients refractory to immunosup-
rejection and recently has been tried in several small, open-label pressive agents.
trials in patients with myasthenia gravis with reported bene- Thymectomy. Because of the large number of patients with
fk. i42.i54.i74.383 Besides improvement in strength, patients have autoimmune myasthenia gravis and thymic abnormalities, re-
been able to be maintained on lower doses of other immunosup- moval of the thymus is often recommended.645-672-673-746
pressive agents, including prednisone. In addition, a few pa- Thymectomy is clearly indicated in patients with a thymoma.
tients have improved with mycophenolate as the sole treatment. However, the role of thymectomy in myasthenic patients with-
Improvement has been noted as early as 2 weeks (usually within out thymoma is unclear and was the subject of a Practice
the first 3 months) after starting the medication, but benefit can Guideline by the American Academy of Neurology. 353 An evi-
be delayed up to 12 months. The dose is 1 gm 2 or 3 times daily dence-based review of 21 published case II studies (nonrandom-
by mouth. Mycophenolate is excreted renally; therefore, the ized observational studies with concurrent controls) of
dose should be decreased (no more than 1 gm/day total) in pa- thymectomy in myasthenic patients without thymoma found
tients with renal insufficiency. A benefit of mycophenolate com- that patients undergoing thymectomy were 1.7 times as likely to
pared with other immunosuppressive agents is the lack of renal improve, 1.6 times as likely to become asymptomatic, and twice
or liver toxicity. The major side effect is diarrhea. Less common as likely to attain medication-free remission.353 The relative rate
side effects include abdominal discomfort, nausea, peripheral of improvement was greater for patients with more severe dis-
edema, fever, and leukopenia. ease. Unfortunately, the degree of improvement and the time
Cyclophosphamide. There are only rare reports of cyclophos- before improvement begins after surgery are variable and not
phamide used to treat myasthenic patients.39-760 Because of sig- predictable in any given patient (e.g., the improvement may not
nificant side effects (i.e., gastrointestinal upset, bone marrow be noted for 5-10 years). In addition, the improvements noted
toxicity, alopecia, hemorrhagic cystitis, teratogenicity, steriliza- in the surgical groups may have been due to multiple differ-
tion, and increased risk of infections and secondary malignan- ences in baseline characteristics between surgical and nonsurgi-
cies), we have avoided cyclophosphamide. However, we would cal groups or the aggressiveness of concurrent medical therapy.
consider cyclophosphamide in patients with severe generalized The panel recommended thymectomy as an "option" to increase
myasthenia gravis refractory to other modes of immunotherapy. the probability of improvement or remission in patients with
Intravenous Immunoglobulin. The administration of IVIG nonthymomatous myasthenia gravis.353 They also recommended
may result in clinical improvement in some patients with myas- prospective, randomized controlled trials with standardized
thenia gravis.4175-250-325-395-429-457 Some studies have found that medical treatment to better address more clearly the role of
IVIG is equivalent to PE,325 whereas other studies suggest that thymectomy in this population.
PE is more efficacious.779-916 IVIG has not been compared with The operative techniques used in the controlled trials con-
standard immunosuppressive agents (e.g., corticosteroids, aza- sisted of the standard transternal or transcervical approach or
thioprine, cyclosporine) in a double-blind prospective fashion. were not identified.353 Some authorities recommend an aggres-
We prefer PE over IVIG in the treatment of myasthenic crisis. sive transcervical-transternal approach to remove accessory
We generally reserve IVIG for patients with generalized myas- thymic tissue in the neck.450 However, the few controlled trials
thenia who are refractory to corticosteroids. We initiate IVIG (2 comparing outcomes in myasthenic patients undergoing different
surgical techniques have yielded inconsistent results.353 Compli- change in myasthenic symptoms, 28% improved, and 4 1 % dete-
cations of thymectomy include exacerbation of myasthenic riorated during pregnancy. 774 In addition, 30% had exacerba-
weakness with respiratory failure in 6%, infection in 11%, and tions in the postpartum period. In general, we try to control the
nerve injury (recurrent laryngeal, phrenic, brachial plexus) in disease with Mestinon and prednisone and avoid other immuno-
2%. Mortality rates are less than 1%.115-353 Newer, less invasive suppressive agents because of their possible teratogenic effects.
surgical techniques, such as video-assisted thoracic surgery, The neuromuscular clinician needs to follow the patient closely
may lower complication rates.586 Thus, randomized controlled with the obstetrician as well as the pediatrician. Magnesium sul-
trials assessing the best surgical techniques also are needed. fate should be avoided, if possible, in patients who become
preeclamptic because of its neuromuscular blocking effect.
Juvenile Myasthenia Gravis Regional anesthesia is preferred for delivery and caesarian sec-
A subclassification of autoimmune myasthenia gravis is juve- tion. There is a theoretical risk of passing the antibodies in
nile myasthenia gravis,295-395-557-805'887-9543-967 which is defined as breast milk, although most infants have no problem with breast
manifestation of the clinical symptoms of typical myasthenia feeding. Of major concern is the occurrence of transient neona-
gravis between the first year of life and 18 years of age. tal myasthenia, which is discussed in detail below.
Approximately 10% of patients with myasthenia gravis fall into
this category. Less than 3% of patients with myasthenia gravis Transient Neonatal Autoimmune Myasthenia Gravis
manifest symptoms before puberty.295 Of importance, some of Clinical Features. Transient neonatal autoimmune myasthe-
these cases reported in the literature may actually represent con- nia gravis develops in approximately 10% of infants born to
genital myasthenia—particularly in patients who were seroneg- mothers with myasthenia gravis.53-97 "6-218-260-296-329-485-540-656-669¬
ative for anti-AChR antibodies. Few studies have been directed 684.723.747.864,917.961 0 n s e t is usually within the first 3 days of life
specifically toward this population; as a result, only a moderate and manifests with a weak cry, difficulty in feeding due to a
amount of data is available. poor suck, generalized weakness and decreased tone, respira-
The mean age of onset for juvenile myasthenia gravis ranges tory difficulty, ptosis, and diminished facial expression (facial
from 7 to 14 years.557-887 The clinical features are similar to muscle weakness). The disorder is temporary with a mean dura-
adult-onset myasthenia gravis. Most patients initially present tion of about 18-20 days. The most important aspect of this dis-
with primarily ocular symptoms. 887 As in adults, serum AChR order is that it is temporary, and the child appears to have no
antibody titers are present in most children. The electrophysio- increased susceptibility to developing the adult form of myas-
logic findings are also identical to those in the adult form of the thenia gravis.
disease.967 Pathogenesis. The pathophysiology results from passive
The efficacy of thymectomy has not been determined in a transfer through the placenta of maternal antibodies against
prospective, controlled trial. In a large retrospective series of AChRs. Why a minority of children born to mothers with myas-
149 patients with juvenile myasthenia gravis, 85 had a thymec- thenia gravis are clinically affected is unknown.
tomy and 64 were managed medically. 805 In the thymectomy Electrophysiologic Findings. The electrical findings in
group, 82% of patients improved, and 48% went into remission transient neonatal myasthenia gravis are essentially the same as
compared with 63% improvement rate and 34% remission rate those in adults (Fig. 25-36).97-218-388 Specifically, there is a decre-
in nonthymectomized patients.805 In another retrospective series ment of the CMAP at low rates of stimulation with postactiva-
of 79 patients with juvenile myasthenia gravis, 65 patients tion excitation and exhaustion. There is also usually a
(82%) underwent thymectomy. 557 Of the thymectomized pa- decrement at high rates of stimulation, depending on the sever-
tients, remission occurred in 60% compared with 29% in the ity of the disease. One can taper the anticholinesterase medica-
nonthymectomized group.557 However, neither of these studies tion at various periods and assess the degree of decrement to
controlled for baseline severity or medical therapy; thus, the determine when the child can be weaned permanently from the
role of thymectomy in juvenile myasthenia gravis is unclear, as medication. The absence of a decrement indicates that the NMJs
it is in adults. 353 Thymic hyperplasia is common in juvenile have recovered to a sufficient degree that the child can be con-
myasthenic gravis, although thymomas are not. Of importance, sidered on the road to full recovery.
removal of the thymus in children does not appear to have any Treatment. Infants with neonatal myasthenia and weakness
deleterious effect on the development of the immune system.836 may be treated with anticholinesterase medications until anti-
Plasma exchange appears to be beneficial in patients with body levels have diminished to the point that sufficient safety
severe weakness.295-557 In addition, IVIG also is effective in factors are reestablished at significant number of NMJs. Infants
some children.395-862 with severe weakness may require mechanical ventilation and
In children, we start pyridostigmine at a dose of 1.0 mg/kg treatment with PE. IVIG does not appear to be effective.55-932
and titrate to an effective dose. Patients with moderate to severe Frequent suctioning may be needed to prevent respiratory infec-
generalized disease are started on oral prednisone, 1 mg/kg/day, tion. The morbidity and mortality rates have improved markedly
and switched to alternate-day prednisone after 2-4 weeks. After with the institution of these simple medical interventions.
strength stabilizes, we slowly taper the prednisone by 1-5 mg
every 2-4 weeks (depending on patient size). We try to avoid PRESYNAPTIC DISORDERS
other immunosuppressive agents when possible, although aza-
thioprine and cyclosporine have been used in this age group Several presynaptic NMJ disorders deserve detailed discus-
with satisfactory results.295-557 However, the possible long-term sion because they may be encountered by the practitioner and it
side effects of these immunosuppressive agents are concerning. provides significant insight into the physiology of NMJ trans-
mission.214-456 In addition, the rare but nevertheless distinct clin-
Myasthenia Gravis and Pregnancy ical presentation of several presynaptic disorders may spare
In an extensive review of the literature involving 322 preg- patients significant morbidity if the physician has a high index
nancies in 225 myasthenic mothers, 31 % of mothers had no of suspicion for certain potentially devastating insults.
Neonatal myasthenia th
Figure 25-36. CMAP decrement. A characteristic CMAP
3Q d a y
decrement found in the abductor digiti minimi to repetitive stim-

ulation of the ulnar nerve in a patient with transient neonatal
myasthenia gravis. A-E, Repetitive stimulation results at rest, im-
mediately after 5 seconds of 50-Hz stimulation, and the time in- for5sec*. '
tervals after the high-rate train of stimuli.The percent decrement

is noted as minus numbers to the right of each trace. F,A dra-
matic repair in the decrement can be demonstrated after Tensilon
administration. G-H,Thirty days after birth a repeat study reveals
only minimal abnormalities during repetitive stimulation studies,
which correlated with the patient's asymptomatic state. (From
Desmedt JE:The neuromuscular disorder in myasthenia gravis. I.
Electrical and mechanical responses to nerve stimulation in hand
muscle. In Desmedt JE (ed): N e w Developments in Electro-
myography and Clinical Neurophysiology. Karger, Basel, 1973, pp
241-304, with permission.)
Lambert-Eaton Myasthenic Syndrome (LEMS) The physical examination in patients suspected of LEMS
Clinical Features. LEMS is the second most common NMJ must be performed with particular care, especially the manual
i disorder after myasthenia gravis. 252 - 2 ^- 285 - 516 ^ muscle test. Muscle strength is potentiated by the testing proce-
LEMS is an immunologic disorder caused by antibodies directed dure itself; therefore, it is easy to conclude erroneously that the
against voltage-gated calcium channels. In approximately two- patient has a normal or near-normal grade of strength.
thirds of cases, LEMS arises as a paraneoplastic disorder, usually Specifically, strength must be graded from the initiation of con-
secondary to small cell carcinoma of the lung. Small cell carci- traction as opposed to several seconds after onset of contrac-
noma of the lung is the culprit in approximately 90% of paraneo- tion. For example, with the patient in the seated position, the
plastic cases of LEMS. Other malignancies associated with examiner places the hip in a flexed position. The patient may
LEMS include lymphoproliferative disorders, pancreatic cancer, have difficulty in maintaining this posture with an initial drop
and breast and ovarian carcinoma. 29542 The LEMS symptoms toward the table but then demonstrates recovery with a rather
usually precede tumor diagnosis by about 10 months (5 months good ability to resist any attempt to break the flexed position.
to 3.8 years). Approximately 84% of patients with LEMS are over Similarly, flexion of the elbow may be overcome initially, but
the age of 40 years with a mean age at presentation of 54 years. with continued contraction against resistance strength may re-
In the remaining third of patients, LEMS occurs as an idio- cover. These findings apply primarily to the proximal hip and
pathic autoimmune disorder without an underlying cancer. Such shoulder girdle muscles but also can be detected to varying de-
cases are more common in women and younger patients and are grees in the distal limb muscles. The improvement in muscle
associated with other autoimmune disorders, including rheuma- weakness after a brief period of contraction usually dissipates
toid arthritis, systemic lupus erythematosus, inflammatory with sustained muscle contraction. This finding can be demon-
bowel disease, primary biliary cirrhosis, and even myasthenia strated clinically by asking the patient to squat several times. At
gravis, as discussed above.360-494-5,6-5,9-525-527-538»692-912-974 The para- first, repetitive squatting may be quite difficult, but it improves
neoplastic and nonparaneoplastic forms of LEMS are otherwise after several attempts and then declines again after several min-
clinically and electrophysiological^ indistinguishable. utes of performing the maneuver. Neck flexor and extensor
Patients with the LEMS usually complain of specific weak- muscle weakness may be observed in some patients as well as
ness and easy fatigability.252*264-516-518-523-727-752-814 Most patients ptosis and facial muscle weakness. Ptosis may be improved
present with proximal lower limb weakness. Proximal upper with sustained voluntary lid elevation, (opposite to a disorder
limb weakness is noted in approximately 80% of patients during such as myasthenia gravis). 99 In advanced stages of the disease,
the course of the illness. One-third of patients complain of muscle atrophy can be observed. A sluggish pupillary reaction
muscle aching and stiffness during or after physical exertion. to light may be noted as well as diminished sweating on a sweat
Approximately 20% of patients note that weakness and fatigue challenge test. Decreased vibration, light touch, or pinprick may
are exacerbated by hot weather or during the course of taking a be detected. Deep tendon reflexes may be diminished or absent
hot bath. Ocular and bulbar symptoms are not as common or as on the first attempt to elicit but become significantly more easy
severe as in myasthenia gravis. Ptosis and diplopia are often to obtain once a slight contraction of the muscle has been per-
transient and mild. Some patients develop dysarthria or dyspha- formed. A few patients with LEMS associated with the anti-Hu
gia, more commonly as a result of dry mouth. Autonomic dys- syndrome (usually seen with small cell carcinoma of the lung)
function (reduced saliva, dry eyes, blurred vision, constipation, also have clinical findings suggestive of a sensory or cerebellar
decreased sweating, and impotence) are commonly seen in pa- ataxia and limbic encephalitis.620
tients with LEMS. 737a Most patients do not have respiratory Laboratory Features. An intravenous Tensilon test can be
problems related to the neuromuscular junction defect, although quite variable in patients with LEMS. Antibodies directed
they may have dyspnea related to lung cancer. Rare cases of against the P/Q type voltage-gated calcium channels of the
LEMS presenting with respiratory failure have been de- motor nerve terminals are detected in the serum in over 90% of
scribed. 697 Occasionally, patients complain of numbness and patients with LEMS (both paraneoplastic and non-cancer-re-
paresthesias in the distal limbs. lated cases).542-544-6963-7373 In addition, antibodies directed against
The trigger for initiating the afferent limb of the autoimmune

response is unknown. In patients with cancer, it is speculated that
the tumor cells express an embryonic-type calcium channel or
calcium channel protein subcomponent that then elicits the pro-
duction of autoantibodies capable of cross-reacting with presy-
naptic neuronal calcium channels in genetically predisposed
people. 193 The antigenic substrate located on the tumorous cal-
cium channels are believed to be the same as or to share similar
protein aspects with the neuronal calcium channels.285-318-319 A
common antigenic relationship between small cell carcinomas
and calcium channels is supported by an interesting polypeptide
neurotoxin secreted by the marine snail Conus geographus (co-
conotoxin). This neurotoxin is specific for neuronal voltage-sen-
I pm sitive calcium channels. Of the several different types of calcium
channels known, this toxin specifically binds irreversibly to volt-
Figure 25-37. Stereometric analysis of the presynaptic age-sensitive channels in the presynaptic nerve terminal. By ra-
axonal terminal membrane opposite the synaptic cleft.The diolabeling the snail toxin and exposing it to tumor tissue, it is
control circle demonstrates the parallel rows of presumed intramem- possible to collect a radiolabeled toxin-channel com-
branous protein calcium channels. In the axon terminal of a patient plex .40^408.541,548.866-869 Exposing this complex to the serum of pa-
with Lambert-Eaton myasthenic syndrome (LEMS), note the reduction tients with LEMS results in attachment of antibodies to the
in parallel rows of particles as well as a conglomeration of these parti- radiolabeled toxin-channel complex.
cles into groups. (From Fukunaga H, Engel AG, Osame M: Paucity and Through an as yet unclear mechanism, the immune system is
disorganization of presynaptic membrane active zones in the Lambert- activated to produce antibodies directed against these nerve ter-
Eaton syndrome. Muscle Nerve 1982;5:686-697, with permission.) minal calcium channels.542-543-884 The antibodies bind to the volt-
age-gated calcium channels and subsequently inhibit the entry
the N-type calcium channels, which are located on autonomic of calcium into the nerve terminal (Fig. 25-38). Additionally,
and peripheral nerves as well as cerebellar, cortical, and spinal the antibodies may cross-link neighboring calcium channels,
neurons, are present in 74% of patients with LEMS and lung thus precipitating the process of internalization and degradation
cancer and 40% of patients without cancer.542,543-7373 Antibodies of the calcium channels. Complement does not appear to be in-
directed against various epitopes of the calcium channel, includ- volved in this process because the nerve terminal maintains a
ing the a l A- and p-subunits have been identified. Some patients grossly normal appearance; i.e., there is no evidence of lytic de-
with paraneoplastic LEMS also have anti-Hu antibodies and the struction.268 Further work in this area may define a selective in-
associated sensory ganglionopathy, cerebellar degeneration, and volvement of complement directed at specific calcium channel
encephalopathy.542-543-620 As many as 13% of patients with sites and sparing the majority of the remaining membrane 407
LEMS also have AChR-binding antibodies. 543 The anti-AChR Antibody binding with the calcium channels reduces the
antibodies are not necessarily pathogenic in patients with LEMS amount of calcium entry during an action potential. The reduced
and may represent an epiphenomenon. Nonetheless, rare patients nerve terminal calcium concentration may limit vesicular re-
may exhibit features of both LEMS and myasthenia gravis. lease from the nerve terminal's internal cytoskeletal bridge-
Histopathology. Light microscopic analysis of muscle biop- work. There is some indication that calcium serves to cleave the
sies are essentially normal except for an occasional finding of bonds holding the vesicles to this intraneural framework. The
type II fiber atrophy.127 727 Grossly, the NMJs appear intact. net result is less availability of vesicles to fuse with the mem-
However, on quantitative electronmicroscopic analysis, a number brane. Cross-linking and internalization of calcium channels
of interesting findings are noted. The nerve terminal appears have the same net result of reduced calcium entry and hence re-
normal, as do the size and number of synaptic vesicles (see Table duced vesicular fusion. If antibody binds to the surface of the
25-10).268 269 Similarly, the postsynaptic membrane is intact, but vesicle during the reformation process, the antibody may hinder
there is an increase in the postsynaptic fold area and the number the vesicle's ability to attach or dock with recognition proteins
of secondary synaptic clefts. The total number and activation at the active zones—in short, another mechanism which vesicu-
properties of the AChRs appears normal. Freeze-fracture analysis lar release is reduced after an action potential.
of the presynaptic membrane demonstrates a marked decrease in In an unclear manner, antibodies may enter the nerve termi-
the number of intramembranous proteinaceous particles that are nal during the endocytotic regenerative process for the regener-
assumed to be P/Q valtage-gated calcium channels. Additionally, ation of new vesicles. Once in the nerve, the antibodies may
there is disorganization of the parallel rows of the calcium chan- interact with proteins involved in the docking and fusion of
nels with aggregation of particles clumps (Fig. 25-37).277-281-318-319 synaptic vesicles and the presynaptic plasma membrane. 546
Pathogenesis and Pathophysiology. LEMS is caused by In patients with LEMS, intracellular microelectrode record-
antibodies directed against P/Q type voltage-gated calcium ings reveal a number of abnormal findings. The MEPP's magni-
channels (VGCC) and to a lesser extent N-type VGCC and tude in LEMS is quite similar to that recorded in normal muscle
synaptotagmin on the presynaptic motor nerve terminals (Fig. (see Table 25-10). Hence the amount of ACh per vesicle is
25 - 38).319-360-494-525-527-538-692-884-912'933a-974 Passive transfer of IgG normal. The frequency of MEPP production, however, may be
from patients with paraneoplastic and nonparaneoplastic LEMS normal or somewhat greater than that of normal muscle
induces all of the morphologic and electrophysiologic features (0.57/second vs. 0.24/second, respectively ).264-526-694 This in-
of the disease in experimental animals. An association with creased frequency of release appears to be incompatible with
HLA-B8 and DRw3 antigens supports the autoimmune founda- the concept of antibodies binding to the synaptic vesicle and
tion for the disease. hindering fusion. If this mechanism holds true, the frequency of
Figure 25-38. The presynaptic membrane in health and LEMS.The upper plate represents the normal presynaptic membrane. Synaptic
vesicles are attached to the cytoskeletal actin network, possibly by the protein synaptotagmin.After an action potential, calcium ions enter the nerve
terminal through the calcium channels to break the synaptotagmin-actin bonds (I) and allow the vesicles to approach (2) and dock with the calcium
channels through a synaptotagmin bond with subsequent vesicle fusion and release of ACh (3). Vesicles then reform and are filled with ACh (4). In
LEMS (lower plate), antibody binds with the calcium channels to block calcium entry (I) as well as cross-linking with the channels to result in inter-
nalization and destruction of these structures (2). Antibodies also may link with the synaptotagmin on vehicles (3) and impede docking between the
vesicles and the calcium channels (4). (From Smith RG.Appel SH:The Lambert-Eaton syndrome. Hosp Pract 1992;27:101-116, with permission.)
MEPPs should decline, not increase. The reason for the in- The histologic and physiologic findings appear to agree
creased MEPP frequency is unknown. quite well. In LEMS, normal-appearing vesicles indeed con-
Of interest is the nerve terminal response to depolarization. tain normal amounts of ACh. Once sufficient amounts of ACh
The mean quantal content in LEMS is roughly 8 (3.3-15), are released, the postsynaptic membrane responds normally,
whereas a normal terminal releases approximately 56 (24-106) as evidenced by EPPs quite capable of reaching threshold. The
quanta. The finding of diminished quantal release is quite similar reduced quantal content is evidenced by subthreshold EPPs
to reduced quantal release to neural depolarization when the ex- that reach threshold after rapid rates of stimulation. This effect
tracellular fluid bathing the nerve terminal is deprived of calcium is due most likely to overwhelming of the binding/sequester-
and/or the magnesium concentration is dramatically elevated. ing mechanism by residual calcium, which increases the prob-
The hypothesis of reduced calcium entry secondary to antibody ability of vesicle release. Hence the increased amounts of
hindrance or antibody-mediated destruction and disorganization residual nerve terminal calcium compensate for the dimin-
is compatible with the physiologic findings of reduced quantal ished amount of calcium entering the terminal per stimulus.
release, A decrease calcium entry decreases the probability of The cumulative effect of calcium is necessary for appropriate
ACh release and thereby the amount of ACh released per nerve amounts of ACh to be released and to generate suprathreshold
terminal depolarization. Recall that n x p = m. If the probability EPPs. All of these physiologic factors directly affect what is
(p) is reduced despite a normal amount of ACh available for re- observed during the electrodiagnostic medicine examination
lease (n), the quantal content (m) is decreased. Activating the of patients with LEMS.
nerve terminal at 1-5 Hz results in the continuous decline of Electrophysiologic Findings. Our electrodiagnostic ap-
ACh released per stimulus until a new baseline of ACh release is proach to evaluating patients suspected of having a neuromus-
reached by about the fifth to eighth responses when mobilization cular junction defect, including LEMS, is illustrated in Table
replenishes the immediately available store. However, stimulat- 25-4.
ing the nerve at greater than 10 Hz generates EPPs that sequen- Sensory Conduction Studies. Sensory nerve conduction stud-
tially increase in amplitude. In terminals at which the EPP is ies are normal in patients with pure LEMS (Table 25-11). How-
subthreshold, rapid rates of stimulation restore the EPP magni- ever, patients with LEMS may have a paraneoplastic sensory or
tude to normal values and hence increase the safety factor. The sensorimotor neuropathy as well. In addition, patients with
failure to reach threshold prior to rapid rates of stimulation re- LEMS conceivably have peripheral neuropathies secondary to
sults directly from the fact that the diminished quantal content other disorders, such as diabetes mellitus, excess ethanol intake,
generates an EPP of insufficient magnitude. and chemotherapy.
(-142%) 10% of patients. Only 4 1 % of patients had doubling of CMAP
amplitude in three distal muscles after brief maximal exercise.
Repetitive nerve stimulation at low rates (2-3 Hz) often
yields a decremental response that is maximal between the first
and second response and continues to decline until the fourth,
500 uV | B fifth, or sixth response, when a stable or slightly increasing
(-33%) 2msec CMAP amplitude is reached.442-706-718-942-943 If the baseline CMAP
amplitude is too low, it is sometimes difficult to appreciate a
decrement. Decrement on 3-Hz stimulation was demonstrated
in the ADM in 98%, in the APB in 98%, in the EDB in 84%, and
500|j.v| in the trapezius in 89% of cases. 943 Another investigation sup-
(+163%) ports use of the ADM, APB, and even the anconeus muscle.5873
(-25.6%) After a brief maximal exercise period of 10 seconds, repeat 2-3-
Hz stimulation usually results in a an increase in the amplitude
of the first response and a complete or partial correction of the
subsequent decrementing responses. This postexercise facilita-
tion effect lasts approximately 20-30 seconds. If the muscle is
1mV
exercised for 1 minute, 2-3-Hz repetitive stimulation produces
(-29.3%) a decrement that peaks at 3-5 minutes after activation and ex-
1 ceeds the decrement in the resting state (i.e., postexercise ex-
haustion). In addition, 1 minute of exercise produces an
H absolute decrease in the initial CMAP amplitudes on follow-up
repetitive stimulation by 3-5 minutes after exercise. For exam-
Figure 25-39. Results of repetitive stimulation of the ulnar ple, the CMAP obtained at rest may be 500 p.V. In the 3-5 min-
nerve during recording of CMAPs from the flexor carpi uinaris muscle utes after 1 minute of exercise, the CMAP amplitude may
in a patient with LEMS. A, A supramaximal response elicits a CMAP decline from normal to lower than 500 p,V. Rarely, postactiva-
with a low amplitude. B, Immediately after exercise there is a dramatic tion exhaustion may last for up to 20 minutes.368 There is no cor-
increase in the size of CMAP from the same muscle. C and D,Typical relation between patients with respect to severity of disease and
decremental response noted at 2 and 3 Hz, respectively. E, G, and H, magnitude of decrement, increment, or amplitude of the CMAP
Decrement in the CMAP magnitude prior to (E), immediately after at rest. In other words, patients with a CMAP amplitude of 300
(G), and 4 minutes after a brief period of 50 Hz stimulation. F, JJ.V at rest that increments to 8 mV do not have more or less
Incrementing response recorded during a train of 50-Hz stimuli.The severe disease than patients with a resting CMAP of 1 mV that
0.5 mV calibration applies to C, D, and E, whereas the I mV calibration increments to 6 mV after brief periods of exercise.
applies to F, G and H. (From Oh SJ: Electromyography: Neuromuscular Over the next 20-30 minutes after 1 minute of exercise the
Transmission. Baltimore, Williams & Wilkins, 1988, with permission.) decrement slowly approaches the resting level. The facilitation
is a true facilitatory response and not a result of pseudofacilita-
Autonomic Neuropathy Evaluation. As noted above, many tion, which may reach 30-50% in normal persons. The differ-
patients with LEMS have clinical symptoms and signs of an au- ence is that LEMS is associated with an increase not only in
tonomic neuropathy. In a large series of 30 patients with LEMS, CMAP amplitude but also in area. Instead of exercise, it is pos-
autonomic testing revealed the following frequencies of abnor- sible to apply high rates of repetitive stimulation of 20 Hz or
mal tests: sudomotor function, 83%; cardiovagal reflexes, 75%; more. This technique allows direct observation of a dramatic
salivation, 44%; and adrenergic function, 37%.737a and serial increase in the CMAP amplitude from the abnormally
Motor Nerve Conduction Studies and Repetitive Stimulation. small to normal CMAP range (Fig. 25-39). High rates of repeti-
Motor nerve conduction velocities and distal latencies are tive stimulation may be necessary in patients who cannot coop-
normal unless the patient has a coexistence peripheral neuropa- erate with the examination because of profound weakness.
thy (see Table 25-11). H-reflexes may be absent on initial at- However, this procedure can be rather uncomfortable and ac-
tempts at elicitation, but after contraction of the muscle the complishes no more than a brief period of exercise. In patients
potential may be significantly easier to obtain.126-458-708 F-waves with severe disease in whom high rates of stimulation are used
occasionally have been reported to be larger than anticipated, in an attempt to demonstrate an incrementing response, it is pos-
although the reason is unclear.391 sible to observe a decrementing response if only a few seconds
The amplitude of the CMAP is another matter. LEMS is asso- of stimuli are delivered. In such cases, it may be necessary to
ciated with a marked reduction in the CMAP amplitude (Fig. stimulate at 20-50 Hz for up to 10 seconds to appreciate fully
25 - 39) 106 * 1 79.264.392.446.492.518.519.587a,613,640.705,706,714.715.7! 8,727,806.820,859.
the incrementing effect.
If LEMS is suspected but cannot be proven electrodiagnosti-
with \q seC onds of exercise, repeat stimulation of
942,943,947,951,953 cally or by the presence of voltage-gated calcium channel anti-
the nerve elicits an increment in the CMAP amplitude due to bodies, it may be worthwhile to repeat nerve conduction studies
postexercise facilitation. In a study of 73 patients with LEMS at regular intervals over the next several months.104-861 Such pa-
(42% with lung cancer), the CMAP amplitude was reduced in tients may have a only a mild decrement at low rates of stim-
the abductor digiti minimi in 95%, in the abductor pollicis in ulation and only a moderately reduced CMAP at rest with
85%, in the extensor digitorum brevis in 80%, and in the trapez- mild to moderate increases in CMAP amplitude after facilita-
ius in only 55%. 943 After maximum voluntary contraction for tion or high rates of stimulation because of mild, early dis-
10-15 seconds, an increase in the CMAP amplitude over 100% ease. Of importance, normal people may have up to a 50%
from the baseline recording was noted in the ADM in 77%, in increment in CMAP amplitude after brief exercise secondary
the APB in 62%, in the EDB in 59%, and in the trapezius in
to pseudofacilitation, and patients with mild LEMS may have pattern at maximal effort demonstrates low-amplitude poten-
only a small increment secondary to either early disease or pro- tials. With continued contraction the amplitude of the interfer-
found end-stage disease.713 ence pattern increases toward a more normal-appearing size. In
The above repetitive stimulation findings can be adequately addition to alterations in the interference pattern with sustained
explained if the basic pathophysiology of reduced quantal re- muscle contraction, the instability in motor units decreases.
lease per nerve stimulus is considered. On a single supramaxi- Carefully observing a single MUAP over time may reveal not
mal peripheral nerve stimulation, the excited muscle previously only an increase in amplitude and less amplitude variability but
at rest generates an abnormally small CMAP. This markedly re- also an increase in duration and reduced number of phases.
duced CMAP amplitude is a direct result of subthreshold EPP Single-fiber Electromyography. Both volitional and stimu-
production at multiple fibers composing each motor unit within lated SFEMG evaluations of patients with LEMS are abnormal
the muscle. Repetitive stimulation at 2-3 Hz results in the antic- (see Table 25-11). 179.392.446.613.727.859.947.951.953G i v e n t h e s m a l l
ipated sequential reduction in quanta released per endplate. At CMAP amplitude after a single stimulus at rest and the CMAP
NMJs with EPPs just above the muscle fiber's threshold level, with low rates of repetitive stimulation, one may anticipate the
NMJ blockade increases as the tenuous safety factors at border- SFEMG results. The CMAP decrement implies a reduced safety
line EPPs begin to fail. The result is a decrementing CMAP. factor with borderline EPPs that are induced to fail with sequen-
After stimulation at 20-50 Hz for several seconds or maximal tial stimulations. This tenuous NMJ transmission suggests that
exercise for approximately 10 seconds, the generation of resid- there should be significant variability in the EPP rise times per
ual calcium greatly enhances the release of calcium toward NMJ. Indeed, the jitter in patients with LEMS is significantly
normal or higher values, thus creating EPPs with significantly elevated. The jitter elevation is statistically increased above that
increased safety factors. Many of the NMJs that previously observed in myasthenia gravis. In addition, essentially all NMJs
failed to produce a single muscle fiber action potential now do examined, regardless of muscle, reveal markedly abnormal
so. Thus an increased CMAP amplitude is generated and the jitter, whereas in myasthenia gravis the spectrum of jitter values
jdecrement seen on low rates of repetitive nerve stimulation is ranges from normal to highly abnormal within the same motor
repaired. This facilitation is short-lived because of reduction in unit as well as from muscle to muscle. The jitter in patients with
calcium facilitated quantal release. In addition to the return LEMS, however, does not depend on the degree of weakness in
toward the baseline state, postactivation exhaustion now pre- a particular muscle.
dominates because of the lag necessary for mobilization to re- The small CMAP suggests that single peripheral nerve exci-
store completely the immediately available store of ACh. The tation fails to elicit an action potential from a large number of
reduced calcium facilitation creates the abnormally small muscle fibers composing the majority of the muscle's motor
CMAP, whereas the reduced ACh stores, combined with cal- units. With routine needle EMG examination of motor units,
cium-mediated decreased safety factors, produces the decre- failure of NMJ transmission is reflected as MUAPs with de-
ment in addition to a CMAP smaller than baseline value. After creased amplitudes and durations as well as possibly increased
20-30 minutes the resting state is again achieved. numbers of polyphasic potentials. The intermittent failure of
Needle Electromyography. Insertion of the needle EMG EPPs to reach threshold generates the MUAP's variable shape
recording electrode results in normal to slightly reduced inser- with consecutive firings. MUAP variability results from in-
tional activity (Table 25-11). Positive sharp waves and fibrilla- creased blocking at the SFEMG level. Some of the highest per-
tion potentials are usually absent in patients with LEMS.106-179- centages of documented blocked potentials occur in LEMS.
264.392.518.519.640.705.806 However, minor membrane instability of this In addition to an increase in jitter and blocking, an alteration
type may be observed. Abnormalities of motor unit action po- is observed in the jitter and blocking that is frequency-depen-
tential (MUAP) morphology are certainly apparent in weak dent. Specifically, at low rates of voluntary firing (e.g., 5-10
muscles, if carefully assessed, in LEMS. Diminished numbers Hz) jitter and blocking can be quite impressive. Asking the pa-
of muscle fibers firing in response to nerve terminal depolariza- tient to increase the rate of motor unit firing to 20-30 Hz results
tion because of a reduced safety factor result in fewer muscle in a reduction of the jitter value as well as a decrease in the
fibers per motor unit. A reduction in active muscle fibers per number of blockings. An attempt can be made to quantify these
motor unit results in the shorter durations and smaller ampli- observations by using stimulation SFEMG. 141 -451.820.949,950
tudes of the MUAPs. Additionally, fewer active muscle fibers Stimulating an intramuscular neural branch and recording from
produces less overlap of electrical activity, thus increasing the the ensuing single muscle fiber potentials allows the ability to
possibility of polyphasic MUAPs. Muscle fibers within the measure jitter relative to the instrument's shock artifact. One
motor unit with borderline EPP magnitudes with respect to study of LEMS patients demonstrated that the jitter decreased
threshold level have a tenuous ability to fire with each neural from a mean of 150 \is at a stimulation rate of 2 Hz to about 90
depolarization. The result is random firing and dropout of JIS at a firing rate of 15 Hz.951 Similarly, when the stimulus fre-
muscle fibers responding to each nerve stimulus. Thus each quency is changed from 2 Hz to 15 Hz, the percent of blockings
MUAP has a different number of muscle fibers per discharge, noted decreases from 70% to fewer than 10%. These findings
and alteration in morphology is reflected primarily as MUAP are understandable if one considers the normal NMJ's response
instability. Reducing the sweep speed while having the patient to a decrease in the interstimulus interval (i.e., high rates of
activate only one or two MUAPs permits the practitioner to ob- stimulation). When the stimulus frequency is increased, residual
serve the sequential firing of the MUAPs, which manifest a con- calcium is left in the nerve terminal because of an overwhelm-
stantly changing amplitude. Close inspection of a single MUAP ing of the terminal's sequestration and binding capacity for free
with a trigger and delay line can demonstrate alterations not calcium. This increased calcium, therefore, acts to increase the
only in amplitude but also in phases and duration. probability of ACh vesicle release. In normal NMJs, increased
Some patients exhibit early recruitment; that is an increased ACh has no effect because all EPPs are suprathreshold. In
number of MUAPs is activated (each firing at an appropriate LEMS, however, NMJs with borderline or subthreshold EPPs
frequency) for a mild degree of measured effort. The "interference" are facilitated to release more ACh, thereby increasing the
safety factor. The increased ACh not only increases the EPP ab- of postactivation facilitation is also prolonged at reduced tem-
solute magnitude and exceeds threshold, thereby reducing the peratures. The mechanism of NMJ repair at lower temperatures
degree of blocking, but also increases the rise times of the indi- is not fully known, but probably results from a number of fac-
vidual EPPs per NMJ. This effect decreases the inter-EPP vari- tors that act in concert (see above). The important point in ex-
ability and thus reduces the jitter. Intermediate stimulation rates amining patients suspected of having LEMS is the same as for
of 5-10 Hz also reduce jitter and blocking. all potential NMJ disorders: maintain a warm surface limb tem-
The above finding at different stimulation rates with respect perature (> 32-33°C) during the duration of the electrophysio-
to jitter and blocking is somewhat distinct from that recorded in logic examination.
patients with myasthenia gravis. Increasing the stimulation fre- Treatment. Patients with LEMS, as documented by history,
quency from 0.5 Hz to 10 Hz produces a progressive elevation physical examination, and electrodiagnostic medicine evalua-
of mean jitter values from about 100 jis to 150 jis.951 Similarly, tion, should undergo an immediate and thorough investigation
the degree of blocking increases from a mean of roughly for underlying carcinoma, particularly involving the thoracic
10-15% over the same stimulation frequency range. Between cavity (i.e., small cell lung cancer). When a tumor is identified,
10 Hz and 20 Hz, however, the jitter falls from a mean of 150 jis it should be removed if at all possible, especially if the patient's
to 90 JIS and the percentage of blocking is reduced from 10% to condition warrants aggressive intervention. After tumor removal
about 5%. The increased jitter and blocking at stimulation rates and appropriate chemotherapeutic interventions, a number of
below 10 Hz result from the normal running down of available patients recover quite well from the muscle symptoms and
ACh in immediately available stores. Thus the safety factor de- demonstrate improved electrophysiologic studies. The CMAP
creases and variability of EPP generation increases, generating amplitude at rest increases and the decrement decreases.
a higher number of blocked potentials and increasing mean Additionally, jitter and blocking improve. In patients with no
jitter values. At stimulation rates above 10 Hz, facilitation, aug- definable tumor, careful observation and serial evaluations are
mentation, and potentiation come into play secondary to resid- necessary to ensure the earliest possible identification of tumor
ual calcium and enhance the probability of ACh release. The appearance.
increased stimulation frequencies repair the previous jitter and In patients with paraneoplastic LEMS, muscle strength may
blocking, which is the basis for postactivation facilitation. improve with tumor removal, radiation therapy, and chemother¬
Therefore, simply comparing a low and high rate of stimulation a py j n patients with and without tumor, a number of
i37.387.943
does not allow one to distinguish patients with myasthenia therapeutic medications can assist with the symptoms of weak-
gravis from patients with LEMS. Although the average degree ness and fatigue.634-752-884 In most cases, the medication must be
of jitter and blocking is statistically different between the two given on a long-term basis and is directed at two general aspects
patient populations, for any given patient they may look quite of physiology: (1) increasing the safety factor for NMJ trans-
similar in terms of degree of jitter and blocking, depending on mission and (2) suppressing the autoimmune response.
the severity of the disease. The difference is in the overall pat- Anticholinesterase medication, for example, can be tried in
tern of jitter and blocking as one increases the stimulus fre- LEMS to increase the amount of ACh in the NMJ.106-392'5,8'58°-609-
quency from roughly 1 Hz to 20 Hz. Patients with myasthenia Equivocal or minimal to moderate improvements can
705.706.708.943
gravis reveal a gradual increase in jitter and blocking until fre- be noted in CMAP amplitude after Tensilon injection. A
quencies greater than 10 Hz are reached. On the other hand, pa- 50-100% increase in amplitude can be seen in the CMAP.
tients with LEMS demonstrate a continuous decline in both Additionally, the difference between the resting CMAP value
jitter and percent blocking. This type of pattern recognition may and the value after maximal exercise or high rates of stimulation
be of value in attempting to distinguish electrophysiologically is less. We generally treat patients with mestinon, 60 mg 4-5
between the two diseases in questionable cases, although one times/day, as in patients with myasthenia gravis. However, in
must be expert in the technique of SFEMG, which may limit its our experience the response is variable and often modest in
practicality. Additionally, caution must be exercised in attempt- comparison with myasthenia gravis.
ing to apply this method too rigorously because of the potential The amount of ACh released per neural stimulation can be j
variability at different NMJs in patients with myasthenia gravis boosted by administering guanidine, which is believed to pro- I
and LEMS. 834 When the percent blocking increases, the relative long the action potential at the nerve terminal, thereby allowing
assurance of accurate jitter measurements declines. The muscle entry of more calcium and facilitating an increase in quantal
fiber action potential propagation velocity also changes, with content.I06J47-392-943 Although this medication may be successful
increasing rates of stimulation that tend to elevate jitter values. from the neuromuscular standpoint, there are a number of un-
The lack of a dramatic decline in jitter and blocking is not in fortunate side effects, such as bone marrow, renal and hepatic
and of itself reason to dismiss the diagnosis of LEMS if it is sus- toxicity, and gastrointestinal dysfunction.
pected on clinical grounds. The aminopyridines block voltage-dependent potassium con-
The fiber density is typically normal in patients with LEMS ductance, thereby prolonging nerve terminal depolarization and
and no other paraneoplastic effects, resulting in dysfunction of facilitating ACh release. 4-Diaminopyridine can be effective in
the peripheral nervous system. In people with a peripheral neu- improving muscle strength, but its use is limited by the in-
ropathy or axonal damage secondary to direct tumor invasion or creased incidence of central side affects (e.g., seizures, agita-
paraneoplastic effects, the fiber density may be mildly to mod- tion, and confusion).578-579-681-828 A related medication with
erately elevated. limited central nervous system side effects is 3,4-diaminopyri-
Temperature Effects. In patients suffering from LEMS, the dine (3,4-DAP). Several studies report clinical and electrophys-
degree of electrophysiologic abnormalities is directly affected iologic improvement in LEMS with 3,4-DAP.492-580-58,-587a-633-696a-
by variation in muscle temperature.797-979 A decrease in muscle 82o.838.943^ recently published randomized, prospective, placebo-
temperature improves the absolute CMAP amplitude at rest. controlled trial of 3,4-DAP in 26 patient with LEMS (paraneo-
Additionally, the degree of decrement at low rates of stimula- plastic and nonparaneoplastic) revealed improvement in
tion is less than at relatively higher temperatures. The duration strength and summated CMAP amplitudes.838 The starting dose
was 20 mg 3 times/day and was adjusted gradually to achieve necessarily pathogenic in patients with LEMS and may repre-
maximal benefit. The medication appears to be well tolerated, sent only an epiphenomenon. 483 - 543 Nonetheless, rare patients
with a few patients experiencing perioral and acral paresthesias. may exhibit features of both LEMS and myasthenia gravis. In
Doses should not exceed 80 mg/day because higher doses may such difficult cases, it may be necessary to obtain microelec-
result in seizures.838 3,4-DAP is not yet approved by the FDA. trode studies of intercostal or anconeus muscle preparations to
However, the medication can be obtained on a compassionate- define the NMJ disorder more clearly. Obviously these investi-
use basis for patients with LEMS. gations are not routinely available, and patients may need to be
The second approach is to attempt immunosuppression with referred to specialized centers. Continued investigation into this
corticosteroids or azathioprine.495-633-693-912-913 These drugs must potentially unique disorder is required to elucidate more fully
be given over a long period, and although they are of benefit, re- the underlying pathophysiology. Care also must be taken not to
lapses occur on withdrawal. Dosing is similar to that described confuse mild LEMS associated with less than fulminant electro-
for myasthenia gravis. physiologic findings and overlap syndrome.
Unlike myasthenia gravis, thymectomy has no role in the
treatment of LEMS. Plasmapheresis may be helpful in patient Botulism
with LEMS, but the effect wears off after a few weeks and treat- Botulism is a serious and potentially fatal disease caused by
ment must be repeated.190-206208'507'693-696a-943 Both clinical and one of several protein neuroexotoxins produced by the bac-
electrical improvement in CMAP amplitudes at rest as well as terium Clostridium botulinum. The term "botulism" is well
after exercise or high rates of repetitive stimulation may be seen known by the general public because of the occasional well-
following plasmapheresis. 190,206 The peak response is observed publicized illnesses and fatalities associated with contaminated
by about 2 weeks after treatment with a diminution in effective- food served at particular restaurants or home-canned vegetable
ness by the end of 3-4 weeks. As in myasthenia gravis, plasma- products. Unfortunately, because of its relative rarity, disease is
pheresis is a temporizing measure. Patients need the addition of considered low on the list of potential differential diagnoses in
an immunosuppressive agent if a response is to be sustained. patients presenting to community emergency facilities or local
IVIG has been beneficial in small, uncontrolled series of pa- urgent care centers.
tients with LEMS. 72-793'943 Dosing is similar to that outlined for Five clinical forms of botulism have been described: (1) clas-
myasthenia gravis. Prospective, double-blind, controlled trials sic or food-borne botulism, (2) infant botulism, (3) hidden botu-
are necessary to assess efficacy more accurately. lism, (4) wound botulism, and (5) inadvertent botulism.150 The
term "botulism" is derived from the Latin word for sausage
Myasthenia Gravis—LEMS Overlap (botulus) because one of the outbreaks was due to sausages
A small number of patients present quite a diagnostic chal- tainted with botulinum toxin.185 The eight immunologically dis-
lenge. Patients may present with a history and physical exami- tinct types of botulinum neurotoxin (BTX) are designated al-
nation consistent with either or both myasthenia gravis and phabetically in order of discovery: A, B, CI, C2, D, E, F, and
LEMS, thus defining a so-called overlap myasthenic syn- G.824 Types A, B, and E, account for most reports of food poi-
drome.84-1 86-312.632,860.876.934 p a tients may have oculobulbar symptoms soning, but D, F, and G have been responsible for a few
that respond nicely to a short-acting anticholinesterase, suggest- deaths.891 Type C affects animals, not humans. Although BTX is
ing myasthenia gravis. However, they also have depressed deep most potent at the neuromuscular junction, it also inhibits ACh
tendon reflexes, which may improve with brief periods of vol- release from pre- and postganglionic nerve endings of the auto-
untary muscle contraction. Antibody testing to AChRs is usu- nomic nervous system.161
ally positive, although the titers may vary widely from Obvious public health issues have prompted the Center for
borderline abnormal to clearly elevated. Electrophysiologically, Disease Control and Prevention (CDC) to maintain a nation-
the resting CMAP is relatively reduced; low rates of stimulation wide surveillance program for all forms of botulism. This pro-
result in a decrementing response; and a dramatic increase is gram is maintained by the classification and cataloging of cases
noted in the CMAP amplitude with exercise as well as decre- when requests are received for botulinum antitoxin. A potential
mental repair. Postexercise exhaustion may or may not be obvi- patient is classified as having botulism if the reported illness has
ous. In patients with "typical" myasthenia gravis, significant neurologic manifestations of descending paralysis and clear
elevations in the CMAP amplitude after rapid rates of repetitive sensorium associated with one of the following: identification
stimulation compared with resting values may represent overlap of C. botulinum in the stool or wound; documentation of botu-
syndrome. Routine needle EMG examination demonstrates linum toxin in the serum, wound, stool, or portions of suspected
MUAPs suggestive of a "myopathy" with successive MUAP contaminated food; or a clinical presentation compatible with
variation that improves with voluntary contraction. Single-fiber other reported cases of food-borne illness.
EMG reveals abnormalities similar to those found in LEMS, i.e. Classic or Food-borne Botulism. Perhaps the earliest de-
markedly abnormal jitter and significant blocking that improve scription of an outbreak of food-borne botulism occurred as
with increases in firing rate. These electrophysiologic abnor- early as 1897 when members of a music club became ill and
malities also improve with guanidine administration. SFEMG several died as a result of eating contaminated ham.964 Of im-
studies can reveal improvements in jitter and blocking in both portance is the recognition that food-borne botulism is not an
myasthenia gravis and LEMS and may not be a good test for infection but an intoxication secondary to the consumption of a
categorically distinguishing between the two or defining an toxin in the consumed food. Over the 78 years from 1899 to
overlap patient. 1977 in the United States, 766 outbreaks of food-borne botu-
Most cases of myasthenia gravis overlapping with LEMS are lism were reported.134 From 1976 to 1984 124 outbreaks were
based on the presence of anti-AChR antibodies in a patient who reported. 585 Roughly two-thirds of these cases affected only a
clinically and electrophysiological^ has LEMS. As noted single person, but the mean number of persons per outbreak is
above, as many as 13% of patients with LEMS also have 2.7. Approximately 54% of patients are male, and the median
AChR-binding antibodies. 543 The anti-AChR antibodies are not age of all patients is 44 years. Reported incidence rates suggest
that the top three states are Alaska (8.6/100,000), Washington consumption of a preformed toxin.32,34-150,766,853 Spores produced
(0.43/100,000), and Oregon (0.41/100,000).585-977 by the C. botulinum inadvertently enter the infant's intestinal
In the United States BTX A accounts for about 60% of re- tract, germinate, colonize the region, and then produce the toxin,
ported cases, whereas BTX B is responsible for 30% of cases which is absorbed through the intestinal lumen. Infant botulism is
and BTX E for only 10%. Of interest, the majority of BTX A in- considered a unique manifestation of botulism because infants
toxication occur west of the Mississippi River, whereas BTX B and children less than 1 year old (particularly those younger than
cases tend to cluster east of the Mississippi River, particularly in 6-8 months) are especially prone to developing the disease. There
the Atlantic states.882,883 This geographic association is due to is little doubt that children older than 1 year and adults commonly
the prevalence of specific toxin-producing organisms found in ingest small quantities of botulinum spores simply because of its
the soil. The BTX E outbreaks are primarily, but not exclusively, ubiquitous nature on essentially any food product grown in the
found in Alaska and believed to be secondary to the consump- soil. Why, then, are young children so susceptible to the ingestion
tion of particular fish or marine mammals colonized by BTX re- of spores? The answer is unknown, but a postulate has been ac-
producing organisms. The method of transmitting the botulinum cepted as the probable explanation.358-986 A number of infants less
toxin is usually through poorly prepared home-canned vegeta- than 6 months and occasionally between 6 months and 1 year of
bles. Outbreaks of botulinum toxin associated with restaurants age are preferentially breast-fed. As a result, the gut flora are be-
account for a small portion of the total number of outbreaks but lieved to be relatively inhospitable to the growth of botulinum
tend to involve larger numbers of people. spores compared with infants receiving formula. Infants consum-
The number of fatalities resulting from food-borne botulism ing formula may succumb to the toxin relatively quickly com-
has declined from about 50% before 1950 to approximately pared with a less florid manifestation in breast-fed infants.
7.5% from 1976-1984. 134,585 This decline in mortality is no Breast-fed infants survive long enough to develop multiple clini-
doubt a direct result of heightened physician awareness, im- cal manifestations suggesting a problem, whereas formula-fed in-
provements in the delivery of prompt emergency care, expedi- fants expire over a short period, thus accounting for the higher
tious institution of mechanical ventilation, and possibly the incidence of disease among breast-fed infants. Some investigators
administration of antitoxin in early diagnosed cases.32,150,865,930 have suggested that infant botulism may be one of the causes for
Patients over 60 years of age are particularly prone to more seri- so-called sudden infant death syndrome (SIDS).30-763-890 However,
ous complication, possibly less complete recovery, and certainly a large 10-year study involving 248 cases of SIDS did not find a
a higher mortality rate.133,498,929 People who are the first or only single case attributable to infantile botulism.121
affected patient in an outbreak have a reported 25% mortality Epidemiologic studies reveal a risk for botulism in infants
rate compared with people who develop symptoms subse- consuming honey. 31 BTX B-producing organisms are more
quently. The reason is unknown but may be related to a shorter common than BTX A bacteria. As many as 25% of tested honey
incubation period, greater consumption of toxin, or possibly a products contain clostridial spores. 853 As a result, honey should
low index of suspicion for botulism with the first patient. Once be avoided in infants. The organism also has been found in
the diagnosis is made, other patients presenting with similar vacuum cleaner dust in the homes of affected patients as well as
symptoms are recognized more quickly. in dust around new construction sites.
No doubt the best method of dealing with botulism is preven- Hidden Botulism. Hidden botulism is believed to be a form
tion through proper public education. People canning their own of "infantile" botulism in people over the age of 1 year.150-550-930
foods should use properly manufactured jars with containment Patients have a typical clinical presentation suggestive of botu-
seals as well as a pressure cooker to kill botulinum spores. Of linum intoxication with supportive laboratory findings but do not
importance, the bacterial spores are resistant to heat and may have an obvious food or wound source for the disease. The disor-
survive home-canning techniques at temperatures below 120°C. der usually manifests in patients with intestinal abnormalities
Boiling food before canning at high altitudes (e.g., in the moun- (e.g., Crohn's disease, gastrointestinal surgery) that allow colo-
tains) may not provide sufficient heat to kill the spores. Foods nization by C. botulinum.*51-m**5 The combination of a gastroin-
also should be acidified with vinegar, thus ensuring a pH less testinal disorder and antimicrobial administration may be
than 4.6, which is known to inhibit the growth of C. botu- predisposing factors by altering the normal intestinal flora.52120-661
linum.930 Of note, boiling quickly inactivates the toxin produced Normal flora, in turn, are believed to have an inherent ability to
by the bacteria, but this process can drive off oxygen, thereby suppress C. botulinum growth, as documented in animals.
favoring an environment conducive to bacterial growth. Hence a Colonization of the gut by C. botulinum may lead to the in vivo
pressure cooker is recommended to kill the heat-resistant production of the toxin.229,605 The most common serotypes in-
spores. Any home-canned food should be boiled before serving volved are A and B, although in rare cases F is responsible.714
to ensure toxin inactivation. Any person suspected of being in- Wound Botulism. The infection of a wound by C. botu-
toxicated should receive immediate medical attention and be re- linum with subsequent production of toxin in vivo defines
ported to the CDC. wound botulism.119-,50-,92-375-4°9-512-585-603-618 The toxin is produced
Infant Botulism. Infant botulism is the most common form in the wound site as opposed to the gastrointestinal tract. Of all
of botulism in the United States with an incidence of 1/100,000 forms of botulinum intoxication, wound botulism is the most
live births. 33 The mortality rate among recognized infants in- rare. However, reports of wound botulism have increased in IV
fected with botulinum spores is under 4%. 991 The most common drug abusers.618 The typical insult is some type of focal trauma
types of botulinum intoxication involving infants are BTX A to a limb with or without a compound fracture. BTX A is more
and BTX B with occasional reports of BTX E and BTX F, par- often the offending agent, but type B also has been impli-
ticularly in Europe. cated. 646 A mortality rate of 12.5% is associated with the dis-
The basic mechanism of symptom production in infants is ease. Of particular interest is the emergence of a new
different from that in patients with food-borne botulism. In in- association between illicit drug use and botulism.491-584 Needle
fants, the pathophysiology involves an enteric bacterial infec- injection sites and maxillary sinusitis related to nasal sniffing of
tion with subsequent BTX production in vivo as opposed to cocaine have been implicated.
Inadvertent Botulism. Iatrogenic causes are responsible for with an occasional asymmetry noted. Deep tendon reflexes may
inadvertent botulism, the most recent form.150 BTX is now com- be normal or diminished initially, with progression to complete
monly used to treat focal dystonias and other movement disor- loss in severely affected patients.
ders (see Chapter 13). Rarely patients may develop distant or It is important to measure pulmonary functions. Forced vital
generalized weakness after focal injections of BTX.27-44 capacity is reduced in most cases, and ventilator support eventu-
Autonomic dysfunction also has complicated therapeutic BTX ally is required in 32-81% of patients.226-854 The duration of me-
injections. 340 Additionally, SFEMG studies in patients treated chanical ventilation depends on the severity of the illness and
with focal BTX injections have demonstrated increased jitter serotype of the infecting organism with a mean of 58 days for
and blocking at muscle sites distant from injected mus- type A and 26 days for type B.226854
cles.529-726-830 Abnormalities on muscle biopsies also have been Careful examination can reveal disturbances of autonomic
shown at distant sites.44 The mechanism is probably hematoge- function affecting both sympathetic and parasympathetic sys-
nous spread of the toxin. tems. Specific examples include loss of vagal cardiac control,
Clinical Features. Adult Form. The clinical presentation of ileus, hypothermia, and urinary retention, possibly requiring
botulinum intoxication in adults is similar, regardless of whether catheterization. Hypotension without tachycardia also may be
the disease is acquired through the food-bome, wound, or hidden present, along with a lack of vasomotor responses to postural
route. The food-borne and hidden forms are discussed first be- change. In addition, pupils are often poorly reactive to light. In
cause the number of reported cases permits a more thorough dis- cases of suspected wound botulism, the integument should be
cussion of the symptoms. Despite minor statistical differences in searched carefully not only for gross disruption and wound con-
the most common presenting symptoms for BTX A and BTX B tamination but also for apparently minor bruises with or without
intoxication, in individual patients these differences are inconse- signs of infection. These areas should be cultured for anaerobic
quential. Symptoms can be considered from three general cate- organisms. The nasal mucosa also should also be evaluated
gories: neurologic, gastrointestinal, and miscellaneous. carefully.
I A number of neurologic symptoms are quite characteristic of Infant Form. In infants, botulinum intoxication can manifest
botulinum intoxication. Patients develop dysphagia, dry mouth, with an entire spectrum of disease from mild symptoms to
diplopia, and dysarthria, which begin rather acutely and sudden death. A relatively constant complaint voiced by most
progress over the course of 12-36 hours. The time depends in parents, in addition to neurologic manifestations, is several days
part on the amount of toxin consumed. A careful history may of constipation. Occasionally, this may be the only presenting
document involvement of the upper cranial nerves before nerves symptom, particularly in mild forms of intoxication. Most par-
located more distally in the brainstem. Over the same period, ents, however, bring the child to a physician for more severe
gastrointestinal symptoms of nausea, occasional vomiting, and symptoms. The child may appear listless with diminution in
initial diarrhea followed by constipation may occur just before spontaneous movements. Parents may note that the child has a
or coincident with the cranial nerve symptoms. Associated com- poor ability to take in nutrition secondary to diminished suck. In
plaints of abdominal cramps, undue fatigue, and dizziness also more severe forms of the disease, the child has a diminished
may be described during the disease's evolution. After symp- tone throughout and appears as a "floppy baby." Excessive
toms manifest, patients develop progressive weakness, affecting drooling accompanied by a weak cry is particularly worrisome,
first the upper and then the lower limbs. The patient may begin for both parents and physician.
to notice shortness of breath before limb involvement. It is spec- Overall, the child may appear lethargic secondary to dimin-
ulated that the cranial muscles are affected before the limb mus- ished tonus. Ptosis and "smoothing" of facial expression may be
cles because of the higher temperature of the face. There is a noted. Repeated testing may reveal fatigue of pupillary constric-
distinct lack of sensory complaints, although an occasional pa- tion. Reduced head control and gag reflex also may be noted.
tient may note an alteration in sensation affecting either the face Insertion of a finger into the infant's mouth reveals a weak suck-
or limbs. ing action compared with healthy infants. Deep tendon reflexes
In wound botulism, the symptoms are quite similar with a may be present or diminished; with disease progression they
few modifications. The patient may relate a history of a major disappear completely.
or even minor traumatic event, although such a history may be Respiratory function should be monitored closely, because
absent, particularly in users of various illicit drugs. The disorder approximately 50% of infants require assisted mechanical ven-
should be considered in patients who are IV drug abusers. tilation. The need for respiratory assistance may be due not only
Gastrointestinal complaints of nausea, vomiting, and usually to respiratory muscle weakness but also to airway obstruction
abdominal cramps are less common than in food-borne botu- secondary to pharyngeal muscle weakness and loss of tonus.
lism. In wound botulism, other persons are not affected in con¬ Several weeks may be required before the patient shows any
trast to outbreaks due to tainted food. The period of symptom signs of recovery. Like adults, infants infected with BTX-A
development is longer in wound botulism; 4-14 days are re- toxin tend to have a more severe disease course with more time
quired for an incubation period compared with hours for toxin required for recovery compared with BTX-B intoxication.
or spore ingestion. During the recovery phase, toxin and organisms may continue
Patients usually present to the emergency department in acute to be obtained from the stool; this finding should be expected
distress with anxiety due to the evolution of symptoms. Cranial and does not indicate failure to recover. Eventually the bowel
nerve evaluation reveals ptosis, diminished gag reflex, dyspha- flora returns to normal.
gia, dysarthria, facial paralysis with loss of facial creases, diffi- Histopathology. BTX produces changes similar to those
culty in protruding the tongue or offering resistance against seen after nerve sectioning, including bouton loss, decrease in
external cheek pressure, and occasional nystagmus. Depending and retraction of dendritic profiles, and increased numbers of
on the length of time between presentation and examination, the astrocytes.921 In addition, BTX causes sprouting of motor nerve
upper and lower limbs may be involved to varying degrees. The endings from the original terminal arborizations. 242 Denervated
upper limbs are typically more affected than the lower limbs muscle may secrete a motor nerve growth-simulating factor that
induces this sprouting.390-490 Noncollateral sprouting begins because obviously it serves no offensive or defensive purpose.
from the nodes of Ranvier of the preterminal motor axon, from All of the botulinum toxins are synthesized within the bac-
the terminal axon just proximal to the endplate, and from the ar- terium and consist of two molecular moieties, a heavy (H) chain
borization over the endplate. Growth proceeds preferentially (100,000 Daltons molecular weight) and light (L) chain (50,000
along the longitudinal axis of muscle fibers.662 New NMJs are Daltons), joined together end to end. This molecule is then bent
formed and may be near the original NMJ or"at some distance. on itself to form a "U," with a disulfide bond holding it in this
New NMJ formation enlarges the endplate region and results in position. BTX folds into three functionally distinct domains.
muscle fibers with multiple endplates that may be innervated by The carboxy-terminal of the H chain binds to neuronal cells.
more than one axon. The amino-terminal H chain is implicated in membrane translo-
Electronmicroscopic evaluation of nerve terminals reveals no cation. The L chain is a zinc endopeptidase responsible for in-
obvious structural abnormalities except for an appearance of a tracellular toxic activity. After autolysis of the bacterium, the
"log-jam" of vesicles next to the nerve terminal membrane, sug- toxin is only moderately toxic. A proteolytic enzyme contained
gesting a "piling up" of vesicles prohibited from fusing with the either within the bacterium or in the organism, such as trypsin,
membrane. 467 After injection of botulinum toxin in mice, a is required to cleave or "nick" the bond joining the heavy and
number of interesting morphologic findings are noted.243-245-246 light chains end to end at the bottom of the "U," thus producing
The muscles are no longer functional from a contraction stand- two separate chains held together by the disulfide bond. The
point and are rendered "physiologically denervated," although nicking process is thought to activate the molecule into its
the nerve-muscle junction remains physically intact. In slow- highly toxic form. This form of the toxin is one of the most poi-
twitch muscle, new nerve sprouts begin to emerge from the sonous substances known in terms of quantities required to pro-
nerve terminal within 6-7 days. The muscle fibers atrophy for duce death. The minimal lethal dose in humans is estimated to
about 3-4 weeks, by which time the nerve sprouts have success- be approximately 1.4 x 10~2 |ig/kg of body weight.847
fully established new endplates. Maturation of these NMJs re- Once the toxin is present within the intestines, it is wholly ab-
sults in the establishment of normal muscle function. Similar sorbed and transported into the vasculature. If a contaminated
findings are noted in fast-twitch muscle except all phases of wound is present, the toxin is absorbed into the blood stream.
nerve terminal sprouting and new NMJ formation are delayed The net effect is hematogenous spread of the activated toxin
by an additional 4-6 weeks, thus producing significantly more throughout the body. The actual site at which the toxin produces
atrophy. Neurogenic atrophy also has been noted in humans its physiologic effects is generally localized to the presynaptic
with inadvertent27 and wound botulism. 618 portion of cholinergic neuromuscular junctions, autonomic gan-
Pathogenesis and Pathophysiology. The organism respon- glia, postganglionic parasympathetic nerves, postganglionic
sible for causing botulinum intoxication is a gram-positive sympathetic nerves, and adrenal glands.355-356 Of particular con-
(gram-negative with maturation), spore-forming, rod-shaped cern for this discussion is the neuromuscular junction, which
bacterium. This bacterium is only one of more than 100 anaero- accounts for the profound weakness and associated morbidity
bic species belonging to the genus Clostridium.mM*%n C. botu- and mortality.
linum is divided into four major groups based on their ability to The general pathogenic mechanism of the various types of bot-
digest proteins (proteolytic) or breakdown sugars (saccha- ulinum toxin is now appreciated (see Chapter 13).3S5,363,873,874,875
rolytic). Group I bacteria are both proteolytic and saccharolytic Cell intoxication by BTX is a four-step process: (1) cell binding,
and include all strains capable of producing BTX A as well as (2) internalization, (3) membrane translocation, and (4) target
several strains able to produce BTX B and F. Group II bacteria modification in the cytosol.665 BTX receptors are located on the
are nonproteolytic but saccharolytic and include all strains gen- motor neuron plasmalemma at the neuromuscular junction.
erating BTX E toxin as well as other strains that produce BTX Sialoglycoproteins are the candidates for toxin-specific recep-
B and F. Group III organisms are nonproteolytic but can digest tors.45 Each serotype is believed to have a unique receptor.161701
gelatin and produce BTX C and D. Group IV consists of only The H chain acts first as a binding protein through a ligand-
one organism that is proteolytic but not saccharolytic; it is des- receptor action, which attaches to specific receptor sites on the |
ignated as BTX G. All of the toxin-producing strains appear presynaptic portion of the nerve terminal. After binding to the I
morphologically similar and cannot be differentiated by any nerve membrane the toxin becomes internalized by receptor-
means other than biochemical (proteolytic/saccharolytic) and mediated endocytosis. After internalization, the L chain pack-
antigenic (toxin type) methods. Most organisms, regardless of aged in endosomes is moved across the endosomal membrane
strain can produce only one type of toxin, but a few have the ca- into the cytosol. The amino-acid terminal of the H chain is
pability to generate small quantities of a secondary toxin type. thought to form transmembrane ion channels at acidic pH, al-
Of interest, all C. botulinum organisms are "infected" with a lowing passage of the L chain and at least part of the H chain
bacteriophage (viral genetic material incorporated into the bac- into the cytosplasm. 3,3849 At low temperatures there is little if
teria's genetic substance). This bacteriophage has been shown any transport of toxin into the nerve terminal. In addition, at
to have a direct role in the eventual production of toxin in BTX normal temperatures substantially more toxin is transported into
C-producing organisms but not in other toxin-producing types, the nerve terminal if the terminal is stimulated to release ACh
as of yet. If the bacteriophage is eventually implicated in the compared with a terminal that is relatively inactive. Clinically,
production of toxin affecting humans, it may be possible to active nerve terminals result in a more rapid toxin effect. Both
direct treatment toward rendering the organism nontoxic low temperatures and minimal activity serve to minimize synap-
through immunologic means. Plasmids (genetic material within tic vesicle fusion with the nerve terminal membrane, whereas
the cell but not directly incorporated into the host genetic sub- elevating temperature and activity have the opposite effect.
stance) also have been detected in C. botulinum organisms. Activity or elevations in temperatures are thought to cause
Their role in toxin production is unclear. synaptic vesicle fusion, which in turn promotes the reformation
The toxin produced by the organism is released only after the of vesicles by endocytosis of new membrane. The toxin bound
cell has undergone lysis. This finding is somewhat puzzling, to the membrane is thought to be transported into the nerve
terminal by way of the formation of new synaptic vesicles be- motor nerve conduction velocities.631-709-958 Again, the exact
cause it is bound to the membrane. Newly formed synaptic vesi- mechanism of this slowing is unknown. The major abnormality
cles are known to have a membrane-bound proton pump that of motor conduction in patients with botulism is reduced CMAP
decreases the internal pH (increases acidity) of the vesicle com- amplitudes.6183 The CMAP amplitudes are usually on the order
pared with the nerve terminal's cytoplasmic pH. Lowering the of several millivolts and thus not as reduced as in patients with
pH is believed to cause the heavy chain portion of the toxin LEMS. The amplitudes may even be found to be in the normal
either to create a large opening in the vesicle or to lyse a portion range in clinically affected muscles. 7393 The normal range for
of the vesicle's wall, thus releasing the whole toxin into the ter- motor amplitudes is rather large. Although an individual patient
minal's cytoplasm. may have a "normal" amplitude compared with statistically de-
Several distinct SNARE proteins are necessary for docking rived reference data, the amplitudes are probably indeed re-
and fusion of ACh synaptic vesicles in the motor nerve termi- duced compared with baseline values before intoxication with
ng] 665.850,855.965 j n e toxic intracellular activity of the different BTX. Furthermore, like most diseases, botulism is a progressive
forms of BTX are mediated by zinc-dependent specific pro- disease despite its relatively acute clinical presentation. It is not
teases, which target these specific polypeptides. 8093 BTX B, D, uncommon for patients examined relatively early after symp-
F, and G specifically recognize and cleave vesicle-associated tom onset to demonstrate normal CMAP amplitudes.7037393 Over
membrane protein (VAMP)/synaptobrevin). BTX A, D, and E the next several days to weeks, however, the CMAP amplitude
cause specific hydrolysis of SNAP-25 (synaptosomal-associ- may decline to unquestionably small values as neuromuscular
ated protein of 25 kDa), whereas BTX C cleaves syntaxin. junction blockade progresses. As with LEMS, 10 seconds of ex-
BTX D and F also cleave cellubrevin. BTX does not cleave ercise may result in an increase in CMAP amplitude (postexer-
short polypeptides containing the cleavage site of the target pro- cise facilitation).
teins. Only long polypeptides are cleaved, suggesting that the Several patterns of the CMAP response to repetitive stimula-
proteases recognize other segments or require a specific amino tion may be observed, depending on whether the patient is an
acid conformation in the vicinity of the cleavage site that is adult or infant and the severity of disease. In infants, the initial
found only in larger polypeptides. evoked CMAP from a rested intrinsic hand muscle is usually re-
Electrophysiologic Findings. Microphysiologic recordings duced to 110-4000 p.V with 88% of patients demonstrating am-
in nerve terminals intoxicated with botulinum toxin demonstrate plitudes less than 2000 p.V and 52% of patients with amplitudes
a number of interesting findings.89 379 618 The frequency and am- below 1000 p.V (amplitude measured baseline to peak). 173 At
plitude of the MEPPs usually are markedly reduced. In addition, low rates of repetitive stimulation, 56% of infants demonstrate
the EPP amplitudes are sequentially diminished with time until a decremental response with a mean decrement of 14%
they are effectively reduced to the amplitude of the MEPP (i.e., (5-41%) (Fig. 25-40). Approximately 24% of patients reveal
below the muscle membrane's threshold). Not all investigators no change at low stimulation rates, whereas 20% have a mean
have observed this shift toward smaller MEPPs, and some have incremental change of 37% (5-116%) from the first to fifth re-
actually noted larger than normal MEPPs during disease pro- sponse. Repetitive stimulation at 20 Hz and 50 Hz results in an
gression. In human botulism, microphysiologic techniques
reveal a significant reduction in EPP amplitude and frequency of
MEPPs but not in MEPP amplitude.616-618 Additionally, there is a
significant variability in the time required to reach threshold
after nerve terminal depolarization. Direct electrical stimulation
of intramuscular nerve branches usually reveals low-amplitude
EPPs, which progressively increase in size as the stimulation fre-
quency is increased from 1 to 20 Hz.618
Sensory Nerve Conduction Studies. The sensory nerve find- 10 Hz
ings in botulism are a bit confusing. In the vast majority of pa-
tients with documented botulism intoxication carefully studied
with electrophysiologic techniques, the SNAP amplitudes and
conduction velocities are completely normal during the entire
course of the disease (Table 25-11). Even subjecting the periph- 20 Hz
eral sensory nerves to different rates of repetitive stimulation
does not produce results even remotely resembling an abnor-
mality. However, a few patients have demonstrated clearly ab-
normal SNAPs from the perspective of both markedly abnormal
conduction velocities and even total absence of a re-
sponse.515-611-709 This finding could be attributed to an underlying 50 Hz
peripheral neuropathy if it were not for the fact that the abnor-
mal and even absent responses return to normal at some time 100 uV |
after clinical recovery. The pathophysiologic explanation of this 3ms
finding is unknown, given the proposed mechanism of toxin
action. Abnormal sensory studies should lead one to search for Figure 25-40. The left median nerve is stimulated with
a cause other than botulinum intoxication. recording from the abductor pollicis brevis muscle in an infant
Motor Nerve Conduction Studies and Repetitive Stimulation. with botulism. Note the decrement at 5 Hz (8%) and varying incre-
Motor nerve conduction velocities in patients with botulism ments with stimulations of 10 Hz (25%), 20 Hz (38%), and 50 Hz (94%).
ShOUld be normal (Table 25-1 l).n9.150.158.173,198,361,373,512,603,6!8.630,767.865 (From Cornblath DR, Sladky JT, Sumner AJ: Clinical electrophysiology of
infantile botulism. Muscle Nerve 1983;6:448-452, with permission.)
However, there have been a few documented cases of reduced
incremental change of 73% (23-313%) in 92% of infants with until several days later when or if the limbs become involved. A
botulism (Fig. 25-40). If an increment is not found at 20 Hz, a decrement at low rates of stimulation is less commonly ob-
50-Hz stimulation should be performed. Repetitive nerve stimu- served in adult patients. Facilitation is certainly common, but
lation results are found in patients with significant disease who the caution about pseudofacilitation should be kept in mind.
progress to respiratory failure or inability to handle secretions. In True facilitation persisting after a 10-second period of maximal
patients with less profound disease and hence less toxin expo- exercise or several seconds of high rates of stimulation should
sure, the above pattern of electrophysiologic findings is no doubt be looked for in all cases. The resting CMAP and increment are
less severe in terms of decrementing and incrementing re- usually less in botulism than in LEMS but can be rather impres-
sponses. A decrement may not be present in a number of patients sive in select patients. It is important to examine proximal as
with less severe disease, and an increment may be found in the well as distal limb muscles in addition to a muscle innervated
majority of patients. With respect to an increment, it is important by a cranial nerve, such as the trapezius or nasalis muscles.
to note several factors. It is impossible to ask infants to contract Particular attention should be given to clinically weak muscles.
maximally; therefore a 20-50-Hz impulse train should be ap- In LEMS, on the other hand, an abnormality to repetitive stimu-
plied for about 5 seconds. In addition, facilitation should be lation generally can be found in any muscle examined.
compared with the baseline CMAP (i.e., postactivation facilita- An attempt can be made to understand the electrophysio-
tion). Pseudofacilitation may occur and give a "false-positive" logic findings in botulism by considering the quantal content
increment, because normal persons may demonstrate this find- per NMJ. 768 In human botulism only about 7 total quanta are
ing. Calculating the area under the CMAP negative peak can released per 100 nerve terminal activations (a mean of 0.07
avoid this error because a true increment produces an increase in quanta per nerve terminal depolarization). 522 The postsynaptic
area, whereas pseudofacilitation results only in a amplitude membrane is known to be normal in botulism, thus generating
change with little area alteration. a MEPP of about 1 mV for each ACh quantum. The mean
The most reliable finding in infants with botulism is the docu- summated MEPP or EPP, therefore, is the number of quanta
mentation of postactivation facilitation in excess of 40% compared (0.07) times the amplitude of each quantum (1 mV) yielding
with the baseline CMAP amplitude.298-361'367 The important feature an EPP amplitude of 0.07 mV. The threshold for individual
of this facilitation unique to botulism is its persistence for approx- NMJ varies between 7 and 20 mV above the resting membrane
imately 4—20 minutes. If postactivation facilitation lasts for this level. Clearly, if a number of NMJs possess EPPs with magni-
length of time, botulism should be suspected. Of note, however, tudes approaching several hundred times less than the magni-
prolongation of facilitation also may be seen in LEMS and mag- tude minimally required to depolarize the muscle fiber, there
nesium-induced NMJ transmission disorders.713 After a rapid stim- will be multiple NMJs with compromised safety factors and
ulus train is delivered, one need stimulate the nerve only with a hence failure of transmission. As a result of this failure, poten-
single impulse and compare the CMAP with the resting value. tially large numbers of muscle fibers no longer contribute de-
This type of comparison is valid because of the long period of fa- polarization voltage to the total MUAP. The net result is a
cilitation in botulism. It is best to measure the CMAP at rest, to reduction in the MUAP. Since the CMAP is nothing more than
apply a 50-Hz train for several seconds, and simultaneously to the relatively synchronous summation of all activated MUAPs,
record the amplitude. Then after several seconds a single supra- a reduced CMAP is generated. The reduced numbers of func-
maximal stimulus should be delivered to compare this CMAP tioning NMJs also alter the duration and amplitude of the
with the resting value and thus measure postactivation facilitation. MUAP (see below). At NMJs with borderline transmission,
Similar patterns of abnormality noted for infants can be ob- low rates of stimulation can result in additional failure of NMJ
served in adults, primarily patients with significant disease. transmission because the immediately available store is de-
Lesser abnormalities are noted in patients with mild and moder- pleted. High rates of stimulation also create an excess of cal-
ate amounts of intoxication. 96 - n9 • 145 • ,46 • ,48 ^^ cium, which facilitates ACh release and temporarily restores
6i8.646j39a.767,778.865 T addition, the CMAP and repetitive stimula-
n NMJ transmission at more NMJs than at the resting level, thus
tion abnormalities may be absent on first examination, become resulting in the larger CMAP. The detected prolongation of fa- i
manifest at the peak of the disease, and return to normal after cilitation for several minutes longer than typically observed is I
several months. Patients with relatively mild disease may not readily explained by this mechanism unless free calcium
demonstrate the following effects in clinically affected muscles: sequestration is also altered in botulism.
(1) normal to low-normal CMAP resting amplitude; (2) no Needle Electromyography. Like repetitive nerve stimulation,
change in CMAP at low rates of stimulation; and (3) significant the needle EMG examination of patients with botulinum intoxi-
true incremental response at high rates of repetitive stimulation cation can be somewhat variable, depending on the time of ex-
or after 10 seconds of maximal voluntary contraction. If severe amination.96-144-158-173-32^ Early in the course of the
disease is present and associated with respiratory failure, it is disease, needle insertional activity usually is normal, with no
not unusual to observe (1) an abnormally low resting CMAP; abnormal spontaneous activity. However, fibrillation potentials
(2) either an absent or present decrement at low rates of stimula- and positive sharp waves may be found in severely affected
tion; and (3) an insignificant to mild incremental response to muscles. The MUAPs may be somewhat mixed, with a combi-
high rates of stimulation or maximal voluntary contraction. nation of some normal potentials and a preponderance of short-
Rarely, a pattern of decremental response at high rates of stimu- duration, small-amplitude potentials giving the appearance of a
lation may be seen 4-7 weeks after the initial presentation even myopathic pattern. There is often an abnormal early recruitment
if no decrement was noted previously.373 This finding may result pattern. In addition, a reduced interference pattern of relatively
from significant reinnervation with relatively high numbers of low amplitude is observed initially during attempts at maximal
immature NMJs because of the high stimulation challenge. With voluntary contraction. During sustained effort, some patients
continued recovery the abnormal decrement resolves. may demonstrate a slight increase in the overall amplitude of
If a patient presents with bulbar paralysis and little limb electrical activity and hence in the sound generated. A number
weakness, examining the limbs may reveal no abnormalities of muscles should be examined, both proximally and distally, in
Table 25-12. Electrodiagnosis of Botulism and Related Disorders
Axonal Neuropathy Myopathy
Botulism MFS LES + MG AQM + Axonal Neuropathy
NCVs
iNCV + +
iCMAP amplitudes + ++ ++
iSNAP amplitudes + +
EMG
Fibrillation and positive waves + ++ ++
Short duration MUPs ++ + ++
Myopathic recruitment + + +
Repetitive nerve stimulation
Decrement (slow rate) + ++
Increment (fast rate) + +++
AQM, acute quadriplegic myopathy; CMAP, compound muscle action potential; EMG, electromyography; LES, Lambert-Eaton syndrome; MFS, Miller-Fisher syndrome;
MG, myasthenia gravis; MUP, motor unit potential; NCV, nerve conduction velocity; SNAP, sensory nerve action potential.
From Maselli RA, Bakshi N: Botulism. Muscle Nerve 2000;23:l 137-1144, with permission.
the upper and lower limbs, along with the bulbar muscles. degree of blocking is somewhat independent of jitter severity.
Because the bulbar muscles (e.g., masseter, orbicularis oculi The exact physiologic explanation for this finding is not clear,
and nasalis, hypoglossus, trapezius muscles) are usually af- but it may be due to a relatively sudden decrease in the quantal
fected first, they tend to demonstrate greater degrees of abnor- release of ACh, which results in failure of the safety factor at the
mality before muscles in the limbs. This observation is NMJ under investigation. A finding in botulism that is similar to
especially true of mild disease. With symptom progression and LEMS is the decrease in jitter value with an increase in the
increasing time from disease onset (more than about 10 days), muscle fiber's firing rate (Table 25-11). An increase in the firing
both the numbers and duration/amplitude of MUAPs are re- rate leads to a temporary increase in the nerve terminal's free cal-
duced significantly, and both positive sharp waves and fibrilla- cium, thus increasing the probability of ACh release, which acts
tion potentials may be detected. This is especially true for to repair the NMJ defect. As the patient improves clinically, the"
patients with profound disease in the proximal limb and cranial degree of abnormal jitter and blocking decrease. One would not
muscles. As the disease resolves, there is a gradual reduction in expect to find significant decreases in CMAP amplitude when
membrane instability as well as an increase in the duration and the jitter is abnormal, but there is little in the way of neuromus-
amplitude of MUAPs. After several months, MUAP parameters cular block. The documentation of significant numbers of
tend to show a rather complete electrophysiologic recovery. blocked potentials suggests that the disease is more serious, and
Needle EMG observations can be readily understood if the that an increment at high rates of stimulation and occasionally a
basic pathophysiology is considered. Multiple endplates within low rate-dependent decrement should be found.
a motor unit begin to fail because of EPPs that are subthreshold. The fiber density may be relatively low on the initial SFEMG
As a result,motor units have an early propensity for effective study and increases as the patient's condition improves,973 proba-
loss of large numbers of muscle fibers, which results in a con- bly as a result of the reduced number of potential pairs detected
comitant loss of electrical generators. The net effect is genera- secondary to outright failure of NMJ transmission. If a number
tion of less voltage per motor unit (reduced MUAP amplitude of NMJs do not reach threshold, a single-fiber muscle action po-
and duration). Although the muscle fibers are not physically tential fails to occur. If such failure is sufficiently widespread,
separated from the nerve terminal, the failure of transmitter potential pairs are much harder to find than under normal condi-
(ACh) and other poorly defined "trophic" substances to reach tions and fiber density is reduced. A reasonable assumption is
the postsynaptic membrane renders the muscle fiber physiologi- that reduced fiber density on initial examination implies a more
cally denervated. This not only results in physical disruption of serious form of the disease because of the failure of increased
the muscle fiber's internal structures but also causes the muscle number of endplates to fire. This finding is best observed over
fiber to produce both fibrillation potentials and positive sharp time in the same patient so that a pattern of fiber density normal-
waves. The MUAP parameter alterations and membrane insta- ization can be observed. A few cases have demonstrated fiber
bility, if present, persist until nerve terminal sprouts form new density increased into the abnormal range with patient recovery;
NMJs at some other site on the associated muscle fiber. It ap- this increase persisted for the relatively limited period of foUow-
pears that each nerve terminal reinnervates its own muscle fiber, U pj 8o.256.83o Severity of the disease and method of NMJ recovery
with little collateral sprouting to neighboring fibers. This in botulism may explain these disparate findings. Reduced fiber
process permits the motor unit architecture to remain the same density may be seen in relatively mild cases, in which a limited
and hence to generate few giant motor unit potentials when the number of NMJs are affected to varying degrees, creating a de-
patient is examined in the recovery phase. creased number of potential pairs in the measured area.
Single-fiber Electromyography. The small number of patients Recovery of the more severely affected NMJs with functional
studied with SFEMG does not allow a comprehensive discussion denervation requires nerve terminal sprouting and restoration of
of "typical" findings for botulism.96-339-603-703-739a-85'^3 Abnormal NMJ transmission with minimal motor unit remodeling. In more
increases in jitter can be observed early in the disease in 40-50% severe disease with significant loss of multiple NMJs, substantial
of SFEMG studies. In one trial, 100% of patients demonstrated nerve terminal sprouting may be required to restore NMJ trans-
abnormalities on SFEMG, while more conventional studies were mission, thus creating a situation for collateral sprouting to re-
normal.1393 Blocking of potentials also can be observed. The model the motor unit and hence lead to increases in fiber density.
The value of SFEMG is its increased sensitivity in detecting toxin in vitro, but human trials have reported mixed results as
minor abnormalities of NMJ transmission. In patients with sus- well as disturbing side effects.150 Potential future options for pa-
pected botulism intoxication, repetitive stimulation usually is tients affected by botulinum toxin include administration of
performed first because of ease of application and availability. drugs that antagonize the effects of the toxin.930938
When there is no detectable increment into the abnormal range,
consideration should be given to SFEMG, particularly to look Tetanus
not only for blocking and elevated jitter but also for a decrease Tetanus intoxication affects synaptic transmission in both
in jitter with increases in voluntary rate of firing or, in the case central and peripheral nervous systems. Although the primary
of stimulated jitter, increases in the stimulus rate.141 aJ39a clinical manifestations are due to central hyperactivity, one can
Differential Diagnosis. A number of disorders may appear observe abnormal electrophysiologic findings typical of a
similar to botulism (Table 25-12) 618a but on careful considera- presynaptic NMJ disorder. Tetanus is a serious and potentially
tion may be distinguished from botulism from an electrodiag- life-threatening disorder arising from the in vivo production of a
nostic medicine perspective. neurotoxin from the bacterium Clostridium tetani385 This or-
Treatment. The major hurdle in treating botulism is prompt ganism is a gram-positive (gram negative with maturation),
recognition of the disease, which all too often is unrecognized spore-forming strict anaerobe. Unlike C. botulinum, all toxin-
because of its relative rarity. The combination of a rapidly pro- producing C. tetani organisms are phenotypically similar. All
gressive descending type of paralysis, beginning with cranial toxigenic bacteria produce two types of toxins: (1) tetanolysin
nerves; clear sensorium; absent or minimal sensory complaints; and (2) tetanospasmin. Tetanolysin produces hemolysis on
and autonomic manifestations suggests acute botulinum intoxi- blood agar plates, but its exact role in the production of tetanus
cation. An atypical form of GBS may be considered, but in GBS is unclear. Tetanospasmin is the primary toxic substance pro-
abnormal cerebrospinal fluid protein levels and some form of duced by all C. tetani organisms, regardless of their phenotype.
sensory complaints are expected. Few other disorders present in C. tetani is found in soil samples throughout the world as well
quite the same manner. Infectious etiologies usually present with as in 25-35% of human fecal samples. The typical route of
a septic appearance accompanied by altered temperature and entry in humans is a contaminated wound.
sensorium. Some types of metabolic disorders can mimic pare- It is estimated that over 1 million people per year demonstrate
sis, but not in a descending manner, and may be accompanied by signs of clinical intoxication secondary to infections with C.
cognitive changes. Toxins such as heavy metals, narcotics, and tetania The annual mortality rate is variable, depending on the
organophosphates can present acutely, but a more generalized sophistication of emergent health care delivery and immuniza-
presentation is expected. Few neuromuscular disorders present tions. In Africa, the annual mortality rate is estimated at
in such an acute manner in previously well patients, aside from 28/100,000, whereas in Asia and Europe it is 15/100,000 and
tick paralysis, which has more of an ascending pattern of paresis 0.5/100,000, respectively.135136 182 In the United States, mortality
(see below). Similar illnesses in the patient's family are certainly due to tetanus intoxication is less than 0.1/100,000. About 150
suspicious for botulism. A reduced CMAP in affected muscles, cases of tetanus are noted each year in the United States by var-
combined with the above clinical manifestations, is highly sug- ious governmental agencies. It is likely that some cases of
gestive of botulism. Antibiotics that can potentially disrupt neu- tetanus still are not reported. Of known tetanus intoxications in
romuscular transmission, such as the aminoglycosides, should the United States, the majority of patients are older than 60
be avoided because they can potentiate clinical symptoms. years. This finding is believed to be due to waning tetanus im-
If the clinical identification is accurate, appropriate stool and munity. About 70% of tetanus cases in the United States are a
serum samples can be sent for analysis, but toxin and organism direct result of acute injuries, 22% are secondary to miscella-
identification takes time. Electrophysiologic studies can quickly neous causes (e.g., parenteral drug use, chronic wounds), 7%
demonstrate a marked reduction in CMAP amplitude with arise from an unidentified source (probably forgotten minor
normal motor conduction velocities and sensory nerve studies. trauma), and about 1% is due to neonatal tetanus. Worldwide,
Antitoxin should be considered, provided that it is administered neonatal tetanus represents about 50% of known cases with a
within 24 hours of symptom onset, before all of the toxin binds mortality rate reaching 90%.
and enters the nerve terminals.585-929-930 Once toxin has entered Clinical Features. The clinical presentation of tetanus is sub-
the nerve terminals, the antitoxin can no longer neutralize its ef- divided into four major categories: (1) local, (2) generalized, (3)
fects. There is also a potential for initial adverse reaction to the cephalic, and (4) neonatal. This does not reflect different patho-
antitoxin in the form of an allergic or serum sickness response physiologic mechanisms but the manner in which patients tend
as well as a prolonged sensitization to the drug if it is required to present clinically. Perhaps the most common presenting form,
in the future. The main focus of care is supportive, including but least clinically appreciated by both patients and physicians,
maintenance of adequate ventilation and preparation for prompt is local tetanus, which usually presents with a feeling of in-
mechanical ventilation intervention. Secretions must be handled creased "tightness" of the muscles near the wound. Both pain
and adequate nutrition provided. Constipation must be kept and muscle stiffness can persist for months and remain localized
under control. Psychological support and a clear understanding with eventual spontaneous dissipation. If the condition is ignored
of the disease course should be given to the patient or parents (if or brought to the attention of a physician but not recognized,
an infant is involved). Recovery is usually satisfactory in all pa- most cases progress to the more generalized form of disease.
tients, provided that they are cared for in a hospital setting from When the patient chooses to ignore the initial symptoms of
the first manifestations of the disease. In elderly patients, asso- focal limb abnormalities, lockjaw or trismus (difficulty in
ciated complications can lead to death. Long-term sequelae in- opening the mouth secondary to masseter muscle contraction)
clude fatigue and mild reduction in respiratory capacity in associated with risor sardonicus (sneering grin) and straighten-
selected patients. Guanidine and several aminopyridine deriva- ing of the upper lip appearing as a wry grin may well be noted.
tives (4-aminopyridine and 3,4-DAP) can increase the amount These troublesome symptoms can progress relatively quickly
of ACh released from nerve terminals damaged by botulinum into the more recognized form of generalized tetanus with
tonic contraction of either entire limbs or the whole body sec- (e.g., trismus) is the incubation period. The period of onset is
ondary to relatively mild noxious stimuli. The generalized defined as the interval between first symptom and first reflex
whole-body muscle contraction, opisthotonos, consists of ex- spasm. The shorter the period of either parameter, the poorer the
treme spinal extension, flexion and adduction of the arms, fist prognosis. The degree of recovery also depends on the portal of
clenching, facial grimacing, and extension of the lower limbs. disease entry. Burns, major trauma, umbilical stump contamina-
This generalized contraction may impair breathing. Muscle tion, and illicit drug injections have a poor prognosis, which re-
contractions are associated with severe pain. Some patients de- flects the number of bacteria or spores entering the body.
scribe the pain as a whole-body cramp or "charley horse." Of note, the primary presentation and subsequent develop-
In infants, the generalized whole-body contraction may be ment of generalized muscle contractions are no longer the major
the reason that parents bring the child to the emergent care cause of death in developed countries because of timely me-
center. A careful history may reveal several hours to days of chanical ventilation. Patient survival over this critical period re-
feeding difficulty (poor suck), general irritability, and possibly sults in manifestation of potentially life-threatening autonomic
less than normal mouth opening or generalized "stiffness." disturbances, such as hypertension, hypotension, and occasion-
Neonatal tetanus is usually due to an infected umbilical stump, ally cardiac dysrhythmias or asystole.418 All patients with a clin-
which may result from substandard obstetric care in underde- ical history and physical findings suggestive of tetanus should
veloped countries or tribal rituals in which soil, animal fecal be admitted to the hospital for critical care intervention.
material, or other substances are placed on the umbilical stump. Pathogenesis and Pathophysiology. The pathogenic basis
Of note, infants born to immunized mothers rarely have diffi- and pathophysiology of tetanus intoxication explain both upper
culty with tetanus because the immunity is passively transferred and lower motor neuron findings. The pathophysiologic basis is
from mother to infant. Once the massive whole-body contrac- similar to that described for botulism. Botulinum and tetanus
tions start, there is little doubt about the diagnosis. toxins are proteases that lyse SNARE proteins required for
A form of local tetanus is known as cephalic tetanus because docking and fusion of vesicles and the presynaptic plasma
of preferential involvement of the muscles of facial expression, membrane. 665 850855-965 The different clinical manifestations
particularly those about the mouth.'88-309'326 The lower cranial depend on the selectivity of the neuron cell types to which the
nerves also can be affected. Patients usually complain of an in- toxins bond. The selective binding is determined by the H
ability to smile symmetrically or to close the eyelid completely chains of the specific toxin and the receptor sites for the toxin
on the affected side as well as difficulty in swallowing and turn- on neuronal membranes.
ing the head secondary to stiff neck muscles. Unilateral weak- The bacteria or their spores gain access to the body typically
ness of facial muscles with bilateral tightness of the neck and through a minor wound that is forgotten until elicited by careful
muscles of mastication may be noted. Patients may recall an questioning. Spores are quite hardy and can be destroyed only
injury to the head near the stylomastoid foramen or complain of by heating to 100°C for 1-4 hours or autoclaving for 10 min-
ear pain, decreased hearing, and drainage from an ear. utes. 7 If spores are present, they develop into the bacterial form
The physical examination in early tetanus is consistent with a of the organism within the region of injured tissue. A plasmid
central nervous system hyperirritability state. There is continu- (independent circular form of DNA contained within the bacte-
ous muscle contraction of the affected body part with increased ria) directs the formation of tetanolysin and tetanospasmin. 257
tone and resistance to attempted passive ranging of the limb. In Tetanospasmin is similar in general appearance to the botu-
the head, the jaw jerk is exaggerated and the mouth can be linum toxin in that it consists of a heavy and light chain bound
opened only a few centimeters. Manual muscle testing of the af- by several disulfide bonds. 627 The toxin released by the tetanus
fected limb is somewhat difficult because of the continuous tone organism requires four times as many molecules to cause death
and associated deep muscle pain. Sensation is usually normal as botulism, but it is still 1-100 billion times more lethal than
during the initial stages. Deep tendon reflexes are exaggerated cyanide or curare. 647 Endogenous bacterial proteases nick the
and may result in gross limb movement with crossover to the toxin so that the heavy and light chains are attached by a single
other side as the disease progresses. disulfide bond, which causes the toxin to become activated into
With progression to the more generalized form, increased ab- its most potent form. The bacteria then undergoes autolysis,
dominal muscle tone may be noted first. The deep tendon re- which releases the toxin into the host's bloodstream. Through
flexes are increased at all sites and may initiate a local or the hematogenous route, the toxin gains access to neuromuscu-
generalized contraction of both agonist and antagonist muscles. lar junctions and sensory end-organs throughout the body. The
Although symptoms may resemble a generalized seizure, pa- local spread of the toxin also affects the neuromuscular junc-
tients do not lose consciousness and complain of the pain after tions and sensory end-organs in close proximity to the wound.
generalized contraction. The concern is adequate ventilation. Tetanus toxin, like botulinum toxin, binds to the presynaptic
The massive contraction of muscles may not last more than a membrane through its heavy chain and translocates into the cy-
minute, but patients may be unable to breathe because of invol- tosol of the nerve terminal through the process of endocyto-
untary diaphragmatic and abdominal contraction as well as sis.671-809a The process of internalization is facilitated by activation
upper airway obstruction. Neonatal tetanus has similar findings. of the NMJ and supports the hypothesis that endocytosis is cou-
Of interest are the physical findings of cephalicus tetanus. pled to exocytosis through the recycling of the terminal mem-
Patients may have a combination of flaccid paresis of the mus- brane. Once in the cytosol, the heavy chain is believed to lyse the
cles innervated by the facial nerve with a concomitant increased vesicle and thus deposit the free toxin into the nerve terminal.
tone in the masseter and neck muscles. There appear to be phys- Two independent but mechanistically similar modes of toxin
ical signs of lower and upper motor neuron insult. A focal action begin: local and distant effects. The local effect is con-
wound about the head and neck should be sought as well as a fined to the NMJ close to the site of inoculation. The distant
thorough otologic examination for chronic otitis media. effect occurs later secondary to the hematogenous spread of the
The prognosis of each form of tetanus depends on temporal pro- toxin to distant NMJs. The action of tetanus toxin at the NMJ is
gression. The time from spore introduction to the first symptom similar to that of botulinum toxin.642 As in botulinum intoxication,
tetanus neurotoxins block transmitter release by proteolytic diminution of EPP magnitude, but the retrograde transport re-
cleavage of SNARE proteins.665-850 855-965 This blockage leads to a sults in the more generalized disinhibition phenomenon of
reduction in the EPP magnitude on neural stimulation or volun- muscle overactivity. Despite the disinhibition of the anterior
tary contraction. 241247 The MEPP magnitude is mildly affected horn cell innervating the profoundly affected and hence flaccid
and, in severe cases, shifted to the lower amplitude form, as in muscles, the effector organ or NMJ is no longer functional, thus
botulism. Although the EPP is subthreshold, high rates of repet- preventing the muscle from responding to the hyperactive cen-
itive stimulation or increasing extracellular calcium concentra- tral state. As the peripheral effects wear off, the originally flac-
tions can evoke an EPP of sufficient magnitude to create cid muscle may increase in tone before regaining a normal state
successful NMJ transmission. The effect of tetanus toxin at the when the central effects have finally diminished.
NMJ is similar but significantly less potent than that of botu- Electrophysiologic Findings. Relatively few electrodiag-
linum toxin, which acts preferentially at the NMJ. nostic medicine evaluations have been reported in patients with
The central effects overshadow the NMJ defects associated tetanus intoxication. This is certainly understandable, given the
with tetanus. However, large doses of tetanus toxin may result in emergent nature of the disease. Available information provides
flaccid paralysis secondary to NMJ transmission failure. Tetanus interesting insights into the little discussed peripheral aspects of
toxin is approximately 2000 times more potent in central than in tetanus intoxication.
peripheral NMJ actions and about 1000 times less potent than Sensory Nerve Conduction Studies. In patients with signifi-
botulinum toxin with respect to NMJ dysfunction.71-241-370 cant clinical symptoms, including not only weakness of primarily
The unique feature of tetanus toxin is its ability to be trans- distal muscles but also disturbances in sensation, a number of
ported through retrograde axoplasmic flow to the cell bodies of interesting sensory findings are noted.573-878 The SNAP ampli-
the motor neurons.75-369 Botulinum toxin is also transported in a tudes may be normal or slightly reduced. Sensory nerve con-
retrograde fashion, but its peripheral effects are far more promi- duction velocities are similarly reduced, but again only mildly.
nent.371-372 Transport can occur not only from the terminal portion The sensory slowing is more pronounced distally than proxi-
of motor and sensory axons, but also from sympathetic and mally, implying the possibility that a "dying-back" type of neu-
parasympathetic axons. Once the tetanus toxin is transported into ropathy may be operative secondary to adverse effects on the
the terminal aspect of the nerve, some of it acts locally (NMJ), cell body's metabolic machinery. In cephalic tetanus, peripheral
whereas the remainder is transported at roughly 3 mm/hour in the sensory studies should be normal. 309 Rarely, abnormal sensory
vesicle or free form bound to the transport mechanism. 908 The studies may be obtained in persons who receive a tetanus toxoid
toxin accumulates in the anterior horn cell, then crosses to the in- injection.790 Complete absence of a SNAP response may occur,
terneurons by unclear mechanisms. For example, tetanus toxin with limited degrees of recovery depending on the patient's sen-
gains entry into a distal motor nerve terminal by crossing the sitivity to the inoculation.
presynaptic membrane. It is then transported to the motor nerve Motor Nerve Conduction Studies. In general, the motor con-
body in the spinal cord or brainstem. At this level the toxin is ex- duction studies are similar to the sensory studies.573-878 The con-
ocytosed to diffuse into the nerve terminals of Renshaw cells or duction velocities and amplitudes are slightly reduced, whereas
other types of inhibitory terminals, making synaptic connections the distal motor latencies are at the upper limits of normal. There
in the spinal cord with the cell body of the alpha motor neu- is preferential slowing distally compared with proximally. High
rons.372-985 This process can be repeated to the next higher-order and low rates of repetitive stimulation reveal no abnormal decre-
neuron. The same process occurs in sensory nerves, but the toxin menting or incrementing responses, and postactivation facilita-
accumulates primarily in the dorsal root ganglia and rarely con- tion or exhaustion is absent. Little electrophysiologic evidence
tinues into the central somatosensory neurons. from repetitive stimulation suggests NMJ blockade. Occasional
In the CNS, tetanus toxin lyses the SNARE proteins necessary reports of a 30-40% increment have been documented in
for the release of neurotransmitters (glycine and gamma- cephalic tetanus during high rates of facial nerve stimulation, but
aminobutyric acid [GABA]) that mediate inhibitory postsynaptic complete lack of facilitation in the period immediately after acti-
potentials.61-103-665-850-855-965 The reduction in segmental and vation suggests that this finding is probably pseudofacilitation.
suprasegmental inhibitory influences overwhelms the excitatory The central disinhibition in tetanus can be demonstrated by
influences (excitatory postsynaptic potentials [EPSPs]). The net an absent masseter inhibitory reflex (in the case of cephalic
result is a lowering of the alpha motor neuron's resting mem- tetanus) or by an absent or reduced silent period after motor
brane potential closer to threshold, permitting the cells to fire nerve stimulation during continuous voluntary activation.919
more easily in response to minimal stimuli as well as spread of In a few reported cases of cephalic tetanus, the peripheral
contraction to muscle agonists and antagonists. Thus, the clinical motor conduction velocities, latencies, and amplitudes were
findings of hyperreflexia, continuous motor unit firing, and normal.239 F-waves and H-reflexes were also normal. Some pa-
opisthotonus are a result not of an increase in excitatory drive but tients with cephalic tetanus have abnormal blink reflexes.309602
of a reduction in inhibitory central influences. Excitatory central The Rl and R2 latencies are relatively normal. However, the
influences also are inhibited, but these effects occur much later amplitudes are usually diminished on the side of facial paraly-
and are overshadowed by the above findings.60-70-465 Additionally, sis, as is consistent with peripheral nerve conduction block,
the observed autonomic effects are similarly mediated by lack of NMJ transmission failure, or axonal loss. The side-to-side facial
inhibition. Peripheral effects on the nerves conveying the toxin nerve CMAP amplitudes, however, are comparable, favoring
also can be monitored during the electrodiagnostic medicine ex- conduction block as opposed to axonal loss or NJM failure.
amination (see below). Rarely a diminished CMAP on the involved side of the face may
The net clinical effect of tetanus toxin depends on the amount be commensurate with mild axonal loss. In otologic infections
of toxin inoculated into the patient. Large amounts of toxin ini- facial nerve damage may result from edema in the tight confines
tially may produce a local flaccid paralysis with hyperactivity in of the facial canal. This may be an indirect mechanism of facial
the surrounding muscles exposed to less toxin. The diffusion of nerve compromise as opposed to direct facial nerve injury by
the toxin to other neuromuscular junctions can result in some tetanus toxin. A laceration to the face may allow retrograde
transport of tetanus toxin to the facial nucleus with some loss of anesthesia, or therapeutic neuromuscular blockade. After the
motor neurons. Chromatolysis of anterior horn cells has been patient contracts maximally for relatively few seconds, a brief
documented in tetanus intoxication.935 This finding may be indi- period of relaxation may be seen, at which point one may at-
rect evidence for the dying back neuropathy and supports the tempt to find abnormal insertional and spontaneous activity.
concept that longer nerves have a higher metabolic demand and Eliciting a reflex at times may produce a short silence for spon-
hence a higher probability of failing. This is, of course, specula- taneous potential observation, although success is rather vari-
tion. Further work is required to elucidate such fascinating as- able. When the muscle is relatively quiet, positive sharp waves,
pects of tetanus intoxication. fibrillation potentials, and complex repetitive discharges may be
In animals injected with high dosages of tetanus toxin, it is observed.
possible to demonstrate definite NMJ transmission defects to Single-fiber Electromyography. SFEMG examination of
repetitive stimulation. 460 At low rates of stimulation, either an tetanus has been reported in only one patient with cephalic
absent or variably decreased CMAP can be observed. Stim- tetanus of the frontalis muscle.309 Approximately 60% of the po-
ulation at 3 Hz results in only a small degree of decrement. High tential pairs demonstrated jitter increased into the abnormal
rates of stimulation, however, produce an incrementing re- range. Twenty percent of the potential pairs revealed intermit-
sponse in excess of 400% in some instances, with sustained tent blocking. Different potential pairs belonging to the same
postactivation facilitation exceeding 1 minute. These studies motor unit had normal or abnormal jitter. Increasing the firing
have not been duplicated in humans but substantiate a NMJ rate voluntarily resulted in a decreased amount of jitter for a
defect with profound tetanus toxin, as indicated by microphysi- given potential pair, similar to that found in botulism and
ologic studies. LEMS. These findings are supported by microphysiologic stud-
Rarely, an individual patient may develop a severe peripheral ies of NMJs affected by tetanus toxin in animals. 240 The EPPs
neuropathy after a routine tetanus toxoid injection. 790 The are markedly reduced; an increase in magnitude at higher rates
CMAP is reduced, and conduction velocities are moderately of stimulation documents an improvement in NMJ transmis-
slow. The reduced CMAP is suggestive of axonal loss, which is sion. There is also an increase in the dispersion of individual
confirmed by needle EMG documention of membrane instabil- synaptic event delays, which decrease with increases in firing
ity. Variable degrees of return can be expected, depending on rate. Thus, an increase in NMJ safety factor and decrease in EPP
the severity of the peripheral neuropathic process. dispersion with higher firing rates accounts for the reduction in
Needle Electromyography. The routine needle EMG exami- jitter and blocking at higher firing rates.
nation can display a wide range of findings, depending on the Treatment It is first necessary to be alert to symptoms sug-
severity of disease.247-4903'573'878 919 Continuous firing of motor gestive of tetanus. 81 The differential diagnosis for potential
units at different levels of intensity can be found in various mus- tetanus intoxication is rather small, given the normal mentation
cles and is consistent with the clinical finding of increased and painful muscle contractions. Cerebral events are unlikely.
muscle tone. During a major contraction of multiple muscle Strychnine poisoning is the only other disorder that presents in
groups, potentially induced by the needle electrode secondary to a similar manner. Patients with suspected tetanus intoxication
the central disinhibition, a complete interference pattern of should be hospitalized immediately and evaluated for existent
normal-appearing motor unit potentials may be observed. If it is or impending airway compromise. Preparation should be made
possible to observe relatively few motor units during voluntary for endotracheal intubation with accompanying sedation and
contraction, they appear normal with little variation from one neuromuscular blockade. Human tetanus immunoglobulin
firing to the next. It may be difficult to achieve complete patient should be administered as well as adsorbed tetanus toxoid at a
cooperation because of the nature of the disease and general different site. The antibiotic of choice is metronidazole (500 mg
level of discomfort and anxiety. IV every 6 hours for 7-10 days). If airway compromise is noted,
In patients with cephalic tetanus, one should expect normal it may well persist for some time. A tracheotomy should be con-
findings in the limb muscles.309 Specifically, there is an absence sidered. Benzodiazepines should be administered in rather large
of continuous motor unit firing, and MUAPs are of normal size, dosages to control muscle contractions. If they are ineffective,
duration, amplitude, and phases. Positive sharp waves and fib- therapeutic neuromuscular blockade is warranted in addition to
rillation potentials are also absent in limb muscles. Examination the benzodiazepines to maintain somnolence. If autonomic
of weak facial muscles can reveal abnormalities of recruitment symptoms or signs develop, they should be treated immediately
as well as abnormal spontaneous potentials, suggesting muscle with appropriate medications. Physical and occupational ther-
fiber denervation through axonal loss or "physiologic" muscle apy are usually needed during recovery to restore strength, en-
denervation from NMJ dysfunction.188-326-748 durance, and function.
Rarely a patient receiving either one or multiple tetanus
toxoid injections may experience a markedly adverse reaction Tick Paralysis
and essentially develop a profound peripheral neuropathy both Epidemiology. Ticks are blood-consuming (hemato-
clinically and electrophysiologically.790 This neuropathy is of an phagous) parasites that belong to the insect classes Arachnida
axonal loss type, and significant amounts of positive sharp (possessing eight legs), which includes spiders and scorpions,
waves and fibrillation potentials can be found in multiple and and Acarina.223-331-804 There are three major families of ticks,
preferentially distal muscles. Depending on the severity of the Ixodidae (hard body ticks), Argasidae (soft body ticks), and
neuropathy, patients may either fully recover or continue to re- Nuttalliellidae. Ticks belonging to the first two families are re-
quire ankle-foot orthoses for foot drop. sponsible for causing human paralysis. They are found world-
In patients with complaints consistent with a concomitant pe- wide, primarily in rural and wilderness areas. In North America,
ripheral neuropathy, abnormal spontaneous potentials (e.g., fib- the tick, Dermacentor andersoni (common wood tick) usually
rillation potentials and positive sharp waves) may be observed. causes the paralysis, but D. variabilis (dog tick) also can cause
They may be difficult to find in some patients because the mus- the disorder. Occasionally, ticks such as Amblyomma ameri-
cles are never completely relaxed except during sleep, general canum and Amblyomma macula turn, have been implicated in
human paralysis. A particularly notorious tick in Australia, magnitude to reach threshold and propagate an action potential.
Ixodes holocyclus (Australian marsupial tick) causes especially Animal studies demonstrate failure of conduction over long seg-
severe disease in humans.347-502-619 Usually gravid female ticks ments of the peripheral nerve as well as in the terminal arboriza-
are implicated in the production of human paralysis because tions of the motor unit.678-680 Some evidence suggests defective
they feed for considerably longer periods (days). Thus, they calcium entry into the nerve terminal or dysfunctional ACh syn-
inject more toxin produced by the salivary "glands into their thesis. 678 Perhaps one of the most important findings in tick
hosts than nongravid females and males. Peak occurrences of paralysis is the critical dependence of ACh release on tempera-
paralysis caused by ticks are in the spring and summer months, ture.172 In significantly affected endplates, EPPs of insufficient
the breeding season that coincides with the human desire to ex- magnitude to reach threshold were noted at physiologic temper-
plore wilderness areas. atures. After the temperature is lowered below 25°C, the same
Of interest, ticks transmit a greater variety of infectious "paralyzed" endplates produce relatively normal EPPs.
agents than any other type of arthropod and are considered Elevating the temperature produces failure of neuromuscular
second only to mosquitoes as a vector of human illness. The tick transmission. It is speculated that in North American cases of
is capable of transmitting various disease-bearing microorgan- tick paralysis, the toxin may block the sodium channel at the
isms to humans, such as bacteria, viruses, and protozoans.848 Of nodes of Ranvier and the distal motor nerve terminals. However,
importance for this discussion is the second mechanism of af- ixovotoxin, which is released by the Australian /. holocyclus tick,
fecting humans through secretion of a toxin that can stimulate most likely interferes with the release of ACh at the NMJ, per-
an immune response or directly act as a tissue toxin. Ticks usu- haps similar to the effect of BTX and tetanus.307
ally climb to the uppermost aspect of tall grasses and weeds, The toxin excreted by the tick is believed to arise from the
waiting for their hosts, animals or humans, to walk through the salivary glands and is either intentionally or coincidentally se-
high vegetation, and brush against the waiting tick, which creted into the host. Considerably more research on microphys-
latches onto the animal's fur or person's clothes. It then attempts iologic, chemical, and electronmicroscopic levels is required to
to climb to the highest place on the victim, such as the back of elucidate the exact method by which ticks produce paralysis.
the animal or scalp of the human host. The slow progression and Electrophysiologic Findings. There are only a few docu-
delicate insertion of mouth parts into the victim frequently take mented electrophysiologic studies in tick paralysis.
several hours and go unnoticed. Sensory Nerve Conduction Studies. The sensory nerve con-
Clinical Features. Children are three times as likely to be duction studies usually reveal normal amplitudes, latencies, and
involved as adults.249-307-347-848-856 Although the reason for this dis- hence velocities. 143-,94-227-3°7-347-670-925 Of interest, however, when
tribution is not known, children's shorter stature predisposes the patient is evaluated after recovery, the identical sensory pa-
them to having their heads at the same level as tall brushes rameters for the same nerves are larger, shorter, and faster, re-
where the tick resides. It is probable that girls are more likely spectively. Although the sensory parameters may fall within
than boys to be affected because their longer hair gives the tick normal limits for a group mean, they clearly are abnormal for
a better chance to attach to the victim. On the other hand, adult the patient's normal healthy state of neural function. Tick paral-
men are more likely to be affected than women because of the ysis, therefore, produces a mild sensory neuropathy by dimin-
desire to hunt in wooded areas and pause for long periods in tall ishing SNAP amplitudes and prolonging latencies. The recovery
grasses waiting for the prey to approach. of electrical parameters appears to follow the physical resolu-
Patients typically present with ascending weakness that de- tion of paralysis, suggesting that indeed the primary pathology
velops over the course of a few hours or days and may progress is conduction block as opposed to axonal loss or demyelination.
to flaccid paralysis.2-12-346-347-461-664-755-807-848-903-997 Children often Motor Nerve Conduction Studies and Repetitive Stimu-
are noted to be quite irritable. Early cranial nerve involvement, lation. Motor conduction velocity is usually slow or border-
including internal and external ophthalmoplegia, facial weak- line normal in both upper and lower limbs if the limbs are
ness, dysarthria, dysphagia, and respiratory muscle weakness, is paretic.143-194-227-307-347-670-925 This finding contrasts with sensory
a salient feature. Patients may complain of pain, itching, burn- studies, as normal parameters are not reached in at least several
ing, or numbness in the limbs. Despite the complaints of numb- of the nerves. The CMAP amplitudes are borderline or decreased
ness, there is usually only a mild decrease in sensation, in size. As with sensory studies, removal of the tick within sev-
particularly during the initial stages of the disease. However, eral days of clinical presentation results in prompt resolution of
patients may develop a sensory ataxia manifested by a positive amplitude and conduction velocity abnormalities. Repetitive
Romberg sign, past-pointing, and decreased coordination of nerve stimulation at both low and high rates usually fails to
heel-to-shin and finger-to-nose ability. The deep tendon reflexes reveal either a significant decrement or increment. It is certainly
are diminished or absent. Onset and course usually are more possible to observe an increment secondary to pseudofacilita-
abrupt than in most cases of GBS, but it can be difficult to dis- tion. In a few reported cases a documented increment has been
tinguish the two disorders clinically and electrophysiologically documented, but it is within accepted parameters conforming to
(see below). 497 Unlike GBS, CSF protein concentration is usu- pseudofacilitation. This phenomenon, combined with early in-
ally normal in tick paralysis. complete microphysiologic studies, probably explains why tick
Pathogenesis and Pathophysiology. The pathophysiologic paralysis has been mistakenly been considered a NMJ disorder.
mechanism involved in tick paralysis is still not clear.307 As indi- Needle Electromyography. A needle EMG evaluation of pa-
cated above, the neurotoxin is secreted form the saliva of an en- tients with acute tick paralysis performed within several days of
gorged tick. Early studies documented reduced release of ACh weakness onset or after tick removal usually demonstrates abnor-
from the nerve terminal, which seemed to implicate the malities only of recruitment. This pattern is more suggestive of
NMJ.266-808 Only a few microphysiologic studies have been per- failure of motor units as opposed to loss of individual muscle
formed on animals affected by tick paralysis. The results demon- fibers. Positive sharp waves and fibrillation potentials are absent.
strate a normal frequency of MEPPs with normal to slightly In one child with apparently over 5 0 attached ticks, positive sharp
increased amplitudes.172-636 However, the EPPs are insufficient in waves and fibrillation potentials were noted within several days
of paresis onset.227 These abnormal spontaneous potentials per- C O N G E N I T A L MYASTHENIC SYNDROMES
sisted for at least 6 months, the length of follow-up. The number
of ticks and subsequent degree of intoxication most likely ac- An increasing number distinct congenital myasthenic syn-
count for the findings suggesting axonal loss, which appear to be dromes (CMS) are becoming better characterized (Table 25-13).
an exception to the rule of primarily reduced MUAP recruitment. The individual types of CMS within this category are subdi-
Treatment. The most appropriate course of action in sus- vided according to the scheme of presynaptic, synaptic space,
pected tick paralysis is prompt removal of the tick with hospi- and postsynaptic locations of the presumed site for the abnor-
talization for observation of potential impending respiratory mality. 282.283.285.288 Unlike autoimmune myasthenia gravis, these
failure.307-347-848 This course of action can be taken only if the disorders may manifest in the first year of life. Response to
clinician has an appropriate level of suspicion. In most patients Tensilon is variable and depends on the specific subtype of
with acute to subacute onset of ascending paralysis over the CMS. Because CMSs are not autoimmune in etiology, antibod-
course of hours to days, GBS is the first suspected diagnosis.497 ies to AChR are not present. Therefore, treatments aimed at
Relatively normal sensory findings and normal CSF protein can modulating the immune system (e.g., plasma exchange, IVIG,
be seen in early cases of GBS. If the patient has a recent history thymectomy, corticosteroids and other immunosuppressive
of camping or other types of leisure activities involving wooded agents) are not effective in CMSs. However, in certain subtypes
or high grassy areas, the suspicion of tick paralysis should be of CMS, drugs aimed at increasing ACh at the NMJ (i.e., mesti-
raised. Even if GBS is suspected, a thorough search for a tick non and 3,4-DAP) may be beneficial.
should still be pursued. Certainly, a history of eating home-
canned preserves or potentially spoiled food requires considera- PRESYNAPTIC DISORDERS
tion of botulinum intoxication.792
A meticulous and comprehensive search for ticks is required Familial Infantile Myasthenia (Defective ACh
if the disorder is suspected. One of the most common locations Resynthesis or Packaging)
for a tick is about the inferior hairline in the neck or under sig- Clinical Features. Familial infantile myasthenia manifests
nificant folds of hair about the parietal scalp region. Additional in infancy or early childhood with feeding difficulties (fatigue
places for ticks to lodge are in the skin fold areas of the axilla, during suckling), intermittent ptosis, weak cry, and a propensity
inguinal region about the external genitalia, and under breasts.
Close inspection of the external and internal ear canal is impor- Table 25-13. The Congenital Myasthenic Syndromes
tant because ticks occasionally are found posterior to the auricle
or in the external auditory canal. Gluteal, labial, and scrotal skin Mode of Gene
folds must be searched with care. The scalp, underarm, and Disease Inheritance Location Gene Product
pubic hair regions are good places for ticks to hide. There is sig- Presynaptic disorders
nificant folklore about the best manner in which to remove a Familial infantile AD 17pter
tick. It is inappropriate to douse the tick with gasoline, lighter myasthenia (defect
fluid, petroleum jelly, or any other type of substance.856-997 Ticks in ACh resynthesis
do not pull back voluntary when exposed to these substances or packaging)
and can survive with little oxygen for extended periods. Paucity of synaptic AR
Burning the tick is also ill-advised because it may do more harm vesicles and reduced
to the patient than to the tick. It is best to use a pair of tweezers quantal release
or forceps and firmly grasp the tick as close to the patient's skin Synaptic disorders
as possible (i.e., near its mouth parts). A firm, steady pull should Endplate acetylcholin- AR 3p24.2 Collagen Q
be applied. Close inspection of the tick typically reveals a sticky esterase deficiency
white substance about the mouth, which is secreted by the tick (type IC)
to help maintain its attachment to the victim. If tweezers are un- Postsynaptic disorders
available, the hands may be used in a similar fashion but only if
gloves are worn. The body of the tick should not be pierced be- Slow-channel syndromes
cause more toxin may be released. It is unlikely that the tick's AD 2q24-32 AChR a subunit
head and body will separate if removal is attempted in the above AD I7pl 1-12 AChR P subunit
manner. The wound site then should be cleaned thoroughly with AD I7pl3 AChR e subunit
a medicinal disinfectant or gentle soap and water. Fast-channel syndromes
After removal of the tick, the patient usually demonstrates an AD 17p 13 AChR £ subunit
almost miraculous functional recovery in a matter of hours. AR 2q24-32 AChR a subunit
Within 24-48 hours of tick removal most patients are well CMS with mode- AR?
enough to be discharged from the hospital, provided that the switching kinetics I7pl3 AChR e subunit
tick is removed prior to profound functional loss. An exception AChR deficiency AR
is the Australian variety of the tick,347-619 which causes a particu- I7pl3 AChR e subunit
larly virulent form of paralysis that may continue to progress to Partially characterized disorders
respiratory failure even after the tick is removed. Therefore, an Familial limb girdle AR
antitoxin in the form of polyclonal dog antiserum should be myasthenia
used. However, the antiserum treatment is expensive and effec- CMS with abnormal AR
tive only if given in the early stages of paralysis. Furthermore, it ACh and AChR
may be associated with serum sickness. Continued ventilator interaction
support is required for several additional hours until the patient CMS, congenital myasthenic syndrome; LEMS, Lambert Eaton syndrome;AD, au-
can sustain voluntary ventilation. tosomal dominant; AChR, acetylcholine receptor; AR, autosomal recessive.
to develop respiratory infections as well as apnea (see Table 25¬ proximal muscles, such as the deltoid and biceps brachii mus-
! ) 17.274,282.283,285.288,332.348.802 Crying, vomiting, or febrile illnesses
3 cles, whereas the hand intrinsic muscles demonstrate a normal
can exacerbate weakness. This disorder is inherited in an auto- response. Exercise in excess of 1 minute may be required to
somal recessive fashion, and a family history of this type of induce a decremental response, particularly during the 3-4 min-
symptom complex should be sought. Symptoms may improve utes after exercise (postactivation exhaustion). Needle EMG in
as the patient reaches adolescence or adult life." affected muscles reveals MUAPs with variable amplitudes and
Histopathology. Morphologic investigations of the muscle morphology secondary to NMJ blocking. Positive sharp waves
and NMJs are quite normal. Routine histochemistry reveals a and fibrillation potentials are absent.
normal distribution of fiber types. AChE is present in normal
amounts and locations. There is a distinct lack of AChR antibody Congenital Paucity of Synaptic Vesicles
deposition on the NMJs. Gross appearance of the presynaptic and Reduced Quantal Release
and postsynaptic regions is normal on electronmicroscopic eval- Clinical Features. A single female patient has been de-
uation. Number and morphology of mitochondria are normal, scribed with this disorder (Table 25-13). She presented with
but a normal to 60% increase in density of synaptic vesicles may complaints of generalized weakness and fatigue since in-
be appreciated. The vesicles may be normal or slightly reduced fancy. 282,283.285,288,978 ngr siblings were unaffected. Physical ex-
in size. Postsynaptic membrane junctional fold area and total amination revealed ptosis, ophthalmoparesis, facial weakness,
length are comparable to control NMJs, and an optimal number and generalized limb weakness.
of AChRs is located on the membrane in the typical distribution Histopathology. Electronmicroscopic analysis of NMJs re-
about the summits of the folds. vealed a reduction in the synaptic vesicle density compared with
Pathogenesis and Pathophysiology. Microphysiologic stud- normal (15.1/jim 2 versus 50.3/|im 2 ). Nerve terminal size is
ies of excised intercostal muscle preparations demonstrate that comparable to normal control values. Postsynaptic analysis
in muscles at rest the MEPPs and EPPs are of normal amplitude, demonstrates a normal number of AChRs.
suggesting that spontaneous and induced quantal content are Pathogenesis and Pathophysiology. The pathogenic basis is
normal, as is the probability of ACh release.667 After continuous unknown. External intercostal muscle microphysiologic analysis
NMJ activation for several minutes at 10 Hz, the EPP magnitude showed normal MEPP frequency, current time course, and am-
declines to abnormal levels secondary to a decline in MEPP amplitude. The EPP quantal content at 1 Hz, however, was
plitude. This effect can be mimicked by applying hemicholin- markedly reduced. Quantal release probability was similar to
ium, a substance capable of inhibiting the uptake of choline and normal controls. AChR channel open time and ionic conductance
thus decreasing the ACh content, which indicates a presynaptic also were normal. A reduction was noted in readily releasable
location for the EPP and MEPP observations.262-455 quanta at 77 compared with control values of 326. The reduced
The combination of normal MEPP at rest and a greater than safety factor is attributable to the EPP's reduced quantal content,
normal decline in magnitude after several minutes of exercise which, in turn, probably results from the decreased numbers of
suggests the possibility of defective ACh synthesis. The exact quanta in the readily available store. This decrease is reflected in
pathogenic basis is unknown but may be related to problems af- the decreased density of nerve terminal synaptic vesicles.
fecting one of several crucial steps in ACh synthesis (see Fig. 25¬ Electrophysiologic Findings. Routine nerve conduction
17). For example, the facilitated uptake of choline into the nerve studies were normal. Repetitive nerve stimulation generated a
terminal may be impaired. A deficiency in choline acetyltrans- decremental response at low rates that improved with neostig-
ferase may be present. Alternatively, the packaging mechanism of mine administration. Facilitation at rapid rates of stimulation
ACh molecules into the vesicles may be dysfunctional. Reduced was absent.
ACh mobilization also may be responsible for the abnormality. A
remote possibility may be the development of AChR desensitiza- SYNAPTIC SPACE DISORDER
tion after prolonged neural stimulation. This mechanism is
unlikely because the administration of anticholinesterase medica- End-plate Acetylcholinesterase Deficiency
tion should worsen rather than improve the defect. The first three Clinical Features. Patients born with a congenital deficiency
postulated mechanisms may account for the initial normal of acetylcholinesterase present soon after birth or in early child-
MEPPs and EPPs with no decrement because the available ACh hood with fluctuating ptosis, extraocular muscle weakness, gen-
stores can maintain multiple NMJ transmissions. After depletion eralized delay in motor development, weakness exacerbated by
of immediately available ACh stores and the requirement for exertion, poor cry and suck, and respiratory muscle weakness
newly synthesized ACh vesicles, a defective vesicle content of (Table 25-13).271-274-282-283-288-441452 In addition, there is mild slow-
ACh would result in a reduced NMJ transmission safety factor. ing of the pupillary light response. Patients survive into adult-
The end result is a normal CMAP at rest, with a decrement be- hood but tend to have an overall reduced amount of muscle bulk
coming manifest after exercise because of the reduced amounts and significant axial weakness, leading to hyperlordosis and
of newly synthesized ACh. A reduction in the amount of ACh kyphoscoliosis. Facial and limb muscles also are affected. Deep
leads to a diminution in the size of the depolarized postsynaptic tendon reflexes may be normal or reduced.
membrane. Activation of fewer AChRs results in generation of Histopathology. Morphologic examination of neuromuscu-
less current per synaptic vesicle and a subsequent decline in the lar preparations demonstrates normal-appearing muscle tis-
EPP. Further work is required to elucidate more fully the exact sue 27i.274.282.283.44i.452 Q f note is the striking absence of AChE from
mechanism of this type of congenital NMJ disorder. the NMJs by cytochemical criteria. The number of AChRs varies
Electrophysiologic Findings. Motor and sensory nerve con- from muscle to muscle, with normal findings in the external in-
duction studies reveal normal conduction velocities as well as tercostal muscle but a reduction in the biceps brachii muscle.
rested CMAP amplitudes. Clinically weak muscles show a Electronmicroscopic analysis reveals a reduction in the size of
decremental CMAP response to low rates of repetitive nerve the nerve terminals, which do not cover the entire endplate
stimulation. This decremental response may be observed in region. In these small nerve terminals, an appreciable amount of
the surface is covered by Schwann cell processes. There is no ev- SINGLE STIMULUS REPETITIVE STIMULATION
idence of degeneration of either nerve terminals or intramuscular ULNAR NERVE
HYPOTHENAR RESPONSE
SUPRASCAPULAR NERVE
INFRASPINATUS RESPONSE
nerves. The postsynaptic junctional folds vary at the different
NMJs from normal to reduced in number. When they are normal
in number and appearance, they project into the extracellular
space because of the reduced nerve terminal size. The abnormal
junction folds are reduced in number and demonstrate signs sug-
gestive of degeneration. Occasional NMJs have sarcoplasmal evi-
dence of degeneration and autolysis of cellular components. These
findings result in nerve terminals of one-third to one-fourth normal ELBOW
size, elevated synaptic vesicle density per nerve terminal, and a re-
duction in the postsynaptic membrane length per unit area. MINIATURE ENDPLACE POTENTIAL
Pathogenesis and Pathophysiology. The disorder is inher- 1mV
ited in an autosomal recessive fashion. AChE is concentrated at
the endplate regions, where it is attached to a collagen tail
(ColQ), which, in turn, is anchored to the basement membrane. msec
Recently, mutations in the gene encoding for ColQ on chromo- NORMAL PATIENT
some 3p24.2 have been detected in families with congenital de- Figure 25-41. Endplate acetylcholinesterase deficiency. A
ficiency of AChE (Table 25-13). 228 722 These mutations lead to double CMAP with the first larger than the second results from single
defective binding of ColQ to AChE or insertion of ColQ to the peripheral ulnar nerve activation at the wrist and elbow (left upper
basement membrane. Regardless, the net result is loss of AChE. panel). Infraspinatus CMAP decremental response to suprascapular
Microelectrode recordings demonstrate interesting abnormal- nerve stimulation at 2 Hz (right upper panel). Patient MEPP compared to
ities.271 •274-441452 External intercostal microelectrode analysis re- normal MEPP (lower panels). Note the longer decay time. (From Engel
veals a reduced MEPP frequency. The magnitude of these AG, Lambert EH, Gomez MR: A new myasthenic syndrome with end-
potentials is in the low-normal range (0.74 compared with 0.94 plate acetylcholinesterase deficiency, small nerve terminals and reduced
for normal). At a stimulation frequency of 1 Hz, the quantal acetylcholine release. Ann Neurol 1977; 1:315-330, with permission.)
content is between 12 and 26 compared with a normal value of
approximately 56. The decay time of the MEPPs are abnormally
prolonged (Fig. 25-41). The application of neostigmine bromide Positive sharp waves and fibrillation potentials are absent.
should increase the MEPP amplitude, halve decay time and rise Despite clinical improvement with corticosteroids, electrical
time, but in these patients it has no effect. Repetitive stimulation studies remain unchanged.
reveals that the quantal content decreases at both low and high
rates of stimulation despite the reduced quantal content at rest. POSTSYNAPTIC DISORDERS
The low quantal content at rest is similar to LEMS, but the re-
duced amount released at high rates of stimulation is similar to Slow-Channel Syndrome
myasthenia gravis and quite unlike LEMS. A reduction in the Clinical Features. Patients with the slow-channel syndrome
mean store of ACh (58 compared with 315 for controls) also is may present at any time—infancy, childhood, or adulthood (see
noted, but the probability of ACh release is similar to normal Table 25-13).274-276-282-283-286-288-732 The muscles primarily affected
values (0.21 vs. 0.26). are cervical, scapular, and finger extensor muscles. Ocular move-
A lack of AChE from the NMJ certainly explains the in- ment is usually limited, diplopia is occasionally found, and
creased EPP and MEPP duration. More ACh remains in the ptosis, when present, is mild to moderate. Involvement of the
synaptic cleft for a longer period before diffusing away. The masticatory, facial, upper limb, respiratory, and trunk muscula-
prolonged MEPP and subsequently longer than normal EPP ture is variable. The lower limb muscles are usually less involved
outlasts the muscle's refractory period. Thus, in addition to gen- than the upper limb muscles. Affected muscles are relatively
erating an initial single muscle fiber action potential, a second weak and readily fatigue on exertion. Muscle atrophy may be
potential is produced, because the EPP is suprathreshold, when noted when the disease is particularly severe. It is not uncommon
the muscle fiber is capable of being activated again. By the time for the weakness and degree of fatigability to vary. Deep tendon
the refractory period is over for this second potential, the EPP reflexes usually are normal unless the muscle is severely affected.
has declined below threshold, thereby generating only two The disease has a variable progression; it may remain dormant
muscle action potentials. for a number of years then flare for some time and again become
Electrophysiologic Findings. Sensory nerve conduction quiescent. The pattern of inheritance is autosomal dominant with
studies are normal. A single peripheral motor nerve stimulation a high degree of penetrance, but degree of expression is variable.
results in smaller repetitive CMAP responses (Fig. 25¬ Histopathology. Light microscopic analysis reveals type I
4 1 ) 27i.274.44i.452 x n e s e repetitive CMAPs are separated by 6-10 fiber predominance with isolated grouping of atrophic fibers of
ms and may be so small that they are overlooked unless the type I or type II, fiber size variation, tubular aggregates, fiber
electromyographer is paying close attention. At rates of stimula- splitting, endomysial fibrosis, and vacuolization near the
tion between 0.2 and 2 Hz, the amplitude of the secondary re- NMJ.274-276-285-287-732 Histochemical analysis reveals AChE at all
sponses falls to zero after 3-6 stimuli. Repetitive stimulation at NMJs. However, there is an abnormal distribution of endplates
low (2 Hz) and high (40 Hz) rates generates a decrement of the over an excessively large portion of the muscle tissue, particu-
CMAP. Postactivation facilitation and exhaustion are present. larly in more profoundly affected muscles. Increased amounts
The administration of Tensilon does not alter the decrement of calcium are deposited in and about the NMJs.
during repetitive stimulation. Routine needle EMG examination Electronmicroscopic analysis of NMJs demonstrates post-
demonstrates MUAPs with increased variability and phases. junctional folds containing multiple pinocytotic vesicles and
SINGLE STIMULUS REPETITIVE STIMULATION approaches the low end of the normal range. In short, the dura-
MEDIAN NERVE
THENAR RESPONSE
ULNAR NERVE
HYPOTHENAR RESPONSE tion of current flowing into the postsynaptic membrane is
markedly prolonged.
The prolonged EPP is secondary to the summation of pro-
longed MEPPs. An increased MEPP duration is directly propor-
tional to the time of MEPP current flow. This increased current
flow can result from either NMJ AChE deficiency480 or from de-
layed closure of the AChR (i.e., it remains open for an abnor-
mally long time).23-479 A normal amount of AChE at observed
endplates suggests that the prolonged MEPP current flow results
from delayed AChR closure. Delayed closure of AChRs pro-
duces an EPP that is long enough to outlast the refractory period
of the associated muscle fiber, thus creating a second depolar-
ization of the muscle membrane. This is exactly what is ob-
served; a second CMAP following the potential arises from the
nerve stimulation. The fact that the second potential is smaller
than the first implies that only a portion of the muscle fibers
have EPP of sufficient length to persist beyond the refractory
Figure 25-42. Slow-channel syndrome. After median nerve stim- period. However, detection of this abnormality in all muscles
ulation at the wrist and elbow in a patient with congenital slow-chan- implies that it is a ubiquitous endplate finding and is thus as-
nel syndrome, a double CMAP is recorded from the thenar muscles sumed to be the primary abnormality in slow-channel syn-
with the second smaller than the first (left upper panel). Repetitive drome. The weakness and fatigue, therefore, are considered
stimulation at 2 and 40 Hz generates a decrementing response (upper secondary phenomena to the prolonged open time of AChRs.
right panel). Comparison of normal and patient MEPPs. Note the pro- The abnormal open time of the AChRs leads to a prolonged
longed decay time from peak amplitude (lower panels). (From Engel AG, cation flow into the postsynaptic junctional fold region. At least
Lambert EH, Mulder DM: A newly recognized congenital myasthenic some of this current is mediated by calcium ions, thereby leading
syndrome attributed to a prolonged open time of the acetylcholine in- to a transient or possibly permanent elevation in postjunctional
duced ion channel. Ann Neurol 1982;! 1:553-569, with permission.) fold calcium concentrations.294,651 If sufficient calcium is internal-
ized into this aspect of the muscle region, it is possible to over-
whelm the sarcoplasmic reticulum's ability to sequester calcium.
abnormal amounts of intracellular membranous networks. Excessive amounts of calcium have detrimental effects on muscle
Segments of the postjunctional folds are in various stages of de- tissue, such as decreased mitochondrial respiration, microtubule
generation with secondary widening of the synaptic space. depolimerization, and stimulation of intracellular protease activ-
Occasionally the more severely affected NMJs have lost their ity 38,267.998 These adverse effects may be responsible for the de-
nerve terminal with the appearance of unmyelinated nerve struction of junctional fold tissue. Loss of junctional folds readily
sprouts. There is a distinct lack of immune complex deposition. explains the reduced amount of AChRs, and AChR synthesis may
AChRs are decreased at the more severely affected NMJs, as a be inhibited. This loss of AChRs is believed to be responsible for
result of the postjunctional fold destruction; the remaining the reduced MEPP amplitude and hence decreased EPP ampli-
membrane has a normal amount of AChRs. Junctional sarco- tude with a resulting decline in the safety factor. At NMJs with re-
plasm is abnormally swollen and contains evidence of cellular duced amounts of junctional folds and AChRs, an increased
debris and enlarged sarcoplasmic reticulum. Cellular disorgani- AChE-to-AChR ratio results in a decrease in EPP amplitude but
zation and destruction of muscle tissue adjacent to the affected not duration (i.e., a decreased safety factor). This reduction in
NMJs are associated findings. The nerve terminals at affected safety factor generates the clinical symptoms of weakness and fa-
regions reveal a 29-43% reduction in size and a 25-37% in- tigue as well as the decrementing CMAP response. Anticholin-
crease in synaptic vesicle density. Junctional fold destruction esterase medication can be expected to prolong the falling phase
results in a reduction in the postsynaptic membrane length. of the EPP, thereby increasing the amount of calcium entry and
Rarely, elevated amounts of calcium can be detected within the potentially increasing the amount of postsynaptic membrane de-
muscle fiber immediately beneath the NMJ region. struction. Treatment is primarily supportive.
Pathogenesis and Pathophysiology. The slow-channel syn- Electrophysiologic Findings. Sensory and motor nerve con-
drome is genetically heterogenic and can be seen with muta- duction velocities are usually normal. The magnitude of the
tions involving the 0Cr, (3-, or e-subunits of the AChR (Table CMAP may be normal or slightly reduced, depending on the
25-13).286-288'344 Each mutation is dominant and causes a patho- severity of the disease. Of note, a second, smaller CMAP occurs
genic gain of function of the AChR. Some mutations cause de- spontaneously after a single supramaximal stimulation of a
layed channel closure, whereas others lead to an increased motor nerve (Fig. 25-42).276 This second CMAP occurs approxi-
affinity of receptors for ACh, thus resulting in repeated reopen- mately 5-8 ms after the initially evoked response. Following a
ings of the channel. brief voluntary contraction or 3 Hz stimulation, the second
Intracellular microelectrode analysis demonstrates MEPPs CMAP disappears, only to return after a brief rest period. The
and EPPs with amplitudes, either reduced or at the low end of repetitive CMAP response to a single nerve stimulus is similar to
normal. Of note, the half-decay time of both potentials is that observed in patients taking excessive amounts of anti-
markedly prolonged. In particular, the MEPP half-decay time in cholinesterase medication or in congenital AChE deficiency. A
normal people is 1.4-1.9 ms, whereas in patients with slow- decrementing CMAP to low rates of stimulation (2-3 Hz) usu-
channel syndrome it is 3.0-3.5 ms.276 MEPP frequency is essen- ally is observed only in clinically weak muscles (see Fig. 25-42).
tially normal to low normal. EPP quantum content is normal but In the same muscles, postactivation excitation and exhaustion
may be observed. Routine needle EMG analysis reveals MUAPs e-subunit. Electronmicroscopy reveals a reduced number of sec-
with variable amplitudes, increased phases, and decreased dura- ondary synpatic clefts and diminished postsynaptic area.
tions suggestive of a myopathy in some muscles. Rarely, positive Pathogenesis and Pathophysiology. This is an autosomal
sharp waves and fibrillation potentials may be detected. From recessive disorder is caused by homozygous or heterozygous
time to time fasciculation potentials can be observed. mutations of the e-subunit of the AChR (Table 25-13).221-288-698
These mutations cause premature termination of the transla-
Low-Affinity, Fast-Channel Syndrome tional chain or are missense mutations that result in the reduced
Clinical Features. This rare disorder has been described in assembly of the pentameric AChR. Diminution in the AChR
only a few patients. Severe weakness presented at birth with numbers results in fewer available channels for the number of ACh
poor suck and weak cry (see Table 25-13).280282-283>287-288-720 One molecules released. Thus, the MEPPs have decreased amplitudes
patient demonstrated delayed motor milestones from birth to the because of less current flow, which, in turn, produces EPPs that
age of 9 years (age at time of presentation) with continued are either borderline or subthreshold.
weakness of selective bulbar and limb musculature. Tem- Electrophysiologic Findings. Sensory and motor nerve con-
perature elevation and exertion may exacerbate the weakness. duction studies are normal.53,•668•87,'88,•97,'993 Repetitive stimula-
Physical examination demonstrated mild weakness of both tion at 2-3 Hz reveals an abnormal decrement. Routine needle
bulbar and limb muscles. Anticholinesterase administration re- EMG examination reveals no evidence of abnormal sponta-
sults in equivocal improvement in strength. neous activity at rest; however, documentation of MUAP para-
Histopathology. Morphologic analysis reveals a normal meter abnormalities is insufficient. Single-fiber EMG analysis
number of AChRs along the postsynaptic membrane's junc- demonstrates increased jitter and blocking. Microphysiologic
tional folds.280-282 Mild evidence of postjunctional remodeling evaluation documents reduced MEPPs but normal conductance
suggests previous degeneration. Nerve terminals are grossly of individual AChRs.
intact, as are the number and size of synaptic vesicles.
Pathogenesis and Pathophysiology. Heterozygous muta- AChR Deficiency and Short Channel-open Time
tions in the a-subunit of the AChR result in the autosomal re- Clinical Features. A female infant born with the assistance
cessive inheritance of the disorder in one patient, whereas of forceps required ventilator assistance during the first 3 weeks
mutations in the £-subunit of the AChR may cause autosomal of her iife.28o.282.283.284,288 §he had facial diplegia, ophthalmople-
dominant inheritance (see Table 25-13).288-720 Thus, mutations gia, and difficulty with feeding. Within the first year, weakness
in the various subunits of the AChR can lead to either an in- of limb muscles, with susceptibility to rapid fatigue, was noted.
creased response to ACh as in slow-channel syndromes, or a Her motor milestones were delayed. Anticholinesterase medica-
decreased response to ACh, as in fast-channel syndrome, de- tion improved her symptoms. The parents were unaffected.
pending.on the location and type (i.e., null, nonsense, or mis- Histopathology. Morphometric muscle analysis docu-
sense) of the mutation. mented a 93% reduction in AChRs at the postsynaptic mem-
Microphysiologic studies of an intercostal muscle shows a brane. The postsynaptic membrane itself appeared normal.
normal EPP quantal content to 1-Hz stimulation.280-282 Patch- Nerve terminal and synaptic vesicles also appeared normal.
clamp studies demonstrate infrequent AChR channel openings, Pathogenesis and Pathophysiology. Intercostal muscle EPP
brief activation episodes, and increased resistance to desensiti- quantal content and amount of ACh released per nerve terminal
zation by ACh.720 MEPP and current flows are abnormally large, activation were normal. MEPP amplitude was reduced in size
whereas their decay time constants are abnormally short. The with an increment to neostigmine application. AChR conduc-
AChR channel conductance is roughly 1.7 times greater than tance was normal, but the open time was reduced (1.6 ms com-
normal with a 39% reduction in mean open time. pared with 2.3 ms). The combination of a decreased number of
The exact mechanism whereby the NMJ safety factor is re- AChRs with reduced channel open time generates EPPs that are
duced is unclear. An endplate myopathy may be present sec- subthreshold. Continued nerve terminal activation results in the
ondary to abnormal channel kinetics, similar to slow-channel normal decline of ACh to a new level with each stimulus, predis-
congenital myasthenic syndrome. posing borderline NMJs to fail with a resultant decline in se-
Electrophysiologic Findings. Sensory and motor nerve con- quentially obtained CMAPs. The pathogenic basis for this form
duction studies are normal. Repetitive stimulation demonstrates of CMS is not known but probably involves mutations of an
a mild decrement with 3 Hz stimulation. AChR subunit that results in both the observed kinetic abnormal-
ity of receptor physiology and receptor deficiency.
Congenital Myasthenia Gravis With Electrophysiologic Findings. Routine motor and sensory
Primary AChR Deficiency studies are normal. Repetitive stimulation at 2-3 Hz may
Clinical Features. Several patients have presented during demonstrate an abnormal decremental response.
the neonatal period with feeding difficulties, nasal regurgitation,
ptosis, impaired eye movements, and reduced overall tone Congenital Myasthenia with Mode-switching Kinetics
(Table 25- 1 3).282.283.287.288.531.668,698.87I,881,971.993 A s t n e children de¬ Clinical Features. A 39-year old woman experienced ocu-
velop, they have delayed motor milestones with progression of lar, bulbar, and limb weakness from early childhood.657 After an
symptoms. Weakness and exertion-induced fatigue are promi- operation during which she was treated with a nondepolarizing
nent. The inheritance pattern is apparently autosomal recessive. neuromuscular blocking agent, she had prolonged paralysis.
Histopathology. Light microscopic analysis of muscle After recovery she was evaluated for an underlying NMJ defect
tissue may demonstrate type 1 fiber predominance. AChE activ- (see below). The patient had a brother and sister with similar
ity is dispersed over an increased area of individual muscle symptoms. Her mother and daughter had no problems. She had
fibers, with a decreased number of AChRs located on the post- partial improvement in strength with Mestinon.
synaptic membranes. Immunocytochemistry studies reveal the Histopathology. Muscle biopsies demonstrate a deficiency
presence of fetal AChR, that contain the y-subunit instead of the of AChR at the endplates and a compensatory expression of
fetal AChR containing the y subunit.657 Ultrastructural analysis with sparing of the bulbar muscles. Mild weakness also may be
reveals simplification of the postsynaptic region. found in the distal limb muscles. In more severely affected pa-
Pathogenesis and Pathophysiology. Heteroalleic mutations tients, a waddling gait and Gower's sign can be readily demon-
in the AChR £ subunit gene were identified.657 There was an in- strated. Deep tendon reflexes may be normal or hypoactive. An
frame duplication in the long cytoplasmic loop of £ 1254insl8, improvement in strength usually is observed with administra-
which determines physiologic phenotype, in combination with a tion of anticholinesterase medication.
null mutation at £ CI285. The £ 1254insl8 mutation resulted in v Histopathology. Muscle biopsies have revealed tubular ag-
mode-switching kinetics of AChR receptor activation, in which gregates along with nonspecific myopathic changes.224-321 EM
the channel opened more slowly and closed more rapidly than demonstrates normal appearance of the neuromuscular junction.
normal. Density of AChRs and synaptic vesicles also is normal.
Electrophysiologic Findings. The patient had a decrement Pathogenesis and Pathophysiology. The exact cause of this
on repetitive stimulation. No other details of the electrodiagnos- disorder is not known because of the lack of detailed electro-
tic examination were provided. physiologic and morphologic analysis. The limited electrophys-
iologic studies performed to date suggest that the defect is
PARTIALLY CHARACTERIZED CONGENITAL probably at the postsynaptic membrane. Obviously further in-
MYASTHENIC SYNDROMES vestigations are necessary before the disease can be adequately
categorized as presynaptic or postsynaptic.
Congenital Myasthenia With Abnormal Electrophysiologic Findings. Sensory and motor nerve con-
ACh-AChR Interactions duction velocities are normal.224-321-454-639 The initial CMAP is
usually of normal amplitude with a decrement at low rates of
Clinical Features. An adult woman reported complaints of repetitive stimulation. Routine needle EMG examination re-
severe generalized weakness and susceptibility to fatigue from veals MUAP variability; potentials of decreased amplitude and
birth (Table 25-13).280-282-283-288'962 Her parents and two younger duration and increased phases are highly suggestive of a my-
siblings were unaffected. The administration of anticholinesterase opathy. Anticholinesterase medication tends to decrease the
medication only partially improved her symptoms. Additional pa- variability and improve the interference pattern on attempts at
tients may have been reported with similar findings and patho- maximal voluntary contraction. Occasionally complex repeti-
physiology, but inadequate microelectrode analysis limits tive discharges may be observed, but there is a distinct lack of
conclusions about the most appropriate disease category.971 positive sharp waves and fibrillation potentials. SFEMG reveals
Histopathology. Morphologic investigation of NMJs demon- increased jitter and blocking.
strated no detectable presynaptic or postsynaptic abnormality.
The synaptic vesicles were of normal size, and the postjunctional TREATMENT OF CONGENITAL
folds appeared normal. Binding studies revealed a normal MYASTHENIC SYNDROMES
number of AChRs located on the postsynaptic membrane.
Pathogenesis and Pathophysiology. Microphysiologic stud- Plasma exchange, IVIG, thymectomy, corticosteroids, and
ies showed a normal EPP quantal content, but MEPPs and EPPs other immunosuppressive agents are not beneficial in patients
were markedly reduced in magnitude. Microphysiologic analysis with CMS. Edrophonium (Tensilon) and mestinon may improve
of single AChR kinetics demonstrated normal single-channel con- strength in patients with presynaptic defects, primary AChR re-
ductance, but two different channel open times were noted at 0.44 ceptor deficiency, and fast-channel syndrome.282-283 CMS asso-
ms and 4.97 ms compared with a control open time of 2.27 ms. ciated with mode-switching kinetics, slow-channel syndrome,
Clinical symptoms and electrophysiologic findings (see below) and AChE deficiency respond variably or poorly to anti-
leave no doubt that a reduced safety factor is present. Either a de- cholinesterase medications. Quinidine may be helpful in slow-
creased ACh synaptic vesicle content (presynaptic) or some type channel syndromes by shortening and even normalizing the
of AChR abnormality (postsynaptic) may explain the combina- duration of mutant channel openings. Harper and Engel demon-
tion of normal numbers of AChRs and small MEPPs. The strated that administration of quinidine with serum levels of
normal-appearing presynaptic vesicles and dual AChR channel 0.7-2.5 |Lig/ml improved clinical and electrophysiological fea-
kinetics suggest that the abnormality lies in the AChR. A dual tures in patients with slow-channel syndrome.377
population of AChRs may be present—or some abnormality in Because of the presynaptic nature of many types of CMS
the interaction between ACh and the AChR with respect to the and the beneficial response seen in many patients with LEMS,
manner in which the channels respond to ACh. A reduced affinity several investigators have tried 3,4-DAP in different types of
between ACh and AChRs is the likely explanation for clinical and CMS.378-741 In a relatively large study for this rare condition,
electrophysiologic findings. 3,4-DAP was used to treat 31 patients with various forms of
Electrophysiologic Findings. The routine motor and nerve CMS (fast-channel syndrome, 10; primary AChR deficiency,
conduction studies are normal. Repetitive stimulation of periph- 17; and other CMS, 4). 378 All patients improved after a single
eral nerves at 2 Hz reveals a decrementing response. test dose of 3,4-DAP, 0.25 gm/kg. On a maintenance dose of 1
mg/kg/day, the fast-channel patients responded best with sus-
Familial Limb-Girdle Myasthenia tained improvement. Only a few patients with primary AChR
Clinical Features. This autosomal recessive disorder is deficiency responded, whereas the other patients with CMS
characterized by weakness and exertion-induced fatigue of the failed to improve. 3,4-DAP applied to an anconeus muscle
limb-girdle muscles and may present in childhood or early adult biopsy specimens during intracellular micoelectrode record-
life 224.282.283.32i.454.639 jftg w e a kness usually manifests with an in- ings under voltage and current clamp conditions in various
ability to perform activities of daily living requiring overhead types of CMS produced interesting results. 92 The application
activities and difficulty in arising from the commode. Physical of 3,4-DAP increased the quantal release of ACh. This effect
examination reveals marked weakness of the limb-girdle muscles was most pronounced in patients with presynaptic failure and
normal endplate ultrastructure and patients with postsynaptic AChRs, thereby increasing the EPP magnitude and safety
failure with normal AChR channel kinetics. Increased ACh factor. The aminopyridines and calcium partially repair the
quantal release was more modest in patients with postsynaptic block through release of more ACh. The observation of both
failure and altered AChR channel kinetics. 3,4-DAP induced effects with a particular drug or toxin may imply that it can
worsening in patients with slow-channel syndrome. produce both prejunctional and postjunctional adverse effects
on NMJ transmission.
DRUGS A N D T O X I N S MODULATING PRESYNAPTIC DISORDERS (PERIPHERAL NERVE
NEUROMUSCULAR J U N C T I O N AND NERVE TERMINAL)
TRANSMISSION
Sodium Channel Dysfunction
A large number of drugs and naturally occurring toxins have
the capability of either hindering or facilitating NMJ transmis- Toxins. A number of toxins may result in profound neuro-
sion. These substances can be categorized in a number of ways, muscular symptoms and even death, not by directly affecting
all of which can be rather daunting. Perhaps one of the most the NMJ, but by preventing action potential invasion into the
functional methods is that of Rivner and Swift.800 This classifi- nerve terminal. These substances are mentioned for complete-
cation is in keeping with the vulnerable areas in the various ness and to provide some insight into their mechanism of action.
steps of NMJ transmission: (1) peripheral nerve and nerve ter- Two basic effects are possible with respect to the sodium chan-
minal, (2) synaptic space containing AChE, and (3) postsynap- nel. First, the sodium channels may be blocked, which results in
tic membrane and the AChRs. action potential failure. Secondly, sodium inactivation can be
Despite intense research into the mode of action of a number of delayed, thereby prolonging the flow of sodium ions and hence
drugs and toxins, the incompletely understood mechanism of NMJ the action potential. In the case of the nerve terminal, a pro-
transmission limits our understanding of how any drug or toxin ul- longed action potential acts to extend calcium entry and thereby
timately produces NMJ dysfunction. This is particularly true for facilitates increased amounts of ACh release.
the action of various antibiotics. A veritable multitude of individ- Tetrodotoxin and saxitoxin are two of the most lethal toxins
ual case reports and poorly characterized clinical studies cast seri- known; only about 8 p.g/kg is required to cause death in mice. 466
ous doubt on both the true nature of drug-induced block and, in Death results from respiratory paralysis through NMJ failure
particular, its site of action. Because most case reports do not use due to sodium channel blockade. Tetrodotoxin is found in the
electrodiagnostic techniques, no comment can be made about the visceral organs of some fish belonging to the order Tetra-
expected type of electrophysiologic findings. Carefully controlled odontiformes (e.g., Japanese puffer fish). Saxitoxin is produced
investigations of animal tissue are not necessarily related to human by the dinoflagellates (Gonyaulax catanella, and G. tamerensis)
cases of drug- and toxin-induced NMJ disorders. If the reader en- and retained in the various tissues of shellfish that consume
counters patients with any of these disorders and documents elec- these organisms. Under certain conditions, these organisms can
trophysiologic findings, a case report may be of great interest. multiply rapidly and discolor the ocean, accounting for the
The most important aspect of drug-induced NMJ transmission name red tide. Consuming infected fish can result in profound
failure is situations that predispose to development of adverse weakness and respiratory failure, with ensuing death if life-
side effects. This category includes patients receiving some type saving measures are not instituted immediately.
of medication that produces NMJ transmission failure as an un- A number of naturally occurring toxins can facilitate ACh re-
intended adverse effect, such as a number of antibiotics (see lease by prolonging sodium inactivation or directly activating
below). Patients who are elderly, recovering from general anes- sodium channels. Ciguatoxin is a potent toxin produced by the
thesia, or taking neuromuscular blocking agents; patients with dinoflagellate Gambierdiscus toxicus; it is consumed by and ac-
previously diagnosed neuromuscular junction defects, subclini- cumulates in various reef fish.924 People who consume fish con-
cal neuromuscular junction disorders, or compromised renal or taining the toxin develop characteristic symptoms of abdominal
liver function; and patients who receive mistakenly large dosages pain, limb paresthesia, circumoral paresthesias, perception of
of certain medications are prone to develop NMJ failure. cold substances (e.g., water, ice) as hot, arthralgias/myalgias, and
In most clinical evaluations of drug or toxin effects on NMJ other generalized symptoms of gastrointestinal upset. These
transmission, a number of observations help to define whether symptoms arise because the toxin activates the sodium channels
the NMJ block is primarily presynaptic or postsynaptic. 888 A in the nerve terminal. Ciguatera poisoning should be kept in mind
presynaptic NMJ block is essentially defined if the following for patients considered to have atypical GBS. Death is rare and
characteristics are detected: (1) decreased amounts ACh re- occurs only if the person consumes very high concentrations of
leased (quantal content), (2) normal sensitivity of the AChR, (3) the poison and ventilator support is not available. Toxin II pro-
normal muscle response to direct stimulation, and (4) reversibil- duced by the sea anemone (Ammonia sulcata) delays sodium
ity of the block with the application of aminopyridine or 3,4- channel inactivation, thus potentiating ACh release.293 ACh re-
DAP. Both drugs block potassium channels in the nerve lease is also increased by toxin gamma injected into the victim by
terminal and thus prolong the depolarization phase, thereby pro- a Brazilian scorpion (Tityus serrulatus)?75 Similarly, a bite from
longing calcium entry and facilitating ACh release. the spider Phoneutria nigriventer can result in spastic paralysis,
A postsynaptic NMJ block is characterized by (1) normal muscle pain, abdominal cramps, seizures, and cardiovascular dis-
ACh release (quantal content), (2) decreased AChR sensitivity, turbances due to nerve terminal sodium channel activation.317
(3) normal muscle response to direct stimulation, and (4) re-
versibility of the block by anticholinesterase administration and Potassium Channel Dysfunction
partial reversibility with the aminopyridines and solutions con- Drugs. A number of drugs have the potential to modulate the
taining high concentrations of calcium. The block reversal with neural action potential as it descends into the nerve terminal
anticholinesterase medications spares more ACh to interact with region. Altering the action potential can have secondary effects
on transmitter release with an ensuing alteration in NMJ trans- Additional Mechanisms
mission. The aminopyridines prolong the action potential about Drugs. Numerous other drugs can impair NMJ function, but
the nerve terminal by blocking the voltage-gated potassium their exact mechanism of action is even less clear than that of the
channels and slowing the action potential's repolarization discussed drugs above. Corticosteroids are believed to affect the
phase.336 In this instance, the effect is to promote transmitter re- nerve terminal membrane directly by causing depolarization and
lease and at least partially reverse adverse effects secondary to eventually leading to a reduction in the release of ACh as well as
reduced ACh release. As noted above, these drugs have limited alterations in MEPPs and intracellular potassium concentra-
use in clinical situations such as LEMS. tions.927-990 A combination of these effects may explain the wors-
Toxins. Blockade of nerve terminal potassium channels ening of strength in some patients with myasthenia gravis during
with associated prolongation of the action potential and en- the initial phases of corticosteroid administration. Strength even-
hanced ACh release can result from dendrotoxin (venom of tually improves because of the immunosuppressive effects of the
the black and green mamba [Dendroaspis angusticeps and drug. Azathioprine is thought to inhibit the enzyme phosphodi-
Dendroaspis polylepis]) and a particular type of scorpion esterase, which hydrolyzes cyclic AMP. Increased amounts of
sting (Pandinus imperator).999 The net result is an increase in cyclic AMP potentiate ACh release.237-500 Theophylline and pa-
EPP amplitude and repetitive EPPs. Cramps and fascicula- paverine also enhance NMJ transmission through the same
tions may be seen in people particularly sensitive to the toxin mechanism. 386 On the other hand, imidazole potentiates phos-
who are injected with large amounts of the snake venom; phodiesterase and indirectly reduces ACh release.
death may occur. The Australian tiger snake (Notechis scuta- Toxins. Several toxins produced by snakes and arthropods
tus) produces a lethal mouse venom (notexin) that blocks can impair ACh release from the nerve terminal through less than
potassium channels, thus decreasing the release of ACh from fully understood mechanisms. A phospholipase toxin in the
the nerve terminal. 663 venom of the multibanded krait (Bungarus multicinctus), re-
ferred to as (3-bungarotoxin, is injected into victims through the
Calcium Channel Dysfunction snake's fangs.317-641-663 The venom also can be sprayed at the
Drugs. Nerve terminal voltage-gated calcium channels are victim. Crotoxin from the Brazilian rattle-snake (Crotalus duris-
opened by nerve terminal depolarization. Calcium entry facilitates sus) initially increases and then depresses the amount of ACh re-
ACh release through a poorly understood mechanism. Interference leased from the nerve terminal. The symptoms produced by the
with calcium entry or calcium-dependent ACh release adversely bite of these snakes are variable, depending on the amount of
affects NMJ transmission. Several categories of drugs can alter venom injected and the size and tolerance of the victim. Many
nerve terminal calcium conductance and thus influence NMJ snake venoms contain both presynaptic and postsynaptic toxins,
transmission. An example is calcium channel blockers. and it is difficult to separate the effects due to the presynaptic
Different types of calcium channels have specific affinities effect. Local pain and swelling, mild cranial nerve palsies, and
for the various calcium channel inhibitors. Although these drugs variable degrees of respiratory paralysis are common symptoms.
do not affect NMJ transmission in most persons, patients with Both the black widow (Latrodectus mactans) and brown
myasthenia gravis may experience a worsening of weakness widow {Lactrodectus geometricus) produce a number of toxins,
after administration of verapamil and diltiazem.11-535-923 one of which, known as oc-latrotoxin, has been studied rather ex-
Antibiotics (particularly the aminoglycosides) also can ad- tensively.156-423-816 This toxin has an unclear mechanism of action
versely affect calcium nerve terminal entry.549-844 Neomycin and but results in a large increase (500-1000-fold) in the sponta-
polymyxin B can have especially profound effects on NMJ trans- neous MEPP frequency for the first several minutes of exposure
mission.I8-36123-234 Streptomycin is somewhat less potent in reduc- to the NMJ. Over the next 30 minutes MEPPs decline until they
ing NMJ transmission. Both clindamycin and oxytetracycline are no longer observed. The nerve terminal is swollen and com-
have a comparatively reduced ability to prevent voltage-depen- pletely devoid of synaptic vesicles. Patients at first experience
dent calcium entry. Moderate disturbances in NMJ transmission pain at the site of the bite, followed by pain in the limb that mi-
are found in experimental preparations subjected to kanamycin, grates to other large muscle groups. Muscle cramps and abdomi-
lincomycin, gentamicin, tobramycin, and amikacin. nal rigidity also can be observed. Within 2-4 hours patients
The administration of magnesium salts can adversely affect become hypertensive and may demonstrate mild cardiac arrhyth-
NMJ transmission by competitively inhibiting calcium entry mias. Additional signs of autonomic instability may occur, and
into the nerve terminal.54128-509-911-926 Reducing the amount of rarely opisthotonus may be observed in severe envenomations.
calcium entering the nerve terminal reduces the amount of ACh
released. This effect is particularly important in preeclamptic Synaptic Space Disorders (Anticholinesterase Agents)
women who receive magnesium sulphate and have a reduced In this category, the term drug designates anticholinesterases
ability to eliminate the drug and patients with a subclinical NMJ used for therapeutic purposes in various NMJ disorders, and the
defect, such as myasthenia gravis. The electrophysiologic stud- term toxin refers to agents synthesized for the purpose of caus-
ies can be expected to generate a low-amplitude CMAP that fa- ing harm or death to both insects (insecticides) and humans
cilitates with exercise or high rates of stimulation. (wartime poisons).
A unique toxin produced by the marine snail (Conus geogra- The primary action of anticholinesterase agents is to bind with
phies) is known as m-conotoxin.489-724-841 This potent toxin can AChE and effectively act as a substrate for the enzyme, thus re-
severely debilitate or even kill humans and is presently used to sulting in less hydrolyzed ACh. From a therapeutic standpoint, in
study neuromuscular transmission disorders, particularly those disorders in which insufficient amounts of ACh reach the postsy-
affecting the presynaptic nerve terminal. The toxin has the spe- naptic membrane or the AChRs are decreased or react inefficiently
cial ability to bind to voltage-dependent calcium channels, with ACh, an anticholinesterase drug can restore the safety factor.
thereby preventing calcium entry and ACh release. By radiola- Larger amounts of ACh repetitively bind with AChRs to prolong
beling the toxin and allowing it to bind to the nerve terminal, it the current flow into the postsynaptic membrane and hopefully
is possible to identify the calcium channels. reach the muscle membrane's threshold level for depolarization.
Drugs. Three drugs are commonly used in disorders in amount of exposure, and route of administration, death can
which an increase in the amount of synaptic space ACh is occur in less than 5 minutes or after 2 4 hours or more, particu-
deemed beneficial: neostigmine bromide, pyridostigmine bro- larly if treatment is not instituted promptly. Atropine in appro-
mide, and the short-acting edrophonium chloride. 337 These priate dosages, an AChE reactivator (e.g., pralidoxime), and
drugs are reversibly bound to AChE because they are eventually respiratory support are the mainstays of treatment, combined
hydrolyzed by AChE in a similar manner to ACh. Once the drug with elimination of the toxin.
is hydrolyzed, the released ACh has already served its purpose The electrophysiologic presentation of acute organophosphate
in mediating neuromuscular transmission. It is subsequently hy- intoxication is rather unique.67'235-366'448-6'4-803-863-976 Motor and sen-
drolyzed by the unbound AChE or the AChE that has hy- sory nerve conduction velocities are essentially normal within the
drolyzed the drug. first 24-48 hours. A mild slowing may become manifest later. The
Toxins. A large class of organophosphate compounds are CMAP demonstrates a relatively low amplitude in severe intoxica-
toxic anticholinesterase agents.337-357-689-690 These substances are tion, with little if any reduction in less severe cases. In about 6 0 %
toxic because they bind in a relatively irreversible manner with or more of patients, a repetitive response to motor stimulation can
AChE. A number of these compounds are eventually hy- be seen, with more than one CMAP produced to a single nerve
drolyzed, but the rate is so slow that the damaging effects of stimulus. This is believed to be the most sensitive electrophysio-
continuous depolarizing amounts of ACh at the nerve terminal logic indicator of toxicity early in the disease. Specifically, a single
may be fatal before the toxic substances are eliminated from the peripheral nerve shock reveals several CMAPs of decreasing am-
system. Some of the more potent toxins are irreversibly bound plitude after the first CMAP (Fig. 25-43). 6 1 4 Performing diaphrag-
and cannot be removed; clinical recovery requires resynthesis matic CMAP studies may assist in the implementation of
of AChE. Organophosphate agents have two primary uses: (1) mechanical ventilation. Persons requiring ventilation displayed a
nerve agents during war and (2) insecticides/pesticides. The mean diaphragmatic CMAP of 119.1 ± 173.9 JIV compared to
nerve agents tabun, sarin, and soman are among the most potent persons not requiring ventilation (461.6 ± 138.7 U.V) in the acute
neurologic poisons known; less than 1 mg is required to kill ro- period.3223 Edrophonium chloride (Tensilon) administration results
dents. Perhaps the most common insecticide responsible for in marked deterioration of the repetitive stimulation test with a sig-
human intoxications is parathion. nificant reduction in CMAP amplitude that returns to the resting
Accidental exposure usually occurs through the dermal and level of decrement and CMAP magnitude within about 3 0 sec-
pulmonary route, whereas intentional exposure (suicide/homi- onds.612 Application of d-tubocurarine repairs the decrement by
cide) is typically by oral consumption.870-931 The initial symp- decreasing the number of AChRs available to the excessive ACh.
toms of acute exposure are usually the muscarinic effects of The repetitive nature of the CMAP to a single stimulus results
miosis, wheezing (bronchoconstriction plus increased bronchial from prolongation of the suprathreshold EPP duration, which
secretions), and, when the toxin is ingested, gastrointestinal outlasts the muscle membrane's refractory period because of the
symptoms (i.e., abdominal cramping, nausea, and vomiting), persistence of ACh in the synaptic cleft. Patients with significant
sweating, salivation, involuntary urination and defecation, intoxication reveal a decrement to repetitive stimulation at low
bradycardia, and hypotension. Nicotinic or neuromuscular rates, whereas patients with moderate to mild intoxication reveal
symptoms such as weakness and fatigue of skeletal muscles a decrement only at rates greater than 10 Hz. Postactivation fa-
with fasciculations can be noted, eventually leading to respira- cilitation is absent.
tory muscle paralysis. An altered sensorium also may be ob- A rather unique feature of organophosphate toxicity is a decre-
served secondary to CNS effects. Depending on the agent, ment-increment pattern to repetitive stimulation that is observed
Figure 25-43. Typical CMAPs produced to

both repetitive and single peripheral nerve
stimulation in organophosphate poisoning.The
findings are from a rat model, but similar observations
occur in humans. A and B, Control CMAP responses
from repetitive (50-Hz) and single stimuli. C, Note the
significant amplitude reduction from the first to the
second response with an increment thereafter. D , A
single stimulus results in repetitive firing of the muscle
that eventually returns to baseline. E,A profound de-
crease in amplitude of the first several responses
occurs after edrophonium chloride injection. F,
Essentially the same response to a single stimulus
after edrophonium chloride injection as that observed
previously (D). G, Recording performed after the in-
jection of d-tubocurarine with a relative repair in the
decrement and fewer firings after a single stimulus
(H). (From Maselli RA, Soliven BC: Analysis of the
organophosphate-induced electromyographic re-
sponse to repetitive stimulation: Paradoxical response
to edrophonium and D-tubocurarine. Muscle Nerve
1991; 14:1182-1 188, with permission.)
primarily early in the course of the disorder or in later stages of re- Succinylcholine and decamethonium also act on the AChR
covery Fig. 25-43). Specifically, an initial decrement to repetitive but in a totally different manner from curare. 337 Both sub-
stimulation is followed by an increment to the resting level at high stances bind to the AChR and persist in the synaptic space.
rates of stimulation. During repetitive stimulation, the second and Thus the postsynaptic membrane is depolarized and maintained
third CMAPs evoked during single stimulation are fused into the in this state. The net result is a brief period of repetitive activ-
subsequent CMAPs and no longer observed. Needle EMG exami- ity, such as fasciculations with subsequent neuromuscular
nation reveals no positive sharp waves or fibrillation potentials block and flaccid paralysis. Nicotine is a powerful drug with
during the initial stages of the disease. The only abnormality is a the ability to bind to the AChR with an initial depolarization
reduction in the number of voluntary MUAPs. (facilitation effect) and subsequent inactivation of the AChR
Chronic exposure can lead to an axonal neuropathy. The (paralysis).
motor and sensory amplitudes are reduced, along with a mild Several drugs act exclusively at the NMJ's postsynaptic
reduction in the nerve conduction velocity. Membrane instabil- membrane, whereas others act both presynaptically and postsy-
ity during needle EMG can be observed in severe intoxication. naptically.36-123-236-337-428-886-927 Polymixin B, polymixin E, netilmicin,
Recovery is lengthy and may be incomplete. and colistin can produce significant, primarily postsynaptic neu-
romuscular effects, particularly in patients susceptible to this
POSTSYNAPTIC DISORDERS type of dysfunction (see above). Tetracycline, oxytetracycline,
and rolitetracycline can produce postsynaptic blockade but to a
Drugs. The best known postsynaptic drug/toxin is curare (d- less severe degree. A number of the aminoglycosides (strepto-
tubocurarine), a naturally occurring derivative of the plant mycin, neomycin, kanamycin, gentamicin, tobramycin, and
Strychnos toxifera.331 Indigenous peoples of South American use amikacin) can act both presynaptically and postsynaptically.
the substance as a poison for arrow tips in hunting food. Curare Lincomycin and clindamycin have primarily a postsynaptic
binds to the AChRs, effectively prohibiting neuromuscular trans- effect at low concentrations but can also disturb ACh release
mission through competitive blockade with ACh, and thus prevents from the nerve terminal in large dosages. 813 The exact mecha-
an EPP from being generated in profound block or from reaching nism of how these drugs produce their effects remains to be
threshold at lower concentrations. The individual AChR channels fully elucidated. Procainamide can worsen symptoms in pa-
are simply prevented from reacting to ACh through a blockade tients with NMJ disorders through both presynaptic and postsy-
effect. Therefore, the channel conductance and open time are unaf- naptic effects that are poorly understood. 533 There are a few
fected. Related compounds used in anesthesia for neuromuscular reports of verapamil impeding NMJ transmission. 255 It is also
block and relaxation of skeletal muscles are pancuronium, vecuro- possible for persons taking excessive amounts of thiamin to ex-
nium, atracurium, and gallamine. A reduced CMAP that decre- perience an alteration in the kinetics of the AChR with an asso-
ments at low rates or repetitive stimulation can be expected. The ciated elevation in jitter, as documented by single-fiber EMG. 776
results are similar to those observed in myasthenia gravis. The A unique syndrome clinically indistinguishable from auto-
MUAP declines in magnitude as single muscle fibers belonging to immune myasthenia gravis may complicate penicillamine ther-
a particular motor unit serially block with increasing dosages of apy.1 5.16,69.306.625.817 Penicillamine is a chelating agent used in
curare.569 Similarly, doses of curare incapable of producing clinical patients suffering from heavy metal intoxication and Wilson's
weakness nevertheless produce an increase in jitter.259-269 disease. It also is used in patients with rheumatoid arthritis to
Of particular interest is a poorly defined syndrome referred to suppress the adverse effects of the disease. Rare patients de-
as postparalysis paralysis syndrome.345.798.1000 p o r a n u n clear velop clinical features, serum AChR antibodies, and electrical
reason, certain people are particularly prone to developing dys- evidence consistent with autoimmune myasthenia gravis that re-
function of the peripheral nervous and neuromuscular systems solves with drug withdrawal. The mechanism of antibody in-
after prolonged administration of the short-acting neuromuscu- duction directed against the AChR is unclear.
lar blocking agents vecuronium or atracurium, often in combi- Toxins. Most naturally occurring toxins that can bind with
nation with corticosteroid administration. After cessation of the great affinity and, in some cases, irreversibly to the AChR are
NMJ blocking agents for 1-52 days, patients continue to found in the venom of snakes belonging to the families Elapidae
demonstrate clinical signs and symptoms suggestive of both pe- or Hydrophiidae.381-641 Each snake produces several toxins,
ripheral nerve and NMJ dysfunction. Hepatic insufficiency may which generally are referred to as curarimimetic because they
or may not be present. mimic the actions of curare by rendering the AChR incapable of
Electrodiagnostic medicine evaluations demonstrate CMAPs of responding to ACh. The competitive blocking nature of these
reduced amplitudes, normal latencies and velocities, and marked toxins obviously results in a reduced safety factor by rendering
decremental responses during 2-3-Hz repetitive stimulation. This EPPs absent or so small that threshold cannot be reached. Thus
finding can be observed for up to 9 days, after which a decrement paresis or flaccid paralysis is produced.
may no longer be appreciated. Rapid rates of stimulation (20-50 Two of the better known snake toxins, oc-bungarotoxin and
Hz) do not result in facilitation. Needle EMG may reveal mild to a-cobratoxin, are contained in the venoms of the banded krait
significant amounts of positive sharp waves and fibrillation poten- Bungarus multicinctus and the Siamese cobra (Naja naja sia-
tials associated with short-duration, small-amplitude MUAPs mensis), respectively.317-466-663 The ability of these toxins to bind
during the later stages of the disorder. In addition to the prolonged tightly to the AChR allows them to serve as radiolabeled mark-
NMJ blockade after withdrawal of the medication, sural nerve ers for AChRs; they have become valuable research tools, like
biopsy reveals evidence consistent with axonal loss. There appears many other toxins. Other toxins in snake venoms are poorly
to be an early phase of neuromuscular blockade, most likely af- characterized but act in concert with the above toxins to render
fecting both presynaptic and postsynaptic portions of the NMJ, the AChR effectively blocked. The clinical manifestations of
followed by a late-onset axonal neuropathy. The "myopathic" snake bites depend on the amount of toxin injected and the pa-
MUAPs may result from NMJ failure or a direct toxic effect on tient's size and natural tolerance. The combination of presynap-
muscle fibers, resulting in a myopathic process. tic and postsynaptic toxins eventually produces respiratory
paralysis and death. Additional hemolytic and autonomic signs
and symptoms are usually present.
The marine snail Conus geographicus produces oc-conotoxin,
a competitive ligand with ACh for binding with the AChR, for
which it has a high affinity.724 The toxin's binding reduces the
safety factory and produces a flaccid paralysis..This toxin is not
used as frequently as its presynaptically acting counterpart, co-
conotoxin (see above).
OTHER DISORDERS T H A T MAY MANIFEST

W I T H NMJ DYSFUNCTION
Electrodiagnostic medicine testing can reveal CMAP decre-
ments to repetitive stimulation in a number of disorders not
commonly associated with neuromuscular junction disease. It is
perhaps best to consider any disease process that disturbs neuro-
muscular transmission either directly by disrupting some step in
the release and binding of ACh or indirectly by resulting in the
formation of new NMJs secondary to axonal loss. Repetitive ac- Figure 25-44. Amyotrophic lateral sclerosis. A 53-year-old
tivation of the muscle membrane also can result in failure of woman with amyotrophic lateral sclerosis demonstrates a significant
action potential transmission across the muscle fiber in the pres- decrement at low rates of stimulation. Postactivation facilitation and
ence of an intrinsic membrane defect. A number of disorders postactivation exhaustion also are noted.These findings are quite sim-
with abnormal decremental responses to repetitive stimulation ilar to those in myasthenia gravis. (From, Desmedt JE:The neuromus-
are discussed below. cular disorder in myasthenia gravis. I: Electrical and mechanical
Multiple Sclerosis. Two rather interesting situations may responses to nerve stimulation in hand muscle. In Desmedt JE (ed):
occur in patients with multiple sclerosis. The first is the rare N e w Developments in Electromyography and Clinical Neuro-
combination of concurrent myasthenia gravis and multiple scle- physiology. Karger, Basel, 1973, pp 241-304, with permission.)
rosis. 14,132.258.607.754 Patients essentially suffer the clinical symp-
toms associated with both disorders. The relapsing signs and neuromuscular junction defect. Some patients simply may be
symptoms consistent with central nervous system dysfunction unfortunate enough to acquire two rather significant diseases
disseminated in time and space are superimposed on muscle with some type of autoimmune basis, or there may be a spec-
weakness and excessive fatigability. Serum and radiographic trum of neuromuscular transmission defects in patients with
studies are suggestive of multiple sclerosis, whereas electro- multiple sclerosis, with a few who are more prone to developing
physiologic studies reveal typical decrementing responses and significant NMJ dysfunction.
facilitation consistent with myasthenia gravis. The weakness Anterior Horn Cell Diseases. Patients with poliomyelitis
and fatigue respond quite well to anticholinesterase medication, and amyotrophic lateral sclerosis (ALS) may demonstrate a
whereas the central findings are refractory. This combination of mild decrement on repetitive stimulation (Fig. 25-44).215-412-674
diseases may be an overlap syndrome in which the immune The decrementing CMAP response is more likely to be seen in
system is stimulated by unknown factors to respond not only muscle groups with greater atrophy, regardless of the rate of
against postsynaptic AChRs but also against myelin through a progression of disease, whereas patients with more rapidly pro-
process of demyelination/remyelination. gressive disease have a greater chance of expressing a decre-
A second interesting group of patients with typical multiple mental response in both less affected and more severely affected
sclerosis have subclinical disorders of neuromuscular transmis- muscles.65-109-124-16019'-207-209-920 The observed decrement can occur
sion. Specifically, single-fiber EMG has demonstrated increased at any frequency of stimulation, but it is more likely to be ob-
jitter in patients with documented multiple sclerosis.982-983 Unlike served at frequencies in excess of 10 Hz, particularly in rela-
the above patients, however, they do not have overt symptoms of tively less affected muscle groups. When a decrement is present,
weakness and fatigue suggestive of myasthenia gravis. Similarly, the CMAP facilitates to exercise and the decrement repairs.
quantitative needle EMG shows that the individual MUAPs are Postactivation exhaustion is also present. A decrease in temper-
increased in duration and amplitude compared with control ature can completely repair a mild decrement or decrease a pro-
values, suggesting motor unit remodeling through collateral found decrement. Single-fiber EMG reveals an increase in jitter
sprouting, no doubt arising as a result of subclinical denerva- with variable fiber density findings, depending on the chronicity
tion. Some of these patients may have a peripheral neuropathy, of the disease.896-898 Needle EMG examination can reveal large-
whereas others do not. Furthermore, patients with multiple scle- amplitude, long-duration MUAPs with variable configuration
rosis and no signs or symptoms suggestive of a neuromuscular with continuous activation. The documentation of large motor
junction defect require a prolonged time to recover from the ad- units, reduced recruitment, and membrane instability distin-
ministration of d-tubocurarine compared with normal per- guishes this disease from myasthenia gravis despite the decre-
sons. 258 A regional curare test shows a decrement to repetitive menting response.
stimulation that returns to normal only after considerably longer The neuromuscular defect may be a combination of both pre-
periods than in normal persons, again suggesting a latent defect junctional and postjunctional factors. A dying motor neuron may
in neuromuscular transmission. These findings also are consis- have difficulty in supplying the necessary trophic factors to
tent with some form of peripheral nerve axonal loss as well as maintain the neuromuscular junction machinery at peak operating
demyelination 775 or an ill-defined presynaptic or postsynaptic
prestimulus level in about 1-2 minutes. If the nerve is stimu-
lated at 20 Hz or greater, a decrement in the CMAP is noted.
These electrical observations probably result not from a NMJ
defect but rather from muscle membrane channelopathy.
Myotonic Disorders. In the various forms of myotonia (my-
otonia congenita, which can be autosomal dominant or recessive,
and myotonic dystrophy) a unique CMAP response to peripheral
nerve repetitive stimulation can be observed (Fig. 25¬
45) 22.105.499.576,795.914.915 A t stimulation rates greater than 3 Hz, the
first several CMAPs are of similar amplitude, but then a decline in
CMAP amplitude becomes rather evident. At higher stimulation
frequencies, the decrement may become quite dramatic, approach-
ing complete absence of a CMAP at times. The higher the fre-
quency, the faster the CMAP decline is noted. These findings are
the electrophysiologic counterpart of the clinical symptom of the
transient paresis from which such patients suffer.795 An intermit-
Figure 25-45. Myotonia congenita. In a patient with myotonia tent conduction slowing, followed by block of the muscle mem-
congenita a continuous train of stimuli delivered at 10 Hz results in a brane on account of a genetically determined channelopathy,
normal amplitude for several stimuli that decreases significantly in am- seems responsible for this phenomenon.1005 In some patients, if the
plitude to attain its prestimulus level again (upper trace). Once the repetitive stimulation is maintained for periods exceeding 1
prestimulus amplitude is achieved, a brief cessation of stimuli followed minute, the CMAP demonstrates an increment that occasionally
again by a repetitive train no longer produces a decrement Calibration just reaches and rarely exceeds the prestimulus CMAP amplitude.
is 5 mV. (From Aminoff MJ, Layzer RB, Satya-Murti S:The declining elec- If a train of stimuli is given with less than 3 minutes of rest before
trical response to muscle to repetitive nerve stimulation in myotonia. a second train of stimuli, the second train demonstrates less of a
Neurology 1977;27:812-816, with permission.) CMAP decrement during repetitive stimulation. Single-fiber EMG
demonstrates relative normal jitter during the beginning of volun-
levels. This difficulty may lead to alterations in ACh synthesis, tary contraction that increases with blocking and becomes evident
defective protein iontophores, or dysfunction of the substrates during continued muscle contraction. The muscle membrane is
involved in the synthesis, storage, release, and binding of ACh. recognized as the site of the deficit producing the decrement to
In addition, regenerated motor neurons may be unstable and repetitive stimulation because direct muscle stimulation results in
unable to sustain neuromuscular transmission compared with a the same electrophysiologic findings as peripheral nerve stimula-
more mature NMJ. Rapid rates of stimulation may lead to rate- tion. The muscle membrane pathophysiology responsible for the
dependent conduction block secondary to an inability to sustain decrementing and incrementing response is not fully understood.
adequate ACh output, or poorly myelinated terminal nerve seg- McArdle's Disease. McArdle's disease, a type V glycogen
ments may fail. Any of the above and possibly other factors may storage myopathy, results from a myophosphorylase deficiency.
produce a reduced safety factor, thus leading to failure of indi- Repetitive stimulation at high rates (> 15 Hz) for about 40-60 sec-
vidual muscle fibers composing the affected motor units, with a onds results in a significant (> 40%) CMAP decrement200-251-654
resulting decrement to repetitive nerve stimulation. always accompanied by a painful muscle contracture. If this pat-
Peripheral Nerve Injuries/Neuropathies. In patients sustain- tern is observed, the diagnosis of McArdle's disease is almost as-
ing peripheral nerve injuries with significant degrees of axonal sured. The painful contracture may last from minutes to hours
loss, it is apparently possible to observe a decremental response to beginning, during, and after the repetitive stimulation. The tem-
peripheral nerve repetitive stimulation in the early phases of nerve porary loss of muscle tissue capable of responding to the neural
regeneration.110 This finding is thought to result from failure of im- stimulation is the likely explanation for the decrement. j
mature nerve terminals failing to release sufficient amounts of
ACh in response to nerve terminal depolarization.58 In addition,
neurogenic block may occur in the newly formed and hence ELECTRODIAGNOSTIC MEDICINE PITFALLS
poorly myelinated terminal axonal sprouts when they are sub-
jected to repetitive stimulation, particularly at high rates. This The electrodiagnostic medicine evaluation of potential neuro-
mechanism also may account for decrements documented during muscular junction disorders is fraught with pitfalls that can result in
repetitive stimulation in radiculopathies and peripheral neu- erroneous interpretation if care is not exercised in performing the
ropathies with significant axonal loss as well as increases in jitter testing procedures. This is particularly true when attempting to dis-
as determined by single-fiber EMG .40-334-621 -649-650-941 tinguish patients with severe LEMS and MG compared to the less
Periodic Paralysis. The periodic paralyses (hyperkalemic severe forms of these disorders (Table 25-14). Attention to detail in
and hypokalemic) are an interesting group of diseases charac- electrode placement, temperature monitoring, and stabilization are
terized by sudden bouts of flaccid paralysis, occasionally asso- crucial. The most important aspect of determining the validity of
ciated with abnormal potassium levels, in apparently normal any test used in assessing NMJ function is reproducibility. A con-
persons (see Chapter 27).349 During an attack of paralysis and sistent response is viewed in a more favorable light than a result
occasionally between paralytic attacks, the CMAP magnitude is that is different each time that repetitive stimuli are performed.
generally reduced. Repetitive stimulation of a peripheral nerve
at 5-10 Hz for about 10 minutes results in a progressive incre- FALSE POSITIVES
ment in the CMAP amplitude that approaches normal values
toward the end of the stimulating period.122-351 After cessation of A number of potential artifacts and physiologic mechanisms
the stimulation, the CMAP amplitude rapidly approaches its can generate a response to repetitive stimulation suggestive of
Table 25-14. Electrodiagnostic Abnormalities in Myasthenia Gravis and LEMS (Classical vs. Severe)
Classical Electrodiagnostic Abnormalities Abnormalities in the Presence of Severe Weakness
MG LEMS MG LEMS
CMAP Normal Small Small Small
Low rate stimulation Decrement in weak Decrement Decrement may be absent Decrement may be absent
(2-5 Hz) muscles in weak muscles or impossible to detect
High rate stimulation Normal response or Increment > 100% Decrement, increment or Decrement may precede
(10-50 Hz) increment < 100% normal response increment
Single fiber EMG Increased jitter and block- Increased jitter and block-
ing (increase at high rates) ing (improve at high rates)
Needle EMG Variation in MUP size Variation in MUP size and Brief, small, polyphasic MUPs. Brief, small, polyphasic
morphology. Brief, small, Occasional fibrillation MUPs
polyphasic units potentials and PSWs
From Grand Maison F: Methods of testing neuromuscular transmission in the intensive care unit. Can J Neurol Sci 1998;25:536-539, with permission.
a NMJ disorder in a person with normal neuromuscular junc- less than submaximal stimulus may deliver inadequate amounts
tion transmission. 623 The practitioner must take these factors of current from one stimulus to the next simply because of vary-
into account whenever performing a test procedure. ing skin impedances or slight electrode movements. Delivering
Electrodes. Both stimulating and recording electrodes can be a true supramaximal stimulus (> 20-25% of the amount neces-
a source of error, resulting in what appears to be a physiologic sary to deliver a maximum CMAP) ensures that adequate
decrement to repetitive stimulation on cursory examination. amounts of current reach the nerve to depolarize it completely,
Patients presenting for electrodiagnostic testing may be some- even with minimal variations in stimulating conditions.
what apprehensive and perspire about the hands. As a result, the Other Diseases. A number of diseases can result in decre-
recording electrodes may become loose with time, particularly ments to repetitive stimulation. Although the decrement implies
if insufficient amounts of tape have been applied to the elec- a defect in neuromuscular transmission, the disorder may not be
trodes. Stimulating one of the peripheral nerves innervating the a primary NMJ disease, but a secondary NMJ disorder due to
hand intrinsic muscles can result in progressive dislodgement of reinnervation or inherent difficulties with muscle membrane
the electrodes from optimal location over the muscle's motor conduction. At this point the nerve conduction velocity and
point. The electrode may be displaced laterally away from the needle EMG portions of the electrodiagnostic medicine consul-
motor point or separate from the skin with less than optimal sur- tation are combined with the history and physical examination
face contact. In either case, the CMAP may display a sequential to arrive at an appropriate diagnosis. Reduced nerve conduction
decrease in magnitude with each subsequent stimulus as the velocities and significant membrane instability on needle exam-
electrode is continually separated from the ideal location over ination do not suggest the relatively more common NMJ disor-
the muscle. This decrement may appear quite similar to that ders but rather an intrinsic nerve or muscle disease.
physiologically anticipated in NMJ disorders. The practitioner Pseudofacilitation. The phenomenon of pseudofacilitation
must ensure proper electrode placement and adherence to the can lead one to conclude that a facilitatory response is present
skin. It is also possible to observe a decrementing and incre- and thus to assume the patient has some form of NMJ disor-
menting response with a somewhat different amplitude for each der.835 If this is the only finding, care must be taken to ensure
response in the train. This is not a physiologic response. The that both the area and amplitude of the CMAP increase. If only
baseline should be examined for any decrementing or incre- the amplitude changes, pseudofacilitation is present and should
menting response to ensure that it is flat. A wavering baseline be ignored. This type of increment may be as large as several
secondary to recording electrode movement can result in a train percent or even approach a 50% increment. An increment in
of CMAPs appearing as a decrement. On close examination, the excess of 50% is probably the result of true facilitation sec-
individual CMAPs are of the same amplitude; some are above ondary to some abnormality in NMJ transmission, or a combi-
an imaginary baseline constructed by the examiner through all nation of pseudofacilitation and true facilitation. If any doubt is
of the responses, whereas others are below it. Securing the elec- present, the CMAP area should be measured between the first
trodes should rectify this problem. and fifth response. A study of normal individuals using stimula-
Less than adequately secured stimulating electrodes also can tion rates between 0.1 to 30 Hz revealed that CMAP duration
result in a CMAP amplitude decrement that appears to decline from ulnar and median innervated hand intrinsic muscles had
with each subsequent stimuli. In this case the baseline is quite the following changes: (1) shorter CMAP duration, (2) alter-
flat, but the response is seen to diminish progressively. The ation in negative spike amplitude, (3) merging of bifid peaks,
CMAP may disappear completely or even reach a stable level and (4) positive CMAP phases showed more pronounced
similar to physiologic responses if there is a secondary and changes than negative CMAP phases. 963b These changes are
spontaneous stabilization of the stimulating electrodes. A postulated to result from an increase in muscle fiber conduction
number of practitioners may perform hand-held repetitive stim- velocity as well as muscle movement and fiber shortening. The
ulation studies. This is not wise because the hand holding the best criterion for differentiating between true facilitation and
stimulator can move substantially across the patient's skin, thus pseudofacilitation remains to be defined, but the increment of
delivering less than identical currrent intensities with each stim- 50% or more should be adhered to at this time.
ulus. This practice should be discouraged because it invites arti- Edrophonium Chloride. Some persons consider a decre-
fact. The stimulating electrodes should be secured to the patient mental repair after administration of edrophonium chloride to
in a similar manner as the recording electrodes. Furthermore, a be diagnostic of myasthenia gravis. This assumption is certainly
not true.666-716 Patients with a decrement secondary to prejunc- Facilitation/Exhaustion. An electrodiagnostic evaluation for
tional disorders such as LEMS, a reinnervating process, or some a potential NMJ defect is not complete without an analysis of the
other type of peripheral nerve disorder may have a positive re- patient's response to exercise (high rates of stimulation) and
sponse (decremental repair) to edrophonium chloride. postactivation exhaustion. A decrement may be absent at low
rates of stimulation. After a relatively brief period of exercise,
FALSE NEGATIVES the CMAP still may not decrement, but it may demonstrate a sig-
nificantly larger CMAP than previously. This finding is not to be
Some patients with a true NMJ disorder may have a normal confused with pseudofacilitation, which is observed during a
electrodiagnostic examination for a number of reasons. These train of high-rate stimuli. If a larger CMAP is observed com-
considerations, which apply particularly to repetitive stimula- pared with baseline during a train of 2-3-Hz stimulation several
tion studies, should always be kept in mind. If the potential false seconds after exercise, a true facilitatory response is present.
negative factors are taken into consideration and the patient con- This applies if the possibility of technical error is evaluated by
tinues to demonstrate no abnormality despite a history and checking electrode placement. Similarly, the patient should be
physical examination suggestive of an MNJ problem, single- observed with low rates of stimulation at about 1-minute inter-
fiber EMG should be performed by an expert in the technique. vals for the next 5-6 minutes. In patients with mild NMJ disor-
Muscle Selection. Individual single muscle fibers composing ders, a decrement at low rates as well as facilitation after exercise
a single motor unit in patients with a NMJ disorder can have a may be absent, but a decrement may be noted at 3-5 minutes
spectrum of transmission defects in terms of degree of severity. after the exercise period. Failing to perform this procedure can
Some of the NMJs may be normal, others may have mild abnor- result in the erroneous conclusion that no NMJ defect is present.
malities, and others may be significantly affected. These findings
apply to whole muscles, with proximal muscles more severely
involved than distal muscles. Examining only distal muscles in ILLUSTRATIVE CASES
the upper or lower limb can yield essentially normal repetitive
stimulation studies, allowing one to conclude that NMJ trans- CASE I-.GENERALIZED FATIGUE AND WEAKNESS
mission is normal. It is imperative not to consider a study de-
signed to evaluate the presence of a NMJ disorder complete until Reason for Referral. Weakness and fatigue.
either a distal muscle reveals physiologic decrements or several History. A 29-year-old woman presents with a 6 month com-
proximal muscles have been examined when the distal muscles plaint of easy fatigability, particularly near the end of the day.
are normal. The biceps brachii and trapezius are good proximal She reported increasing difficulty with arising from the com-
muscles to explore. The facial muscles also can be studied, but mode and caring for her hair. Mealtime is beginning to be some-
an increased potential for movement artifact and decreased toler- what difficult. Although chewing is acceptable at the start of the ;
ance by some patients require greater examiner expertise. meal, finishing her food presents a problem because of dimin-
Temperature. A cool muscle may not reveal a decrement ished ability to chew satisfactorily. From time to time double
even if a NMJ disorder is present.484 Reduction in temperature vision is noted when she attempts extremes of gaze. By the end
can result in diminution of a decrement to repetitive stimula- of the day drinking a hot cup of coffee results in occasional diffi-
tion. In patients with a mild NMJ defect, a somewhat cool culty in swallowing. The patient denies other medical problems
muscle can result in the absence of a significant decrement. In and is presently taking no medication aside from a daily vitamin.
this instance, one may be tempted to conclude that the study is Physical Examination. The patient is alert and oriented and
normal. Usually the examiner is using significant amounts of attempts to comply with the physical examination to the best of
tape and possibly an arm board to secure the patient's limb her ability. Gross observation reveals a slight ptosis of the right
while applying an uncomfortable electrical stimulation. The compared with left eyelid. The patient can completely bury the
combination of pain and apprehension can result in limb vaso- eyelids bilaterally, but has a decreased ability to keep them
constriction with a rapidly progressive decline in skin and closed against resistance. Ocular movements in all cardinal di- j
muscle temperature after a baseline study has been performed. It rections are normal. Facial sensation is intact. Manual muscle
is important, therefore, to monitor limb temperature about the testing demonstrates a relatively symmetric grade of strength
recording electrodes throughout the examination and to be pre- about the shoulder girdle muscles of 3/5, with the distal arm
pared to warm the limb if necessary. The skin temperature muscles rated at 4/5. Neck flexion and extension are also 3/5.
should be maintained at 32-33°C or greater. Temperature The patient cannot arise from a squat without minor assistance.
should be recorded in close proximity to the recording elec- Hip flexor and extensor muscle strength is 3+/5, whereas distal
trode; a temperature probe located at some distance from the muscles are 4/5 bilaterally. She notes a gradual but definite in-
muscle under study is. of little value. ability to sustain contraction against resistance in all muscle
Anticholinesterase Medication. A good practice is to ask tested about the shoulder and hip girdle regions. Sensation to all
the patient to abstain from anticholinesterase medication ap- modalities is intact in the upper and lower limbs. Deep tendon
proximately 12 hours before the study. The degree of decrement reflexes are 2+/2+ bilaterally throughout.
may be insignificant because of the beneficial effects of par- Nerve Conduction Studies. Nerve conduction studies are
tially neutralizing the action of AChE. If a patient arrives for a performed in the right upper and lower limbs. The mid-palm
consultation on medication, a study can be performed, but temperature is 33.5°C on the right, and the temperature poste-
normal results do not ensure the absence of an NMJ defect. If a rior to the right lateral malleolus is 31.8°C.
normal study is found, the patient should be scheduled for a Nerve DSL S Amp DML M Amp NCV
repeat exam but asked to abstain from taking the medication for (ms) OiV) (ms) (mV) (m/s)
12 hours before the next study. Anticholinesterase medications R median 3.3 39.0 3.2 5.6 58.0
can reduce but usually not normalize single-fiber EMG jitter R median 2.0 44.0
studies.622 (7.0 cm)
R ulnar 3.2 29.0 3.1 7.5 60.0
R peroneal 4.2 5.9 49.5
R sural 3.7 22.0
Repetitive Stimulation: % Decrement on 3-Hz Stimulation
After 10 5 Minute
Nerve Baseline sec PE PE
R ulnar 1.0 0.0 5.2
R musculocutaneous 12.8 1.8 18.7
R spinal accessory 15.2 2.3 19.8
R facial 22.1 3.5 28.7
Note: Temperature at all recording sites was maintained above
33.0°C. Repetitive stimulation was performed at baseline and
then repeated after 10 seconds of exercise to look for postexer-
cise facilitation. Next the muscle was exercised for 1 minute, and
repetitive stimulation was performed at 1 minute intervals for 5
minutes to look for evidence of postexercise exhaustion.
DSL, distal sensory latency; S Amp, sensory amplitude; DML,
distal motor latency; M Amp, motor amplitude; NCV, nerve con-
duction velocity; ms, milliseconds; p.V, microvolts; mV, milli-
volts; m/s, meters/second; PE, postexercise. Motor and sensory
amplitudes are measured baseline to peak. Sensory latencies are
1 measured to peak and motor latencies to initial negative onset.
Needle Electromyography. A needle EMG investigation is
performed on the right upper and lower extremity using a dis- Figure 25-46. Illustrative case I. Electromyography of the exten-
posable monopolar needle. sor digitorum communis reveals variability in MUAP morphology. A
Muscle Rest Activity Recruitment single MUAP is shown at a sweep spead of 50 ms/divison, which is trig-
Supraspinatus Normal Normal gered and viewed at a sweep speed of 5 ms/division. Note the variabli-
Deltoid Normal Normal tiy in the amplitudes from one unit to the next.
Biceps Normal Normal
Extensor digitorum Normal Normal postsynaptic. The variable morphology and amplitude of the
communis MUAPs on EMG and the increased jitter and blocking on
Pronator teres Normal Normal SFEMG are suggestive of a NMJ defect but are not specific in
Abductor digiti minimi Normal Normal regard to the site (i.e., distal motor nerve terminal, NMJ, or
Gluteus medius Normal Normal muscle). Repetitive stimulation studies confirm a postsynaptic
Vastus medialis Normal Normal neuromuscular junction transmission defect. The most likely
Tibialis anterior Normal Normal clinical diagnosis is myasthenia gravis.
Gastrocnemius Normal Normal
Note: Moderate amounts of variability MUAP morphology,
particularly in amplitude, were noted in the tested muscles BLOCKING DETECTOR : G N / |
(Fig. 25-46). MUAP durations appear somewhat reduced, but INS NO! 6 ACCEPTED / EJECTED
quantitative needle EMG was not performed. SMEEPS > 5H 1 FIRING RATE i 13 Hz
Single-fiber Needle Electromyography. SFEMG of the
EDC revealed increased jitter and blocking. The MCD of 20 po- FD: 0.0 SD: 0.00
tentials was 57 ps. An example of SFEMG of 1 of the 20 pairs Fd IHS HO
is shown in Figure 25-47. 250 IPI Cus>
u
Summary of Findings H
0
1. A sensory and motor nerve conduction studies are within
normal limits. S * - ' " *- " *
2. A significant decrement on repetitive stimulation (3 Hz) 2 V" ' '."/-.*
was observed at baseline with postactivation facilitation and ex- E
BLOCK! 0.0 '/.
haustion in the proximally located muscles about the shoulder -250 50 WW 9CEPS 100
girdle and face on the right. HIPI! 633 us
3. Needle EMG examination is essentially normal except for HCOs 57 us
a qualitative impression of MUAPs with possibly reduced dura- SO! 52 us
tion potentials and increased variability when viewed at slowed USD! 38 us
sweep speeds.
4. Single-fiber EMG of the EDC revealed increased jitter and
blocking.
Electrodiagnostic Medicine Impression Figure 25-47. Illustrative case I. Single-fiber electromyography of
The patient presents with a history and physical examination the extensor digitorum communis reveals increased jitter with a MCD
consistent with a neuromuscular junction defect, most likely in this pair of 57 |is.
Recommendations as well as his favorite chair. It is also becoming increasingly
1. Obtain antibody titers for acetylcholine receptors. difficult for him to climb stairs leading from the basement to
2. Other laboratory tests: thyroid function tests, antinuclear the first floor or from the first to the second floor. Combing his
antibodies, CRS, routine serum chemistries. hair and shaving also have been more difficult because of a
3. Chest CT scan for thymic abnormalities. Consider sense of fatigue and weakness in his arms particularly about
thymectomy. the shoulders. The patient states that he used to be able to walk
4. Baseline pulmonary function testing. from the basement to the second floor with little difficulty, but
5. Begin therapeutic administration of anticholinesterase at present he must rest for some time half-way up the staircase
medication. Consider initiating immunosuppressive agents. before proceeding. He complains of a dry mouth. The patient
also notes progressive impotence over the past several months.
Comment A 42-year history of smoking about 2 packs of cigarettes per
The patient's clinical presentation can certainly be con- day is noted. A nonproductive cough has been present for the
sidered classic for myasthenia gravis. A young woman with past 3 months.
complaints of progressive proximal muscle weakness and in- Physical Examination. The patient is alert and coopera-
creasing fatigue as the day progresses suggests the diagnosis. tive. Speech is coherent and fluent without evidence of
Electrodiagnostic medicine testing reveals normal nerve con- dysarthria. He preferred to stand against the examination
duction velocity and latency measurements, establishing no table, stating that sitting in the low chair provided would
evidence of a demyelinating polyneuropathy leading to failure cause significant difficulty with attempting to stand. When re-
of conduction as a possible cause for weakness. Additionally, quested to sit in the chair, about the height of a standard com-
the normal amplitudes of the CMAPs and SNAPs exclude a mode, the patient required mild assistance to arise. He can
severe axonal neuropathy as the cause. Relatively normal hold his arms above his head for a few minutes but then expe-
needle EMG findings with respect to membrane instability ex- riences increasing difficulty with performing this maneuver.
clude a myopathy. The qualitative impression that some of the Muscle bulk appeares normal. There is no evidence of focal
MUAPs may have been reduced in size and variable in appear- atrophy or fasciculations. Manual muscle testing reveals an
ance is suspicious for a myopathic process but also consistent interesting phenomenon: the patient has several seconds of
with a neuromuscular junction defect (Fig. 25-46). Repetitive decreased ability to resist an applied force, which improves
stimulation at low rates reveals a significant decrement in momentarily but again declines over the course of about 1
muscles about the shoulder girdle as well as the face. It is not minute. The muscles are hard to gauge as a result; weakness
unusual for distal hand muscles to demonstrate an absence of (at least 4-/5) is followed by improved strength, which again
decrement to repetitive stimulation, particularly in the early presents as weakness over the course of about 1-2 minutes,
stages of the disease. Postactivation facilitation and exhaus- depending on the muscle group examined. In attempting a
tion are also noted. Single-fiber EMG demonstrates increased sustained force against the examiner, the patient experiences
jitter (Fig. 25-47). These findings are certainly suggestive of a relatively rapid fatigue over 1-2 minutes. External ocular
NMJ transmission dysfunction at the postsynaptic membrane. muscles are intact with no deficits noted on examination. The
The clinical history, physical examination, and neurophysi- patient can smile and close his eyelids successfully for about
ology testing are consistent with a diagnosis of myasthenia 1 minute, but this ability deteriorates with further attempts.
gravis. There is no ptosis, jaw opening, palate or tongue weakness,
Nerve conduction studies are important to ensure that a sub- atrophy, or fasciculations. Sensory examination is intact.
acute or chronic form of demyelinating neuropathy is not pres- Complex motor skills reveal normal coordination for his
ent. If reduced conduction velocities or increased temporal degree of weakness. Muscle stretch reflexes (DTRs) are noted
dispersion of either motor or sensory potentials had been ob- to be trace at best throughout and symmetric in the upper and
served, a totally different diagnosis would be suggested despite lower limbs, but the reflexes improve after brief exercise of
the presence of decrement on repetitive stimulation. As previ- the muscle. His gait is wide-based and waddling.
ously discussed, peripheral nerve disorders can demonstrate Nerve Conduction Studies. Nerve conduction studies are
decrements on repetitive stimulation. Similarly, preserved performed in the left upper and right lower limbs. The mid-palm
CMAP amplitudes do not support a chronic form of axonal temperature is 34.0°C in the left hand, and the temperature pos-
neuropathy. Likewise, if a small CMAP had been observed, the terior to the right lateral malleolus is 32.1°C.
response to exercise would be particularly important with re- Nerve DSL S Amp DML M Amp NCV
spect to the possibility of LEMS. Normal-amplitude CMAP re- (ms) (liV) (ms) (mV) (m/s)
sponses at rest with a decrement to low rates of repetitive L median 3.5 30.5 3.8 1.5 54.0
stimulation, associated with postactivation facilitation and ex- L ulnar 3.0 25.5 2.5 3.4 57.0
haustion, confirm a diagnosis or postjunctional NMJ dysfunc- R peroneal 4.4 0.9 43.5
tion such as myasthenia gravis. Antibody titers for AChRs and R posterior 5.6 2.7 46.2
evaluation for thymic hyperplasia are confirmatory. It is also tibial
important to assess the patient for coexistent subclinical au- R sural 3.9 18.5
toimmune disorders because of their common association with
myasthenia. Repetitive Stimulation 3 Hz 20 Hz
Nerve Baseline 10 sec Rep Stim Rep Stim
Amp exercise
CASE 2: GENERALIZED FATIGUE AND WEAKNESS (% incre- (% incre- (% incre-
ment) ment) ment)
Reason for Referral. Weakness and fatigue. L ulnar 3.4 mV (124%) 7.6 mV 2.1 mV 3.4 mV
History. A 61-year-old man states that over the past 4 weeks (62%) (0%)
he has noted increasing difficulty in arising from the commode (Fig. 25-48)
Chapter 25 NEUROMUSCULAR JUNCTION DISORDERS — 121 I
L Ulnar
Sen 1 ~ Wrist tn Hypothenar enln
L ulnar
Figure 25-48. Illustrative case 2. See 2 - wrist t o ADH p 18 sen ex
Motor nerve conduction study of the
left ulnar nerve recorded from the ab-
ductor digiti minimi reveals a decreased
baseline amplitude of 3.4 mV. Imme-
diately after 10 seconds of isometric
exercise, a repeat stimulation of the
ulnar nerve demonstrates an increase
in the CMAP amplitude t o 7.6 mV.
This finding is consistent with a presy-
naptic neuromuscular junction defect.
2 4 6 e 18 12 14 16 18 28
Seo Dist Ut P Ut cu NPai*> *f»area MParea HPdur WMur PPawp Scale LowF HlghF
(na) CnU/d) (kHz)
Tcnp
CO
it ttml (ro> <«U) <Hx>
Ira)
1 2.5 6.8 3.43 7.96 5.9 N/fi 4.93 2.8 2 18
2 2.6 6.2 7.63 N/fl 19.74 H/A 6.8 hVfi U.ftS 2.8 2 18
R pos- 2.7 mV 5.6 mV 1.5 mV 5.5 mV Muscle Rest Activity Recruitment

terior (42%) (103%) Supraspinatus Normal Normal
tibial (Fig. 25-49) (Fig. 25-50) Deltoid Normal Normal
Temperature at all recording sites were maintained above Biceps Normal Normal
33.0°C. Pronator teres Normal Normal
DSL, distal sensory latency; S Amp, sensory amplitude; DML, Abductor digiti minimi Normal Normal
distal motor latency; M Amp, motor amplitude; NCV, nerve Gluteus medius Normal Normal
conduction velocity; ms, milliseconds; p,V, microvolts; mV, mil- Vastus medial is Normal Normal
livolts; m/s, meters/second; PE, postexercise; Rep Stim, repeti- Tibialis anterior Normal Normal
tive stimulation. Motor and sensory amplitudes are measured Gastrocnemius Normal Normal
baseline to peak. Sensory latencies are measured to peak and Muscles demonstrated a normal recruitment pattern of MUAPs
motor latencies to initial negative onset. but have a reduced amplitude which increase in size as the same force
Needle Electromyography. A needle EMG investigation is in contraction is attempted. A maximal interference pattern, relatively
performed on the right upper and lower extremity using a dis- low amplitude at first, increases over several seconds. Observing a
posable monopolar needle. single MUAP reveals moment-to-moment variability in size.
Resp NPanp NFarea
<M) <*chg> czcha>
X BO 0 8
2 - 2 2 . 9 -23 S 2 2 -23 S
3 -34 3 -3G 0 4 3 -3S 6
4 -42.2 -41 4 -2 2 -44 Q
5 -41.4 - 4 1 3 2 ? -43 2
Figure 25-49. Illustrative case 2. Repetitive stimulation at 3 Hz of Figure 25-50. Illustrative case 2. Repetitive stimulation at 20 Hz
the posterior tibialis nerve recorded from the abductor hallucis of the posterior tibialis nerve recorded from the abductor hallucis
demonstrates a 42% decrement. demonstrates a 103% increment.
Summary of Findings nonparaneoplastic LEMS is more common in young women
1. A sensory and motor nerve conduction studies are within and may be associated with other autoimmune disorders.
normal limits.
2. All CMAP amplitudes are markedly reduced but incre-
ment after 10 seconds of exercise (see Fig. 25 : 48). CONCLUSION
3. Needle EMG examination is essentially normal except for
a reduced amplitude of MUAPs which increases with sustained x Neuromuscular junction physiology is extremely fascinating
contraction. Also, increased MUAP variability is noted when and complex. At present we are at a disadvantage because of in-
viewed at slowed sweep speeds. complete understanding of the intricate mechanisms involved in
4. Repetitive stimulation at 3 Hz demonstrates significant the release of ACh from the nerve terminal at a molecular level.
decrement (Fig. 25-49). This shortcoming has direct clinical implications in both under-
5. Repetitive stimulation at 20 Hz initially produces a decre- standing and treating most, if not all, diseases affecting the NMJ.
menting response for the three stimulations and then gradually Despite this lack of knowledge, sufficient information is available
increments to over twice the baseline amplitude (Fig. 25-50). to make a significant difference in most patients' lives. Continued
research with various toxins and drugs helps to increase our com-
Electrodiagnostic Medicine Impression prehension of how the transduction of nerve to muscle impulses
The patient has signs and symptoms of progressive fatigue occurs. Future research into the genetic and pathophysiologic as-
and weakness associated with dry mouth and impotence. The pects of ion channels and autoimmune mechanisms promises to
repetitive stimulation studies reveal evidence consistent with a be both challenging and exciting and eventually may lead to a
neuromuscular junction dysfunction suggestive of a presynaptic cure for these varied yet related diseases.
defect. The history, physical examination, and electrical studies
are highly suspicious for Lambert-Eaton myasthenic syndrome.
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Chapter 26
Introduction t o Myopathies
and Muscle Tissue's Reaction
to Injury

CHAPTER OUTLINE
Clinical and Laboratory Evaluation Electrodiagnostic Examination
History • Physical Examination • Laboratory Testing Nerve Conduction Studies • Needle Electromyography
• Single-Fiber Electromyography
Muscle Histology and Reaction to Disease
Muscle Tissue Evaluation • Normal Muscle Histology Electrodiagnostic Medicine Classification of Myopathies
• Abnormal Muscle Histology
Electrodiagnostic Medicine Consultation Pitfalls
Electrophysiologic Correlates of Muscle Injury False-Positive Studies • False-Negative Studies
The electrodiagnostic medicine evaluation of patients sus- HISTORY

pected of having a myopathic disease can be somewhat daunt-
ing, particularly to the beginning practitioner, due to the relative The most important aspects of assessing individuals with
rarity and diversity of myopathies. Prior to addressing specific neuromuscular disorders are a thorough history of the patient's
muscle disorders, we discuss our approach to the evaluation of symptoms, disease progression evaluation, medical and family
patients suspected of having a myopathy. In addition, we review history, and a detailed neurologic examination.19-55'5670129 This is
normal muscle histology and the pathologic reactions to muscle not to say that the electrodiagnostic medicine examination, lab-
injury because they correlate well with the electrodiagnostic oratory data, and muscle biopsies are not important. However,
medicine findings. the physician's clinical acumen based on the historical aspects
of the disease and the physical examination provide the guiding
force for performing the most appropriate confirmatory tests to
CLINICAL A N D LABORATORY expeditiously arrive at a correct diagnosis.
EVALUATION During the history, the clinician should attempt to define the
illness' onset and course as well as the distribution of symp-
The electrodiagnostic medicine evaluation is not merely the toms. The differential diagnosis of generalized weakness pre-
performance and interpretation of nerve conduction studies senting in infancy (Table 26-1) is different from that presenting
and needle electromyography, but rather it should entail a later in childhood or early adult life (Table 26-2) or disorders
thorough history, neuromuscular examination, clinical impres- manifesting in late adulthood (Table 26-3). The rate of disease
sion, and recommendations for further work-up and treatment. progression is important to pursue. Certain disorders progress
In our opinion, electrodiagnostic studies are an extension of acutely over days or weeks (Table 26-4), while others evolve
the clinical examination. Therefore, to adequately assess a pa- more slowly, over several months (Table 26-5). The course of
tient, one must perform a pertinent history and neuromuscular the disease may be monophasic, relapsing, or chronic and pro-
examination prior to beginning the electrodiagnostic medicine gressive. The increase in health consciousness of some patients
studies. presents an opportunity to gauge the rate of disease progression
1229
Table 26-1. Differential Diagnosis of the Floppy Infant Table 26-2. Weakness Presenting in Childhood
or Early Adulthood
Central Nervous System Disorders (most common etiology) Anterior Horn Cell Disorders
Anterior Horn Cell Disorders Spinal muscular atrophy type 3
Spinal muscular atrophy type I and 2 Poliomyelitis
Amyotrophic lateral sclerosis (rare)
Peripheral Neuropathy
Congenital hypomyelinating/amyelinating neuropathy Peripheral Neuropathy
CMT3 (Dejerine-Sottas disease) Acute or chronic inflammatory demyelinating polyneuropathy
CMTI and CMT2 (rare) Hereditary neuropathies
Giant axonal neuropathy Neuromuscular Junction Disorders
Neuromuscular Junction Disorders Botulism
Infantile botulism
Infantile myasthenia Lambert-Eaton myasthenic syndrome
Congenital myasthenia Congenital myasthenia
Myopathy Myasthenia gravis
Congenital myopathies (all can present in infancy) Myopathy
Muscular dystrophies Congenital myopathies
Congenital muscular dystrophies Central core
Dystrophinopathy/sarcoglycanopathy (rare) Multicore
Congenital myotonic dystrophy Centronuclear
Metabolic myopathies Nemaline
Glycogen storage defects Myofibrillar
Acid maltase deficiency Muscular dystrophies
Debrancher deficiency Dystrophinopathy (Duchenne or Becker)
Branching enzyme deficiency Limb-girdle muscular dystrophies
Myophosphorylase deficiency (rare) Congenital muscular dystrophy (partial merosin deficiency)
Disorders of lipid metabolism Myotonic dystrophy
Carnitine deficiency Other dystrophies (e.g., FSHD, EDMD)
Fatty acid-acyl-CoA dehydrogenase deficiencies Metabolic myopathies
Mitochondrial myopathies Glycogen storage defects
Benign and fatal infantile myopathy Acid maltase deficiency
Leigh's syndrome Debrancher and branching enzyme deficiency
Endocrine myopathies (e.g., hypothyroidism) Disorders of lipid metabolism
Carnitine deficiency
with respect to distance previously run, weight lifted, or games Fatty acid-acyl-CoA dehydrogenase deficiencies
played. A steady reduction in exercise-related parameters may Mitochondrial myopathies
be an important clue for establishing a pattern of gradual and Periodic paralysis
progressive physical decline. Electrolyte imbalance
The distribution of symptoms or pattern of weakness is of Hyperkalemia
utmost importance. 56 - 70 Most myopathies preferentially affect Hypokalemia
the proximal more than distal muscles. Proximal muscle weak- Hypophosphatemia
ness is not specific for myopathies and can be seen in other neu- Hypercalcemia
romuscular disorders (Tables 26-4 and 26-5). Further, in certain Endocrine myopathies
myopathies the distal muscles are weaker than the proximal Toxic myopathies
muscles (Table 26-6). 8 Unusual patterns of weakness (e.g., Inflammatory myopathies
scapuloperoneal, humeroperoneal, and facioscapulohumeral) Dermatomyositis
are seen in specific neuromuscular diseases. Finally, some neu- Polymyositis (after age 20 years)
romuscular disorders, including myopathies, predominantly Infectious myositis
affect the ocular muscles (Table 26-7). FSHD, facioscapulohumeral muscular dystrophy; EDMD, Emery-Dreifuss mus-
cular dystrophy.
In adults, the most common symptom associated with my-
opathies is weakness. Early manifestation of proximal lower
limbs weakness is progressive difficulty arising from a chair or increasingly difficult. As the hip girdle muscles continue to de-
the floor. One of the first times a patient may note a problem is teriorate, there may be a reduced ability to place objects on high
in the bathroom when attempting to arise from the commode. shelves that previously presented no problem. Weakness of the
While previously, the patient may have been able to stand unas- anterior compartment of the distal lower limb results in foot-
sisted, the upper limbs may now be required to provide assis- drop, which can manifest as frequent tripping. Involvement of
tance where none was required previously. Easy fatigability to the posterior compartment of the distal legs leads to difficulty
repetitive activities is commonly first noted when attempting to standing on one's toes.
climb the stairs. Initially, the first several steps present little in Weakness about the shoulder girdles may insidiously affect
the way of a challenge and it is the last several at the top that re- the patient's ability to perform activities of daily living, such as
quire the most effort. With disease progression, even attempting brushing hair and lifting objects. Distal upper limb weakness
to lift the leg to position the body for ascending stairs becomes usually presents with progressive difficulty with grip. Patients
Chapter 26 INTRODUCTION TO MYOPATHIES AND MUSCLE TISSUE'S REACTION TO INJURY — 1231
Table 26-3. Weakness Presenting in Middle Table 26-4. Neuromuscular Disorders Presenting with
to Late Adulthood Acute or Subacute Proximal Weakness
Anterior Horn Cell Disorders Anterior Horn Cell Disorders
Spinal muscular atrophy type 3
Kennedy's disease Poliomyelitis
Poliomyelitis Peripheral Neuropathy
Amyotrophic lateral sclerosis Guillian-Barre syndrome
Peripheral Neuropathy Porphyria
Hereditary neuropathies Diphtheria
Acute or chronic inflammatory demyelinating polyneuropathy Tick paralysis (may also affect the neuromuscular junction)
Drug-induced or toxic neuropathies Toxic neuropathies
Diabetic neuropathy Diabetic amyotrophy
Amyloid Carcinomatous infiltration (e.g., leukemia, lymphoma)
Paraneoplastic neuropathy
Vasculitis Neuromuscular Junction Disorders
Neuromuscular Junction Disorders Botulism
Botulism Lambert-Eaton myasthenic syndrome
Myasthenia gravis Myasthenia gravis
Lambert-Eaton myasthenic syndrome Myopathy
Myopathy Periodic paralysis
Congenital myopathies Electrolyte imbalance
Myofibrillar myopathy (other types are uncommon) Endocrinopathies
Muscular dystrophies Inflammatory myopathies
Dystrophinopathy (Becker) Dermatomyositis
Limb-girdle muscular dystrophies Polymyositis
Oculopharyngeal dystrophy Infectious myositis (note: inclusion body myositis does not
Bent-spine/dropped-head syndrome present acutely)
Metabolic myopathies Toxic myopathies
Glycogen storage defects Metabolic myopathies
Acid maitase deficiency Glycogen and lipid disorders in association with myoglobinuria
Debrancher deficiency
Disorders of lipid metabolism (rare)
Mitochondrial myopathies Observant patients may also detect a progressive loss of
Periodic paralysis muscle bulk about various aspects of their body, particularly in-
Familial hypo-KPP manifest within the first three decades volving the anterior thigh, shoulder, and occasionally face and
Familial hyper-KPP usually manifests in the first decade small intrinsic hand muscles. Alternatively, some muscle groups
Electrolyte imbalance may be enlarged. Some myopathic disorders are associated with
Hyperkalemia myalgias, cramps, stiffness or myotonia, periodic paralysis, and
Hypokalemia myoglobinuria. When the patient does not mention these symp-
Hypophosphatemia toms, the clinician should inquire about their presence or ab-
Hypercalcemia sence. In addition, the examiner should ask about the presence of
Endocrine myopathies sensory symptoms, fasciculations, and extreme fluctuations in
Toxic myopathies strength during the day or associated with physical activities be-
Myopathy associated with systemic disease (e.g., cancer), poor cause these symptoms suggest a disorder other than a myopathy.
nutrition, disuse atrophy Fatigue is a very nonspecific complaint. Most patients re-
Amyloid myopathy ferred to a neuromuscular clinic or the neurophysiology labora-
Inflammatory myopathies tory for evaluation of fatigue do not have a primary
Inclusion body myositis (most common inflammatory myopathy neuromuscular disorder. Their symptoms are best characterized
after the age of 50 years) as asthenia or the subjective loss of energy. Although such pa-
Dermatomyositis tients often complain of "feeling weak all over," examination of
Polymyositis muscle strength is typically normal or limited by give-way. This
Infectious myositis is not to say that patients with myopathies and other neuromus-
Hypo-KPP, hypokalemic periodic paralysis; hyper-KPP, hyperkalemic periodic cular disorders do not experience fatigue. Pathologic fatigue can
paralysis. be demonstrated in patients with neuromuscular junction de-
fects and certain metabolic myopathies by electrophysiologic
testing (e.g., repetitive stimulation) or by provocative exercise
describe difficulty opening jar tops, and twisting or turning testing. However, in myopathic disorders, objective muscle
doorknobs. weakness and loss of function usually accompany fatigue.
Patient with neck weakness often complain of difficulty lift- Muscle pain is another common complaint in patients referred
ing their head off a pillow. Further, sudden braking or accelerat- to a neuromuscular clinic. Most muscle diseases are not associ-
ing in a car can cause the head to jerk back and forth. ated with severe muscle pain (myalgias) or tenderness. Some pa-
Involvement of cranial muscles may result in ptosis, diplopia, tients with various forms of muscular dystrophy or inflammatory
dysarthria, or difficulty chewing and swallowing. myopathy describe mild or moderate myalgias. The pain associated
Table 26-5. Differential Diagnosis of Chronic Progressive Table 26-6. Differential Diagnosis of Distal Weakness
Proximal Weakness
Anterior Horn Cell Disorders Cervical Disease
Multilevel radiculopathy (C7, C 8 . T I )
Amyotrophic lateral sclerosis Lower trunk brachial plexopathy
Spinal muscular atrophy Syringomyelia
Kennedy's disease Tumor of the cord
Peripheral Neuropathy Lumbosacral Disease
Chronic inflammatory demyelinating polyneuropathy Tumor of the conus medullaris
Multifocal motor neuropathy (usually affects the distal Ijmbs) Polyradiculopathy (L4, L5, SI, S2)
Toxic neuropathies Lumbosacral plexopathy
Neuropathy associated with systemic disorders
Connective tissue disease (e.g., vasculitis) Motor Neuron Disorders
Diabetes mellitus Distal spinal muscular atrophy
Uremia Amyotrophic lateral sclerosis
Amyloidosis Neuromuscular Junction Disorders
Paraneoplastic Myasthenia gravis (rare)
Carcinomatous infiltration (e.g., leukemia, lymphoma)
Neuromuscular Junction Disorders Congenital myasthenia gravis (e.g., slow ion channel defects)
Lambert-Eaton myasthenic syndrome Peripheral Neuropathies
Myasthenia gravis Charcot-Marie-Tooth disease and related hereditary neuropathies
Myopathy Multifocal demyelinating motor or sensorimotor neuropathies
Muscular dystrophy Vasculitis
Periodic paralysis Toxic/metabolic neuropathies
Electrolyte imbalance Intrinsic Muscle Disorders
Endocrinopathies Distal myopathies/dystrophies
Inflammatory myopathies Facioscapulohumeral muscular dystrophy
Dermatomyositis Scapuloperoneal syndromes
Polymyositis Emery-Dreifuss muscular dystrophy
Infectious myositis Oculopharyngodistal muscular dystrophy
Inclusion body myositis Myotonic dystrophy
Toxic myopathies Acid maltase deficiency
Metabolic myopathies Debrancher enzyme deficiency
Glycogen and lipid disorders in association with myoglobinuria Phosphorylase b kinase deficiency
Myofibrillar myopathy
Central core disease
with these disorders is typically described as a deep aching Centronuclear myopathy
muscle discomfort. Usually the pain is diffuse rather than local- Nemaline myopathy
ized and the muscles are not tender to palpation. The pain is Inclusion body myositis
seldom severe enough to warrant analgesics. However, severe Focal myositis
myalgias and tenderness often accompany fasciitis, myositis re- Modified from Barohn RJ, Amato AA, Griggs RC: Overview of the distal my-
lated to infections, and rhabdomyolysis/myoglobinuria caused opathies: From the molecular to the clinical. Neuromuscul Disord I998;8:
by various metabolic myopathies, electrolyte disturbances, and 309-316, with permission.
toxins.
In many patients referred for evaluation of severe muscle hereditary disorder is suspected, it is valuable to examine af-
pain, the symptoms are psychosomatic rather than organic in fected family members. Some patients may claim a family his-
etiology. Such patients typically describe severe generalized tory of a particular disorder but upon examining affected family
muscle pain and tenderness unrelieved by analgesic medica- members a different disease may be diagnosed. In addition,
tions. The symptoms of severe muscle pain are usually accom- some family members who are asymptomatic may be found to
panied by complaints of generalized weakness. In addition, have mild signs of disease on a thorough examination. Thus, the
patients frequently describe exquisite tenderness to even light medical and family histories as well as a pertinent review of
touch. Despite these severe symptoms, there often is no objec- symptoms provide insights into the type of disorder potentially
tive evidence of a neuromuscular disease on clinical examina- affecting the patient.
tion, laboratory testing, electrophysiologic studies, or muscle In patients with progressive weakness, a history regarding pos-
biopsy. sible toxin exposures is important. Various environmental toxins
The medical history of patients should be addressed because and drugs can result in damage to the peripheral nerves, neuro-
various diseases can be associated with neuromuscular disor- muscular junction, or muscle. The -severity of the pathologic
ders. For example, inflammatory myopathy may be seen in pa- insult may be related to the dose and duration of the exposure.
tients with connective tissue disease. In addition, the review of When children are concerned, the parents must be questioned
symptoms should assess systemic complaints that may be asso- with great care and sensitivity. The heightened concern of the
ciated with a myopathic disorder (e.g., arthralgias to assess for parents may cause them to unconsciously omit important details
underlying connective tissue disease). A careful family history of the patient's status as related to various other associated child-
is also vitally important in attempting to define the possible hood illnesses or having to being a "clumsy child." Also, parents
mode of inheritance or degree of genetic penetrance. When a may bring a considerable amount of guilt to the examination and
Chapter 26 INTRODUCTION TO MYOPATHIES A N D MUSCLE TISSUE'S REACTION TO INJURY — 1233
the physician must be aware of this potential problem. The par- Table 26-7. Neuromuscular Causes of Ptosis
ents' fears and associated guilt should be dealt with and not ig- or Ophthalmoplegia
nored. If necessary, professional counseling should be offered in Peripheral Neuropathy
addition to treating the patient. Often, a child's illness affects the Guillain-Barre syndrome
entire family, which in turn can have profound physical and psy- Miller Fisher syndrome
chological repercussions on more than just the patient. Neuromuscular Junction Disorders
Botulism
PHYSICAL EXAMINATION Lambert-Eaton myasthenic syndrome
Myasthenia gravis
Following the historical details, a complete neurologic exami- Congenital myasthenia
nation should be performed.19-55-56-70-129 The physical examination
actually begins during the taking of the history. Extraocular, Myopathy
facial, jaw, pharyngeal, tongue, and neck weakness may be ap- Mitochondrial myopathies
parent by just observing the patient during the interview. For ex- Kearns-Sayre syndrome
ample, a mitochondrial myopathy or myasthenia gravis should Progressive external ophthalmoplegia
be considered in patients observed to have ptosis or ophthalmo- Oculopharyngeal and oculopharyngodistal muscular dystrophy
paresis. Patients with myotonic dystrophy often have facial Myotonic dystrophy (ptosis only)
weakness, temporalis muscle wasting, and frontal balding. A Congenital myopathy
characteristic rash is typically present in patients with dermato- Centronuclear (myotubular)
myositis. Thus, specific myopathic disorders can be diagnosed Nemaline (ptosis only)
or at least strongly suspected by casually observing the patient Hyperthyroidism/Graves' disease (ophthalmoplegia without ptosis)
while taking the medical history.
It is essential that the patient undress except for undergar-
ments and a gown for an adequate examination. The patient's have a steppage gait. Distal lower limb weakness should also be
posture while sitting in a chair, standing still, and ambulating assessed by having the patient walk on the heals and toes.
should be assessed. Weakness of the spine extensors may require Weakness of the shoulder girdle can result in winging of the
the patient to lean forward on the arms or rest against the exam- scapula. In addition, a "trapezius hump" caused by the scapula
ining table to maintain an upright posture, particularly for more rising up the shoulder secondary to poor scapular fixation may
than a few minutes. Some patients may have head-drop related be noted, particularly in patients with facioscapulohumeral
to neck extensor weakness. When standing, the patient should be muscular dystrophy. Proximal arm weakness also may result in
observed from the side as well as from the front and back. On drooping of the shoulders and inward rotation of the arms. In
side viewing, the clinician can detect excessive lumbar lordosis, addition, shoulder girdle weakness can cause the horizontal or
knee extensor weakness (genu recurvatum), and ankle contrac- downward rotation of the clavicles, diagonal or horizontal dis-
tures. An excessive lordosis implies the hip extensors are too placement of the anterior axillary lines, and the dorsum of the
weak to maintain the center of gravity in its normal position hands to face forwards rather than to the side.
without accessory muscle assistance. The weight line is purpose- During both standing and ambulation, the muscles should be
fully brought posterior to the hip joints so that the patient can inspected for any signs of wasting or hypertrophy not only in
rest on the hip ligaments by way of the center of gravity being the limbs, but also about the head and neck. The clinician
posterior to them. This is all accomplished through the compen- should observe for fasciculations, which are not a sign of my-
satory excessive lumbar lordosis. With disease progression, the opathy but rather motor neuron or peripheral nerve disease.
knee extensors may become weak and unable to resist the Visible muscle cramping and the presence of continuous muscle
normal knee flexion moment during stance with a potential for activity (e.g., myokymia) should be noted. Muscles should be
falling secondary to buckling at the knee. As a result, the patient palpated for tone and tenderness.
attempts to compensate by shifting the weight line anterior to the Muscles can be percussed in the upper and lower limb as well
knee, thus creating a knee extension moment and stability during as the face, including the tongue. Percussion of the muscle di-
standing. Unfortunately, with time this can produce lax knee lig- rectly may reveal a pronounced contraction of a small portion
aments as well as stretching of the knee joint's posterior capsule. with a delayed relaxation (percussion myotonia). Myotonia can
The above maneuvers can result in an unfavorable dorsiflexion predominantly affect proximal or distal muscles depending on
moment at the ankle that is compensated by plantar flexion and the specific myopathy. Myotonia typically can be demonstrated
slight heel rise. When observing the patient from either the ante- distally and in the tongue in myotonic dystrophy, while proxi-
rior or posterior position, a wide-base stance may be detected. mal limb muscles are affected in proximal myotonic myopathy
This position may be a result of hip abductor tightness. (PROMM). Having the patient sustain a grip for a brief period
During ambulation the patient may be observed to have a and then try to relax can also assess for action myotonia, in
wide-based waddling gait with hyperlordosis, genu recurvatum, which one sees a slow relaxation. Myotonia generally improves
and failure to heel strike. The waddling gait is essentially a with repetition. In contrast, paramyotonia worsens with repeti-
result of hip abductor weakness that is incapable of preventing tive activity. This is best demonstrated in patients with paramy-
the pelvis from dropping excessively, i.e., a positive otonia congenita by having them repeatedly open and close
Trendelenburg sign during ambulation. Compensatory abnor- their eyes; eventually patients have difficulty completely open-
mal shoulder motions can also be seen as a result of attempting ing their eyes. When myotonia or paramyotonia is elicited, the
to control gravity throughout the gait cycle and prevent falling. physician should inquire about the patient's response to activity
With disease progression, the patient begins to fall more fre- and cold temperatures because these conditions worsen the
quently and display associated signs of bruises and superficial symptoms in specific myotonic disorders. Myotonia congenita
skin lesions about the knees and hands. Patients with footdrop may also show a peculiar "transient paresis" after rest, which
and eversion, and toe flexion and extension. As the MRC scores
reflect movement against gravity, muscle groups must be tested
against gravity. Thus, neck flexion should be assessed with the
patient supine; neck extension, hip extension and knee flexion
with the patient prone, and hip flexion with the patient on the
side. Examining the patient in these positions is essential in ac-
curately assessing the strength and can detect weakness not
noted if the patient were examined only while seated.
A functional assessment of strength should also be per-
formed. In order to evaluate hip girdle weakness, the patient
should be observed arising from a chair or the floor. In patients
with proximal leg weakness, a rather characteristic sequence of
events is seen to occur. First, the patients assume a position on
the hands and knees and then they push themselves up by
marching their hands up the legs, eliciting the so-called
Gowers' sign or maneuver (Fig. 26-1). 55 One can also observe
the patient perform a deep knee bend, arise from a squat, climb
stairs, run, or hop on one foot to detect subtle weakness.
Sometimes, we record the time it takes to perform specific tasks
(e.g., climbing 10 steps or walking 30 feet), especially in moni-
toring a functional response to a particular therapy or in follow-
ing the natural progression of the disorder.
Deep tendon or muscle stretch reflexes are usually present
during the early phases of myopathic disorders. As the disease
progresses, previously present reflexes may diminish or become
unobtainable. Specific myopathies are associated with de-
creased or absent reflexes and may have a predilection for cer-
Figure 26-1. Gowers* sign. A patient with progressive spinal mus- tain muscle groups. For example, the knee jerk is reduced early
cular atrophy is requested to arise from the floor. He first assumes a in the course of inclusion body myopathy when other reflexes
position on his hand and knees. A semi-upright posture is achieved by are still relatively normal. On the other hand, certain reflexes
positioning the trunk over extended arms and legs.The patient then appear to be spared even late in the course of the disease (e.g.,
pushes his trunk upward with the use of the arms by "climbing" up the ankle jerks are frequently present in patients with Duchenne
legs. (From Gomez MR:The clinical examination. In Engel AG, Franzini- muscular dystrophy despite severe generalized weakness).
Armstrong C (eds): Myology, 2nd ed. N e w York, McGraw Hill, 1994, pp Sensations to various modalities (temperature, pain, touch,
746-763 with permission.) vibration, and proprioception) are all usually normal in patients
with intrinsic muscle disease. Various cutaneous reflexes are
also normal (abdominal, corneal, plantar). If there is some form
improves with repeated muscle contraction. Other abnormali- of sensory loss, then a disorder affecting the peripheral nervous
ties can be noted on percussion. A peculiar wave of muscle con- system should be considered. This does not mean that a con-
traction emanating from the site of percussion is seen in comitant muscle disease is also not present.
so-called rippling muscle disease. Occasionally, a "mounding" Examining children, particularly infants, can be a challenge.
of the muscle as opposed to a contraction indentation can be ob- Infants can be positioned prone to observe if they are capable of
served. This phenomenon is referred to as myoedema and it can extending the head. An inability to do so suggests weakness of j
be observed in patients with profound cachexia or myxedema. the neck extensor muscles. Most infants have considerable subcu- j
Manual muscle testing is extremely important and we recom- taneous fat that makes muscle palpation quite difficult. Palpating
mend using the Medical Research Council (MRC) scale for uni- neck extensor muscles is a good place to attempt this evaluation
formity: grade 0 (no visible contraction); grade 1 (trace because little subcutaneous fat overlies this muscle group.5 Neck
contraction); grade 2 (full movement across the joint with grav- flexion strength can be assessed as the child is pulled by the arms
ity eliminated); grade 3 (full movement across the joint against from a supine to sitting position. Crying during the examination
gravity); grade 4 (full movement across the joint against gravity allows the opportunity to assess the child's vocalization (e.g.,
plus some resistance); grade 5 (normal strength). 84 We use a presence of a weak cry) and fatigability to the physical examina-
modification of this scale by adding plus (e.g., 4+) or minus tion. Muscle weakness in infants is usually characterized by over-
signs (e.g., 3-) to the numbers for a finer distinction or degrees all decrease in muscle tone and many children with profound
of muscle weakness between the larger grades. The MRC scale weakness are characterized as "floppy infants." This terminology
has excellent intraobservor and interobservor reliability. Face, does not necessarily imply a neuromuscular disorder. In fact,
neck, and upper and lower limb muscles should be tested and most floppy infants exhibit decreased tone secondary to a central
documented in the patient's chart to be able to document any nervous system problem. It is important to examine the parents of
changes over time. We routinely grade the strength of the orbic- floppy infants for possibility of a neuromuscular disorder. This is
ularis oculi, jaw, tongue, neck flexion and extension, shoulder particularly important in children suspected of having myotonic
abduction, flexion and extension, elbows flexion and extension, dystrophy. We have diagnosed a number of infants with congeni-
wrist flexion and extension, finger and thumb flexion, extension, tal myotonic dystrophy by examining the mother who was
and abduction, hip flexion, extension, and abduction, knee flex- asymptomatic. In addition, weakness can transiently develop in
ion and extension, ankle dorsiflexion, plantar flexion, inversion, infants born to mothers with myasthenia gravis.
The above historical and physical descriptions are meant to serum protein electrophoresis or immunofixation test looking
serve only as a rough guide to the approach one may wish to for a monoclonal gammopathy should be ordered to help ex-
consider when evaluating a patient for a myopathic process. 65 clude primary amyloidosis. With the explosion in our under-
The clinical presentation of myopathies is as varied as the dif- standing of molecular genetics, there is an ever-expanding list
ferent types of intrinsic muscle disorders. As noted above, not of hereditary myopathies that can be diagnosed by way of DNA
all patients present with symmetric proximal muscle weakness testing. These include various types of muscular dystrophy, mi-
worse in the lower than upper limbs. Some individuals may tochondrial myopathy, congenital myopathy, and hereditary
have an asymmetric distribution of muscle complaints, with the forms of periodic paralysis.
upper limbs more affected than the lower or the distal muscles
preferentially weak compared to the proximal muscles. Some
disorders manifest with exertional muscle pain, cramps, and fa- MUSCLE A N A T O M Y
tigue rather than weakness. The clinician must be prepared to
have an open mind when examining a patient and not get The basic gross anatomic and ultrastructural details of muscle
trapped into a set format or preconceived expectations as to how tissue have been discussed previously (see Chapter 1). The
specific disease entities manifest. The electrophysiologic find- reader is encouraged to read this brief section regarding normal
ings can be of considerable help in localizing the lesion to the anatomy prior to delving into the pathologic aspects of muscle
anterior horn cell, peripheral nerve, neuromuscular junction, or disorders.
muscle.
LABORATORY TESTING MUSCLE HISTOLOGY AND
REACTION T O DISEASE
The single most useful blood test in a patient presenting with
weakness is a serum creatine kinase (CK) level. The upper limit MUSCLE TISSUE EVALUATION
of normal in the ambulatory population for serum CK is depen-
dent on the sex and race. For instance, the upper limit of normal Despite the fact that the physiology of muscle tissue is ex-
for serum CK in black males is about 500 IU/L; in black fe- tremely complex, the number of ways in which muscle can react
males, white males, and Hispanics the CK is about 300 IU/L; in to disease is limited.5-15-18*23-34'4-'67 The manner in which these re-
white females the upper limit of normal is about 200 IU/L. 59a actions are critically evaluated is through either an open (minor
Importantly, mild elevations in serum CK can be seen in neuro- surgical procedure) or closed (needle/punch) muscle biopsy.
genic processes such as motor neuron disease or other rapidly Some authorities prefer open muscle biopsy because several
denervating process in which large amounts muscle tissue is large samples can be obtained and processed for routine and
damaged. However, serum CK is rarely elevated above 1000 electron microscopy, metabolic analysis, and protein analysis
IU/L in these conditions. In addition, it is important to note that (Western blot). Others recommend needle muscle biopsies in
not all patients with myopathies have elevated serum CK levels. which the individual samples sizes are small, but many more
Further, serum CK levels do not correlate with the degree of areas of potentially affected muscle tissue can be assessed via
muscle weakness in all patients. smaller incisions.33-42-60'81*97 The diagnostic yield of needle biop-
Clinicians should be aware that other enzymes that are rou- sies in experienced myopathology laboratories appears high. 81
tinely screened for on laboratory tests (e.g., AST, and LDH) We favor open biopsy, especially in multifocal processes, such
may also be elevated in muscle disorders. Many physicians are as in inflammatory myopathies, and in myopathic disorders that
under the false assumption that these enzymes are specific for require electron microscopy for confirming a diagnosis. MR or
liver disease. One must recall that AST, LDH, and even aldolase CT imaging may be useful in selecting which muscle to
are expressed in muscle as well as the liver. Unfortunately, it is biopsy.82-105 The muscle selected for biopsy should be mildly
not uncommon for patients with primary muscle disorders to weak, preferably MRC grade 4. If the muscle is too weak (i.e.,
have undergone liver biopsies before the correct diagnosis of a MRC grade 3 or less), the tissue typically has end-stage damage
myopathy was made. In order to distinguish elevation of these and it is often impossible to distinguish certain myopathic dis-
enzymes due to liver disease versus a myopathic process, serum orders from severe neurogenic atrophy. In patients with little or
CK, which is specific for muscle disease, and GGT, which is no weakness on examination, electromyography can be helpful
specific for liver disease, should be obtained. In this regard, cer- in selecting the muscle to biopsy. However, it is important to
tain immunosuppressive agents used to treat inflammatory my- biopsy the contralateral muscle in order to avoid artifact from
opathies (e.g., azathioprine and methotrexate) are hepatotoxic. the electromyographic needle.
In following the liver functions tests of such patients on treat- We analyze the muscle specimen by light and electron mi-
ment, it is essential to also check GGT and CK levels, because croscopy. In addition, biochemical assays for various enzyme
they may become elevated from an exacerbation of the underly- deficiencies (e.g., glycogen and lipid storage diseases), Western
ing myositis rather than from liver damage. blot for specific protein abnormalities (e.g., dystrophin), and
Other blood work that is routinely ordered in patients sus- DNA analysis for genetic mutations (e.g., mitochondrial my-
pected of having a myopathy are electrolyte assays. Hyper- and opathies) can be performed on the biopsy tissue. The histologic
hypokalemia can be caused by a number of conditions and can evaluation of muscle biopsies assesses the size, shape, and fiber
result in generalized weakness, as well as hyper- and hypocal- type distribution of the muscle fibers. Modified Gomori
cemia. Thyroid function tests are obtained because both hyper- trichrome and hematoxylin and eosin (H&E) stains are most
and hypothyroidism are associated with myopathies. In patients commonly used to assess the morphologic appearance of the
suspected of having an inflammatory myopathy, an erythrocyte muscle fibers as well as the associated connective tissue and
sedimentation rate (ESR) and antinuclear antibody (ANA) are vasculature. Inflammatory and dystrophic changes are easily
ordered to assess for an underlying connective tissue disease. A demonstrated with these stains. In addition, some abnormalities
Table 26-8. Muscle Fiber Type Characteristics
Type I Type 2A Type 2B
Gross Appearance
Color Dark Dark Pale
Capillary density High High Low
Muscle fiber diameter Smallest Large Largest
Comparative Histochemical Activity
ATPase 4.3 Strong Weak Weak
ATPase 4.6 - Strong Weak Strong
ATPase 9.4 Weak Strong Strong
NADH reductase Strong Strong Weak
Glycogen content Low High High
Glycogen phosphorylase Weak Strong Strong
Myoglobin content High High Low
Lipid content High High Low
Cytochrome oxidase Strong Weak Weak
Electron Microscopy
Mitochondria Numerous Numerous Few
Z-disc Intermediate Wide Narrow
Physiologic Characteristics
Twitch speed Slow Fast Fast
Fatigability Resistant Resistant Suscepti
Axons
Diameter Smallest Largest
Conduction vejocity Slowest Fastest
Other Classifications
Intermediate (red) Red White
S FR FF
SO FOG FG
B C A
FR.fast, resistant; FF, fast, fatigable; S, slow, FOG, fast, oxidative glycolytic; FG, fast, glycolytic; SO, slow oxidative. Modified from Karpati G, Carpenter S: Skeletal muscle
pathology in neuromuscular diseases. In Rowland LP, DiMauro S (eds): Handbook of Clinical Neurology,Vol. 18. Amsterdam, Elsevier, 1992, pp 1—48.
are best appreciated under light microscopy with modified subcellular organelles have characteristic appearances in normal
Gomori trichrome stains (e.g., ragged red fibers associated with muscle tissue. In disease states, these same organelles and
mitochondrial myopathies, tubular aggregates, cytoplasmic membrane subcomponents display both gross and subtle mor-
bodies). Myofibrillar adenosine triphosphatase (ATPase) stains phology alterations. In the majority of disorders, a number of
at various pHs are used to distinguish the different muscle fiber changes are nonspecific and merely indicate some form of phys-
types (Table 26-8). Specific stains are used to evaluate for ical or biochemical muscle fiber insult. Although most histo-
glycogen (e.g., periodic acid-Sniff or PAS stain) and lipid (oil logic abnormalities are not disease-specific, significant insight
red O and sudan black) storage abnormalities. Oxidative into the pathogenesis of neuromuscular disorders can be gained
enzyme stains (NADH dehydrogenase, succinate dehydroge- using the combination of both light and electron microscopy.
nase or SDH, cytochrome-C oxidase or COX) are useful for
identifying mitochondrial and intermyofibrillar network abnor- NORMAL MUSCLE HISTOLOGY
malities. Phosphorylase stain is employed to diagnosis
McArdle's disease. A myoadenylate deaminase (MAD) stain Normal muscle tissue examined in cross-section under the
can be used in patients with possible MAD deficiency (e.g., light microscope should appear polygonal with visible, but not
muscle pain syndromes, myoglobinuria). Amyloid deposition excessive, amounts of connective tissue. There should be few
can be detected using. Congo red, crystal violet, or immunos- inflammatory cells or necrotic muscle fibers. The distribution of
taining. Immunostaining techniques are of utmost importance in muscle fiber types is assessed with myofibrillar ATPase at three
the diagnosis of specific muscular dystrophies (e.g., dystrophin pHs: 4.3, 4.6, and 9.4.5 68 Muscle tissue exposed to ATPase at
staining for Duchenne and Becker muscular dystrophy, merosin these different pHs results in the muscle fibers displaying dis-
staining for congenital muscular dystrophy, sarcoglycan and tinct staining qualities based upon their biochemical substrate
dysferlin stains for limb-girdle muscular dystrophies). Immuno- mechanisms (Fig. 26-2, Table 26-8). These staining qualities re-
staining is also useful in the early diagnosis and in understand- flect the distinct physiologic and metabolic functions of the in-
ing the pathogenesis of the different inflammatory myopathies dividual muscle fibers and are classified into four different fiber
and vasculitic disorders (e.g., stains for complement, membrane types based upon their staining characteristics: type 1 (slow-
attack complex, immunoglobulins, human leukocyte antigens, twitch, fatigue-resistant, oxidative metabolism), 2A (fast-
and cell markers). twitch, intermediate fatigue resistance, oxidative and glycolytic
Electron microscopy (EM) is used for detailed evaluation of metabolism), 2B (fast-twitch, poor fatigue-resistance, glycolytic
the ultrastructural components of muscle fibers. Cellular and metabolism), and 2C (undifferentiated, embryonic). The specific
Figure 26-2. The normal checkerboard appearance of healthy muscle tissue when exposed to ATPase at pH 9.4 (A), and at pH 4.6
(B), as well as an NADH reaction (C).There is a relative abundance of type 2 fibers (dark staining in A and light staining in B) compared to type I
fibers with type 2 fibers further subdivided into types 2A, 2B,and 2C.This further subdivision of type 2 fibers is based upon the degree to which
individual fibers stain when exposed to different pHs and compared. Specifically, the darkly staining type 2 fibers in A can be seen to stain differ-
ently in B, i.e., all lighter than type I with the lightest being type 2A, a somewhat darker appearance for type 2B, with type 2C fibers being the dark-
est of all type 2 fibers but still lighter in appearance than type I fibers. (From Banker BQ, Engel AG: Basic reactions of muscle. In Engel AG,
Franzini-Armstrong C (eds): Myology, 2nd ed. New York, McGraw Hill, 1994, pp 832-888 with permission.)
muscle fiber type is determined by the innervating motor approximately 2 pm per year until age 5 years, and then by 3 jxm
neuron. Identifying individual fiber types allows one to assess per year until 9 years of age. At 10 years of age, mean muscle di-
whether there is a predilection for a particular disease to prefer- ameters range from 38-42 Jim. Normal adult muscle fiber size is
entially affect one fiber type over another (e.g., type 2 fiber at- reached between the ages of 12 and 15 years. 18 In normal
rophy associated with disuse) or if there has been denervation muscle, there is less than 12% difference in the largest mean
with subsequent reinnervation (fiber type grouping). fiber diameters between all three muscle fiber types. Both type 1
Type 2C muscle fibers are infrequently found in adults but and type 2 adult muscle fibers are larger in men than women. In
are the primary muscle type in humans before the last three men, type 2 fibers are usually larger than type 1 fibers, whereas
months of gestation, i.e., an embryonic muscle type. After about the opposite is true in women. The diameter of muscle fibers is
22 weeks of fetal life, the expected mosaic or so-called checker- also dependent on the specific muscle biopsied. For example, in
board appearance of individual fiber types begins to become the biceps brachii, the diameters of muscle fibers are as follows:
manifest but is not clearly defined until about 30 weeks. 5 type 1 fibers 64.3 ± 3.7 p.m and type 2 fibers 72.7 ± 5.3 Jim in
Coincidentally, this is the development of the adult type of males; type 1 fibers 56.8 ± 4.8 Jim and type 2 fibers 54.6 ±7.0
unineuronal innervation, i.e., a single nerve twig per single |im in females. In the vastus lateralis, the diameters of muscle
muscle fiber. The muscle fibers continue to progress toward the fibers are slightly different: type 1 fibers 59.5 ± 6.4 |im and type
adult metabolic profile throughout the first several years of life. 2 fibers 64.8 ± 8.1 Jim in males and type 1 58.8 ±6.1 pm and
In the adult, only about 1-2% of muscle fibers are the undiffer- type 2 fibers 49.9 ± 6.2 pm in females.15
entiated type 2C fibers.32
The percentage of type 1, 2A, and 2B fibers vary in different ABNORMAL MUSCLE HISTOLOGY
muscle groups depending on their physiologic function, and
knowledge of normative data per muscle is mandatory for accu- True abnormalities on muscle biopsy need to be distinguished
rate muscle biopsy evaluation.66 In the most commonly biopsied from artifact. Muscle tissue can be damaged during the biopsy
muscles (i.e., biceps brachii, triceps, and quadriceps), there are procedure or with processing of the tissue for histologic analy-
approximately equal amounts of the three major fiber types. sis. Muscle fibers can become stretched or hypercontracted.
Importantly, all muscle fibers from a single motor unit are of the Autolysis can occur if the tissue is not frozen or fixed promptly.
same fiber type. One exception is that motor units are never In addition, ice crystal artifact within muscle fibers may develop
composed of only type 2C fibers. Because muscle fibers from a if the tissue is not frozen appropriately. Necrosis may be evident
single motor unit are randomly distributed amongst muscle if a needle electromyogram was recently performed on the
fibers of different motor units and fiber types, a checkerboard or muscle selected for biopsy.
mosaic pattern is appreciated on ATPase stains. In addition, type When considering muscle tissue's reaction to disease, it is
1 fibers stain more intensely with modified Gomori trichrome, important to keep in mind that muscle is a syncytium formed
esterase, lipid, and oxidative enzyme stains than type 2 fibers from the joining of hundreds or thousands of myoblasts.
because of the increase number of mitochondria and oxidative Because of the syncytial nature of muscle, focal injuries usually
metabolism associated with type 1 fibers. In contrast, type 2 affect only a small portion of muscle tissue and do not result in
fibers, which are involved with glycolytic metabolism, stain the destruction of an entire fiber. Some acquired myopathies
more intensely with PAS. (e.g., inflammatory myopathies) are multifocal in nature. In
As noted, muscle fibers are normally polygonal in shape. The addition, genetic disorders can manifest at discrete sites with
size of muscle fibers is assessed by measuring the range and other regions appearing relatively normal (e.g., oculopharyn-
mean cross-sectional diameter for each fiber type. 15-18 Mean geal and facioscapulohumeral muscular dystrophies). Thus, a
muscle fiber diameter is 16 Jim at 1 year of age and increases by patient can have a myopathic process and yet a muscle biopsy
in its physiologic properties to reflect its parent motor neuron. In
this way, the normal checkerboard appearance of muscle tissue
is converted to groups of single muscle fibers with the same bio-
chemical properties—fiber type grouping (Fig. 26-3).
Depending upon the number of denervation/reinnervation cycles
or extent of denervation and disease chronicity, variable degrees
of fiber type grouping can be observed. Reinnervated fibers
regain their polygonal appearance once successful neuromuscu-
lar transmission has been reestablished.
Disorders intrinsic to muscle tissue produce a more random
loss of muscle fibers belonging to different motor units. Thus,
fiber type grouping is not evident on muscle biopsy in my-
opathies. Small groups of atrophic fibers may be present in my-
opathies secondary to muscle fiber splitting, degeneration, and
regeneration. Larger areas of group atrophy are more typical of
neurogenic atrophy. In addition, the atrophic muscle fibers are
Figure 26-3. Fiber type grouping of muscle tissue from an indi- more rounded in appearance in myopathies in contrast to the
vidual with a chronic neurogenic process with multiple cycles of den- more angulated shape associated with neurogenic disorders.
ervation and reinnervation. A section of affected muscle exposed to However, rounded muscle fibers can also occur with denerva-
myofibrillar ATPase at pH 4.6. Note the disappearance of the normal tion and angulated fibers can be seen in myopathies. Certain
checkerboard mixture of type I and type 2 fibers. Large groups of type myopathic disorders (e.g., myotonic dystrophy and various con-
I (darker staining) and type 2 fibers (lighter staining) are found. genital myopathies) are associated with preferential type 1 fiber
atrophy or hypotrophy. Selective type 2 fiber atrophy is a rela-
tively common finding and can result from different mecha-
may demonstrate little if any abnormal tissue on muscle biopsy nisms (e.g., high-dose corticosteroids or disuse).
because of sampling bias. A normal muscle biopsy, therefore, The actual cause of the reduction in muscle fiber size is prob¬
does not completely rule out a myopathy. ably reduced myofibrillar girth secondary to myofilament loss.
Despite the complexity of muscle tissue, it has a relatively An imbalance occurs for unclear reasons in the amount of tissue
limited ability to respond to disease. It is necessary to always normally undergoing degradation compared to synthesis. The
keep in mind that the tissue's reaction to disease is not necessar- mechanism of myofibrillar protein loss may be secondary to
ily specific for any one disorder, but it may react in similar ways downregulation of ribosomal protein production.85 An actual in-
to different disease processes. Although there is no "best" way crease in degradation may also be present. Further work is re-
to consider pathologic reactions to disease, a systematic ap- quired to more fully elucidate the molecular basis for these
proach at least allows us to categorize observations based upon gross observations of size reduction.
cellular mechanisms. Hypotrophy. The term hypotrophy is best applied to disor-
Atrophy. One of the most common histologic abnormalities ders with small fibers that never fully develop to a normal
is muscle fiber atrophy. Atrophy of single muscle fibers is de- mature size, i.e., an arrest in the maturation process. It is better
fined as a reduction in size compared to its previously normal to use the term hypotrophy to describe small fibers resulting
state consequent to some form of insult. Various pathologic dis- from a failure to develop or mature (e.g., nemaline myopathy,
orders can result in muscle fiber atrophy. These individual dis- centronuclear myopathy, and fiber type disproportion) as op-
orders may be best appreciated as belonging to three general posed to those that are small secondary to atrophy. The cause
categories: (1) loss of nerve/muscle integrity (e.g., some form of for this lack of maturation is not known; however, a defective
denervation), (2) inhibition of contraction (e.g., immobiliza- neurotrophic influence during myogenesis is postulated to have
tion), and (3) pathologic stimuli (e.g., intrinsic muscle disease, some effect.3-46
corticosteroid excess).34 Hypertrophy. An increase in single muscle fiber size,
Diseases affecting some portion of the peripheral nervous muscle hypertrophy, can occur in normal and pathologic situa-
system as well as those intrinsic to muscle tissue are capable of tions. A common example of muscle fiber hypertrophy is the
producing muscle atrophy. In motor neuron and peripheral nerve result of physical training where either or both types of muscle
disease, all of the muscle fibers belonging to a single motor unit fibers (types 1 and 2) can enlarge depending upon the specific
are affected—denervation atrophy. Early denervation is appar- form of exercise. Endurance training has a tendency to hyper-
ent histologically by scattered, atrophic angulated muscle fibers. trophy type 1 fibers, whereas progressive resistance training
With further degeneration of more motor nerves, group atrophy (lifting weights) can preferentially increase type 2 fiber size.
is noted on the biopsy. In group atrophy, there are groups of The addition of anabolic steroids or growth hormone can mag-
small, intermixing type 1 and 2 muscle fibers. Once denervated, nify the results of progressive resistance training with signifi-
these muscle fibers send out poorly understood messages that cant increases in both muscle size and strength.
induce neighboring intact terminal axons to generate collateral Gross muscle hypertrophy is common in myotonia con-
sprouts and attempt to reinnervate the newly denervated muscle genita. 10 Significant muscle hypertrophy also occurs in
fibers. Once successful reinnervation is accomplished, a number acromegaly and hypothyroidism. Compensatory muscle hyper-
of important consequences ensue. Recall that the biochemical trophy may also be noted in lesions causing partial denervation
apparatus, as reflected in fiber typing, is directly dependent such as radiculopathies and some forms of spinal muscular atro-
upon the neurohumoral influence of the individual anterior horn phy and muscular dystrophies. Presumably, the weakness result-
cells. When a muscle fiber is reinnervated by an anterior horn ing from atrophic fibers causes the remaining intact muscle
cell with a different biochemical nature, it undergoes a change fibers to undergo some degree of weakness-induced compensatory
hypertrophy. A hypertrophic muscle does not contain signifi-
cantly more muscle fibers than a nonhypertrophic muscle, but
instead each muscle fiber has an increased number of myofibrils.
The exact mechanism whereby the muscle responds to stress by
producing more myofibrils is incompletely understood.
Muscle pseudohypertrophy results not from an increase in
myofibrils but from the deposition of cellular breakdown prod-
ucts, increase in substrates secondary to faulty enzymatic path-
ways, or an increased amount of fat and connective tissue
surrounding muscle fibers. A common example is the calf en-
largement noted in Duchenne muscular dystrophy. This form of
pseudohypertrophy is a combination of single muscle fiber hy-
pertrophy and deposition of fat and connective tissues.
Pathologic hypertrophic muscle tissue usually loses its polygo-
nal shape and appears more rounded.
Variability of Fiber Size. Because both myopathic and neu-
rogenic disorders can result in atrophic and hypertrophic fibers, Figure 26-4. Necrotic fibers (arrows) are seen in this muscle
it is not surprising that increased variability of muscle fiber size biopsy (modified Gomori trichrome stain) of a patient with Duchenne
is common to both of these pathologic processes. The variabil- muscular dystrophy.
ity of muscle fiber size is best measured by plotting a histogram
of the different muscle fibers according to their fiber types and
their individual diameters. In myopathies, the spectrum of di- begins to have a featureless ground-glass appearance, i.e., loss
ameters is broad and can preferentially affect type 1 or type 2 of detail delineating the myofibrillar network. Complement pre-
fibers. In neurogenic disorders, atrophic and nonatrophic fibers cipitation can also be detected early in the process of necrosis.
provide at least two peaks on the histogram in both type 1 and Abnormal mitochondria can be distinguished relatively early
type 2 fibers. with the use of epoxy resin preparations. On longitudinal sec-
Fiber Type Predominance. In the biceps brachii, triceps, tion, the affected muscle fibers display Z-discs that are difficult
and vastus lateralis, muscle fibers types 1, 2A, and 2B fibers are to distinguish by 2 hours following the initiation of necrosis.
present in similar frequencies. Fiber type predominance refers At approximately 6 hours following the first signs of necro-
to an increase in frequency of one of the above fiber types to sis, the affected segment is physically isolated from the healthy
55% or more. This is a nonspecific abnormality. However, some portions of the muscle fiber by a limiting membrane, i.e., a rudi-
of the congenital myopathies as well as myotonic dystrophy are mentary lipid bilayer is formed on either side of the necrotic
associated with a predominance of type 1 fibers. region. This does not adversely affect the muscle fiber as a
Fiber Type Preference. Certain disorders preferentially whole because of the syncytial nature of muscle tissue.
affect one fiber type. For example, disuse and chronic corti- By about 10-12 hours after the beginning of necrosis, numer-
costeroid use can result in selective atrophy of type 2B fibers. ous macrophages can be noted to infiltrate the damaged tissue.68
Myotonia congenita is associated with an absence of type 2B The primary role of these macrophages is to digest the disinte-
fibers. In addition to type 1 fiber predominance, myotonic dy- grating muscle tissue. In certain diseases (polymyositis, inclu-
strophy and certain congenital myopathies have type 1 fiber sion body myositis), macrophages and lymphocytes may invade
hypotrophy. non-necrotic tissue such that a muscle fiber can be "severed"
Central or Internal Nuclei. In normal muscle fibers, the into distinct segments. Of importance with respect to segmental
nuclei are located peripherally at the subsarcolemmal regions. necrosis from a physiologic standpoint is the fact that there is
Embryologically, nuclei are located at the center of the muscle loss of continuity for a period of time until muscle fiber regen-
fibers, but they migrate to the subsarcolemma with maturation. eration restores continuity. This loss of continuity effectively
Certain disorders such as centronuclear myopathy, which is renders the segment of muscle not in contact with the endplate
thought to be a maturational disorder, are associated with cen- region physiologically denervated. For all practical purposes
tral nuclei in addition to type 1 fiber hypotrophy. Internal nuclei this isolated segment(s) begins to atrophy and, if isolated long
may develop following recurrent degeneration and regeneration enough, starts to fibrillate.
of muscle fibers and are a nonspecific abnormality present in Rhabdomyolysis refers to the pathologic condition in which
many myopathic disorders of different etiologies (e.g., muscular there is necrosis of large amounts of muscle tissue.4-108
dystrophy and inflammatory myopathies). Myoglobinuria and renal insufficiency can complicate this dis-
Necrosis. A single muscle fiber can undergo either total or order. Rhabdomyolysis can be seen in alcohol intoxication,
segmental necrosis. Total muscle fiber necrosis is relatively rare snakebites, adverse drug reactions, and inflammatory my-
in that most muscle fibers are quite long and a profound lesion opathies. Various metabolic defects, electrolyte abnormalities,
is required to result in destruction along the entire fiber length. dystrophies, and mitochondrial disorders can also produce this
The more common form of muscle tissue loss is referred to as type of muscle breakdown. Muscle infarction secondary to is-
segmental necrosis in which a relatively small segment chemia leads to wedge-shaped areas of necrosis and can be seen
(300-5,000 pm) of the single muscle fiber is affected by the in- in vasculopathies related to diabetes mellitus, vasculitis, and
citing pathology. The site of necrosis may be somewhat focal at dermatomyositis.
first, but it extends laterally with disease progression. Regeneration. The process of regeneration whereby
Segmental necrosis is usually recognized histologically by necrotic muscle tissue is replaced with functional muscle tissue
the affected portion of the single muscle fiber being more is quite a robust process in most instances. The degree or capacity
rounded as opposed to polygonal (Fig. 26-4). The sarcoplasm of muscle regeneration is dependent upon the reserve capacity
connective tissue elements remain intact, then the muscle tissue
is able to reconstitute itself along the original sarcolemmal tube.
This is similar to nerve regrowth along the original endoneurial
Plasma membrane tube.
Basal lamina During the process of necrosis, the basal lamina and satellite
Myoblasts \ SateBto eel
cells (myoblasts) are eventually stimulated to proliferate.11-57
Macrophage
The proliferation of satellite cells creates a large number of
these cells that align next to each other to form myotubes (Fig.
26-5). Several myotubes form per segment of regenerating
muscle tissue and adhere to the surrounding basal lamina.
Individual myotubes continue to expand through mitosis and
Possible Consequences
production of cellular materials. Eventually, the myotubes fuse
ST— with each other provided the invading macrophages have re-
moved sufficient amounts of cellular debris. The expansion of
Completely success lui restoration ot normal myotubes occurs not only laterally but longitudinally as well,
fiber calibre
eventually reaching the limiting membrane encasing the
necrotic segment and fusing with the healthy muscle tissue
stumps. An intact vascular system is required for not only
macrophage invasion of necrotic tissue, but also the stimulation
Regenerated segment
and proliferation of satellite cells. Various defects can arise in
the process of regeneration with less than perfect reconstitution
is ot smaler cafbre than the rest
ot the fiber
of the muscle fiber (Fig. 26-5).

Muscle Fiber Splitting. Muscle fiber splitting is frequently
associated with myopathies, especially muscular dystrophies. It
is also possible for work-induced hypertrophy to result in
Forked fibers
due to incomplete lateral fusion of myotubes muscle fiber splitting. Muscle fiber splitting is suspected when
two or more closely apposed fibers occupy the space typically
reserved for a single fiber. On longitudinal sections, the muscle
fiber appears to fork or branch into smaller fibers. Membranous
Surviving independent
regenerated fber
debri and capillaries are frequently found at the branch points
Mufripie independent fibers due to lack of fusion suggesting that focal damage to the muscle fiber occurred in
of myotube with the surviving stump
that region of the muscle fiber.5 Splitting may also occur in hy-
& V* "•..,.,.,.„«•', r s * pertrophic fibers as the result of attempting to maximize the
physiologic processes such as nutrient dispersion and removal
© J.,.,*'" *"—.... ( O Q
of metabolic waste products more efficiently. Perhaps, once a
16
Empty basement membrane sleeve

fiber reaches a certain ill-defined size, the above metabolic
due to lack ol regeneration
processes may only be carried out by a compensatory reduction
Figure 26-5. Muscle fiber regeneration. Following removal of in size, i.e., fiber splitting.
necrotic tissue, satellite cells (myoblasts) are stimulated to proliferate Vacuoles. Vacuoles within muscle fibers are a nonspecific
and form myotubes.The myotubes fuse t o reconstitute the necrotic abnormality evident in a myriad of myopathic and, less com-
portion of muscle tissue. A number of events can occur secondary to monly, neurogenic disorders. Vacuoles may be the result of a
faulty regeneration. (I) successful regeneration of muscle should result glycogen or lipid storage defect or a lysosomal enzyme defi-
in an intact and healthy muscle fiber; (2) residual cellular debris, defec- ciency. Autophagic vacuoles are membrane-bound vacuoles that
tive basal lamina, or other causes can result in less than perfect muscle contain degraded cytoplasmic debri. These vacuoles display
fiber regeneration; (3) if some of the multiple myotubes fail to fuse, acid phosphatase activity. Rimmed vacuoles are a form of au-
forked fibers can be observed; (4) failure of myotubes to penetrate the tophagic vacuole frequently associated with inclusion body
limited membrane produces multiple segments of muscle fibers inde- myositis, oculopharyngeal muscular dystrophies, and certain
pendent of each other with the potential for reinnervation; and (5) distal myopathies.
when satellite cells fail to proliferate secondary to ischemia or intrinsic Cytoplasmic Inclusions. Sarcoplasmic, hyaline, cytoplas-
disease, an empty basement membrane results with independent mic, spheroid, and inclusion bodies as well as tubular aggregates
muscle fibers replacing the previously single muscle fiber. (From Karpati and nemaline rods may be evident by light microscopy in vari-
G, Carpenter S: Skeletal muscle pathology in neuromuscular diseases. In ous disorders (Fig. 26-6). Although some of these abnormalities
Rowland LP, DiMauro S (eds): Handbook of Clinical Neurology,Vol, 18. are more common in certain diseases (e.g., rods in nemaline my-
Amsterdam, Elsevier Science, 1992, pp I —48, with permission.) opathy, cytoplasmic bodies in myofibrillar myopathy), they are
not disease-specific.
Central Cores and Multicores. Cores and multicores are
of the muscle, which in turn is affected by the extent of the dis- best visualized on oxidative enzyme stains in which there are
ease process. If the muscle's basal lamina and supporting con- sharply circumscribed areas of decreased activity (Fig. 26-7).
nective tissue elements, especially the endomysium, are The lack of staining is due to the decreased number of mito-
relatively well preserved and the inciting agent is no longer pre- chondria in the cores. Central cores are restricted to type 1
sent, the functional restorative capacity of muscle is quite high. fibers, while multicores may be evident in type 1 or 2 muscle
As more and more of these elements are destroyed, the quality fibers. Individual muscle fibers can contain more then one core
and quantity of muscle regeneration begins to fail. If the original in both central and multicore myopathy. The cores are termed
structured or nonstructured depending on whether or not the
cross-striations associated with the sarcomere are present or
obliterated. The areas of decreased oxidative enzyme activity
are smaller in multicore (also known as minicore) myopathy as
opposed to central core. In addition, on longitudinal sections,
central cores extend the length of individual muscle fibers,
while multicores usually extend only a short distance. Central
cores are relatively specific for central core myopathy, but mul-
ticores are a nonspecific myopathic feature. So-called moth-
eaten fibers resemble multicores but are more pleomorphic in
shape and are likewise nonspecific.
Target Fibers. Target fibers consist of three zones in the center
of the muscle fibers. The innermost zone is devoid of mitochondr-
ial, phosphorylase, and ATPase enzymatic activity, the second
zone has increased enzymatic activity, whereas the third zone ex-
hibits intermediate enzymatic activity (Fig. 26-8). Targetoid
fibers refer to similar-appearing fibers without a distinct interme-
diate zone of enzyme activity. Target and targetoid fibers preferen- Figure 26-6.A muscle biopsy in a patient with myofibrillar
tially affect type 1 fibers and resemble central cores but occur in myopathy (modified Gomori trichrome stain) demonstrates numer-
neurogenic disorders in the course of reinnervation. ous cytoplasmic bodies within muscle fibers.
Ragged Red Fibers. Ragged red fibers are evident on modi-
fied Gomori trichrome stain as randomly distributed fibers that
are irregular in shape and display intense subsarcolemmal red ELECTROPHYSIOLOGIC CORRELATES
staining secondary to abnormal mitochondria. The mitochon- OF MUSCLE INJURY
dria are typically abnormal secondary to their morphology or
increased number. Oxidative enzyme stains are also useful in Prior to discussing the electrophysiologic effects of muscle
delineating muscle fibers with abnormal mitochondria. Ragged injury, it is important to remember how the motor unit action
red fibers are common in mitochondrial myopathies secondary potential (MUAP) is generated. Each single muscle fiber gener-
to the compensatory proliferation of mitochondria evident in ates a propagating action potential subsequent to the develop-
many of these disorders. Mutations involving mitochondrial ment of a suprathreshold endplate potential. This action potential
genes and nuclear genes coding for mitochondrial proteins are traverses along the muscle fiber through depolarization of the
involved in the pathogenesis. The frequency of ragged red fibers sarcolemma (muscle fiber's plasma membrane) encompassing
increases with age reaching a maximum of 0.4% by the eighth the entire muscle fiber. The voltage difference between an active
decade. This probably reflects the accumulation of mitochondr- recording electrode and its reference electrode generated by the
ial mutations in muscle fibers with the aging process. An abnor- action potential's transmembrane current (passive and active
mal frequency of ragged red fibers is observed in inclusion body portions) is what is actually recorded during electromyography.
myositis and has been associated with an increased frequency of In short, that activity observed on the electrophysiologic instru-
secondary mitochondrial defects. ment's cathode ray tube is merely the difference in voltage be-
Inflammation. The histologic abnormalities associated with tween the above noted two electrodes. The temporal and spatial
inflammatory myopathies and vasculitis are discussed in detail summation of each of the single muscle fibers' voltage belong-
in the chapter on acquired myopathies (see Chapter 28). ing to a particular motor unit constitute the recorded MUAP.
Increased Connective Tissue. Connective tissue replaces
destroyed muscle fibers and is thus increased in myopathic dis-
orders, particularly the dystrophies. Increased connective tissue
can also be seen in severe neurogenic disorders in a severely at-
rophic and weak muscle (end-stage muscle) if biopsied. In myo-
pathic disorders, increased fibrous connective tissue is first
appreciated in the endomysium and is followed by fatty tissue
replacement when there has been severe loss of muscle fibers.
In neurogenic disorders, increased fibrous connective tissue is
first noted in the perimysium, while increased endomysial con-
nective tissue is evident only if the number of muscle fibers
within the fascicle is significantly reduced.
Ultrastructural Changes. A multitude of morphologic ab-
normalities occurring at the ultrastructural level involving indi-
vidual organelles, components of the muscle fiber, the
neuromuscular junction, and intramuscular capillaries are ap-
preciated using electron microscopy. The details of these
changes are beyond the scope of this discussion but are compre-
hensively reviewed elsewhere. 45 When individual disorders are Figure 26-7. Central core myopathy. Muscle biopsy (NADH-
discussed, the pertinent aspects of ultrastructural changes are tetrazolium reductase stain) reveals central and eccentric areas devoid
detailed with respect to the consequences of the electrodiagnos- of oxidative enzyme staining.These cores occur predominantly in type
tic medicine evaluation. I muscle fibers (darker-staining fibers).
If there is an increase in the total amount of muscle fiber
membrane (true hypertrophy) for a given single muscle fiber,
then the transmembrane current is greater, which subsequently
generates a larger voltage difference between the two recording
electrodes. Similarly, comparatively larger muscle fibers (e.g.,
type 2 versus type 1) also generate larger single-fiber action po-
tentials. When the increased single-fiber action potentials sum-
mate, the ensuing MUAP is also larger. Another method of
producing a larger MUAP is the incorporation of more muscle
fibers into the motor unit. More muscle fibers generate a net in-
crease in voltage, which is reflected in the needle recording of
larger MUAPs.
As detailed in the discussion of muscle tissue's reaction to
various insults, muscle fibers may decrease in size, fail to de-
velop to a normal size, or portions may undergo segmental
necrosis. These alterations in myopathic conditions are the un-
Figure 26-8. Target fibers. Reinnervated muscle fibers demon- derlying cause for the observed electrical findings in virtually
strate a central light zone surrounded by a smaller dense staining all myopathic conditions. 9 ^-21'22-25-29-30-59 The anatomic alter-
region (NADH-tetrazolium reductase stain).Target fibers occur pre- ations in disease states as well as the associated electrical find-
dominantly in type I muscle fibers. ings are inextricably intertwined. In order for the practitioner to
fully appreciate the electrical consequences of muscle disease,
Table 26-9. Electrodiagnostic Medicine Evaluation

History
Careful questioning regarding progressive weakness, fatigability, and limitations in activities of daily living. A family history for related symp-
toms of weakness is important to establish the presence of a genetic disorder.
Physical Examination
A detailed manual muscle test performed using standard criteria allow one the ability to detect progressive muscle strength deterioration.
Activities to elicit weakness secondary to repetitive activities and arising from the floor are helpful. Sensory examination, deep tendon re-
flexes, and plantar responses are assessed. Observe for abnormalities of posture and gait.
Laboratory Evaluation
Serum creatine kinase, thyroid function tests, routine electrolytes (including potassium, sodium, calcium, and phosphate), renal and liver func-
tion tests, complete blood count, antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, serum protein electrophoresis.
Electrophysiologic Tests
I. Sensory nerve conduction studies
Perform at least two sensory studies in an upper and lower limb. If an abnormality is found, a more extensive evaluation may be neces-
sary to document the presence of a peripheral nerve disorder that may be present in addition to an intrinsic muscle disorder.
NA. Motor nerve conduction studies
A. Perform at least two motor studies in one upper and lower limb.An abnormality of conduction velocity suggests a peripheral nerve
disorder.A reduction in CMAP amplitude is to be expected in some myopathic disorders and should not be misconstrued as sug-
gesting an axonal loss lesion.
B. A decrease in CMAP amplitude can also be seen in myasthenic syndrome. If a low-amplitude CMAP is record, the muscle should be
isometrically exercised for 10 seconds and then restimulated.An increment from the baseline amplitude is usually appreciated fol-
lowing short exercise (post-exercise facilitation) in Lambert-Eaton myasthenic syndrome and occasionally in botulism.
MB. Repetitive stimulation: CMAP assessment
A. Perform repetitive stimulation (3 Hz) on a nerve to a distal and proximal muscle such as the trapezius or biceps brachii if a neuro-
muscular junction disorder is suspected.
B. Include post-activation facilitation and exhaustion evaluations.
C. Repetitive stimulation studies should be normal in most myopathic conditions, however, patients with some forms of myotonia or
forms of periodic paralysis may have a decrement on repetitive stimulation.
HI. Needle electromyography
A. Examine proximal, intermediate, and distal muscles in one upper and lower limb as well as the paraspinal regions.
B. If there is a suggestion on qualitative assessment of MUAPs with short durations or low amplitudes, a quantitative evaluation of 20
MUAPs with appropriate filter settings is necessary in order to comment on the MUAPs duration, amplitude, or number of phases.
C. Early and full recruitment of MUAPs with minimal effort is suspicious for a myopathic type of disorder.
D. All muscles examined should also be assessed for the presence of positive sharp waves and fibrillation potentials.The presence or
absence of these spontaneous potentials is certainly compatible with a disorder intrinsic to muscle tissue.
E. Additional spontaneous potentials such as complex repetitive discharges or myotonic discharges should be documented.
IV. Single-fiber electromyography
The use of single-fiber electromyography may demonstrate abnormalities of jitter and fiber density.This technique is primarily of re-
search benefit in most myopathic conditions.
the above noted fundamental reactions to muscle injury must be Motor Nerve Conduction Studies. Disease intrinsic to
understood. muscle tissue should not produce any abnormalities in motor
nerve conduction velocities or distal motor latency measure-
ments (Table 26-9). The primary abnormality that may be noted
ELECTRODIAGNOSTIC EXAMINATION is a mild to moderate reduction in the compound muscle action
potential (CMAP) amplitude, particularly if the proximally lo-
The electrodiagnostic medicine examination provides the cated upper (deltoid, biceps brachii) and lower limb (vastus me-
clinician with a number of important diagnostic options when dialis, tibialis anterior) muscles are evaluated. This is
attempting to determine if a particular patient has a disease in- understandable if one considers the described pathologic find-
trinsic to muscle tissue (Table 26-9). 134 Myopathic processes ings in some muscles. A number of muscle disorders produce a
can be multifocal in both the muscles affected as well as the random loss of muscle tissue. The affected muscle fibers experi-
territory within a specific muscle. Both motor and sensory ence necrosis and are no longer capable of generating an action
nerve conduction studies can be performed on multiple upper potential. The loss of muscle tissue results in an absent action
and lower proximal as well as distal nerves within a relatively potential and hence a reduction in the total voltage generated to
short time. Additionally, the needle electromyographic exami- indirect activation of the muscle tissue. The net result of this
nation is capable of sampling multiple axial and limb muscles. muscle loss is a reduction in the muscle's CMAP. The exercise
Also, within each muscle, a significant portion of the muscle stimulation test should be considered in patients suspected of
can be critically evaluated in an extremely efficient manner. having a channelopathy or periodic paralysis.75-83 The test is per-
Because the number of muscles that are routinely used for formed by obtaining a baseline ulnar CMAP recording from the
biopsy is limited (e.g., deltoid, biceps brachii, triceps, quadri- abductor digiti minimi following supramaximal stimulation at
ceps, gastrocnemius, peroneus brevis), the electrodiagnostic the wrist. Next, the patient isometrically exercises the muscle
medicine examination is considerably more flexible than a for 5 minutes. Ulnar CMAPs are recorded once a minute during
single muscle biopsy—an important feature in determining the the exercise period and then every minute for the next 20-25
extent and distribution of the disease process. The electrodiag- minutes after exercise. The normal response is a small incre-
nostic medicine examination is a valuable diagnostic aid from ment during exercise (mean 11 %, range 0-27%) followed by a
the standpoint of suggesting muscles most appropriate to small decrement in the post-exercise period (mean 15%, range
biopsy in order to maximize the diagnostic yield of this tech- 0-30%). In patients with periodic paralysis, there is an abnor-
nique. Generally, the electrodiagnostic medicine examination mal increment during the exercise period (mean 35%, range
is performed on one side of the body while the muscle biopsy 0-300%) and decrement during the post-exercise phase (mean
is performed on the contralateral limb in a homologous muscle 48%, range 10-82%) (Fig. 26-9).83
demonstrating appropriate degrees of electrodiagnostic pathol- Repetitive Stimulation. Repetitive stimulation studies are
ogy. Depending upon the type and degree of electrophysiologic not necessary in most patients suspected of having a myopathy
pathology, considerable insight can be gained as to the patient's
most likely major disease category. The combination of nerve 15
conduction studies and needle evaluation may determine that
the patient has a disorder affecting the anterior horn cells, pe-
ripheral nerves, or neuromuscular junction as opposed to a my- 39%
••
opathic process that may not be readily distinguished on > increase
•
history or physical examination. Occasionally, an astute practi- ~~ ». 62% decrease
•
tioner may detect abnormalities not suspected by the referring
physician because of the nature of the disease only manifesting •
electrically at the time of the patient's presentation, or suggest •
an entirely different differential diagnosis. Limitations and pit-
falls of the electrophysiologic evaluation of muscle are dis- 5 minutes ^
cussed in detail at the end of this chapter. exercise
0
I I I i i i i i i i
NERVE CONDUCTION STUDIES 5 15 25 35 45 55
Sensory Nerve Conduction Studies. Sensory nerve con- Minutes after exercise
duction studies can be anticipated to be normal in disorders in- Figure 26-9. The exercise test.The hand is immobilized and ulnar
trinsic to muscle tissue (Table 26-9). Specifically, sensory nerve CMAPs are recorded following stimulation at the wrist. Several base-
action potential (SNAP) amplitude, latency, and conduction ve- line CMAPs are obtained.The patient is then asked to isometrically ex-
locity should meet all normal parameters for individual nerves. ercise the muscle for 5 minutes with brief rests periods (about 5
If an abnormality is detected, a detailed electrodiagnostic medi- seconds) every 20 seconds. Ulnar CMAPs are recorded every minute
cine and laboratory investigation is warranted to fully elucidate during the exercise period and then for 20-25 minutes after exercise.
the etiology of a potential peripheral nerve disorder. Two excep- Normal patients may have a mild increase in amplitude (mean I l%)
tions are noted:134 (1) in persons over the age of 60, a number of during exercise and a slight decrease in amplitude following exercise
the lower limb sensory nerve studies may reveal an absent or re- (mean 15%). Patients with various forms of periodic paralysis demon-
duced amplitude response secondary to the natural effects of strate exaggerated increase in amplitude during exercise and decre-
aging; (2) patients with long-standing shoulder-girdle weakness menting amplitude following exercise.The figure demonstrates the
may present with carpal tunnel syndrome or ulnar neuropathy at abnormal exercise test in a patient with periodic paralysis. (From
the wrist because of the undue stress placed on the hand due to McManis PG, Lambert EH, Daube JR:The exercise test in periodic
compensation for the proximally weak muscles. paralysis. Muscle Nerve 1986;9:704-710, with permission.)
about the electrical properties of a patient's muscular tissue. The
routine needle electromyographic examination is performed
with particular attention paid to MUAP duration, morphology,
amplitude, and recruitment. It is also important to assess the pa-
tient for the presence of abnormal insertional and spontaneous
activity. A thorough examination of multiple muscles is neces-
sary, especially in mild or moderately severe disease states. This
implies that each muscle may require several separate needle in-
sertion sites to detect subtle abnormalities. Also, the proximal
c muscles must be examined in detail, including those located
posteriorly, i.e., supra/infraspinatus, trapezius, gluteus max-
imus, and most importantly cervical, thoracic, and lumbosacral
paraspinal muscles. 110 I28 B4 When investigating the paraspinal
muscles, it is a good idea to explore several spinous levels on
one side at these three major anatomic levels.
D Needle Insertion
In addition to the electrical activity noted during needle inser-
tion, it is recommended that the practitioner also pay attention
to the "feel" of the needle electrode as it penetrates the skin and
underlying muscle tissue. In patients with chronic connective
E tissue disorders such as scleroderma or myxedema, the skin
may offer considerable resistance to needle penetration. On the
other hand, persons either taking large amounts of exogenous
corticosteroids or suffering from endogenous overproduction
(Cushing's disease) may have extremely "thin" skin with little if
any resistance during needle puncture. Attention to this seem-
ingly inconsequential detail may offer insight into the patient's
Figure 26-10. Examples of anticipated findings during the primary disorder.134
needle electromyographic examination. A, Electrical silence of Muscle that is fibrotic or experiencing significant degenera-
normal muscle at rest. B, Positive sharp wave potentials detected in a tion with connective tissue replacement may have a so-called
muscle at rest. C, Fibrillation potentials with occasional positive sharp "gritty" feel, i.e., as the needle is advanced, there is a varied re-
waves in a muscle at rest D, Complex repetitive discharge firing in a char- sistance to the needle as the tissue is penetrated. This is particu-
acteristic pattern of a group of single muscle fibers. E,A myotonic dis- larly notable in chronic inflammatory myopathies, dystrophies,
charge is observed to both decline in amplitude as well as decrease its and occasionally in conditions resulting in ischemic muscle
firing rate.Time/voltage marker: A, B, C (10 ms and 50 uV); D, E: (40 ms necrosis.134 In some patients who have received multiple intra-
and 200 pV). (From Bromberg MB,Albers JW: Electromyography in idio- muscular injections, this sensation may be noted secondary to
pathic myositis. Mount Sinai J Med 1988;55:459-464, with permission.) muscle trauma or a direct toxic effect of the medication on
muscle fibers.
Insertion of the needle electrode into muscle results in a brief
but are useful in distinguishing neuromuscular junction disor- burst of electrical activity. Many myopathic and neurogenic dis-
ders (i.e., botulism, Lambert-Eaton myasthenic syndrome, con- orders are associated with muscle membrane instability result-
genital myasthenic syndromes, and myasthenia gravis) from ing in increased insertional activity. This increased activity can i
myopathies. Repetitive stimulation studies are occasionally ab- be in the form of runs of positive sharp waves, fibrillation po- I
normal in primary muscle disorders and generally reflect a sar- tentials, or myotonic discharges. Reduced insertional activity
colemmal abnormality or failure of neuromuscular transmission can be seen in end-stage myopathies or neurogenic disorders
at immature neuromuscular junctions secondary to significant when muscle tissue is replaced by fat or connective tissue.
muscle fiber degeneration with subsequent reinnervation. An Decreased insertional activity can also be in contractures of pa-
abnormal repetitive stimulation response may be obtained in tients with glycogen storage defects (e.g., McArdle's disease) or
persons with different types of myotonic disorders and periodic in patients severely weak from periodic paralysis.
paralysis.
Late Responses (H-reflexes, F-waves, Blink Reflexes). Spontaneous Activity
Late responses are characteristically normal in primary myo- A number of different types of spontaneous or rest activity
pathic diseases with respect to latency. The only potential ab- can be observed in myopathic conditions during the needle ex-
normality is a reduction in the potential's magnitude secondary amination (Fig. 26-10). These potentials are best observed after
to a loss of muscle fibers in profound disorders. a brief insertion of the needle electrode serving as a provocative
factor inducing mechanical muscle fiber depolarization.
NEEDLE ELECTROMYOGRAPHY Positive Sharp Waves and Fibrillation Potentials. Either
of these two potentials may be observed following insertion of
It is the author's opinion that the most useful electrophysio- the needle electrode for brief periods, i.e., increased insertional
logic test in evaluating a patient with a possible myopathy is activity. Similarly, these potentials can be seen to persist for
needle electromyography. A properly performed needle electro- variable periods following cessation of the needle movement,
myographic examination should provide significant information i.e., sustained spontaneous activity (Fig. 26-10, Table 26-10). 14
Table 26-10. Spontaneous Activity in Myopathic Disorders
Fibrillations-Positive Sharp Waves Complex Repetitive Discharge s Myotonic Discharges
Inflammatory myopathies Inflammatory myopathies Myotonic dystrophy
Muscular dystrophies Muscular dystrophies Hyperkalemic periodic paralysis
Familial inclusion body myopathies Distal myopathies Paramyotonia congenita
Myofibrillar myopathy Myofibrillar myopathy Other potassium-aggravated myotonias
Myotubular myopathy Acid maltase deficiency Myotonia congenita
Nemaline myopathy Debrancher deficiency Schwartz-Jampel syndrome
Channelopathies Myofibrillar myopathy
Periodic paralysis Myotubular myopathy*
Lipid storage disease (rare) Acid maltase deficiency*
Acid maltase deficiency Debrancher deficiency*
Debrancher deficiency Inflammatory myopathies*
Mitochondrial myopathy (some forms) Hypothyroid myopathy*
Direct muscle trauma Chloroquine myopathy*
Toxic myopathies Cholesterol-lowering agent myopathy*
Inclusion body myositis Cyclosporine-induced myopathy*
* Electrical myotonia only without clinical myotonia. From Daube J: Electrodiagnosis of muscle disorders. In Engel AG, Banker BQ (eds): Myology. New York, McGraw-
Hill, I986,pp 108l-l 121,with permission.
The designation between these two inciting factors is primarily than in profound neuropathic disorders, particularly with signif-
a matter of degree. The origin of positive sharp waves and fibril- icant axonal loss. If florid positive sharp waves and fibrillation
lation potentials is basically a single muscle fiber with an unsta- potentials are observed, particularly in association with small
ble surface membrane that arises from a number of causes numbers of relatively normal or large-appearing MUAPs firing
including denervation, abnormal ion channels, and possibly at high rates and low levels of force production, a neurogenic as
other factors. For example, several days after purposefully dis- opposed to myogenic disorder should be considered. However,
connecting a muscle fiber from its neuromuscular junction, an an occasional myopathy also can have significant numbers of
unstable resting membrane potential ensues that creeps toward positive sharp waves and fibrillation potentials.
the threshold value for action potential initiation. Once thresh- In myopathies, it is especially important to attempt to elicit
old is reached, a spontaneous depolarization occurs followed by fibrillation potentials and positive sharp waves properly. These
repolarization, with the cycle beginning over again. The inser- potentials may have rather slow firing rates in myopathic condi-
tion of a needle electrode facilitates this process through me- tions requiring relatively long periods (several seconds) of si-
chanical stimulation of the muscle fiber, bringing the resting lence prior to moving the needle electrode. 36134 A brief needle
membrane potential closer to threshold. A positive sharp wave insertion followed by several seconds of rest is the preferred
is basically a variation on the fibrillation potential theme with method in muscle when there is an absence of frank sponta-
more muscle damage to the muscle fiber at the recording site neous activity but a myopathic disorder is suspected clinically.
secondary to the physical presence of the needle electrode. In Also, recall that muscle fibers in myopathic conditions have
other words, both positive sharp waves and fibrillation poten- considerable variation in size with a predominance of smaller
tials may be detected in myopathic conditions when segmental fibers. Smaller fibers generate less voltage, and thus small fib-
necrosis, inflammation, or connective tissue proliferation has rillating myopathic muscle fibers generate fibrillation potentials
resulted in a physical separation of the neuromuscular junction and positive sharp waves with relatively small amplitudes. It can
from the muscle fiber or when there are defects in the ion chan- be easy to miss small spontaneous potentials when they are not
nels contained within the sarcolemma. 37 - 38 The net effect in very abundant and amplifier sensitivities of 100-200 pV/div are
these instances is a muscle fiber with an unstable resting mem- used. When spontaneous potentials are searched for in myo-
brane potential. Spontaneous depolarizations of single muscle pathic conditions, it is good practice to use an amplifier sensi-
fibers, i.e., positive sharp waves and fibrillation potentials, may tivity of 50 pV/div, especially with concentric needle
also be produced by some form of metabolic derangement re- electrodes, because amplitudes for all recorded potentials are
sulting in an unstable resting membrane potential secondary to smaller compared to monopolar needles.134 As always, complete
altered ionic conductance and/or a less than optimal sodium- relaxation is mandatory to optimally detect membrane instabil-
potassium pump functioning.107'130 The comparative abundance ity. Generally, the degree of membrane instability parallels the
of these spontaneous potentials in myopathic conditions is less degree to which the muscle displays myopathic MUAP changes.
As for MUAPs, each muscle as well as each location within a stimuli commonly facilitate the detection of myotonic poten-
particular muscle can vary with respect to the amount of mem- tials. It is possible to simply tap the muscle next to the needle
brane instability present. In patients strongly suspected of location and generate these potentials. Also, a brief muscular
having a disorder intrinsic to muscle tissue, a thorough search contraction can result in the appearance and persistence of the
must be made in each muscle even if multiple insertion sites are potentials constituting the so called "persistent afterdischarge."
required. This also applies to searching multiple muscles in a A so-called dive bomber sound has been attributed to these po-
given limb. Of interest with regard to membrane instability is tentials by practitioners who grew up during World War II.
that it may be preferentially located in the more superficial as- Perhaps a more contemporary analogy is a motorcycle at low
pects of the muscle.134 It is good practice to turn on the amplifier idle whose engine is intermittently accelerated. In any event,
as soon as the skin is penetrated so as to not overlook any super- once these potentials are identified, the sound associated with
ficially located fibrillation potentials or positive sharp waves. them is unforgettable. A decrescendo run of positive sharp
There is a belief that the amount of membrane instability is pro- waves, commonly seen in both myopathic and neurogenic dis-
portional to the severity of the disease, although this is primar- orders is not, in the authors' opinion, a myotonic discharge.
ily a clinical impression and has not been prospectively studied Although we have frequently seen such discharges labeled as
in various disorders. myotonic, we feel they are best considered as pseudomyotonic
Complex Repetitive Discharges. These potentials have discharges, because the potentials do not wax and wane in fre-
been previously referred to as bizarre repetitive discharges, quency or size. This commonly seen phenomenon is likely to be
bizarre high-frequency discharge, and pseudomyotonia (Fig. an unsustained run of positive sharp waves that simply dies out.
26-10).14 The term complex repetitive discharge is the preferred Myotonic potentials are not always a widespread phenome-
terminology at this time. Recall that a complex repetitive dis- non. For example, in acid maltase deficiency they are preferen-
charge is simply a group of single muscle fibers (grouped fibril- tially localized to the paraspinal muscles. 134 In myotonic
lations) spontaneously depolarizing in a set pattern directed by dystrophy only a few of the intrinsic hand muscle may demon-
a primary pacemaker fiber.'32 They may be seen in relatively strate prominent myotonic discharges, especially in persons
chronic disorders where a group of adjacent muscle fibers failed who carry the abnormal gene but do not manifest the disease
to be reinnervated or an unstable resting membrane potential is clinically. Importantly, myotonic discharges may be so promi-
generated for some other reason (Table 26-10). The mechanism nent that it is simply impossible to adequately analyze the
of activation is thought to be an ephaptic cross-talk between ad- MUAP characteristics and assess if there are short-duration po-
jacent muscle fibers activating supersensitive regions on the tentials present. This may be important in attempting to differ-
muscle fiber in a repetitive manner. The hallmark of these po- entiate myotonia congenita from myotonic dystrophy, although
tentials is a distinctive machinery-like sound that abruptly the distinction can be made clinically in most cases. In this in-
ceases as opposed to decrescendo type of stop. The pacing or stance, single-fiber electromyography can be of assistance be-
driving potential may cause the entire complex to fire at 30-40 cause the fiber density is normal in myotonia congenita but can
Hz with a range of roughly 2-60 Hz.127 Complex repetitive dis- be increased in myotonic dystrophy.115
charges can occasionally be found in the iliopsoas muscle in Myotonic Potential Production. Despite an incomplete un-
persons without known pathology; therefore, when detected derstanding of exactly how myotonic potentials are produced, it
solely in this muscle, they must be interpreted with caution and is worthwhile to consider some of the proposed mechanisms of
most likely do not suggest disease. repetitive or myotonic potential generation. It is now clear that
Myotonic Discharges. Myotonic discharges are unique po- although the myotonic potentials may have similar morpholo-
tentials that also originate from single muscle fibers and can gies (positive sharp waves or triphasic spike potentials), the un-
have the appearance of either a triphasic spike (fibrillation po- derlying manner in which these potentials are produced is
tential) or positive sharp wave (Fig. 26-10, Table 26-10).14 These different depending upon the disorder considered. There are
potentials are not necessarily associated with clinical myotonia some corresponding, but not substantiated, data to suggest that
(delay in relaxation following a contraction). The important the firing pattern in different myotonic diseases is also some- i
characteristic of these potentials is that although they look like what distinct and that all myotonic potentials are not the |
potentials observed in states where the muscle fiber is dener- same. 109 This postulate requires significantly more substantia-
vated, they arise from innervated muscle fibers with membrane tion with respect to quantitative analysis of firing patterns in all
instability due to abnormalities of the conductance of various forms of myotonic-associated diseases, acquired and inherited,
ions. These abnormalities in ion conductance are frequently re- prior to assigning any clinical or basic science relevance.
lated to mutations in various ion channels located in muscle Myotonia Congenita and Chemical Induction of Myotonia.
membranes. It is understandable that myotonic potentials should The mechanism of myotonic discharge production in myotonia
look like fibrillation potentials and positive sharp waves because congenita (autosomal dominant and recessive forms) is related
they originate from the same source, i.e., a single muscle fiber. to mutations in the gene encoding the muscle chloride channel.
The reason for their generation, however, is quite different from The physiologic consequence of these mutations is decreased
simply a denervated fiber. The primary defect is in the muscle chloride conductance. Impaired chloride conductance has also
membrane's ionic characteristics because neither nerve nor neu- been demonstrated in animal models for myotonia congenita—
romuscular junction blockade inhibit the myotonic potentials. the myotonic goat and the ADR (arrested development of right-
The potentials, irrespective of their morphology, characteris- ing) mouse. Myotonia can develop in patients taking aromatic
tically fire rather rapidly and wax and wane in frequency and carboxylic acids such as 2,4-dichlorophenoxyacetic acid, sterol
amplitude. That is, the potentials alter both their firing rate and inhibitors of cholesterogenesis such as 20,25-diazocholesterol,
magnitude during a series of repetitive firings. The firing rate of and agents such as simvastatin, 3-hydroxy-3-methylglutaryl
these potentials can be quite variable within a single run of po- coenzyme A (HMG-CoA) reductase inhibitor.72 These agents
tentials ranging from 2 to 100 Hz with increases or decreases are thought to cause a steric conductance block of chloride
from 50 to 10 Hz or 10 to 50 Hz, for example. 20 Mechanical channels.
The following explanation is simplified for instructional pur- attempts at relaxation are thwarted by the recurrent action poten-
poses but nevertheless provides a basic understanding of the tial generation and hence continued contraction, i.e., myotonia.
repetitive nature of myotonic potentials in myotonia congenita There may also be minor abnormalities in both sodium and
and the above chemical agents.1-2-6-7106109 One of skeletal potassium conductance in myotonia congenita.51 Potassium out-
muscle's main functions is to contract in response to an action ward flow during repolarization is larger, thus contributing to an
potential. The action potential accomplishes this feat by not abnormal increase in extracellular potassium concentration in
only traversing the surface of the muscle fiber but by propagat- the transverse tubules. Also, sodium channel inactivation may be
ing into the core of the muscle through the muscle membrane slowed such that it continues for an abnormally long time thus
forming the transverse tubules (T-tubules). These T-tubules are potentiating an inward or depolarizing sodium current during the
extremely small but serve to increase the muscle fiber mem- action potential's repolarization phase. Although each of these
brane surface area. In normal muscle, following an action po- factors is insufficient to cause repetitive firing in the presence of
tential the membrane's repolarization is accomplished not only normal chloride conductance, they may contribute to both the
by sodium channel inactivation but also an increase in potas- spontaneous development and sustained nature of myotonic po-
sium permeability. As a result, there is an increase in the extra- tentials. Depending upon the degree of chloride abnormality, a
cellular potassium concentration in the T-tubules. The rising brief voluntary contraction or movement of the needle electrode
extracellular potassium concentration on the muscle membrane may result in sufficient build-up of T-tubule potassium to initiate
surface is usually of no consequence because of potassium ions the myotonic burst and associated muscle contraction.
diffusing away from the membrane. In the small confines of the Myotonic Dystrophy. The membrane defect in myotonic dy-
T-tubules, however, diffusion is slow and the accumulated ex- strophy that is responsible for generating the runs of myotonic
tracellular potassium is of consequence and results in a depolar- discharges is unclear. Myotonic dystrophy is caused by a muta-
ization after-potential of about 0.1 mV per action potential. tion in the gene that codes for myotonin protein kinase. The
This may be better understood if the Goldman-Hodgkin-Katz function of this kinase and how the mutation leads to muscle
equation is considered (see Chapter l). 79 Recall that in the rest- membrane defects remain to be elucidated. In general, protein
ing state the permeability of sodium is very small and can be ig- kinases are enzymes that phosphorylate specific protein sub-
nored, thus leaving only potassium and chloride: Em = -62 log strates. Protein subunits of ion channels can become phosphory-
{(p[K+]i + p[CM 0 ) + (p[K + ] 0 + plClli) where E m is the resting lated and this may represent a mechanism of modulating ion
membrane potential and "p" designates the ionic permeabili- channel function. 106 Chloride conductance may be normal or
ties.80 Normally, chloride is reciprocally distributed with respect slightly abnormal in persons with myotonic dystrophy, suggest-
to potassium and passively shifts. This passive shift tends to ing that a completely different mechanism is responsible for the
"clamp" the membrane potential at the equilibrium potential for observed abnormalities. Potassium conductance is also found to
both ions. Thus, small shifts in the potassium concentration or be normal. Of particular importance is the documentation of a
permeability is compensated by equal and opposite shifts in the lower resting membrane potential closer to the muscle mem-
chloride ion. In the T-tubules, the extracellular accumulation of brane's threshold level. The most important finding in myotonic
potassium tends to depolarize the cell and this can be seen in the dystrophy membrane kinetics is an alteration in sodium channel
above equation. To make things simple, let us ignore the chlo- inactivation. Specifically, the sodium channels reopen (sponta-
ride ion as it is passively distributed, thereby reducing the equa- neous sodium channel reactivation) during the repolarization
tion to the familiar Nernst equation: E m = -62 log (p[K + ]j -r phase, thus shortening the refractory period and generating ad-
p[K+]Q). Suppose the intracellular concentration (i) of potassium ditional inwardly directed sodium currents.
is 100 mmoI/L and the extracellular concentration is 10 Mechanically stimulating the muscle membrane may be a
mmol/L. The resting membrane potential is then: -62 mV: E m = sufficient stimulus to result in spontaneous depolarization sec-
-62 log 100/10; E m = -62 log 10 = -62 mV (ignore permeabil- ondary to the abnormally small difference in potential between
ity for simplicity). If the extracellular concentration were to in- the elevated resting membrane potential and threshold level.
crease to 100 mmol/L, then the membrane potential would Voluntarily contracting the muscle initiates a depolarization
change to 0 mV ({Em = -62 log (100 ~ 100)) = -62 log 1 = 0 wave along the muscle membrane. In both cases, the abnormal
mV). Only a small amount would have to leave the cell to in- reopening of some of the sodium gates during the period of
crease the concentration in the confines of the transverse tubule, sodium inactivation and repolarization may create a large in-
which would not substantially alter the intracellular concentra- wardly directed depolarizing sodium current to again depolarize
tion. The net result is a depolarization of the membrane from the muscle membrane. Repetition of this process continues for
-62 mV to 0 mV. In this way a localized increase in the extra- some time, thus generating the observed myotonic potential dis-
cellular potassium concentration would tend to depolarize the charge and ensuing sustained muscle contraction. An abnor-
muscle membrane in the T-tubules. In normal tissue, the chlo- mally high threshold for sodium-potassium pump activation
ride ions would compensate and dampen the depolarization to may play some role in the elevated resting membrane poten-
only 0.1 mV as opposed to the 62 mV shift. However, in myoto- tial.50 Significantly more work is required to fully elucidate the
nia congenita, the decreased chloride conductance allows each actual mechanism involved in this disease.
depolarization to generate an after-potential depolarization of Paramyotonia Congenita and Hyperkalemic Periodic
about 1 mV. This 1 mV adds up so that following multiple depo- Paralysis. Paramyotonia congenita and hyperkalemic periodic
larizations, the after-potential depolarization actually exceeds paralysis are allelic disorders caused by mutations in the gene
the membrane's threshold level. This results in inhibition of the that codes for the a-subunit of voltage-gated muscle sodium
sodium channel inactivation and permits the cell to sponta- channel. These mutations lead to a delayed inactivation of the
neously fire again because the resting membrane level now ex- sodium channel. The persistent opening of the sodium channel
ceeds the threshold level. Clinically, when the patient contracts results in prolonged depolarization and myotonic discharges as
a muscle, multiple action potentials are generated that result in described above with myotonic dystrophy. Cold temperature
an increased potassium concentration in the T-tubules. Voluntary probably alters the conformation of the sodium channel subunits,
Figure 26-/ /. Myokymic potentials. Myokymic potentials are a subclass of grouped repetitive discharges.The bursts usually fire at a uniform
rate (2—60 Hz) but the frequency can vary.The discharges can be better appreciated by increasing the sweep speed as seen in Figure 12: A, sweep
speed 10 ms/div; B, sweep speed 50 ms/div; C, sweep speed 200 ms/div.
exacerbating the myotonia in this condition. In patients with hy- Persistent shortening of muscle can appear as a muscle spasm
perkalemic periodic paralysis, an elevation in extracellular potas- in primary myopathies. This is typically seen in the various my-
sium somehow adversely affects the sodium channel kinetics. otonic disorders in which a needle electrode records the my-
Prolonged delays in repolarization due to inactivation of the otonic discharges. An intrinsic muscle disease can also result in
sodium channels may also be responsible for episodes of weak- a shortening of muscle with an absence of electrical activity as-
ness that can occur in these disorders. In disorders resulting from sociated with this muscle contraction. A shortened muscle com-
sodium channel abnormalities, the primary result is a prolonged bined with electrical silence is known as a contracture. This
action potential due to impaired inactivation or repetitive open- phenomenon is usually observed in several glycogen storage
ing of the sodium channel—i.e., "bursting." The prolonged diseases (e.g., myophosphorylase deficiency or McArdle's dis-
action potential potentiates excess potassium ion accumulation ease) and in Brody's disease (a type of calcium channelopathy).
in the T-tubule, so that the ability of normally functioning chlo- Motor Unit Action Potential Morphology. The majority of
ride channels to repolarize the cell toward the resting membrane primary muscle disorders encountered by the practitioner result
potential is overwhelmed. The elevated potassium concentration in either actual anatomic or functional physiologic disruption of
within the confined space tends to depolarize the cell, leading to the muscle fiber's ability to conduct an action potential. This
repetitive discharges and hence myotonia. abnormality can be distributed in a random manner throughout
Other Myotonic Disorders. The membrane abnormalities as- the affected muscle groups. The concept of a randomly distrib-
sociated with the many other myotonic disorders are less well uted abnormality is important in that this type of pathology is
understood. Demanding microphysiologic techniques and pa- different than can be expected in a disorder affecting the periph-
tient rarity combine to impede a full understanding. eral nerves or anterior horn cells. Specifically, in a "neurogenic"
Fasciculation Potential/Myokymic Discharges. Fascicu- type of lesion, muscle fibers belonging to an entire motor unit
lation potentials and myokymic discharges (Fig. 26-11) can be are denervated. In "myopathic" diseases, muscle fibers from all
occasionally observed in patients with primary myopathic dis- motor units are affected to variable degrees. These two quite
orders, i.e., parathyroid and thyrotoxic myopathy.58-113 They are distinct pathologic processes have rather profound conse-
thought to arise not because of the intrinsic muscle disease, but quences with respect to the ensuing electrical activity recorded
because of a superimposed neurogenic disorder. These poten- from the affected muscle tissue.
tials are generally believed to originate at some location along The most consistent MUAP parameter for measurement is
the motor unit extending from the anterior horn cell to the ter- duration and it should always be assessed when a patient is ex-
minal arborizations of the intramuscular nerves. A hyperirrita- amined with a needle electrode for a potential myopa-
ble focus at some location generates an action potential that ^ 2 1 , 2 5 , 2 6 . 4 9 . 7 7 . 9 3 , 9 4 , 1 1 0 , 1 3 4 ^J s o ? t m s , s Q n e Q f m e m o s t sensitive
activates all or a significant number of muscle fibers belonging
to an entire motor unit in fasciculation potentials and groups of parameters of the electrophysiologically recorded potential for
motor units with myokymic discharges. They are motor unit po- diagnosing muscle disease. MUAP duration is generated from
tentials as opposed to single muscle fiber potential discharges. all the muscle fibers comprising a motor unit. The best way to
Muscle Spasm/Cramp Potential. A so-called "cramp poten- document a MUAP's duration is through quantitative elec-
tial" represents normal MUAPs firing at high rates in a sponta- tromyographic means (Fig. 26-12). 29 In the most common tech-
neous manner (not under voluntary control) associated with nique, the needle electrode is located as close as possible to the
shortening (muscle spasm) of the affected muscle.36 Cramps are tissue generating the MUAP, which can be easily accomplished
associated with disorders generating irritable focus in muscle by minimizing the major spike's rise time (see Chapter 8). Both
fibers, sensorimotor, or motor nerves. Cramps can also occur in visual inspection and measurement are necessary to accomplish
normal individuals and may arise secondary to fatigue of the this task, but listening for a crisp or sharp sound to MUAP firing
muscle or an electrolyte imbalance. The morphology of the helps determine if the needle electrode should be advanced or
MUAPs may be abnormal if there is an underlying myopathic or withdrawn. Also, a low-frequency filter of 2-5 Hz should be
neurogenic process responsible for the cramps. used if normative data generated by Buchthal are used.69 A trig-
ger and delay line are mandatory to ensure that a single and not
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Figure 26-12. A 14-year-old male with Duchenne muscular dystrophy. A, A full effort interference pattern demonstrating overall low-
voltage of MUAPs. B, Examples of multiple MUAPs recorded randomly from the biceps brachii muscle with a multilead needle electrode. C,
Histogram of MUAP durations.Top diagram from patient demonstrating mean duration of all potentials to be 7.0 ms while the duration of only the
simple (nonpolyphasic) MUAPs is found to be 5.4 ms. Polyphasic MUAPs (shaded region) duration is 10.9 ms. Lower histogram is an example of
normal MUAP durations, with a mean of 9.3 ms. Note how using only the simple MUAPs increases the diagnostic yield of the examination. D,
Polyphasic potentials recorded from the patients resulting in a total of 29% polyphasic potentials. E, Examples of different MUAP recorded from
the multilead electrode. F, Left biceps brachii muscle biopsy demonstrating muscle fiber size degeneration, fiber size variation, and connective
tissue proliferation. G, Muscle fiber histogram comparing patient's results to a control population. (From Buchthal F, Rosenfalck P:
Electrophysiological aspects of myopathy with particular reference to progressive muscular dystrophy. In Bourne GH, Golarz MN: Muscular
Dystrophy in Man and Animals. New York, Hanner Publishing Company, 1963, pp 194-262, with permission.)
multiply overlapped MUAPs are evaluated. Twenty MUAPs are The combination of fiber size diameter and collateral sprout-
measured and a mean-MUAP duration is calculated and coming may lead to excessively long-duration MUAPs in some dis-
pared to normal values. It is recommended that when measur- orders. Time-locked satellite potentials represent a small group
ing MUAP duration, satellite potentials and potentials with five of muscle fibers belonging to the major constituent muscle
or more phases should not be included, so as to increase the ex- fibers of the motor unit comprising the MUAP but are inner-
amination's diagnostic yield (Fig. 26-12). 24 This is because vated by long and possibly thinly myelinated collateral sprouts.
polyphasic potentials may be a result of muscle fiber drop out, The satellite potentials should never be included when quantify-
differences in muscle fiber conduction velocity, and regenera- ing MUAP duration. These time-locked potentials can best be
tion with collateral sprouting, which can result from neuro- appreciated when a trigger and delay line are used. Otherwise,
genic and myopathic causes. The increase in duration can they may be missed as blending into the recruitment of other
simply be due to a decrease in muscle fiber conduction velocity motor units.
secondary to atrophy and may not accurately reflect the total Either disposable monopolar or concentric needle electrodes
number of muscle fibers within a motor unit. Therefore, to pri- can be used and compared with the data originally developed
marily evaluate MUAPs resulting from a myopathic disease for nondisposable concentric needles provided the rise time is
without influence from compensatory mechanisms, it is best minimized, which for monopolar needles is 0.5-1.0 ms versus
not to use polyphasic MUAP durations when calculating the 0.3-0.5 ms for concentric needles. This assumption appears to
muscle's mean MUAP duration. Proper quantification of be supported by several clinical studies.64-71-96-99 It appears that
MUAPs increases the diagnostic yield of electromyography the physical recording characteristics of how monopolar and
from about 64% to 95%.23-24-95-133 concentric needle electrodes record distant electrical activity are
Figure 26-/3. Comparison of recording territories of a concentric and monopolar needle electrode directly resulting in the MUAPs
characteristics with respect to amplitude, area, duration, and phases. A, MUAPs recorded with a concentric needle electrode are primarily derived
from single muscle fibers comprising a single motor unit (black dots) forming a hemisphere as the remaining single fibers are to some extent elec-
trically shielded by the cannula. Fibers within the inner semicircle contribute to the main MUAP spike while those contained in the larger semicircle
preferentially delineate the MUAP's duration. B,A monopolar needle electrode has a comparatively spherical and smaller recording area than the
concentric needle with more muscle fibers contributing to the MUAP's spike but a similar number of fibers forming the MUAP's duration. (From
Nandedkar SD, Sanders DB: Recording characteristics of monopolar EMG electrodes. Muscle Nerve 1991;14:108-1 12, with permission.)
similar and record essentially the same duration for MUAPs. total functioning muscle fibers in the investigated motor unit. In
Amplitude, possibly number of phases, and MUAP area, how- general, MUAPs tend to be smaller in myopathic diseases (Fig.
ever, are larger for monopolar than concentric needle electrodes. 26-12), but the profound dependence of amplitude on distance
MUAP mean rectified area is a very sensitive parameter that and fiber size limits the utility of this parameter in diagnosing
is proportional to the number of muscle fibers in a motor unit muscle diseases. 93 Another important factor influencing the
similar to MUAP duration.92-93-94 Quantitative investigations MUAP is the type of needle electrode used to record the activ-
reveal that MUAP area is both a very sensitive parameter to ^ 64,93,94,96.99 Monopolar needle electrodes generate larger ampli-
assess the presence of myopathic disease, and less subject to op- tudes for the same motor unit compared to concentric needle
erator error. Unfortunately, the ability to calculate this MUAP electrodes (Fig. 26-13). Unlike recording durations that are de-
parameter is not readily available on all instruments and further pendent on the total number of muscle fibers in the motor unit,
work is required to establish reference data for neurogenic and amplitudes are not comparable between the two types of record-
myogenic disorders of various types. ing electrodes. All of the above variables limit the utility of
If there is both a random and profound loss of multiple muscle MUAP amplitude compared to duration as a significant diagnos-
fibers comprising many motor units in a diseased muscle, each tic parameter. When the MUAP rise time has been minimized
MUAP should be smaller than normal. 73 - 74J03 Losing muscle and the amplitude is still small compared to normal values, the
fibers leads to a reduction of potential voltage generators that finding may be considered abnormal.
contribute to the MUAPs. Also, a number of muscle fibers may Keep in mind that the maximum peak-to-peak MUAP ampli-
be reduced in size secondary to the disease process that can con- tude is preferentially dependent upon only a few and sometimes
tribute to the reduction in MUAP size. It is important to recall one muscle fiber within about 0.5 mm of the recording elec-
that the maximum peak-to-peak amplitude of a MUAP is primar- trode. 89 The remainder of the MUAP's peak is formed from
ily influenced by the number of muscle fibers in close associa- muscle fibers located within about 1 mm of the recording elec-
tion with the active recording surface of the needle electrode. On trode.94-95 If this fiber is of normal size, then a relatively normal
average, the MUAP amplitude is reflective of less than 12 amplitude potential may be observed. On the other hand, if the
muscle fibers and most likely 1-3 muscle fibers within a record- muscle fiber's size is reduced, the accompanying voltage and
ing radius of about 0.5 mm (Fig. 26-13).43-88-93-94-131 Muscle tissue hence peak-to-peak amplitude are also reduced. Occasionally,
acts as a low-pass (high-frequency) filter and allows low fre- relatively large MUAPs may be encountered in myopathic con-
quencies to pass readily but attenuates high frequencies. The ditions if the recording electrode is close to a hypertrophic fiber.
MUAP spike is preferentially comprised of high-amplitude, If the disease process is relatively mild and there is little in the
high-frequency components and is therefore prone to distance way of abnormal fiber sizes combined with minimal fiber loss,
effects. Small displacements of the needle electrode from ac- normal-amplitude MUAPs can be anticipated. As noted above,
tively firing muscle fibers results in a significant drop in ampli- amplitude is extremely variable and dependent primarily upon
tude.53-54 The combination of how close one locates a needle the closest fibers and their individual characteristics. These con-
electrode to any one muscle fiber or group of muscle fibers di- cepts permit an understanding of the potential MUAP amplitude
rectly influences the MUAP's amplitude. Also, placing a needle variability that can be seen in myopathic disorders.
electrode close to a number of hypertrophic muscle fibers can MUAPs recorded in myopathic disorders also tend to contain
generate a normal or even large-amplitude MUAP, despite fewer more phases (baseline crossing plus 1) and turns (changes in
MUAP direction greater than 20 pV) than normal, i.e., normal
being four phases or less and five turns or less (Fig. 26-14). 76126
This can be understood if one considers why a normal MUAP
typically appears triphasic or biphasic. As noted above, the
major spike component's amplitude and to some extent appear-
ance is dependent upon the fibers closest to the active recording
surface (Figs. 26-13 and 26-14). Portions of the MUAP spike are
also contributed to by muscle fibers within 1 mm of the record-
ing electrode. There are considerably more muscle fibers located
at greater distances from the electrode. The high-frequency com-
ponents of the single-fiber action potentials are significantly at-
tenuated as distance from the electrode increases. The portions
of the waveforms recorded by the needle electrode from the
more distance fibers is usually a low-amplitude positive/nega-
tive/positive waveform. These potentials are too small to signif-
icantly affect the major negative spike, but do contribute to the
initial and terminal positive components of the MUAP. They
contribute to the MUAP's duration as they are volume-con-
ducted through the tissue, appearing prior to the main spike of
the MUAP and persisting after the main spike has passed by the
needle's recording surface (Fig. 26-14). This is a second reason
for the importance of duration with respect to MUAP quantifi- duration
cation and diagnosis. The MUAP duration reflects all or most of spike duration
the muscle fibers belonging to the motor unit, which is already
filtered by the muscle tissue and is less subject to distance ef- Figure 26-14. Schematic representation of how a MUAP is
fects compared to the MUAP's spike. All of the voltage from generated from the various fibers comprising a single motor
the distant muscle fibers smoothly summates to create a tripha- unit. A, Eleven single muscle fibers are depicted all belonging t o a
sic-appearing MUAP. If the needle is close to the endplate zone, single motor unit. The active recording surface of the concentric
a biphasic initially negative MUAP is typically recorded as a needle electrode is positioned closest to the 3 or 4 fibers in the
significant degree of the electrical activity originates at the middle while 7 muscle fibers are considerably further from recording
recording electrode and then travels away from it (see Chapter surface.The low-frequency volume-conducted electrical activity from
2). The manner in which the electrical activity summates in both the distant fibers arrives and persist at the recording surface before
space and time with respect to the recording electrode is likened and after the high-frequency components from the fibers closest t o
to a blanket covering a large number of objects, the so-called the recording surface are recorded. In short, the MUAP's spike is pro-
blanket principle. 98 duced by the nearby fibers while the distant fibers contribute to the
The blanket concept can help us better appreciate the devel- overall duration. B, MUAP components as defined by Stalberg. 126
opment of polyphasic potentials. Suppose a large blanket covers Closed circles represent phases while open circles designate turns (3
many relatively closely packed sticks of different height with phases and 7 turns).The small potential following the main MUAP is a
larger sticks near the center of the blanket to represent the pref- time-locked satellite potential. (From Stalberg E.Trontelj J: Clinical neu-
erentially increased influence those sticks (muscle fibers) have rophysiology: The motor unit in myopathy. In Rowland LP, DiMauro S
on the final MUAP shape. Because of the large number of (eds): Handbook of Clinical Neurology,Vol 18. Amsterdam, Elsevier
sticks, the blanket forms a smooth contour when viewed in pro- Science, 1992, pp 49-84, with permission.)
file (Fig. 26-15). If we then randomly remove an increasingly
greater number of sticks, several alterations in the original with an increase in muscle fiber loss, the more pronounced the
shape occur. The total length of the shape decreases because recorded abnormalities.
there is an overall decrease in the total number of fibers, hence a In addition to the random loss of single muscle fibers belong-
shorter-duration potential. Additionally, a number of sticks have ing a motor unit, the nonuniform size of individual single
also been removed from the central regions under the blanket. muscle fibers contained in the motor unit is also an important
This results in two different alterations in the shape formed by cause of polyphasicity.94-119 The random nature of muscle dis-
the blanket. First, fewer sticks, particularly the larger ones, re- ease implies that single muscle fibers contained within a single
sults in a reduction of the maximum height of the potential, i.e., motor units can have a spectrum of disease affecting the indi-
a reduction in amplitude. Secondly, there are regions where few, vidual fibers. Thus, within a motor unit some of the fibers may
if any, sticks are present and can no longer support the blanket. be quite small and atrophic, others are larger and hypertrophic,
As a result, the blanket approaches the ground creating an and there are those normal in size.5-68 Muscle fiber size, just like
empty space where none was previously present. In short, the nerve size, is an important parameter influencing action poten-
potential no longer has a smooth contour but appears with mul- tial conduction velocity. Larger fibers have less internal resis-
tiple peaks, i.e., an increase in the number of phases and turns. tance to current flow compared to smaller fibers with higher
Similarly, a random dropout of single muscle fibers from a internal resistance to current flow. The greater the internal resis-
motor unit leaves "gaps" in the summated voltage contour of tance (smaller fibers), the slower the action potential travels as
the MUAP with a reduction in amplitude and duration and a it takes longer to generate a current intensity sufficiently large
concomitant increase in phases and turns. This is a simple anal- enough to reach threshold and excite the adjacent membrane
ogy that helps to better comprehend the generation of polypha- region. Thus, in a single motor unit the normal variability in the
sicity in myopathic disorders. The more profound the disease sizes of individual muscle fibers leads to a conduction velocity
to a greater degree, this may result in a complete phase. In other
words, the difference between a turn and a phase may be depen-
dent upon the degree of fibers size variability and hence individ-
ual muscle fiber conduction velocities.
Wilk
Short duration, small amplitude MUAPs with increased
phases can also be seen in profound neurogenic lesions during
early reinnervation. These are the so-called nascent potentials
and represent only a few newly reinnervated muscle fibers ran-
domly distributed about the muscle belonging to one motor unit.
The small number of fibers creates the reduced amplitude. A
relatively small number of widely distributed muscle fibers re-
sults in the above-described voltage gaps, thus generating a
B .
highly polyphasic MUAP. This same reduced complement of
single muscle fibers also produces the potential's short duration.
As more and more muscle fibers are reinnervated, the amplitude
and duration of the MUAP increase. Similarly, the previous
voltage gaps are filled in and the number of phases decreases. In
partial neurogenic lesions, the process of collateral sprouting
adds more muscle fibers to a MUAP. This is the same as adding
more sticks under the blanket. Voltage gaps are again created
because of the random addition as opposed to subtraction of
muscle fibers.
The above examples provide a very simple description for
both myogenic and neurogenic alterations in the MUAP during
C needle electromyography. In myopathies, the MUAPs are usu-

ally smaller and shorter in duration compared to normal, while
in neurogenic disorders the MUAPs tend to be larger and longer
in duration with increased numbers of phases in both types of
disease states (Fig. 26-16). It is critical to realize that these
( changes can certainly be appreciated during routine needle elec-
; J 11/ J
tromyography by an experienced practitioner, but any attempt to
quantify this process requires the use of a trigger and delay line.
The novice practitioner can easily be mistaken into evaluating a
Figure 26-/5. Drawing of multiple sticks of different height

supporting a "blanket." A, Smooth contour formed by the blanket
being supported by multiple sticks. B, Removing some of the sticks in a
random manner results in regions where there are insufficient sticks
to support the blanket generating a less than smooth surface contour.
C, Eliminating still more sticks creates a highly polyphasic contour
compared to the original.
range of about 1.5-6 m/s (e.g., mean NCV: 3.7 ± 0.75 m/s for
the biceps brachii).126 The increased variability in size of muscle
fibers in myopathies results in an increased range of conduction
velocities among diseased muscle fibers. As a result, there is an
increase in the temporal dispersion of action potential arrival at
the recording electrode and thus less synchronized summation
of the MUAP's voltage under the recording "blanket" of our
needle electrode. The net result is more action potential tempo-
ral dispersion and an increase in the degree of polyphasicity. Figure 26-16. Quantitative electromyography. Comparison of av-
Thus, both a random dropout of single muscle fibers as well as a eraged MUAPs in patients with limb-girdle dystrophy (myopathy), no dis-
greater dispersion of muscle fiber conduction velocities com- ease (normal), and polyneuropathy (neuropathy). In the myopathic
bine to increase the degree of phases observed in myopathic disorder the MUAPs are clearly shorter in duration and smaller in ampli-
conditions. tude. Note that the bottom trace reveals a MUAP with a normal to some-
The degree to which individual muscle fibers are temporally what large amplitude and normal duration.There is a satellite potential
dispersed with respect to their electrical summation in space can that should not be included in the duration measurementThe MUAPs in a
produce an increase in turns, phases, or both.94-95 A mild degree neuropathy are both larger and slightly longer in duration.There is a dis-
of asynchronous electrical summation may be sufficient to pro- tinct increase in both phases and turns in these potentials. (From Stalberg
duce a turn. This is likely to be observed in the major spike E, Trontelj J: Clinical neurophysiology: The motor unit in myopathy. In
component or fibers within the above-noted 1 mm of the recording Rowland LP, DiMauro S (eds): Handbook of Clinical Neurology,Vol. 18.
electrode. If the temporal dispersion or muscle fiber size increases Amsterdam, Elsevier Science, 1992, pp 49-84, with permission.)
free running trace as containing an increased number of manner and thus influencing the most reliable parameter avail-
polyphasic potentials. This may in reality merely be the super- able for analysis, i.e., amplitude. A gross increase in the ampli-
imposition of multiple individual MUAPs appearing as a tude is helpful in some profound neurogenic diseases, but subtle
polyphasic potential. Using a trigger and delay line allows one increases or decreases are difficult to quantify and most likely
to analyze a single MUAP and clearly distinguish when similar do not represent an acceptable method of providing a diagnostic
but different potentials are momentarily "time-locked" with the impression as the sole criteria of abnormality.
potential under investigation. This cannot adequately be appre- A final caveat regarding so-called myopathic MUAPs (small-
ciated unless a trigger and delay are used. An additional prob- amplitude, short-duraticm, increased numbers of phases) is that
lem with calling an increase in polyphasic potentials is that these types of MUAPs can be seen in disorders not only produc-
many practitioners are not aware of what can be considered a ing a myopathy, but those affecting the neuromuscular junction,
normal amount of polyphasic MUAPs when using different motor nerves, and peripheral nerves, i.e., any process resulting
needle electrodes. A concentric needle electrode may record up in the dropout of single muscle fibers from a motor unit ("disin-
to 12-15% polyphasic potentials, while a monopolar needle tegration" of the motor unit) (Fig. 26-17). 134 For example, con-
may record up to 30% polyphasic potentials in normal duction block in the terminal axons of a motor unit from acute
people.24.3i.64.76.96.99 Also, the same MUAP can change its ap- inflammatory demyelinating polyradiculoneuropathy (Guillain-
pearance depending upon the needle location within the spatial Barre syndrome) can result in the random dropout of single
distribution of the motor unit territory as it is influenced by dif- muscle fibers comprising the motor unit. The ensuing MUAP
ferent groupings of single muscle fibers with slightly different appears "myopathic," but the process is "neurogenic." Profound
voltage characteristics. All of the above variable factors reduce neuromuscular junction transmission disorders can affect differ-
polyphasicity as a reliable diagnostic parameter. Polyphasic ent muscle fibers to various degrees within the same motor unit
potentials are considered by some to be the earliest finding in thus producing short-duration and small-amplitude potentials.
myopathic conditions and most likely reflect the muscle fiber Inherent muscle disease can also produce these types of
size variation, but this cannot be properly assessed without the MUAPs. These concepts must be kept in mind when evaluating
aid of quantitative electromyographic means. 29 Although both patients with suspected "myopathic" conditions in order to
amplitude and number of phases demonstrate physiologic avoid erroneous conclusions.35-47-48 Despite previous objections,
changes in myopathic processes, the most consistent and hence it is the authors' opinion that it is not inappropriate to character-
reliable diagnostic parameter in the diagnosis of myogenic dis- ize MUAPs as "brief, small, abundant, polyphasic potentials
orders continues to be MUAP duration.93 (BSAPP)" provided one does not assume that this pattern of ab-
The only MUAPs that can be reliably evaluated with quanti- normality automaticaHy defines a disease process as myopathic.
tative electromyography are the first recruited potentials. 126 There is no single finding that is pathognomonic of a myopathic
After several MUAPs have been detected arising from a single process. It is a compilation of findings from the history, physi-
region of muscle, the instrument's screen is filled with different cal examination, laboratory data, and electrical findings that
MUAPs and the baseline between MUAPs is obliterated. It is no must be assessed to determine a disease's etiology.
longer possible to accurately measure the potentials' durations, Motor Unit Action Potential Recruitment. The physio-
amplitudes, or phases because of an increasing chance of poten- logic principles regarding MUAP recruitment were previously
tials overlapping. The first recruited motor units are the rela- described in detail in the chapter discussing needle electromyo-
tively small or type 1 motor units. The term "small" when graphy (see Chapter 7). Briefly, a MUAP begins to fire at a fre-
designating motor units does not refer to the size of the muscle quency between 6 and 10 Hz, the so-called onset frequency. As
fiber, but to the number of muscle fibers per motor unit over more force is generated, the MUAP increases in frequency and
roughly the same area. This implies that type 2 MUAPs are a second MUAP begins to fire. The firing frequency of the first
larger than type 1 MUAPs. Hence, the observed first recruited
MUAPs arise preferentially from the type 1 muscle fibers and 0 1 . Nerve fiber
are comparatively smaller than the much later recruited conduction block
MUAPs. This poses a significant problem in disorders in which (Gullain-Barre syndrome).
there is preferential type 2 muscle fiber dysfunction. MUAP 2. Regeneration after axon
morphology is normal in patients with type 2 muscle fiber atro- loss mononeuropathy
phy from disuse atrophy or chronic corticosteroid use because or polyneuropathy).
only type 1 muscle fibers are routinely quantified.61-104 A Neuromuscular block
Relocating the needle to a different location does not solve this (myasthenia gravis)
problem as type 2 fibers are only recruited after multiple num- neuron (myasthenic syndrome)
bers of type 1 fibers are already firing repetitively. An attempt is terminal nerve fiber • 1. Muscle inactivation
made to circumvent this problem through the use of sophisti- (periodic paralysis)
cated computer programs performing so-called decomposition neuromuscular junction 2. Muscle degeneration
techniques. These methods have a number of technical and muscle fiber (polymyositis)
practical limitations at present but they may become quite 3. Variations in muscle fiber
useful once significant reference databases have been estab- conduction velocity
lished and the programs are readily available on most commer- (polymyositis)
cial instruments. At present, the fact that only preferentially
type 1 fibers can be examined must be an accepted limitation of Figure 26-17. Schematic depiction of various processes that
quantitative methods. An indirect way of only qualitatively ana- can cause "disintegration" of the motor unit with random dropout
lyzing type 2 fibers is through observing a maximal interference of individual muscle fiber from the motor unit as opposed to entire
pattern. This cannot be considered a quantitative technique be- motor units. (From Wilbourn AJ:The electrodiagnostic examination with
cause of multiple motor units potentially firing in a time-locked myopathies.J Clin Neurophysiol 1993; 10:132-148, with permission.)
units such that an increased number of fibers compared to
normal now belong to the remaining motor units. These poten-
tials can become very polyphasic with large amplitudes and long
durations. As the collateral sprouts and newly formed neuromus-
cular junctions mature, the synchronicity of depolarization for
the individual muscle fibers comprising a single motor unit in-
creases with a resultant decrease in the temporal dispersion of
the MUAP's single muscle fiber's electrical activity. As a result,
the MUAP further increases in amplitude with a concomitant re-
duction in the number of its phases and possibly duration. The
remodeled MUAP can have amplitudes that approach 20 mV
with associated significant increases in duration.
"Myopathic Recruitment." A disease process intrinsic to
muscle produces MUAP recruitment that is distinct from neu-
rogenic disorders. 73 ' 74103 The random distribution of the dis-
ease implies that all motor units are affected with some
containing more damaged fibers than others. 93 This potentially
results in many MUAPs with abnormalities as opposed to
some that are completely nonfunctional while others are
normal as described above for a neurogenic type of insult. The
random dysfunction of multiple muscle fibers results in the
same number of motor units in the muscle compared to that
prior to the disease onset. However, each motor unit is capable
Figure 26-18. Examples or voluntary motor unit recruit- of generating less force than it normally could be due to the
ment in relation to various disease states. A, Normal muscle reduction in muscle fibers per motor unit. In mild myogenic
contracting at low levels of force generating the typical recruitment disorders, recruitment abnormalities can unfortunately be very
pattern expected in normal muscle. N o t e that the first and third subtle. At mild force production attempts, the central nervous
MUAP are the same while the one in the middle begins firing just as system "senses" that insufficient force is being generated for
the first described MUAP fires at roughly 10 Hz, i.e., recruitment fre- the given number of motor units activated. The initial MUAPs
quency of 10 Hz. B, In a myopathic disorder, low levels of force pro- fire at a normal or only a mildly increased onset frequency.
duction result in multiple MUAPs firing at relatively rapid rates, Additional motor units are recruited at frequencies close to the
producing a so-called increased or early recruitment. C,A characteris- onset frequency of the first MUAP. The net result is so-called
tic type of recruitment found in a profound neurogenic disorder such early recruitment in which multiple MUAPs are detected in
as motor neuron dysfunction with a single MUAP firing at roughly 30 excess of that anticipated for firing the rate of the first re-
Hz. Calibration: 200 pV; 10 ms8. (From Bromberg MB, Albers JW: cruited motor units (Fig. 26-18). For example, there are typi-
Electromyography in idiopathic myositis. Mount Sinai J Med I988;55: cally several MUAPs firing at 5-10 Hz with only minimal
459-464, with permission.) effort. In fact, patients are able to recruit just one or two
MUAPs and produce a rather complete interference pattern at
MUAP when the second MUAP is generated is known as the re- relatively low levels of force production. In order to measure
cruitment frequency. The recruitment frequency is approxi- and interpret the form and duration of single motor units in
mately 10 Hz and usually less than 15 Hz. As the muscle is myopathies, it is very important for the practitioner to evoke
contracted more, the frequencies of the MUAPs are further in- only a minimal contraction. This can be accomplished by
creased. The recruitment ratio refers to the mean firing fre- asking the patient to raise the thumb slightly while investigat-
quency of the recruited MUAPs divided by the total number of ing the biceps brachii with an EMG needle. Often, such a min-
MUAPs. The normal recruitment ratio is 5 or less. For example, imal change in position can evoke the recruitment of some
if there are three MUAPs firing at 20 Hz, 15 Hz, and 10 Hz, re- motor units in a proximal muscle. The early recruitment seen
spectively, the recruitment ratio is 15/3 or 5. in myopathies contrasts with the decreased recruitment seen in
"Neurogenic Recruitment." A needle recording electrode neurogenic disorders, in which there are only a few recruitable
inserted into a muscle that has lost multiple motor units sec- motor units but these are firing at rates of 15 Hz or more.
ondary to a neurogenic process results in decreased recruit- In patients with severe myopathies resulting in the loss of
ment (Fig. 26-18).14-40100-102 For any given amount of attempted significant number of muscle fibers and presumably entire
voluntary force production, there is a decreased number of vol- motor units, the onset and recruitment frequency can be in-
untary motor units that fire at relatively rapid rates. In very early creased similar to neurogenic disorders.40-73-74100-102 A further
phases of the disease process, these MUAPs can appear normal complication is that some myopathic disorders can have large-
in that they have a normal amplitude, duration, and number of amplitude, long-duration polyphasic potentials secondary to
phases. With disease progression, the MUAPs may become sig- chronicity of the disease and significant motor unit remodel-
nificantly altered. Quantification of the recruitment process re- ing. 86 There are no clear-cut findings establishing a disease
veals an increase in the onset and recruitment frequency. For process with certainty. The finding of large-amplitude long-du-
example, MUAPs can fire in isolation at 15 Hz or more before a ration MUAPs in myopathies and short-duration low-amplitude
second unit is recruited. Decreased recruitment may precede the potentials in neuropathies is important to realize as many erro-
generation of spontaneous activity of positive sharp waves and neous claims and hence confusion exist in the literature be-
fibrillation potentials that are apparent only after about 2-3 cause of failure to appreciate the electrical consequences of
weeks. Collateral reinnervation remodels the remaining motor nerve and muscle pathology.
Single-Fiber Electromyography
Performing single-fiber electromyography in most patients
with a suspected myopathic disorder does not add significant
information beyond that obtained from routine needle or quan-
titative electromyography. However, it is a valuable research
tool in attempting to better define the underlying pathophysiol-
ogy in various myopathic diseases.43-44-113-126 There is an in-
crease in jitter in a number of intrinsic muscle diseases, which
may reflect reinnervation where segments of muscle fibers or
regenerating ones are newly innervated. From time to time,
jitter may be abnormally low (< 5 ps) and suggest partial fiber
splitting without separate neuromuscular junctions. Fiber den-
sity can also be measured with single-fiber electromyography.
Fiber density can increase secondary to remodeling of the
motor unit with various degrees of fiber splitting or collateral
sprouting. In areas of severe end-stage damage with loss of
muscle fibers and increased endomysial connective tissue, the
fiber density is decreased.
Research Techniques
A number of primarily research electrophysiologic tech-
niques are available to investigate the underlying pathophysiol-
ogy in most myopathic disorders. Macro electromyography
(macro-EMG) is a technique using specially designed needle
electrodes to assess the electrical activity arising from a signif-
icantly larger motor unit territory than conventional needle
electromyography (see Chapter g).116'118120-121 Scanning elec-
tromyography consists of pulling a conventional concentric Figure 26-19. Drawing of the macro-EMG recording tech-
needle electrode in graduated steps through a motor unit's ter- nique. A, A special needle recording electrode with 15 mm of bare
ritory and gaining insight into the manner in which the electri- cannula and a single-fiber EMG port 7.5 mm from the tip (middle of
cal activity arising from the motor unit is spatially distributed. bare cannula) is inserted into a muscle. B, A single-fiber potential
Macro EMG. In macro-EMG a 15-mm long bare cannula recorded from the middle of the bare cannula is used to trigger a
of a longer recording electrode has a standard single fiber port second channel. C,The second channel records the electrical activity
in the middle of the bare cannula region. The single fiber port detected by the cannula time-locked to the single fiber potential in B.
is referenced to the cannula and the cannula is referenced to a D.The averaged cannula response constitutes the macro-EMG re-
distant concentric needle cannula (Fig. 26-19). This type of sponse.The cannula of a distant concentric electrode is used as the
recording montage permits two simultaneous recordings: one reference electrode for the macro-EMG signal. (From Stalberg E,
channel records a single-fiber potential and the second channel Antoni L: Computer-aided EMG analysis. Prog Clin Neurophysiol
records the electrical activity from the 15 mm bare cannula. 1983; 10:186-234, with permission.)
The 15-mm length permits the physical territory of most motor
units (6-10 mm oval)22-114 to be evaluated when the single fiber the surviving motor units through collateral sprouting. The col-
port (middle of the electrode) triggers on an active single lateral sprouting of surviving terminal axons increases the
muscle fiber. The electrical activity time-locked to the single- number of muscle fibers per motor unit over the same physical
fiber potential, as averaged from the cannula, permits one to motor unit territory, i.e., reinnervation from neighboring termi-
analyze a significantly larger portion of the muscle than is eval- nal axons within the same muscle fascicle. The net result of
uated by conventional monopolar or concentric needle elec- more muscle fibers belonging to a motor unit over the same
trodes, hence the term "macro" EMG. Appreciating the physical space is an elevation in fiber density and net amount of
electrical activity from larger portions of a motor unit provides electrical activity, thus producing larger macro-EMG MUAPs.
insight into the electrical properties of muscle fibers in both The increased jitter also supports the concept of newly inner-
health and disease. vated muscle fibers, i.e., reinnervation.
In normal individuals the different macro MUAPs recorded at In pathologic situations, a number of additional insights into
varying levels of force production increase in amplitude with the physiologic properties of myopathies can be gained.62-63-87-122
increases in the amount of force generated. This supports the In normal muscle subjected to immobilization, the macro-EMG
concept that the later-recruited motor units are the larger type 1 MUAP may be normal or slightly reduced. Although there is no
and 2 fibers, which generate relatively larger MUAPs because absolute loss of muscle tissue, type 2 muscle fibers are smaller
of their size (Fig. 26-20).62-63 n6-,,8-,20-»26 Also, as persons age, the in diameter than normal secondary to disuse. Routine needle
simultaneous single-fiber and macro-EMG recordings provide electromyography in patients with type 2 muscle fiber atrophy
significant insight into the normal aging process as it affects reveals normal-appearing MUAPs because the technique pre-
motor units. The size of the macro-EMG MUAP increases along dominately assesses the electrophysiologic function of type 1
with increases in fiber density, jitter, and the amount of single- fibers. Macro-EMG can assess both type 1 and 2 fibers. The
fiber potentials that block. This suggests that with aging there is normal or slightly reduced macro-EMG MUAP in disuse atro-
subclinical denervation (either from loss of anterior horn cells phy is believed to occur secondary to an overall spatial collapse
or the peripheral nerves) and reinnervation with remodeling of of the motor unit territory, creating a slightly higher packing
7. Max. force
.2%
F I L E 3516MR .A08 3 0 - 3 f t N - 6 1
MACRO EMG
R- 0 . 8 4 0 2 N- 19 K- 2.69 M- 58.1
20% or
MAX. FOtCE
F I L E 3516MA .fl08 30~3flN-81

6% MftCRO EMG
R- 0 . 8 7 2 5 N- 19 K- 16.1 M- 364.
]200,,V NORMAL
Figure 26-20. A macro-EMG recording from the biceps brachii of a healthy person. With increasing force production, the magnitude
of the macro EMG MUAP increases in amplitude.This reflects the sequential recruitment of progressively larger type I or type 2 muscle fibers
that constitute the more later recruited motor units (left panel). At the right the amplitudes (upper panel) and area (lower panel) in relation to
force level. (From Stalberg E.Trontelj J: Clinical neurophysiology:The motor unit in myopathy. In Rowland LP, DiMauro S (eds): Handbook of Clinical
Neurology,Vol. 18. Amsterdam, Elsevier Science, 1992, pp 49-84, with permission.)
FSH Normal ALS
Figure 26-21. Multiple macro-EMG MUAPs are compared in

three different situations.The MUAPs from a patient with facioscapu-
lohumeral (FSH) dystrophy are significantly smaller than normal while
those in amyotrophic lateral sclerosis (ALS) are significantly larger.
Calibration: I mV; 5 ms. (From Stalberg E.Trontelj J: Clinical neurophysiol-
ogy: The motor unit in myopathy. In Rowland LP, DiMauro S (eds):
Handbook of Clinical Neurology,Vol. 18. Amsterdam, Elsevier Science,
1992, pp 49-84, with permission.)
C h a p t e r 26 INTRODUCTION TO MYOPATHIES AND MUSCLE TISSUE'S REACTION TO INJURY — 1257
THE DYSTROPHIC MOTOR UNIT THE M O T O R UNIT
focal lesion
new innervation
focal lesion
splitting
normal neuropathy muscular

dystrophy
7
degeneration
satellite cell — f i b e r
Figure 26-23.The normal motor unit may be remodeled in
a myogenic disorder through both a loss of fibers from the entire
motor unit with a relative increase in fibers at a focal region. This can
neurogenic lesion
result in both a low-amplitude macro-MUAP with increased fiber den-
sity, or a high-amplitude MUAP as recorded with standard needle
z reinnervation
recording electrodes if the active surface is located in the proximity of
the focally increased number of muscle fibers. Recall that the main
spike amplitude of the MUAP is preferentially influenced by the
number of muscle fibers next to the active recording surface. (From
Stalberg E, Trontelj JV: Single Fiber Electromyography. Old Woking,
local hyperexcitability Surrey, Mirvalle Press, 1979, with permission.)
ephaptic transmission
fiber splitting. The net result is still an increase in the number of

Explanation for increased fiber densities in pri-
Figure 26-22. muscle fibers. This apparent contradiction may be reconciled if
marily myogenic disorders. A, Segmental necrosis may lead to a the overall pathology of myogenic disorders is considered (Fig.
single muscle fiber being "segmented" into two or more independent 26-22). As previously stated, there is a random dropout of
fibers, each with a newly developed sprout; as such, these fibers are muscle fibers associated with segmental necrosis and possible
electrically separate. B,A single muscle fiber may split longitudinally loss of innervation of whole muscle fibers as well as metabolic
with each portion generating a separate single-fiber potential. C,The derangements rendering the muscle fiber nonfunctional. These
process of partial degeneration may induce a satellite cell to develop processes affect muscle fibers belonging to multiple motor
into an independent muscle fiber with a nerve terminal from a neigh- units. Collateral sprouting from the same motor unit or from
boring fiber. D, Actual separation of the original terminal axon may other neighboring motor units may reinnervate regenerated
occur secondary to a number of processes (see text) with a collateral muscle fibers. Also, localized regions of fiber splitting may in-
sprout from a different motor unit reinnervating this fiber. E, Single crease the fiber density over a small region of the muscle. The
muscle fibers may be damaged by the myogenic disorder with the de- net result is a total loss of muscle fibers secondary to the myo-
velopment of susceptibility to being ephaptically activated by neighbor- genic disorder; localized pockets of increased fiber density are
ing muscle fibers, becoming an electrical part of the neighboring motor insufficient to significantly alter the overall electrical content of
unit. (From Stalberg E,Trontelj JV: Single Fiber Electromyography. Old the muscle, when considered from the standpoint of the 6-10
Woking, Surrey, Mirvalle Press, 1979, with permission.) mm motor unit territory (Fig. 26-23). Macro-EMG MUAPs in
myopathic process may also be somewhat more polyphasic sug-
density of muscle fibers per motor unit over a given area. This gesting localized regions of motor unit fractionation. Oc-
increased density in disuse is still within normal limits as mea- casionally, macro-EMG MUAP amplitudes can be normal or
sured by the accompanying single-fiber electromyographic increased, which is associated with an increase in fiber density.
electrode as the fibers no doubt are still too far apart to be In these situations, the total number of muscle fibers within the
recorded secondary to volume conduction distance effects.87 motor unit reflects a compensatory increase relative to the pri-
The net effect of smaller muscle fibers packed into a smaller mary destructive nature of the disease through such processes as
region offset each other, thus producing relatively normal or fiber splitting, collateral reinnervation of muscle fibers at the
only mildly diminished macro-EMG MUAP. expense of neighboring motor units, or hypertrophy of remain-
In primary myopathic disorders, the macro-EMG MUAP is ing muscle fibers. The process of fiber splitting can be discerned
generally of low to low-normal amplitude, but the concomi- from regenerative processes by decreased jitter, as opposed to
tantly measured fiber density is increased and the potentials are increases in jitter, because the split fiber does not possess an in-
frequently fragmented, i.e., increased number of turns/phases terposed neuromuscular junction.125
(Fig. 26-21). The low-amplitude potentials suggest there is loss Scanning Electromyography. In this technique a single
of muscle fibers from the entire motor unit. The increased fiber fiber electrode locates a stable firing single muscle fiber.117122126
density implies there is an increase in the number of muscle A standard concentric needle electrode is located in the same
fibers, most likely through collateral sprouting to reinnervated muscle a short distance (10-20 mm) from the single-fiber elec-
neighboring denervated muscle fibers or through a process of trode and a time-locked signal is sought to correlate with the
A silent area is an area of relative absence of the electrical activ-
ity and the peak-to-peak contour plot of amplitude returns to
baseline.
In myopathic disorders, the total length of the motor unit
territory is usually normal or decreased with an occasional
motor unit demonstrating a slightly increased territory and du-
ration (Fig. 26-25). li7J22 - 126 An increase in the number of silent
areas and polyphasic sections is rather characteristic of myo-
pathic MUAPs. 124 These silent regions most likely represent
loss of muscle fibers within the motor unit's territory with re-
placement by fat or connective tissue. It is also typical to ob-
serve an increased number of polyphasic potentials contained
within the scanning-EMG plot, which is likely a result of in-
creased fiber diameter variation and dropout of muscle fibers.
These findings all substantiate the concept of random loss of
muscle fibers with selective areas of increased fiber density
and most likely different fiber sizes leading to an increase in
polyphasicity as well.
Instrument-Assisted MUAP Analysis. The incorporation
of microprocessors and analog-to-digital conversion techniques
into electrophysiologic instruments has permitted investigators
to design software programs with the capability of quantifying
MUAP parameters that were previously laborious and time-con-
suming or simply beyond the reach of investigators. Various
"automatic analysis" programs are available and marketed ,
under the designation of "quantitative electromyography."
These programs assist the practitioner in more efficiently col-
lecting the necessary data to evaluate MUAP duration, ampli-
tude, and phases. Recruitment interval evaluations are still not
readily available. However, even with all of the "automatic"
techniques, the practitioner is still required to critically evaluate
each MUAP and determine if the instrument has properly se-
lected the most appropriate time and amplitude designations.
An extension of these techniques is decomposing the inter-
ference pattern (MUAPs firing at different rates depending
Figure 26-24. Example of a combined macro-EMG and scan- upon force production) and evaluating various MUAP parame-
ning-EMG plot denoting the electrical activity from a normal muscle. ters such as the amplitude or duration of each potential as well
A,The macro-EMG MUAP is depicted containing two relatively large as the number of turns per arbitrary amplitude designation or
peaks of electrical activity. B.The scanning-EMG plot of the same motor per unit of time.52-90'91-92110 By measuring the amplitudes and
unit demonstrating two major areas of electrical activity as the needle is durations of the largest and smallest MUAPs in the interfer-
pulled through the motor unit territory. Of interest is the great variation ence pattern and the degree of polyphasia/turns per unit of
in electrical activity along the motor unit territory reflecting the differ- time, a distinctive "cloud" of normal values is seen in healthy
ent concentrations of muscle fibers in relation to the active recording individuals (Fig. 26-26A, see Chapter 8). Interference pattern
electrode. C.Tfie above two plots is believed to originate from two sep- analysis is quite distinctive from neurogenic versus myogenic
arate concentrations of endplates belonging to the same motor unit. processes with measurements falling outside the normal cloud.
The small region of electrical silence represents the disparate locations In persons with neurogenic disorders, the MUAP interference
of the two endplate concentrations. (From Nandedkar SD, Stalberg E: pattern analysis reveals larger amplitude potentials and a de-
Simulation of macro motor unit potentials. Electroencephalogr Clin crease in the number of small segments (Fig. 26-26B). In con-
Neurophysiol 1983;56:52-62, with permission.) trast, myogenic disorders generate interference patterns with a
normal or reduced amplitude combined with an increase in the
single-fiber potential. The concentric electrode is inserted about N8S (Fig. 26-26C). These parameters can also be measured
10 mm further into the muscle and then slowly withdrawn by a for different levels of force production. Interestingly, com-
step motor with the ensuing electrical activity generated by the puter simulations suggests that the interference pattern is es-
firing motor unit at each location where the step motor pauses sentially a pure measure of the true MUAP amplitudes with
the electrode. A series of recordings can then be placed in the little in the way of erroneous amplitudes secondary to MUAP
order in which they were recorded and the electrical activity overlap leading to either phase superimposition or cancella-
from the entire motor unit can then be appreciated (Fig. 26-24). tion with falsely increased or decreased MUAP amplitudes,
In normal muscle there are usually one to four "fractions" of the respectively. Apparently, even at high rates and numbers of
motor unit designated by increases in electrical activity or am- MUAP firings, there is insufficient synchronization to falsely
plitude over a total length of 3-10 mm with 0-1 silent areas. elevate or depress the overall MUAP amplitudes. Continued
These fractions of motor units are believed to represent prefer- investigation in this area may provided a powerful tool to fur-
ential localization of end-plates originating from common ter- ther explore and use for diagnostic purposes the differences
minal axon branches from the same parent nerve (Fig. 26-24).13 between neurogenic and myogenic processes.
NORMAL B MUSCULAR DYSTROPHY
Figure 26-25. Scanning EMG. Comparison of scanning EMG plots from a normal (A) and abnormal (facioscapulohumeral dystrophy) (B) tibialis
anterior muscle.The peak-to-peak amplitude is noted to the right of each scanning EMG plot (A2, B2).The total electrical territory of the abnormal
muscle is slightly longer than normal in this example and there are increased regions of electrical silence. (From Hilton-Brown R Stalberg E: Motor
unit size in muscular dystrophia macro EMG and scanning EMG study.J Neurol Neurosurg Psychiatry 1983;46:996-1005,with permission.)
ELECTRODIAGNOSTIC MEDICINE only one or two MUAPs that are approaching 15-20 mV in am-
CLASSIFICATION O F MYOPATHIES plitude and 20 ms in duration. When dealing with a myopathy, it
is the authors' opinion that at least 20 MUAPs must be collected
There are multiple ways in which the above-discussed my- at a sufficiently fast sweep speed (2-5 ms/div) from several dif-
opathies can be classified. From the electrodiagnostic medicine ferent sites in the muscle prior to concluding whether the
standpoint it is perhaps best to consider the various diseases MUAPs are indicative of disease. The patient is done a disser-
from the perspective of electrophysiologic findings found in vice when anything less is performed because alterations in
specific muscle diseases (Table 26-10). Prior to using any elec- MUAPs can be quite subtle and a statistical mean is necessary
trophysiologically based classification system, it is important to to arrive at an appropriate diagnosis. It is certainly possible to
keep in mind that a set of electrodiagnostic findings are not misjudge MUAP amplitude, duration, and phases unless the
pathognomonic of any one disease. Also, multiple myopathies MUAPs are individually analyzed without interference from
can have the same electrophysiologic presentation as well as the neighboring MUAPs.
same myopathic process in different persons can appear quite Using Inappropriate MUAP Characteristics. As previ-
different. As with any system of categorization, it should be ously stated, it is best to only use MUAP duration when at-
used only as a rough guide with the understanding that multiple tempting to provide a firm diagnosis of myopathy. Excess
exceptions are to be expected. polyphasic potentials can certainly be found in myopathic con-
ditions; however, attempting to base a myopathic diagnosis
solely on an increase in polyphasic potentials is not appropriate.
ELECTRODIAGNOSTIC MEDICINE Also, when polyphasic potentials are considered, it is important
C O N S U L T A T I O N PITFALLS to keep in mind that concentric needle electrodes may detect up
to 12-15% polyphasic potentials in a normal control popula-
FALSE-POSITIVE STUDIES tion, while a monopolar needle may record up to approximately
30% polyphasic potentials.
Operator Errors: Failing to Measure MUAP Parameters. Amplitude is the most variable and least reliable parameter
Perhaps the most common error made when attempting to eval- because it changes with electrode location. One cannot be sure
uate a patient with a suspected myopathic disorder is not that a MUAP is "abnormally" small unless the MUAPs rise time
making a concerted effort to quantify the electrophysiologic is minimized, i.e., less than 300-500 ps for a concentric needle
findings. One would never perform a nerve conduction study by electrode and 800-1,000 ps for a monopolar needle electrode.
not accurately measuring a distance to calculate a nerve conduc- Only first-recruited MUAPs are measured in standard quantita-
tion velocity or directly measure a CMAP or SNAP amplitude. tive techniques. Attempting to analyze a maximal interference
Yet, practitioners glance at a freely running oscilloscope during pattern is best left to automatic analysis programs utilizing com-
a mild to moderate muscle contraction and determine if a puter algorithms.
MUAP is normal or abnormal. This "qualitative" approach may Recruitment should never be used as the sole criteria for diag-
suffice in persons with pronounced motor neuron disease with nosing a myopathy. Motor unit recruitment is highly dependent
B Activity Cnaac) 1BBB B Activity ( m k ) 1BBB

it Points > IB.8 »U B tl Points > IBM SSSCsc : B
ft Points outside cloud : B M Points outside cloud : B
Hunosr of epochs : 2B
Figure 26-26. Quantitative Electromyography: Expert Quantitative Interference Pattern (EQUIP) analysis. (A)The envelope am-
plitudes (EAMP) and number of small segments (NSS) fall within the "cloud" in normal muscle. (B) In neurogenic disorders, the envelope ampli-
tudes are higher and the NSS are lower than the normal cloud. (C) In myopathic disorders, the NSS is higher than normal while the envelope
amplitudes are lower than normal.
upon patient cooperation. Further, early recruitment is in part disorders. In particular, the reference database most commonly
subjective and based on what the examiner feels should be the used for assessing MUAP duration uses a low-frequency (high-
appropriate number of MUAPs elicited for a particular amount pass) filter of 2-3 Hz. Most practitioners perform a routine needle
of perceived effort. Although recruitment abnormalities are electromyographic examination with a low-frequency filter set at
valuable adjuncts to confirming a myopathic process when short approximately 20 Hz or higher. This tends to shorten the MUAP
duration, polyphasic MUAPs are evident, isolated recruitment duration by eliminating the lower frequencies contained within
abnormalities should be viewed cautiously. the waveform. As a result, the MUAPs may appear shorter than
Inappropriate Instrumentation Parameters. Instrumenta- they really are simply because of an inadvertent instrumentation
tion is an important but frequently forgotten aspect of the elec- truncation effect. Whenever MUAPs are quantified, it is neces-
trodiagnostic medicine quantitative evaluation of myopathic sary to lower the low-frequency filter to about 2-3 Hz.
FALSE-NEGATIVE STUDIES or mechanically induced electrical activity. The same situation

applies to complex repetitive discharges. The net result is that
Operator Errors: Using Inappropriate MUAP Charac- observing any or all of these potentials should not be miscon-
teristics. When attempting to quantify MUAP duration, strued as implying a "denervating" process but merely reflect-
polyphasic potentials should not be used because the polyphasic ing an unstable state of the sarcolemma which is compatible
potentials may skew the simple potential durations toward a with either a neurogenic or myogenic process.
more normal value. Only simple or nonpolyphasic potentials The characteristic voluntary MUAP denoting an intrinsic dis-
should be quantified with respect to duration. A subtle myo- ease in muscle is a short-duration, low-amplitude, and polypha-
pathic process may be missed if too many polyphasic potentials sic potential recruited in large numbers at low levels of muscle
are included in the overall MUAP mean duration calculation. force production. There is no question that this pattern is cer-
Inadequate Sampling. The practitioner must not only tainly suggestive of a myopathic process affecting skeletal
sample multiple muscles but also different regions within the muscle. It is also possible for a myopathic process to be ob-
same muscle. Both proximal and distal limb muscles should be served early in the course of the disease or only mildly affect
examined to increase the examination's yield. Some patients the muscle in which cases insufficient short duration potentials
with preferentially a proximal myopathy can be missed if only are produced. Recall that all normal muscle consists of short,
distal muscles are investigated. Similarly a distal myopathy may intermediate, and long-duration MUAPs. The important issue is
be overlooked if only proximal muscles are evaluated. It is criti- if the mean duration of at least 20 potentials for that particular
cal to always explore the proximal muscle located on the poste- muscle exceeds what is anticipated given not only the specific
rior aspect of the patient about the shoulder and pelvic regions as muscle but also the patient's age. Detecting a number of short or
well as the paraspinal muscles. An early myopathic process may long MUAPs does not imply the patient has a myopathic dis-
only be present in the paraspinal regions or posterior trunk/limb ease. Recording a few short duration MUAPs without actually
muscles. Also, a wide distribution of muscle is required to be ex- calculating a mean duration for the muscle is inappropriate
amined prior to concluding that an adequate portion of muscle when attempting to diagnose a myopathy. Similarly, fiber size
tissue has been investigated. This may require two or more sepa- variation directly influences muscle fiber conduction velocity,
rate needle insertions sites in particularly large muscles. which in turn influences the synchronicity of single muscle
Type 2 Muscle Fiber Atrophy. One of the limitations of the fibers and how they summate electrically within the muscle. A
electrophysiologic evaluation of MUAPs is that only type 1 number of particularly small muscle fibers may result in a re-
fibers can be adequately evaluated with routine needle tech- duction in the electrical synchronicity of a motor unit, thus cre-
niques. These are the fibers readily recruited during minimal ating an electrical fragmentation of the MUAP with an increase
and moderate muscle contractions. In a disease process prefer- in both the MUAP duration and number of phases, even leading
entially affecting type 2 muscle fibers (e.g., steroid myopathy), to satellite potentials. It is certainly possible to not only detect
the abnormal type 2 fibers cannot be assessed with respect to long-duration MUAPs in neurogenic disorders with long collat-
duration, phases, and recruitment. In this sense, the study pro- eral sprouts, but also in primary muscle disease in which there
duces a false negative result. Provided the limitation of elec- is considerable fiber diameter variation. Similarly, large-ampli-
tromyography in this situation is known, other means can be tude MUAPs can also be found in primary muscle disorders.
used to more fully explore the possibility of a myopathy in the This may occur if there are a number of hypertrophied or split
patient. muscle fibers located such that a recording needle electrode is
Normal Muscle Fiber Size and Sarcolemmal Properties. preferentially influenced by the electrical activity from these
If a specific myopathic process does not alter the size of the fibers, thus displaying a relatively large MUAP that may or may
muscle fibers or result in instability of the muscle membrane not have an excess number of phases. Finally, increased jitter or
(e.g., some metabolic myopathies and mitochondrial my- fiber density is also commonly detected in primary muscle dis-
opathies), an electrical abnormality may not be detected. In this orders. These findings should be understood to mean that the
instance, no MUAP abnormalities are found because of the motor unit is experiencing a remodeling process secondary to
nature of defect. Weakness occurring in a random fashion the formation of new neuromuscular junctions. A manner in
amongst the muscle fibers may produce a recruitment abnor- which this can happen is when a diseased muscle fiber under-
mality; however, this can be very subtle and its validity must goes segmental necrosis and a portion is regenerated or satellite
always be questioned unless accompanied by MUAP duration cells have been stimulated to proliferate. In such cases, these
changes. newly formed muscle fibers must be innervated, resulting in an
Abnormal Spontaneous and Voluntary Potentials. For increase in jitter for some time. Also, muscle fiber splitting and
some time there was a mistaken impression that the detection of newly formed muscle fibers no longer conform to the embry-
positive sharp waves, fibrillation potentials, and complex repeti- onic spatial distribution within the muscle, thereby creating an
tive discharges implied that the primary disease process affected increase in fiber density. As a result, an intrinsic muscle disease
the peripheral nervous system with ensuing Wallerian degenera- is compatible with normal and abnormal spontaneous activity as
tion. Wallerian degeneration of axons innervating skeletal well as normal, long-duration, short-duration, low-amplitude
muscle does result in a muscle fiber developing an unstable rest- and high-amplitude MUAPs. It is a mistake to assume that de-
ing membrane potential with a propensity for developing fibril- tecting a certain type of potential automatically implies either a
lation potentials and positive sharp waves. However, an unstable specific disease or disease process.
resting membrane potential can also result from inherited or ac-
quired disorders affecting the various gated and nongated ionic
channels contained within the sarcolemma. Abnormal sodium, CONCLUSION
chloride, and possibly potassium channels may lead to an alter-
ation in the transmembrane ionic concentration favoring the The electrodiagnostic medicine evaluation of suspected my-
generation of spontaneous potentials when activated by voluntarily opathic processes can be quite challenging even for the most
Table 26-11. Myopathic Disorders experienced practitioner given the different types of myopathic
Hereditary Myopathies disorders (Table 26-11). The history and clinical examination
Muscular Dystrophies
are the most critical aspects of the evaluation of patients with
Dystrophinopathies
neuromuscular disorders. Laboratory testing (e.g., serum CK
Sarcoglycanopathies
levels) and electrodiagnostic testing are helpful in confirming a
Other limb-girdle muscular dystrophies (e.g., calpainopathy,
myopathic condition or when the clinical history and examina-
dysferlinopathy)
tion are not sufficient to localize the site of the lesion to muscle.
Congenital muscular dystrophies
Electrodiagnostic studies may also help to narrow the differen-
Facioscapulohumeral dystrophy
tial diagnosis of the type of myopathic condition present. For
Scapuloperoneal dystrophy
example, not all myopathies are associated with increased spon-
Emery-Dreifuss muscular dystrophy
taneous activity (e.g., fibrillation potentials or myotonic dis-
Other regional dystrophies
charges) (Table 26-10). As with all investigations, impeccable
Distal Myopathies/Muscular Dystrophies
technique is necessary to maximize one's chances of finding
Welander type
particularly subtle abnormalities. It must be recognized that
Markesbery-Griggs-Udd type
there are a number of myopathic disorders in which electrical
Nonaka type/autosomal recessive hereditary-IBM
abnormalities may simply not be present, resulting in a rela-
Miyoshi-type/LGMD 2B
tively normal evaluation. It is incumbent upon the practitioner
Laing type
to avoid operator and instrumentation errors in order to mini-
Dystrophic Myotonias
mize false-positive and -negative studies. Of particular impor-
Myotonic dystrophy
tance with myopathic disorders, the electrodiagnostic medicine
Proximal myotonic myopathy
examination is only one portion of the total work-up for a pa-
Non-Dystrophic Myotonias and Channelopathies
tients with a possible myopathy. However, it is directly depen-
Chloride channelopathies (myotonia congenita)
dent upon the biochemical and structural alterations in muscle
Sodium channelopathies: (hyperkalemic periodic paralysis,
tissue. The two chapters that follow discuss the hereditary and
paramyotonia congenita, potassium-aggravated myotonias)
acquired myopathies, respectively.
Calcium channelopathies (hypokalemic periodic paralysis)
Other channelopathies
Congenital Myopathies REFERENCES
Central core
Multicore/minicore 1. Adrian RH, Bryant SH: On the repetitive discharge in myotonic muscle fibers. J
Nemaline myopathy Physiol 1974;240:505-515.
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Chapter 27
Hereditary Myopathies
CHAPTER OUTLINE
Dystrophin-Glycoprotein Complex • Schwartz-Jam pel Syndrome • Toxin/Drug-Induced Myotonic
Dystrophin • Merosin/Laminin * Integrins * Utrophin * Other Syndromes
Sarcolemma! Proteins (Dysferlin, Caveolins) • Myofibrillar Proteins Congenital Myopathies
• Nuclear Membrane Proteins • Function of the DGC Central Core Disease • Multicore/Minicore Myopathy • Nemaline
Specific Hereditary Myopathies Myopathy • Centronuclear Myopathy • Congenital Fiber Type
Muscular Dystrophies Disproportion • Reducing Body Myopathy • Fingerprint Body
Dystrophinopathies • Duchenne Muscular Dystrophy Myopathy • Sarcotubular Myopathy • Trilaminar Myopathy
• Becker Muscular Dystrophy • Limb Girdle Muscular Dystrophy • Hyaline Body Myopathy/Familial Myopathy With Lysis of
• Sarcoglycanopathies • Other Autosomal Recessive Limb Girdle Myofibrils • Cap Disease • Zebra Body Myopathy • Tubular
Muscular Dystrophies • Autosomal Dominant Limb Girdle Aggregate Myopathy • Myofibrillar Myopathy
Muscular Dystrophies • Congenital Muscular Dystrophy Metabolic Disorders of Muscle
Other Regional Forms of Muscular Dystrophy Glycogen Metabolism Disorders
Facioscapulohumeral Muscular Dystrophy • Facioscapulohumeral Type II Glycogenosis (Acid Maltase Deficiency) • Type III
Spinal Muscular Atrophy • Scapuloperoneal Syndromes Glycogenosis (Debranching Enzyme Deficiency) • Type IV
• Scapuloperoneal Muscular Dystrophy • Spinal Scapuloperoneal Glycogenosis (Branching Enzyme Deficiency) • TypeV
Atrophy • Scapuloperoneal Neuropathy (Davidenkow Syndrome) Glycogenosis (Myophosphorylase Deficiency) • Type VII
• Emery-Dreifuss Muscular Dystrophy • Bethlem Myopathy Glycogenosis (Phosphofructokinase Deficiency) • Type VIII
• Rigid Spine Syndrome • Bent Spine/Dropped Head Syndrome Glycogenosis (PBK Deficiency) • Type IX Glycogenosis (PGK
• Oculopharyngeal Muscular Dystrophy Deficiency) • Type X Glycogenosis (PGAM Deficiency) * Type XI
Distal Myopathies Glycogenosis (LDH Deficiency) • Type XII Glycogenosis
Welander Distal Myopathy • Markesbery-Griggs-Udd Distal (p-Enolase Deficiency)
Myopathy • Nonaka Distal Myopathy • Miyoshi Distal Myopathy Disorder of Purine Nucleotide Metabolism
• Laing Distal Myopathy • Distal Myopathy with Vocal Cord
Paralysis and Pharyngeal Weakness • Myofibrillar Myopathy Myoadenylate Deaminase Deficiency
Hereditary Inclusion Body Myopathies Lipid Metabolism Disorders
Carnitine Deficiency • Carnitine Palmityltransferase Deficiency
Hereditary Inclusion Body Myopathy with Cerebral Hypomyelination • Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency
Dystrophic Myotonias • Long-Chain Acyl-CoA Dehydrogenase (LCAD) Deficiency
Myotonic Dystrophy * Proximal Myotonic Myopathy • Medium-Chain Acyl-CoA (MCAD) Dehydrogenase Deficiency
• Short-Chain Acyl-CoA (SCAD) Dehydrogenase Deficiency
Non-Dystrophic Myotonias and Channelopathies • 3-Hydroxy Acyl-CoA Dehydrogenase (HAD) Deficiency
Chloride Channelopathies • Myotonia Congenita • Sodium • Electron Transferring Flavoprotein (ETF) and ETF-Coenzyme Q
Channelopathies • Potassium-Sensitive or Hyperkalemic Periodic Oxidoreductase (ETF-QO) Deficiencies
Paralysis • Normokalemic Periodic Paralysis * Paramyotonia Mitochondrial Myopathies
Congenita • Potassium-Aggravated Myotonias • Hypokalemic Myoclonic Epilepsy and Ragged Red Fibers • Mitochondrial
Periodic Paralysis • Calcium Channelopathies • Primary Myopathy Lactic Acidosis and Strokes • Kearns-Sayre Syndrome
Hypokalemic Periodic Paralysis • Secondary Hypokalemic Paralysis • Progressive External Ophthalmoplegia • Autosomal Recessive
• Thyrotoxic Periodic Paralysis • Other Forms of Periodic Cardiomyopathy and Ophthalmoplegia • Mitochondrial DNA
Paralysis • Klein-Lisak-Andersen Syndrome Depletion Syndromes * Focal Mitochondrial Depletion
Other Channelopathies • Mitochondrial Neurogastointestinal-Encephalomyopathy
Cardiac Sodium Channelopathies • Muscle Potassium Channel • Leigh's Syndrome • Mitochondrial Myopathies Associated with
Diseases • Malignant Hyperthermia * Rippling Muscle Disease Recurrent Myoglobinuria • Succinate Dehydrogenase Deficiency
• Brody's Disease • Diffuse Abnormal Insertional Activity
1265
Having discussed the basic principles of normal and abnor- DYSTROPHIN-GLYCOPROTEIN
mal muscle histology and the electrophysiologic correlates, we COMPLEX
now turn our attention to specific myopathic disorders. We
review the clinical, laboratory, and histologic features of heredi- DYSTROPHIN
tary myopathies as well as their molecular genetics and patho-
genic mechanisms (Table 27-1). In addition", we discuss the The identification and characterization of dystrophin as the
currently recommended treatment options when applicable. missing or deficient protein in Duchenne and Becker muscular
Unfortunately, the electrodiagnostic features of many of these dystrophies were seminal discoveries in the understanding of
disorders can best be described as incomplete. Although there is the genetics and pathogenesis of a variety of muscular dystro-
information on the more common pathologic states/only a few phies.444-445-53,-532'n53 Dystrophin has a molecular mass of 427
lines in scattered case reports with dubious descriptions of the kD and localizes to the cytoplasmic face of skeletal and car-
techniques employed are noted in the less common myopathies. diac sarcolemma, where it constitutes 2% of total sarcolemmal
A certain amount of caution is required when discussing some protein and 5% of sarcolemmal cytoskeletal protein. 751
of the more esoteric disorders because of the limited amount of Dystrophin is predicted to be a rod-shaped molecule com-
information available. Prior to discussing individual hereditary posed of four domains.532-900 The amino-terminal domain binds
disorders, the basic structure and function of muscle mem- to the cytoskeletal filamentous actin. The second domain is
branes, myonuclear membranes, sarcomeric proteins, and other comprised of repeating units of amino acids bearing similarity
related muscle proteins are reviewed. to spectrin, an erythrocyte cytoskeletal protein that provides
structural integrity to red blood cells. The third domain is a
cysteine-rich region, and the fourth domain is the carboxy-ter-
Table 27-1. Hereditary Myopathies minal. The cysteine-rich domain and the first half of the car-
Muscular Dystrophies boxy-terminal domain of dystrophin are important in linking
Dystrophinopathies dystrophin to p-dystroglycan and the glycoproteins that span
Sarcoglycan o path i es the sarcolemma.
Other limb-girdle muscular dystrophies In addition, dystrophin is present in the brain, where it local-
Congenital muscular dystrophies izes subcellularly to the postsynaptic density (PSD), a disk-
Facioscapulohumeral dystrophy shaped structure beneath the postsynaptic membrane in
Scapuloperoneal dystrophy chemical synapses. 518 Studies suggest that the PSD has an im-
Emery-Dreifuss muscular dystrophy portant role in synaptic function by stabilizing the synaptic
Other regional dystrophies structure, anchoring postsynaptic receptors, and transducing ex-
Distal Myopathies/Muscular Dystrophies tracellular matrix-cell signals.
Welander type
Markesbery-Griggs-Udd type DYSTROPHIN-ASSOCIATED
Nonaka type/autosomal recessive hereditary—IBM PROTEINS/GLYCOPROTEINS
Miyoshi-type/LGMD 2B
Laing type Dystrophin is tightly associated with a large oligomeric com-
Dystrophic Myotonias plex of novel sarcolemmal proteins (Fig. 27-1). Together, this
Myotonic dystrophy association is referred to as the dystrophin-glycoprotein com-
Proximal myotonic myopathy plex (DGC).,20,42-,82a-,94'523-622'64,-652-n25 The sarcolemmal pro-
Non-Dystrophic Myotonias and Channelopathies teins previously had been classified according to molecular
Chloride channelopathies (myotonia congenita)
weight and glycosylation as dystrophin-associated proteins
Sodium channelopathies: (hyperkalemic periodic paralysis,
(DAPs) and glycoproteins (DAGs). Subsequently, there have
Paramyotonia congenita, potassium-aggravated myotonias
been changes to the nomenclature of these proteins and are now
Calcium channelopathies (hypokalemic periodic paralysis)
more often referred to as dystroglycans or sarcoglycans. 759
Other channelopathies
Mutations in the various genes that encode for the different pro-
Congenital Myopathies teins of the DGC are now known to be responsible for many
Central core
forms of muscular dystrophy (Table 27-2).
Multicore/minicore In addition to dystrophin, the DGC is composed of an entirely
Nemaline myopathy
cytoplasmic group of proteins referred to as the syntrophin
Myotubular/centronuclear myopathy
complex, the dystroglycan complex, and the sarcoglycan com-
Myofibrillar myopathy
plex (Fig. 27-1). The syntrophin complex binds to the carboxy-
Other
terminus of dystrophin and is composed of three distinct 59-kD
Metabolic Myopathies DAPs that are encoded by separate genes. a-Syntrophin is ex-
Glycogen storage diseases
pressed only in muscle, and the gene has been localized to chro-
Lipid storage diseases
mosome 20ql 1.2. (31-Syntrophin and p2-syntrophin are more
widely expressed, and their genes have been localized to chro-
Mitochondrial Myopathies mosomes 8q23-24 and 16q22-23, respectively.120 Dystrobrevin
MERRF is encoded on chromosome 2p22-23 and is a cytoplasmic pro-
MELAS tein that binds to the syntrophin complex and to the C-terminus
Kearn-Saryes syndrome/progressive external ophthalmoplegia of dystrophin. The dystroglycan complex contains a trans-
Multiple mitochondrial DNA deletion syndromes membrane 43-kD DAG, (3-dystroglycan, which has a cytoplas-
Mitochondrial DNA depletion syndromes mic tail that binds to dystrophin; and an extracellular 156-kD
Leigh's syndrome DAG, a-dystroglycan, which binds to a-laminin, a basal
I
Chapter 27 HEREDITARY MYOPATHIES — 1267
Figure 27-1. The dystrophin-glycoprotein complex and related proteins.Two dystrophin molecules wrap around each other in oppo-
site directions at the cytoplasmic face of the sarcolemma.The amino-terminal (N) of dystrophin binds to filamentous actin, while the carboxy-ter-
minal (C) binds to the syntrophin complex and dystrobrevin in the sarcoplasm.The C-terminal for dystrophin also binds to p-dystroglycan of the
dystroglycan complex, a-dystroglycan binds to a-2 laminin (merosin) of the basement membrane. Merosin also binds to the a 7 subunit of inte-
grin.The sarcoglycan complex is closely linked to dystrophin and the dystroglycan complex.Together, dystrophin, the sarcoglycans, the dystrogly-
cans, the syntrophins, and merosin form what is known as the dystrophin-glycoprotein complex. Other important proteins that are not directly
linked to the dystrophin-glycoprotein complex but are important in stabiliazation of the muscle membrane include dysferlin, caveolin-3, and the in-
tracellular enzyme calpain-3.
lamina protein. Of note, a gene located on chromosome 3p21 laminin-2, which is composed of a2, p i , yl chains. Muscle
encodes for both the a- and (3-dystroglycans. The sarcoglycan also contains laminin-4, composed of oc2, p2, yl subunits.
complex includes four membrane spanning proteins: (1) a 50- Merosin is the collective name for laminins that share a
kD DAG, also known as adhalin or a-sarcoglycan; (2) a 43-kD common oc2 chain. Alpha-dystroglycan binds specifically to
DAG, p-sarcoglycan; (3) a 35-kD DAG, y-sarcoglycan; and laminin-2 but not to the other extracellular components (Fig.
another 35-kD DAG, 5-sarcoglycan. In addition, there is a 25- 27-1). Ligands for the sarcoglycan complex are unknown, but it
kD transmembrane protein, sarcospan, which co-localizes with has been postulated that the complex is directly or indirectly
the sarcoglycan complex. The sarcoglycan complex associates linked to laminin-4. 11,1
with the cysteine-rich domain and/or the first half of the car- Merosin is also expressed in the endoneurial basement mem-
boxy-terminal of dystrophin directly or indirectly via the dys- brane surrounding the myelin sheath of peripheral nerves. 623
troglycan complex. 759 The exact relationship between the Likewise, a- and p-dystroglycan are present not only in muscle
sarcoglycan complex and the dystrophin-dystroglycan complex fibers but also in peripheral nerves. Expression of a- and p-dys-
is still unclear. troglycan is restricted to where the Schwann cell's outer mem-
brane abuts the endoneurium; however, they are not present in
MEROSIN/LAMINiN the inner membrane or on compact myelin. The extracellular ct-
dystroglycan is anchored to the outer membrane of Schwann
The basal lamina surrounding each muscle fiber is closely ad- cells and myelin sheath by the transmembrane p-dystroglycan.
herent to the sarcolemma and is composed of type I and IV col- As in muscle, merosin serves as a ligand in the Schwann cell
lagen, heparan sulfate, proteoglycan, entactin, fibronectin, and dystroglycan complex by binding to a-dystroglycan. This com-
laminin. Laminin is a large, flexible heterotrimer composed of plex appears to have a role in peripheral myelinogenesis. 623 As
three different but homologous a, p, and y chains held together will be discussed below, mutations involving the merosin gene
by disulfide bonds. At present, there are five different a chains, not only result in a form of congenital muscular dystrophy
three p chains, and two y chains that have been characterized. (CMD), but they also are associated with mild dysmyelination
The major isoform of laminin heavy chains in muscle is in the central and peripheral nervous systems.
Table 27-2. Molecular Defects Of Muscular Dystrophies

Disease Chromosome Protein
X-Linked Recessive Dystrophies
DMD/BMD Xp2l Dystrophin
EDMD Xq28 Emerin
Autosomal Dominant Dystrophies
LGMD IA 5q22-3l v Myotilin
LGMD 1B with cardiopathy/AD-EDMD Iqll-I2 Nuclear lamin A/C
LGMD IC 3p25 Caveolin-3
Myotonic dystrophy I9ql 3.2 Myotonin protein kinase
Myotonic dystrophy type 2/PROMM 3q DM2
LGMD ID 6q23 ?
LGMD IE 7q ?
FSHD 4q35 ?
Oculopharyngeal dystrophy I4q Polyalanine binding protein 2 (PABP2)
Bethlem myopathy 1 2lq22.3 Collagen type VI (a-l or a-2 subunits)
Bethlem myopathy 2 2q37 Collagen type VI (oc-6 subunits)
Autosomal Recessive Dystrophies
LGMD2A I5ql5 Calpain-3
LGMD 2B/Miyoshi myopathy 2pl3 Dysferlin
LGMD 2C I3ql3 y-Sarcoglycan
LGMD 2D I7q2l a-Sarcoglycan
LGMD 2E 4ql2 P-Sarcoglycan
LGMD 2F 5q33 8-Sarcoglycan
LGMD 2G I7ql1-12 Telethonin
LGMD 2H 9q3I-q33 )
LGMD 21 I9ql3.3 7
Congenital muscular dystrophy
Merosin-negative classic type 6q2l-22 Merosin (a-2 subunit)
Merosin-positive integrin deficiency I2ql3 a-7 Integrin
Fukuyama type 9q3J-33 Fukutin
Walker-Warburg type 9q3I-33 ?
MEB Ip32-p34 ?
CMD with rigid spine syndrome lp35-36 ?
DMD = Duchenne muscular dystrophy LGMD = limb-girdle muscular dystrophy
BMD = Becker muscular dystrophy FSHD = facioscapulohumeral muscular dystrophy
EDMD = Emery-Dreifuss muscular dystrophy MEB = Muscle-eye-brain disease
AD = Autosomal dominant
INTEGRINS UTROPH1N (DYSTROPHIN-RELATED PROTEIN)

Integrins are transmembrane, heterodimeric (oc/(3) receptors that Utrophin is an autosomal homologue of dystrophin that is
play a key role in establishing linkages between the extracellular ubiquitously expressed but is localized exclusively at the neuro-
matrix and the cytoskeleton as well as transducing extracellular muscular junction in normal skeletal muscle.623-1026 The utrophin
matrix-cell signals.1064 Integrins are vital in the regulation of ad- gene locus is on chromosome 6q24. Utrophin is associated with
hesion, migration, differentiation, proliferation, and cytoskeletal DAPs or their homologues, suggesting that the utrophin-glyco-
organization. The major integrin expressed throughout the sar- protein complex is important in the formation and integrity of
colemma in mature muscle fibers is a 7 p i D . Studies have the neuromuscular junction.1026 Up-regulation of utrophin is ev-
demonstrated that oz7plD integrin binds to merosin in skeletal ident in the dystrophinopathies, perhaps as a compensatory
muscle, and this interaction appears to be equally important as mechanism.
the linkage of a-dystroglycan to merosin in providing structural
stability (Fig. 27-1). In fact, some lines of evidence suggest the FUNCTION OF THE DGC
binding of merosin to integrin plays a pivotal role in the patho-
genesis of some forms of CMD.' 064 First, mutations in the a-2 The DGC is a trans-sarcolemmal complex of proteins and
subchain of merosin (a common cause of classic CMD) result in glycoproteins that link the subsarcolemmal cytoskeleton to the
a markedly diminished expression of a 7 p l D integrin, but a extracellular matrix.,20-622-64, n25 The DGC provides structural
normal or only mildly decreased expression of components of support to the sarcolemma during muscle contraction and
the dystroglycan or sarcoglycan complexes on the sarcolemma. stretch. In addition, the DGC may have a role in regulating in-
Second, the merosin and a7plD integrin are normally expressed tracellular calcium concentration and in signal transduction.
in skeletal muscle in the dystrophinopathies and the sarcogly- Abnormalities in the various components of the DGC pre-
canopathies. Third, as will be discussed, mutations involving the dictably would lead to the loss of integrity of the sarcolemma
a7 subunit of a 7 p l D can result in a rare form of CMD. and subsequent muscle fiber damage.
OTHER SARCOLEMMAL PROTEINS The interaction between the myosin cross-bridges and actin fila-
ments causes the muscle fiber to shorten or contract because the
DYSFERLIN above-noted filaments slide past each other.
One end of the actin filaments are firmly anchored to the Z-
Dysferlin is another cytoskeletal protein present in skeletal disk and the other end projects out between myosin filaments.
and cardiac muscle. It is located predominantly on the subsar- These Z-disks extend from myofibril to myofibril across the di-
colemmal surface on the muscle membrane, but it has a small ameter of a muscle fiber. The region of muscle or myofibril be-
transmembrane spanning tail (Fig.27-1). The protein does not tween two Z-disks is called a sarcomere (see Chapter 1). The
appear to be directly connected to the dystrophin-glycoprotein major protein of the Z-disk is a-actinin. Nebulin is a giant pro-
complex. The function of dysferlin is not known. Dysferlin may tein that is attached to a-actinin at the Z-disk and spans the entire
have a role in membrane fusion, stabilizing the sarcolemmal length of the thin filament. There are two nebulin molecules for
membrane, or in signal transduction.68-6'8 every thin filament. Desmin is an intermediate-size filament that
encircles the Z-disk and helps to link the Z-disk to the sar-
CAVEOLINS colemma, myonuclei, and adjacent myofibers. The cytoplasmic
heat-shock protein aB-crystallin interacts with desmin in the
Caveolae are invaginations in the sarcolemma, whose function assembly and stabilization of the Z-disk. Other filamentous pro-
are not quite clear. Caveolin proteins, including caveolin-3, are teins are also important in providing stability to the sarcomere.
thought to play a role in the formation of caveola membranes, The giant protein titin (also known as connectin) is attached to
where they act as scaffolding proteins to organize and concen- the Z-disk and spans from the M-line to the Z-line of the sarcom-
trate caveolin-interacting lipids and proteins (Fig. 27-1). 155 661 ere. Titin serves to connect the myosin filaments to the Z-disk.
Caveolin-3 is localized by immunostaining to the sarcolemma at Telethonin is another sarcomeric protein present in skeletal and
caveolae. It co-fractionates with the dystrophin-glycoprotein cardiac muscle. It co-localizes with titin to the Z-disks and along
complex, but is thought to be part of a discrete complex. the thick filaments. The interaction of telethonin and titin may be
Mutations in the gene encoding for caveolin-3 are responsible important in myofibrillogenesis. As will be discussed, mutations
for causing limb-girdle muscular dystrophy (LGMD) IC. affecting the genes encoding for these various sarcomeric pro-
teins are responsible for causing different dystrophies, congeni-
tal myopathies, and inherited cardiomyopathies.
MYOFIBRILLAR PROTEINS The sarcoplasm is the intracellular fluid surrounding the my-
ofibrils. Within the sacroplasm lie large numbers of mitochondria
In addition to the above sarcolemmal and related proteins, required for energy consuming contraction of the muscle fibers
there are a number of important myofibrillar proteins that com- (see Chapter 1). The myofibrils are also surrounded by an intri-
pose the sarcomere. The structure and function of the sarcomere cate series of channels called the sarcoplasmic reticulum.
contractile proteins are discussed in Chapter 1. The major con- Longitudinal sarcoplasmic reticulum channels terminate along
tractile myofibrillar proteins are the thick and thin filaments. large terminal cisternae at either end of the sarcomere (see
The major component of the thick filaments is a polymer of Chapter 1). Within muscle fibers, T tubules are closely associ-
myosin. A single thick filament contains about 300 myosin mol- ated with terminal cisternae. Two terminal cisternae are in close
ecules. An individual myosin molecule consists of a single long association with one T tubule forming a so-called triad. Although
"tail" attached to two "head" portions that project out from the these three structures are in very close association, there are no
tail. The head and its projecting part are referred to as a cross- known channels connecting them. The triad is critically posi-
bridge, which has two flexible hinges—one at the head/arm, and tioned next to where the muscle fiber's mechanism produces the
the other at the arm/filament interface (see Chapter 1). In addi- necessary forces for contraction. The T tubule is believed to con-
tion to being a structural protein, each myosin head acts as an duct an action potential into the depths of the muscle and into the
ATPase to cleave a molecule of ATP. The energy liberated by this terminal cisternae (see below). The action potential opens L-type
process is utilized to maintain the cross-bridge in the extended or calcium-gated channels called the dihydropyridine receptor
"cocked" position. The entire myosin filament is twisted about a (DHP), located, on the sarcolemmal membrane (Fig. 27-2). The
central axis, allowing the cross-bridges to extend longitudinally DHP receptor also serves as a voltage sensor for the calcium re-
and circumferentially 360 degrees. lease channel, the ryanodine receptor, located on the sarcoplas-
The thin filament is composed of three subcomponents: mic reticulum. As will be discussed later in the chapter, mutations
actin, tropomyosin, and troponin (see Chapter 1). Two helical in these genes are responsible for hypokalemic periodic paralysis,
strands of filamentous or F-actin, which are composed of poly- malignant hyperthermia, and central core disase. In addition,
merized globular or G-actin molecules, form the primary struc- there is a separate calcium re-uptake channel located on the sar-
ture of the actin filament. Each G-actin molecule contains one coplasmic reticulum called sarcoplasmic reticulum calcium-
molecule of ADP. Two thin strands of a tropomyosin molecules ATPase (SERCA 1). Mutations in the gene encodng for this
wind loosely within the helical structure of the F-actin. The protein (SERCA 1) lead to Brody's disease characterised by im-
tropomyosin molecules overlie "active sites" on the actin mole- paired relaxation of muscles.
cules that link with the myosin heads forming the cross-bridges.
The third major subcomponent of the thin filament, troponin, is
attached two thirds down the tropomyosin molecule and con- NUCLEAR MEMBRANE PROTEINS
sists of three globular proteins: troponin I, T, and C (see Chapter
1). Troponin I binds strongly to actin, troponin T is attached to Emerin, a member of the nuclear lamina-associated pro-
tropomyosin, while troponin C has a large affinity for calcium. tein (LAP) family, is a protein located on the inner nuclear
The troponin complex attaches the tropomyosin molecules to membranes of skeletal, cardiac, and smooth muscle fibers.715-749
the actin molecules, thereby forming the complete thin filament. The nuclear lamina is a multimeric matrix composed of a complex
Cell Membrane pathogeneses (Table 27-1). Within these major groups, multiple
specific myopathies with common clinical and pathologic find-
ings are further delineated.
MUSCULAR DYSTROPHIES
The muscular dystrophies specifically refer to a group of
hereditary, progressive intrinsic muscle disorders in which there
is destruction of muscle tissue and replacement by connective and
fatty tissue. Muscular dystrophies traditionally have been classi-
fied according to their pattern of weakness (e.g., limb-girdle, fa-
cioscapulohumeral, scapuloperoneal) and mode of inheritance
(Table 27-2). Recent advances in genetics have led to the classifi-
cation of muscular dystrophies based on the responsible gene
defect. Clearly the most significant advance in our understanding
of the muscular dystrophies has come with the identification of
dystrophin, the dystrophin-glycoprotein complex, and related sar-
colemmal/basement membrane proteins. Familiarity with these
proteins is essential for clinicians who practice electrodiagnostic
medicine and specialize in neuromuscular disease.
THE DYSTROPHINOPATHIES: DUCHENNE AND
BECKER MUSCULAR DYSTROPHY
Duchenne Muscular Dystrophy
Figure 27-2. Triad junction between a transverse tubule and
Clinical Features. Perhaps the best known of the muscular
the sarcoplasmic reticulum. Calcium release is intiated by the dystrophies is the X-linked recessive disorder of pseudohyper-
action poteintial spreading along the sarcolemmal and transverse
trophic muscular dystrophy or Duchenne muscular dystrophy
tubule (Ttubule). Depolarizing of theT-tubule activates the dihdropyri-
(DMD). The incidence is roughly 1 per 3500 male births with a
dine receptor (DHP).The coupling between the DHP receptor and
prevalence approaching 1 per 18,000 males. 2771102 Approx-
ryanodine receptor is not fully understood. However, activation of the
imately one third of patients with DMD are a result of sponta-
DHP receptor in turn activates the ryanodine receptor leading to cal-
neous mutations.275
cium efflux from the sarcoplasmic reiticulum into the sarcoplasm.
The natural history of children with DMD was well studied
(From Lehmann-Horn F, Jurkat-Rott K:Voltage-gated ion channels and
prior to the discovery of the responsible gene defect. 116 Most
hereditary disase. Physiol Rev I999;79:1317-I372,with permission.)
male children appear quite normal at birth and achieve the an-
ticipated milestones of sitting and standing either normally or
with only slight delay.292-387'391'1102 A few patients, however, may
of intermediate-sized filaments (Iamins -A, -B, and -C) that as- appear hypotonic and weak at birth. Careful inspection of neck
sociate with the nucleoplasm^ surface of the inner nuclear flexors in infants suspected of having the disease usually reveals
membrane. Of note, lamins A and C are produced by alterna- some degree of weakness. Most parents with only the one child
tive splicing of a single gene. Emerin is connected to the inner who is affected do not really begin to become concerned until
nuclear membrane through its carboxy-terminal tail. The rest of the child is about 2 years of age, i.e., time of walking. Parents
the protein projects into the nucleoplasm. The lamins bind to with normal children may note that the affected child ambulates
emerin, specific lamin receptors, and perhaps other LAPs lo- with a wide base gait and there is some hint of a waddle or
cated on the inner nuclear membrane. The complex of these nu- rolling of the hips. Normal running and jumping are never really
clear envelope-related proteins are important in the achieved. A "clumsy" walk and frequent falls are noted by about
organization and structural integrity of the nuclear membrane. 2-6 years of age. At about this time, there is a tendency for the
In addition, LAPs, lamin receptors, and the lamins are known to child to walk on the toes. Calf hypertrophy may also be appreci-
bind to chromatin and promotes its attachment to the nuclear ated. Around this time, patients also have difficulty arising from
membrane. Abnormalities in these proteins may disrupt the the floor. A characteristic maneuver, Gower's sign, is employed
structure of the nuclear membrane, impair the organization of by the child to help him or her rise to a standing position (Fig.
interphase chromatin, or disrupt signal transduction between the 27-3). Weakness is characteristically worse proximally than dis-
nucleus and sarcoplasm. 98 321 Mutations in the genes that code tally and more so in the lower compared with upper limbs. By 8
for emerin and lamin A/C are responsible for X-linked Emery- years of age, affected children are noted to have difficulty
Dreifuss muscular dystrophy (EDMD) and autosomal dominant climbing stairs. The child needs to pull himself up the stairs
EDMD/Iimb-girdle dystrophy IB, respectively. using the handrails or may prefer to crawl up the stairs. At 6-12
years of age, weakness progresses to the point at which the
upper limb and torso muscles are profoundly affected. The
SPECIFIC HEREDITARY MYOPATHIES biceps brachii, triceps, and quadriceps reflexes diminish and are
absent in 50% of children by the age of 10 years.292 The brachio-
We classify the myopathies into hereditary and acquired dis- radialis may persist longer. An interesting finding is the persistent
orders and subcategorize them according to their presumed ability to obtain an ankle jerk in at least a third of patients even
in end stages of the disease. 792 Contractures about the hip and
ankles also significantly impair posture. Ambulation becomes
progressively more difficult, and affected children are confined
to a wheelchair by 12 years of age. The development of contrac-
tures and kyphoscoliosis is facilitated by the non-ambulatory
status of the patient. Respiratory function gradually declines, and
even minor colds become significant life-threatening events late
in the disease. Pulmonary insufficiency combined with chronic
infections eventually results in death by the early twenties.
Cardiac muscle is also affected, although most patients are
asymptomatic. However, dysrhythmias and congestive heart
failure can occur late in the disease. Up to 90% of patients have
EKG abnormalities, most commonly sinus tachycardia, tall
right precordial R waves, and deep narrow Q waves in the left
precordial leads.302-791898 An echocardiogram can demonstrate
dilation and/or hypokinesis of ventricular walls.302 Myocardial
involvement may be complicated by pulmonary hypertension,
and respiratory insufficiency may cause an increase in pul-
monary pressure leading to right-sided heart failure. Smooth
muscle is also affected, and patients can develop gastroparesis
and intestinal pseudo-obstruction. 57 The central nervous system
is also involved in DMD, and the average IQ of the affected
children is one standard deviation below the normal mean. 570
Whether or not the intellectual impairment is related to the loss
of dystrophin at brain synapses remains unknown.
Laboratory Features. The serum CK levels are markedly ele-
vated (50-100 times normal or greater) at birth and peak at around
3 years of age. Subsequently, serum CK levels fall roughly 20% Figure 27-3. Gower's sign. A patient with progressive spinal mus-
per year as a result of the loss of muscle tissue, although normal cular atrophy is requested to arise from the floor. He first assumes a
levels are never reached. A serum CK that is not at least 10 times position on his hand and knees. A semi-upright posture is achieved by
normal at any age is evidence against the diagnosis of DMD. positioning his trunk over extended arms and legs.The patient then
Histopathology. Even early in the course of the disease, the pushes his trunk upward with the use of the arms by "climbing" up the
muscle biopsy reveals evidence of muscle fiber degeneration and legs. Gower's sign is not specific for muscular dystrophy but can be
regeneration.157-292-391-907 Degeneration is characteristically segmen- seen in any neuromuscular disorder with severe proximal weakness.
tal in nature. Endomysial inflammatory cells consisting of cyto- (From Gomez MR:The clinical examination. In Engel AG, Banker BQ
toxic T-iymphocytes (two thirds) and macrophages (one third) are (eds): Myology. New York, McGraw-Hill, 1986, p 829, with permission.)
present to a variable degree and phagocytize necrotic fibers.303
There is considerable fiber size variation with scattered hyper-
trophic and hypercontracted fibers in addition to small, rounded, or rod-domain antibodies, approximately 50% of DMD patients
regenerating fibers (Fig. 27-4). Fiber splitting and central nuclei have some detectable truncated dystrophin. 292 Immuno-
can also be seen but occur less often than in other muscular dystro- histochemical analysis in dystrophinopathies also demonstrates
phies.391 The process of degeneration and regeneration continues a reduction of dystroglycan, dystrobrevin, and all the sarcogly-
until the limited regenerative capacity of the satellite cells is ex- can proteins, including sarcospan (Fig. 27-5).620-759
ceeded, at which time the necrotic muscle tissue is replaced with
fat and connective tissue. This leads to the pseudohypertrophy. Becker Muscular Dystrophy
Immunohistochemistry demonstrates diminished dystrophin Clinical Features. Becker muscular dystrophy (BMD) rep-
staining on the muscle membrane (Fig. 27-4 and 27-5). About resents a milder form of dystrophinopathy than the more severe
60% of DMD patients will have some faint staining of the sar- DMD phenotype with which it is allelic. BMD can be distin-
colemma utilizing antibodies directed against the amino-termi- guished from DMD primarily by its rate of progression com-
nal or rod domain of dystrophin. Antibodies directed against the bined with dystrophin analysis. The incidence of this disorder is
carboxy-terminal of dystrophin are more sensitive, with less approximately 5 per 100,000 with a prevalence of 24 per
than 1 % of muscle fibers demonstrating sarcolemmal staining 100,000. 138 277 Approximately 10% of cases are the result of
in DMD. These few dystrophin-positive fibers are known as re- spontaneous mutations. A number of clinical features help to
vertants and arise secondary to spontaneous subsequent muta- define patients with possible BMD: (1) X-linked recessive in-
tions that restore the "reading frame" and allow transcription of heritance pattern, (2) ambulation maintained past the age of 15
dystrophin, albeit of abnormal size and shape (see below). years, (3) calf hypertrophy (pseudohypertrophy), (4) Achilles
Interestingly, utrophin, which is normally restricted to the neu- tendon contractures early in the disease process, and (5) a pat-
romuscular junction, is overexpressed in DMD and is present tern of muscle weakness similar to patients with Duchenne
throughout the sarcolemma. Immunoblot or Western blot of muscular dystrophy: hip and shoulder girdle muscles.108-394
muscle tissue assesses both the quantity and size of the dys- Some patients exhibit preferential involvement of the quadri-
trophin present. Using carboxy-terminal antibodies demon- ceps muscle (quadriceps myopathy).992,1091 There is a wide spec-
strates 0-3% of the normal amount of dystrophin present, trum of clinical severity depending upon the degree to which
although the size is usually diminished.-445 With amino-terminal dystrophin is altered.855 Interestingly, intrafamilial variability in
Figure 27-4. Duchenne muscular dystrophy. (A) Muscle biopsy in a patient with Duchenne muscular dystrophy demonstrates variability in
fiber size, small regenerating fibers, increased endomysial and perimysial connective tissue, hypercontracted fibers, and scattered pale necrotic
fibers. Modified Gomori-trichrome. (B) Immunoperoxidase stains demonstated a lack of dystrophin staining on the sarcolemma of muscle fibers
(C), but normal staining for a-sarcoglycan (D) and merosin.
disease severity has been reported in a few pedigrees. 185 The with DMD. 74 BMD may be distinguished histologically from
majority of patients develop difficulty walking; however, they DMD with immune staining, which demonstrates the presence
remain ambulatory past the age of 15 years. The mean age of of dystrophin utilizing carboxy-terminal antibodies on muscle
losing the ability to ambulate independently is in the fourth membranes in most patients with BMD. In contrast, immunos-
decade. Exertional myalgias or cramps, particularly in the taining with antibodies directed against the carboxy-terminal of i
calves, occur in over 90% of patients and is the presenting dystrophin is usually negative in DMD. However, the degree ;
symptom in 28%.I85-292 The life expectancy is reduced, with an and intensity of the dystrophin staining is usually not normal in
age of death ranging from 23 to 89 years (mean 42 years).108139 BMD. The staining pattern may be uniformly reduced or can
With the advent of molecular genetics, some patients manifest- vary between and within fibers. Western blot analysis of muscle
ing with only myalgias,376-379 myoglobinuria, 254 cardiomyopa- tissue typically reveals an abnormal quantity and/or size of the
thy, 7081041 " 36 and asymptomatic hyper-CK-emia have been dystrophin protein.446
demonstrated to have mild forms of dystrophinopathy.
Cardiac abnormalities are similar to those described for Outliers
DMD. 230 As noted above, some patients manifest with a car- This is an older term referring to children who have a clinical
diomyopathy with little or no skeletal muscle weakness. Mental phenotype in between that of DMD and BMD.391 These children
abilities have not been investigated as thoroughly as in DMD, continue to ambulate after the age of 12 years but are confined
but some series have demonstrated a borderline or mildly im- to a wheelchair by the age of 15 years. They may be distin-
paired IQ in BMD patients.139185 guished from those with the more severe DMD clinical pheno-
Laboratory Features. Serum CK levels are elevated, often type in early childhood by the presence of antigravity neck
20-200 times normal. Patients with only exertional myalgias flexion strength. Children with DMD cannot lift their heads
may have only slightly elevated serum CK levels (3 times fully against gravity when lying supine (MRC grade less than
normal).376 3), whereas outliers and BMD children typically have this abil-
Histopathology. The histologic features are similar to those ity. Immunologic studies on muscle tissue usually reveal the
observed for DMD but are less severe. Split fibers and fibers presence of some dystrophin, although often reduced in amount
with central nuclei occur with greater frequency in BMD compared and/or size.445
mmmm w w p ^ ^ i
ft
Figure 27-5. (A-G) Immunofluorescent staining for components of the dystrophin-glycoprotein complex in a normal patient, (H-N) a child
with Duchenne muscular dystrophy, and (O-U) a patient with y-sarcoglycanopathy. (A, H, and O) These muscles were stained for dystrophin, (B,
I and P) P-dystroglycan, (C, J, and Q) a-sarcoglycan, (D, K, and R) p-sarcoglycan, (E, L, and S) y-sarcoglycan, (F, M, and T) 5-sarcoglycan.
(A-F) Note the characteristic diffuse sarcolemmal localization of dystrophin, the sarcoglycans, and p-dystroglycan in the normal patient and (G)
restriction of utrophin to the neuromuscular junction. (H-M) The patient with DMD demonstrates absent dystrophin staining and reduction of
the sarcoglycans and to a lesser extent p-dystroglycan, (N) while utrophin is abnormal expressed diffusely along the sarcolemma. (Q-T)The pa-
tient with y-sarcoglycanopathy not only demonstrates diminished y-sarcoglycan staining, but also reduced staining of all the sarcoglycans. (O and
P) Dystrophin and p-dystroglycan stains were normal, although they can occasionally be reduced in sarcoglycanopathies. (U) A slight increased ex-
pression of utrophin is seen along the sarcolemma. (From Ozawa E, Noguschi S, Mizuno Y, et al: From dystrophinopathy to sarcoglycanopathy:
Evolution of a concept of muscular dystrophy. Muscle Nerve 1998;21:421-438, with permission.)
Female Carriers integrity to the muscle membrane (Fig. 27-l).,82a-759 Lack of this
The daughters of males with BMD (males with DMD are usu- important substance results in the muscle losing its ability to
ally infertile) and the mothers of affected children who also have a maintain its integrity during contraction. 622 The membrane
family history of DMD or BMD are obligate carriers of the mu- tears, resulting in segmental necrosis and regeneration. Re-
tated dystrophin gene. Mothers and sisters of isolated DMD or generation is futile because of the lack of dystrophin, which
BMD patients are at risk for being carriers. It is always essential to again leads to a continuous breakdown, and repair until the lim-
determine the carrier status of "at-risk" females for genetic coun- ited number of regenerative cycles is exceeded.
seling (see below). There is a 50% chance that males born to car- The dystrophin gene is located on chromosome Xp21 and is
rier females will inherit the disease, while 50% of the daughters huge, composed of approximately 2.4 megabases of genomic
bom will become carriers themselves. Carrier females'are usually DNA, and includes 79 exons that code for a 14-kb tran-
asymptomatic, but rarely, dystrophinopathies clinically manifest script.444-53 K532 The large size of the gene accounts for the high
in females. Approximately 8% of DMD carriers have mild muscle mutation rate, which accounts for one third of new cases. Large
weakness.292-447 These cases are usually explained by the Lyon hy- deletions, several kilobases to over 1 million base pairs, can be
pothesis, in which there is a skewed inactivation of the normal demonstrated in approximately two thirds of dystrophinopathy
X-chromosome and dystrophin gene resulting in increased tran- patients. Approximately 5-10% of DMD cases are caused by
scription of the mutated dystrophin gene. Females with transloca- point mutation resulting in premature stop codons. 811
tions at the chromosomal Xp21 site or Turner's syndrome (XO Duplications are evident in another 5% of cases. Smaller muta-
genotype) may also develop dystrophinopathies.1078 tions, which are not readily detectable, account for the remain-
Usually, manifesting female carriers have a mild limb-girdle der. Mutations are not random in location but rather occur
phenotype similar to BMD. Prior to the recent advances in mol- primarily in the center (80%) and near the amino-terminal
ecular genetics, these females were often diagnosed with limb- (20%) of the gene.641-811 Mutations disrupting the translational
girdle muscular dystrophy, particularly when there was no reading frame of the gene result in near total loss of dystrophin
family history of DMD or BMD. Rarely, females can manifest and usually lead to DMD, while in-frame mutations result in the
severe weakness as seen in DMD. translation of semifunctional dystrophin of abnormal size
Laboratory and histologic features of manifesting carriers are and/or amount typically resulting in outlier or BMD clinical
similar to those discussed above for DMD and BMD. Im- phenotypes. 445 Although there are exceptions to the "reading-
munostaining for dystrophin demonstrates an absent, decreased, or frame rule," 92% of phenotypic differences are explained by
mosaic pattern of staining in carriers.30-79-176 447 However, immune in-frame and out-of-frame mutations. 641811 The location of mu-
staining can be normal.30-79-292-660 Thus, immunostaining and tations does not appear to correlate with clinical severity in
Western blot analysis are not very sensitive in identifying carrier DMD. Perhaps this is related to the near absence of any func-
status of asymptomatic females. tional dystrophin in DMD regardless of the site of the mutation.
Serum CK levels may be elevated in female carriers early in Some large series of BMD patients report worse clinical pheno-
life. However, a normal serum CK does not exclude a carrier type in patients with mutations in the amino-terminal region of
status. Elevated serum CK levels are identified in less than 50% of the gene (promoter through exon 9). 185 Some studies have
obligate carriers, and there is a false-positive rate of 2.5%.391'386a-387 shown that the amount of dystrophin does not necessarily corre-
The most reliable method of detecting carrier status is with late with disease severity in BMD. 185 It would appear that the
DNA analysis. First, affected male relatives should be evaluated quality or remaining functional capability of the mutated dys-
for mutations in the dystrophin gene. The detection of a mutation trophin protein is more important than the actual quantity. The
in such DMD patients makes carrier detection of at-risk female reduction in the various sarcoglycans, which is also evident on
relatives much easier and also allows for subsequent prenatal de- immunohistochemical studies of DMD and BMD, suggests that
tection in at-risk fetuses. If a mutation is demonstrated in an af- normal dystrophin is important for the integrity of the sarcogly-
fected male relative, at-risk females can be screened for the same can complex (Fig. 27-5).752-759
mutation. However, it should be noted that the carrier status of a
mother of a sporadic DMD case must be interpreted cautiously Electrophysiologic Findings in the Dystrophinopathies
because of the potential for germline mosaicism 48 In a germline The electrophysiologic findings of the dystrophinopathies are
mosaic, the mutation involves only a percentage of the germ discussed together because the findings are similar. There may
cells (i.e., oocytes) but is not present in the leukocytes in which be a tendency for the DMD patients to have more fibrillation
DNA analysis is performed. An affected child may have an iden- potentials and positive sharp waves and the BMD patients to
tifiable mutation on DNA analysis, while the mother could have have more long-duration polyphasic MUAPs; however, these
no demonstrable mutation in the leukocytes, but she might still differences cannot be quantified reliably for definitive diagnos-
be a carrier. The recurrence rate in germline carriers is unknown tic purposes. The role of electrodiagnostic testing in dys-
and dependent on the number of mutated oocytes but has been trophinopathies is shrinking, particularly in DMD, when there
estimated to be as high as 14%.48 Prenatal diagnosis can be made is a family history of the disorder. For example, an electromyo-
with DNA analysis of chorionic villi or amniotic fluid cells when gram adds little in the evaluation of a 5-year-old male child with
there is an identifiable mutation in the family. When mutations calf hypertrophy and markedly elevated serum CK levels. The
are not evident in affected DMD cases, carrier detection depends child needs a DNA analysis, and if that is unrewarding, a
on the less reliable linkage analysis of many family members muscle biopsy. Electrodiagnostic testing may be helpful in spo-
using restriction fragment length polymorphisms.420 radic cases and in BMD, in which CK levels can be only mildly
elevated and the differential diagnosis is much broader.
Molecular Genetics and Pathogenesis Nerve Conduction Studies. Both motor and sensory nerve
of the Dystrophinopathies conduction studies can be expected to be normal.855-912 The only
Dystrophin, as discussed before, is a structural protein that exception is a reduction in CMAP amplitudes in severely affected
is intimately bound to the sarcolemma and provides structural muscles. It is important to document normal nerve conduction
studies to ensure that some disorder other than a primary muscle A Normal 12 yts B Duchenne dystrophy 11 yrs
disease is not responsible for the patient's symptoms. The distal (case 6 )
motor latency of the peroneal nerve has been reported to be ab-
normal in a few patients with DMD.632 It is most likely that this
rare reported finding (we have not observed prolonged distal la-
tencies in dystrophinopathies) is an unrelated coincidental find-
ing or a result of uncontrolled temperature.
Needle Electromyography. The needle electromyographic
investigation demonstrates abnormalities consistent with an in-
trinsic muscle disease.132-800 Upon needle insertion, there is
characteristically a prolongation in the insertional activity in
which positive sharp waves and fibrillation potentials persist
following needle movement cessation. This finding is noted in « £ _ ^ —
the early stages of the disease process. As muscle tissue is pro-
gressively replaced with both adipose cells and connective
tissue, the amount of electrical activity noted following needle
movement declines. Additionally, the needle begins to "feel" as
if it is penetrating sand, i.e., a gritty sensation is noted during
needle insertion.
Documentation of positive sharp waves and fibrillation po-
tentials is relatively easy in most patients with DMD. 228 This is
especially true prior to the muscle tissue being replaced with fi-
brous and fatty tissues. In BMD, the degree of membrane insta-
bility is variable depending upon the degree of muscle
membrane defect and the hence the amount of muscle destruc-
tion and fragility. Positive sharp waves and fibrillation poten-
tials have a widespread distribution, although one may detect
particularly prominent degrees of these potentials proximally
compared with distally during the early phases of the disease.
Complex repetitive discharges can also be observed in both Figure 27-6. Multiple examples of the types of MUAPs capa-
DMD and BMD. ble of being recorded in patients with Duchenne muscular
An early recruitment pattern of MUAPs is evident at low force dystrophy. (A) Normal MUAPs recorded from a 12-year-old boy for
thresholds. The mean amplitudes of nonpolyphasic MUAPs are reference purposes. (B) Simple and complex MUAPs from an 11-year-
reduced compared with normals. Both short- and long-duration old boy with Duchenne muscular dystrophy. Potentials I, 2,5,and I I
MUAPs can be demonstrated in individual muscles, reflecting are both simple in morphology and short in duration. MUAPs 7 and 8
the chronicity of the myopathic process (Fig. 27-6).108-229-514-912 are polyphasic, while the remaining potentials are complex with late or
Of particular interest and source of controversy are the long- satellite components. (From Desmedt JE, Borenstein S: Regeneration
duration MUAPs consisting of late components or satellite po- in Duchenne muscular dystrophy: Electromyographic evidence. Arch
tentials. It was initially proposed that these satellite potentials Neurol 1976;33:642-650, with permission.)
are a result of long collateral sprouts or poorly myelinated col-
lateral sprouts reinnervating segmented muscle tissue.227-229
Careful morphologic and terminal innervation ratio studies in variation contributes to the MUAP's increase in duration and
DMD patients failed to substantiate any increase in the subter- phase characteristics.
minal axon ramification, and the terminal innervation ratios Prior to advances in molecular genetics, a number of investiga-
were normal.1-79 There was noted to be an increase in the disper- tors attempted to use quantitative needle electromyography to iden-
sion of the end-plate zone per motor unit suggesting longitudi- tify carriers of X-linked muscular dystrophies.66-273-364-365-677-826-1070
nal separation (segmental necrosis) and reinnervation of these Some disease carriers have abnormal MUAP morphology, but
muscle fibers after they have separated or pulled apart by sev- detailed analysis of these patients reveals that the sensitivity of
eral millimeters increasing from a normal distance of 1-10 mm. needle electromyography is insufficient to consistently detect a
This finding could result in longer duration polyphasic poten- high proportion of these patients. The muscle refractory period
tials but not account for satellite potentials with durations of 56 may be abnormal in female carriers as it is in patients with
ms from the MUAP's initial baseline deflection. The large vari- DMD.164 Normal persons demonstrate a refractory period of 3.9
ation in fiber size combined with possibly immature myelina- ± 0.2 ms, while female carriers and patients with muscular dys-
tion of subterminal collateral sprouts may be the responsible trophy have reduced refractory period times (2.7 ±0.15 ms).
factor in generating such long-duration satellite potentials. This method has not been studied systematically to assess its
Large-amplitude polyphasic potentials can be recorded in DMD clinical utility. The diagnostic procedures of choice for detecting
patients. These potentials most likely arise from an increased carriers remains DNA analysis as outlined above.
number of muscle fibers belonging to the same motor unit close Single-Fiber Electromyography. The two components
to the needle electrode's recording surface, or several hyper- measured with single-fiber electromyography are fiber density
trophic fibers in close proximity to the recording surface. and jitter. Both of these parameters are increased in patients
Muscle fiber hypertrophy is certainly observed histologically, as with dystrophinopathies. An increase in fiber density is postu-
is small fiber type grouping, thus permitting two different lated to occur from a number of possible mechanisms (Fig. 27¬
mechanisms to generate large MUAPs. The muscle fiber size 7) 44i.9i2.966 Muscle fiber splitting, ephaptic conduction,
27i.3io.3ii
THE DYSTROPHIC MOTOR UNIT sprouts and increases in terminal innervation ratios must mean
that these late components are slowly conducting newly formed
subterminal collaterals within the same motor unit territory. A
decrease in jitter (less than 5 ps) is also sometimes observed in
focal lesion dystrophy patients. The explanation for this finding can be
V / / / / / / > ^ / Z z „ „„.,~,o recording the potentials between partially split muscle fibers. A
w i n
partially split fiber lacks an interposed neuromuscular junction

between the two fiber segments, thus generating a very low
jitter. Also, ephaptic conduction between different muscle fibers
can result in low jitter values as a muscle fiber activates a neigh-
bor without the need for a neuromuscular junction.
Motor Unit Counting. A technique using an incremental pe-
ripheral nerve stimulation to identify discrete increases in the
CMAP and then dividing the supramaximal CMAP amplitude
by this number is believed to be proportional to the number of
motor units in the muscle, i.e., motor unit counting. Using this
technique, older studies suggested patients with DMD have a de-
crease in the number of motor units.632-633 This finding was inter-
preted to mean that there may be a disease process affecting not
only the muscle tissue, but also a subpopulation of affected ante-
rior horn cells. Histologic findings of the patients' spinal cords
failed to reveal any significant decreases in the anterior horn cell
population. Also, a number of investigators have failed to sub-
stantiate a reduction in the amount of motor units and have criti-
cized the motor unit counting technique as too insensitive and
subject to a number of technical errors.49-50 765 There is little sup-
port for the concept of anterior horn cell pathology in DMD.
Treatment of the Dystrophinopathies
Figure 27-7.Explanation for increased fiber densities in pri- Steroids. The Clinical Investigation in Duchenne Dystrophy
marily myogenic disorders. (A) Segmental necrosis may lead to a study group has demonstrated that prednisone (0.75 mg/kg/day) is
single muscle fiber being "segmented" into two or more independent effective in increasing strength and function (peaking at 3 months)
fibers each with a newly developed sprout, and as such these fibers are and the subsequent slowing of the rate of deterioration in children
electrically separate fibers. (B) A single muscle fiber may split longitudi- with DMD.325-38M70a The effects are noted as early as 10 days and
nally with each portion generating a separate single muscle fiber poten- are sustained for at least 3 years. Lower doses of prednisone (< 0.75
tial. (C) The process of partial degeneration may induce a satellite cell to mg/kg/day) are not as effective. These apparent benefits are accom-
develop into an independent muscle fiber with a nerve terminal from a panied by an increase in muscle mass and decline in the rate of
neighboring fiber. (D) Actual separation of the original terminal axon muscle catabolism.388 The mechanism is not believed to be related
may occur secondary to a number of processes (see text) with a collat- to the immunosuppressive action of prednisone on inflammatory
eral sprout from a different motor unit reinnervating this fiber. (E) Single infiltrates in the muscle but rather by altering muscle metabolism,
muscle fibers may be damaged by the myogenic disorder with the devel- particularly protein synthesis and/or breakdown. Dystrophin ex-
opment of susceptibility to being ephaptically activated by neighboring pression is enhanced in vitro in fusion-arrested BMD muscle cul-
muscle fibers becoming an electrical part of the neighboring motor unit tures,4'9 but this clearly is not the explanation for improved function
(From Stalberg E,Trontelj JV: Single Fiber Electromyography. Old Woking, in DMD patients. There have been no large, double-blinded,
Surrey, Mirvalle Press, 1979, with permission.) placebo-controlled studies assessing the efficacy of steroids in
BMD, although small series suggest a possible benefit.47
and remodeling of the motor unit through segmental necrosis Unfortunately, high-dose prednisone is associated with signifi-
and regeneration may all play some role in producing abnormal cant side effects including weight gain, stunted growth, cushin-
fiber density studies. Increased jitter arises from abnormalities goid appearance, excessive hair growth, irritability, and
in electrochemical transduction at the neuromuscular junction. hyperactivity.325-388-389-470,1 In addition, prednisone is also associated
This is thought to arise in muscular dystrophy patients through with an increased risk of infections, cataract formation, hyperten-
the process of newly formed and hence immature neuromuscu- sion, glucose intolerance, osteoporosis, and osteonecrosis. An ana-
lar junctions at the regenerated muscle fibers that must be rein- logue of prednisone, deflazacort (not as yet FDA approved), has
nervated following the initial event of fiber necrosis. Of been studied in a few clinical trials.24-96*-260 Preliminary results sug-
particular interest is the finding of large changes in fiber density gest deflazacort at doses of 0.9 mg/kg/day and 1.2 mg/kg/day may
over small increments of distance. This is consistent with the be as effective as prednisone 0.75 mg/kg/day and associated with
hypothesis that there are small groupings or clusters of muscle less side effects. A pilot study of oxandrolone, an anabolic steroid,
fibers from the same motor unit secondary to a remodeling given to 10 boys with DMD for 3 months reportedly led to im-
process such as fiber splitting or reinnervation of regenerated proved strength.326 The magnitude of improvement was similar to
fibers. An increase in jitter is particularly prominent in late or that noted with prednisone. A subsequent randomized, double-
satellite components. This finding strongly suggests that these blind, placebo-controlled trial of oxandrolone in 51 boys with
MUAP components arise not because of fiber size variation but DMD demonstrated no statistically significant improvement in
through collateral reinnervation. The lack of long collateral manual muscle testing after 6 months of treatment.3263 There was a
trend toward improvement in the treatment group and a deteriora- 10-20% of normals.65 Cell culture studies have suggested that the
tion in the placebo group. Quantitative muscle testing demon- level of aminoglycoside-induced stop codon readthrough is de-
strated a significant improvement in the treatment group. No pendent on the stop codon sequence, flanking nucleotides, and
adverse reactions to oxandrolone were noted. the specific aminoglycoside 461 A trial of gentamicin in patients
Modest improvement in strength has been reported in a small with DMD and stop codon mutations is currently on-going.
number of patients with DMD and BMD treated with short Supportive Therapy. The best management of patients with
courses of creatine monohydrate (5-10 gm/day).1006-1100 Creatine muscular dystrophies and most chronic neuromuscular disorders
supplementation may increase the muscle supply of phospho- utilizes a multidisciplinary approach to patient care.470a Ideally,
creatine and increase the ATP resynthesis. Further, creatine may neuromuscular clinics should involve neurologists, physiatrists,
have a cytoprotective effect.527 physical therapists, occupational therapists, speech therapists,
Gene Therapy. Two potential strategies for replacing the de- respiratory therapists, dietitians, psychologists, and genetic
fective dystrophin protein are somatic gene therapy via myoblast counselors in order to assess all the needs of individual patients.
or stem cell transplantation and direct gene replacement utilizing Physical therapy is a key component in the treatment of patients
modified viral vectors. In animal models, myoblast transfer was with muscular dystrophy. Contractures develop early in the dis-
demonstrated to be a promising method of delivering normal dys- ease, particularly at the heel cords, iliotibial bands, and at the
trophin. 504559 The technique involves injecting normal fusion hips; therefore, stretching exercises must also be started early in
competent myoblasts (donor: an asymptomatic brother or father) the disease. Long leg braces can be beneficial in prolonging am-
into the skeletal muscles of an affected boy. In theory, the donor bulation. Scoliosis is a universal complication of DMD and re-
myoblasts fuse with the host muscle fibers, and the normal donor sults in patient pain, aesthetic damage, and perhaps respiratory
dystrophin genes are transcribed, thereby replacing the defective compromise. We consider spinal fusion in children with 35-
protein. Uncontrolled studied of human myoblast transfer sug- degree scoliosis or more and who are in significant discom-
gested that muscle strength could be increased.462-560 However, fort.4703 Ideally, forced vital capacity (FVC) should be greater
similar improvement has not been demonstrated in control than 35% to minimize the risk of surgery. Quality of life seems
trials.400-506-642-657-1043 The reasons for the poor efficiency of my- to be improved following spinal stabilization; however, scoliosis
oblast transfer are not entirely clear. In part, the increased connec- surgery does not appear to increase respiratory function.4703
tive tissue may serve as a barrier to myoblast mobility and fusion.
Immune-mediated rejection may also play a role.462-463 Myoblast Duchenne Muscular Dystrophy, Glycerol Kinase
transfer in animals using tacrolimus (FK506) as the immunosup- Deficiency, and Adrenal Hypoplasia Congenita
pressive agent has been demonstrated to be more efficacious than DMD and glycerol kinase deficiency (GKD) may occur to-
with cyclosporine. 519 Nonetheless, prospects for the future suc- gether as part of a contiguous gene syndrome at chromosome
cess of myoblast transfer in DMD are not promising. Xp21 with or without adrenal hypoplasia congenita
Direct gene replacement therapy involves the introduction of (AHC). 14 - 21 3.397.630.905.921,1040 The gene order for the contiguous
artificially engineered dystrophin gene constructs into plasmid loci is: Xpter—AHC-GK-DMD—centromere. Microdeletions
or viral vectors.40-41-263-563-829-1109 Intramuscular injection of plas- can span these contiguous genes, producing a clinical pheno-
mids carrying the entire dystrophin cDNA (14 kD) or minigenes type that is different than seen in patients who have mutations
(6.3 kD) into muscles of mdx mice generated dystrophin-posi- only within the individual DMD, GK, or AHC genes. Most chil-
tive fibers that are protected from dystrophic damage. Efficacy dren with combined DMD and GKD exhibit severe psychomo-
is increased with injections of minigene constructs utilizing the tor delay. In addition to early muscular weakness, affected
replication-defective adenovirus vector. However, a cell-medi- children often experience episodic nausea, vomiting, and stupor
ated immune response occurs against these adenovirus-trans- as a result of GKD, which are not features of isolated DMD.
fected muscle fibers, limiting viability of these muscle cells. Further, mutations involving the DAX1 gene responsible for
Better methods of immunosuppression and delivery of the dys- AHC can result in life-threatening adrenal insufficiency mani-
trophin gene via plasmid or viral constructs need to be devel- fested by addisonian hyperpigmentation of the skin, hypogo-
oped. A double-blind, placebo-controlled trial of gene therapy nadotropic hypogonadism/crypto-orchidism, hyperkalemia,
utilizing a adenovirus vector is currently underway. Gene ther- hyponatremia, and hypoglycemia.
apy is clearly in its infancy, but the future is promising.571 Glycerol kinase is responsible for the first step in glycerol
Because the molecular structures of utrophin and dystrophin are metabolism:
so similar, another novel therapeutic approach would be to increase glycerol + ATP <-> glycerol 3-phosphate + ADP
utrophin gene expression. In fact, utrophin expression is increased
in muscle tissue in patients with dystrophinopathies, perhaps as a The enzyme is important in glycolysis, gluconeogenesis, and
way to compensate for the loss of dystrophin. Recently, mdx mice triglyceride metabolism. GKD results in glyceroluria and hy-
(a mouse model for DMD in which dystrophin is deficient) were perglycerolemia. GKD should be considered if extremely ele-
transgenically altered to express a truncated utrophin molecule at vated serum triglyceride levels are detected in a young child. In
high levels.1027 The histology of the mdx mouse muscle tissue im- actuality, this represents "pseudohypertriglyceridemia" because
proved, suggesting pharmacologic utrophin up-regulation may be the serum triglyceride test measures free glycerol.905 The neuro-
potential treatment of DMD and BMD in the future. logic side affects of GKD are responsive to a fat-restricted diet
As noted above, approximately 5-10% of DMD cases are and avoiding prolonged fasting.
caused by point mutation resulting in premature stop codons (i.e., AHC is caused by mutations in the DAX1 gene, which stands
UGA, UAG, UAA).811 Aminoglycosides have the ability to cause for "dosage-sensitive sex reversal, AHC, X-chromosome, gene
translation^ read of stop codons, which may have therapeutic im- 1 ."399,905 p ro tein encoded by the DAX1 is part of the nuclear
plications in this small subset of DMD patients. In the mdx hormone receptor superfamily. The protein is involved in tran-
mouse, gentamicin partially reversed the effects of the stop codon scriptional regulation of genes involved in the normal develop-
mutation, allowing translation and integration of dystrophin to ment of the adrenal glands. Further, decreased serum levels of
gonadotropins and a subnormal increase in serum Cortisol in re- Sarcoglycanopathies (LGMD 2C, LGMD 2D,
sponse to exogenous administration of adrenocorticotropic hor- LGMD 2E, LGMD 2F)
mone may be demonstrated. Treatment of adrenal insufficiency Approximately 40% of muscular dystrophies have normal
is replacement of glucocorticoids, mineralocorticoids, and dystrophin.262 Of these, 10% may be due to mutations in one of
testosterone. the sarcoglycans (a-sarcoglycan 6.6%, (3-sarcoglycan 3.1%, y-
Most, if not all, mutations involving the 31 (carboxy-termi- sarcoglycan 1.5%, 6-sarcoglycan < 1%).26 261262 The frequency
nal) portion of the dystrophin gene span into the GK of sarcoglycan mutations in muscular dystrophy may be as high
locus. 10401124 Thus, DMD patients who have such mutations as 20%, in proximal dystrophies (SCARMD/LGMD) with
should be evaluated for the contiguous gene syndrome. Most normal dystrophin. The clinical, laboratory, and histologic fea-
patients have a DMD phenotype, but a Becker muscular dys- tures of the sarcoglycanopathies are quite similar to those of the
trophy phenotype can also occur.213'397'1040 Diagnosis of X- dystrophinopathies. Onset of weakness can be early and in-
chromosomal microdeletions has traditionally relied upon volvement severe as in DMD (these cases were previously re-
Southern blotting and DNA amplification through PCR. ferred to as severe childhood autosomal recessive muscular
Fluorescent in situ hybridization (FISH) analysis provides a dystrophy), or late onset and slow progression similar to BMD.
rapid and accurate evaluation for these microdeletions and can Proximal leg and arm muscles are affected early, and calf
also be used for carrier detection and prenatal diagnosis. 3991124 pseudohypertrophy can often be appreciated as noted above. In
Treatment of GKD includes a fat-restricted diet and avoidance addition, serum CK levels are markedly elevated. In contrast to
of fasting. Importantly, children with the contiguous gene syn- the dystrophinopathies, there is no significant intellectual im-
drome should be evaluated for evidence of concurrent adrenal pairment or significant cardiac abnormalities in the sarcogly-
insufficiency, as this condition can be life-threatening if not canopathies. Muscle biopsies demonstrate normal dystrophin;
treated. however, each of the sarcoglycans are absent or diminished on
the sarcolemma, regardless of the primary sarcoglycan mutation
LIMB-GIRDLE MUSCULAR DYSTROPHY (see Molecular Genetics and Pathogenesis).
A deficiency of a-sarcoglycan (previously known as adhalin—
The limb-girdle muscular dystrophies (LGMD) are a heteroge- Arabic for "muscle") was initially reported in North Africa where
neous group that clinically resemble the dystrophinopathies except LGMD 2C/SCARMD type 1 is prevalent, but subsequently was
for the equal occurrence in males and females (Table 27-2). The demonstrated in SCARMD and LGMD patients throughout the
reported incidence and prevalence of LGMD are approximately world T n e a-sarcoglycan (adhalin) gene
46.76.262.306.6i9.735.929.ii4o
6.5 per 100,000 live births and 2 per 100,000 population, respec- mapped to chromosome 17q21; however, several North African
tively.692 These disorders are inherited in an autosomal recessive families linked to chromosome 13ql2 (LGMD 2C). Thus, it was
or, less commonly, autosomal dominant fashion.1411421823'370'486'940 apparent that the deficiency of a-sarcoglycan in the chromosome
In the past, diseases with a phenotype similar to DMD have been 13q-linked SCARMD families had to be secondary to some other
called "severe childhood autosomal recessive muscular dystro- primary defect. Subsequently, it has been demonstrated that a pri-
phies" (SCARMD), whereas diseases .with milder phenotypes mary deficiency/mutation involving any of the sarcoglycan pro-
similar to BMD have been labeled with the term "limb-girdle teins result in a secondary deficiency in the other sarcoglycans.
muscular dystrophy" (LGMD). Specific SCARMD/LGMD disorders have now been linked to
In most of the affected patients, progressive muscle weakness mutations in (3-, y-, and 5-sarcoglycans as well as a-sarcoglycan.
begins in the pelvic girdle musculature (i.e., the hip flexors, ex-
tensors, and abductors). The quadriceps and hamstring muscles LGMD 2C
are affected later. The proximal leg weakness gives rise to a Clinical Features. The age of onset usually ranges from 3 to
characteristic waddling type of gait during ambulation associ- 12 years.26142-2621002 The severity and progression of the disease
ated with prominent lumbar lordosis and hyperextension of the can be variable between and within families. Approximately
knee. Many patients eventually become wheelchair-dependent. 20-25% of patients have severe weakness and are confined to a
The proximal upper limb muscles (i.e., deltoid, serratus ante- wheelchair by 10-15 years, while 55% are wheelchair-bound
rior, supra/infraspinati, biceps brachii, triceps, and sternal head by 20 years. The glutei, iliopsoas, thigh adductors, pectoralis,
of the pectoralis major muscles) are also particularly affected and trapezius muscles are affected the earliest. Pseudo-
early in the course. Winging of the scapula can lead to diagnos- hypertrophy of the calves is present in most patients. Scoliosis
tic confusion with facioscapulohumeral and scapuloperoneal is also common.
muscular dystrophies. Laboratory Features. Serum CK levels are elevated
Recent advances in molecular genetics have demonstrated 50-200 times normal in early stages of the disease.
that there are several distinct forms of LGMD/SCARMD and Molecular Genetics. LGMD 2C is caused by mutations in
that the mild and severe phenotypes can be allelic (Table 27- the y-sarcoglycan gene located on chromosome 13q 12.46/76
2 ) j 4 o . i 4 i . i 4 2 . i 8 2 a , 2 5 9 j i 2 5 Autosomal dominant LGMDs are classified
as type 1 (e.g., LGMD 1), while recessive forms are termed type LGMD 2D
2 (e.g., LGMD 2). Further alphabetical subclassification has Clinical Features. The age of onset typically ranges from 2
been applied to these disorders as they have become genotypi- to 15 years, and progression is variable, with some patients con-
cally distinct (e.g., LGMD 2A, LGMD 2B, etc.; Table 27-2). fined to wheelchairs by the age of 10 years while others remain
For the most part, the histopathologic and electrodiagnostic fea- ambulatory past 30 years of age. -'86.262.298,509.598.601.776.798,85s
142
tures of the LGMDs are non-specific and are discussed at the Some variability in clinical severity has also been noted within
end of this section on the various genetically distinct LGMDs. families. The pelvic and shoulder girdle muscles are affected
Our discussion will begin with the autosomal recessive first. Calf pseudohypertrophy is common.
LGMDs, which are the result of mutations in one of the sarco- Laboratory Features. Serum CK levels are elevated
glycan genes, the so-called sarcoglycanopathies. 20-100 times normal.
Molecular Genetics. LGMD 2D is caused by mutations in of onset is 13.5 years with a range of 2—45 years. Pelvic girdle
the a-sarcoglycan (adhalin) gene located on chromosome muscles (gluteus maximus, thigh adductors, and to a lesser
17q21 .262,509.598,776.798.858 A1 j t h e sarcoglycans are reduced on im- degree the gluteus medius, psoas, and hamstrings) are clinically
munohistochemistry. 149 759 The clinical phenotypes appear to affected first. Distal lower limb muscles are normal in strength,
correlate with the expression of a-sarcoglycan.26-148-261-798 Pa- but contractures at the calves are typically present. Periscapular
tients who are homozygous for null mutations and therefore ex- weakness and atrophy predominantly affecting the latissimus
pressing no a-sarcoglycan have severe phenotypes. Patients dorsi, serratus anterior, rhomboids, and the pectoralis major
with missense mutations have varying levels of a-sarcoglycan become involved 2-5 years later. The deltoid, biceps brachii,
expression and are less severely affected. and brachioradialis are less affected, while the supra- and infra-
spinati, triceps, brachialis, and forearm muscles are relatively
LGMD 2E spared. Only mild weakness of neck muscles can be detected.
Clinical Features. The age of onset and progression are Facial muscles are usually unaffected. Ocular and velopharyn-
variable even within families.26-71"-578 The pelvic and shoulder geal muscles are never involved. Tendon reflexes are absent or
girdle muscles are affected first. Calf pseudohypertrophy can be diminished. There is often slight scoliosis. Abdominal muscles
seen. are more affected than spinal muscles. Progression is steady but
Laboratory Features. Serum CK levels are markedly elevated. variable between different affected kinships. However, there ap-
Molecular Genetics. LGMD 2E has been linked to muta- pears to be little variability within families. For the most part,
tions in the (3-sarcoglycan gene located on chromosome the earlier onset of symptoms and signs correlates with a faster
4ql2.71-99-142-578 Homozygous missense mutations in this (3-sarco- evolution of the disease process. Approximately 50% of patients
glycan gene have been reported in several Amish families from are non-ambulatory by the age of 20 years, but some are able to
southern Indiana.578 Truncating mutations in the gene can lead walk late in life. Respiratory function is only moderately af-
to a severe DMD-like or SCARMD phenotype. All the sarco- fected. Similar to the sarcoglycanopathies, cardiac function is
glycans are reduced on muscle biopsy.759 normal and there is no intellectual impairment. However, calf
hypertrophy is rare.
LGMD 2F Laboratory Features. Serum CK levels are usually increased
Clinical Features. This is the most recent genetically con- up to 20 times normal early in the disease but decrease close to
firmed sarcoglycanopathy. Age of onset and progression can be the normal range later when patients are wheelchair-bound.
variable even within families.731 The pelvic and shoulder girdle Molecular Genetics and Pathogenesis. LGMD 2A is
muscles are initially affected. Calf pseudohypertrophy may be caused by mutations in calpain-3 that maps to chromosome
evident. 15ql5.71-841 963 Large molecular and biochemical studies suggest
Laboratory Features. Serum CK levels are markedly elevated. that calpainopathies account for approximately 20-26% of dys-
Molecular Genetics. LGMD 2F was linked to mutations in trophies with normal dystrophin and sarcoglycans. 27301 a-1066
the 8-sarcoglycan gene located on chromosome 5q33. 731 As Approximately 69% of patients with calpainopathy manifest
with the other sarcoglycanopathies, reduction in 8-sarcoglycan with a BMD-like phenotype, 11% present early similar to
is accompanied by loss of the other sarcoglycans. DMD, 3% have a distal myopathy and 6% have asymptomatic
hyper-CK-emia.27-301a
Congenital Fibrosis of the Extraocular Muscles The mutations lead to an absence or reduction of calpain-3,
Mutations in the sarcospan gene located on chromosome which is a muscle-specific, calcium-dependent, non-lysosomal,
12pl 1.2 are associated with congenital fibrosis of the extraocular proteolytic enzyme present in muscle. The pathophysiologic
muscles, a rare form of muscular dystrophy.194 mechanism of how mutations involving this enzyme result in a
dystrophic process is unknown. Calpain-3 exists in both the cy-
Pathogenesis of the Sarcoglycanopathies tosol and nuclei of skeletal muscle fibers (Fig. 27-1) where it
The proteins of the sarcoglycan complex appear to function may be directly involved in or participate in the activation of an-
as a unit (Fig. 27-1).141142148-261-262-759 Mutations involving any of other enzyme involved in muscle metabolism.841 Dysfunction of
the sarcoglycans results in destabilization of the entire complex the enzyme could theoretically lead to the accumulation of toxic
and reduced expression of the other proteins (Fig. 27-5). The substances in muscle cells. Alternatively, calpain-3 may play a
role of the sarcoglycan complex within the larger DGC is not role in gene expression by regulating turnover or activity of tran-
known, but it is just as important as dystrophin. Dystrophin is scription factors or their inhibitors.841 Importantly, prenatal diag-
usually present at normal physiologic levels in the sarcogly- nosis of LGMD 2A is possible through DNA analysis of fetal
canopathies, but a slight reduction, in addition to a mild in- cells obtained by amniocentesis or chorionic villus sampling.
crease in utrophin, is sometimes observed.759 As apparent with
the dystrophinopathies, the clinical severity of the sarcogly- LGMD 28
canopathies may correlate with the type of mutation (i.e., Clinical Features. The reported age of onset of LGMD 2B
whether the reading frame is preserved) and subsequent level of ranges from 13 to 35 years (mean 21 years).67-473>601 Progression
functional protein expression.26.i4i.i42.i48.26u 125 is usually slow, with the earliest loss of ambulation occurring in
Other Autosomal Recessive Limb-Girdle patients by their mid-20s, while many remain ambulatory until
Muscular Dystrophies (Table 27-2) late in life. The pelvic girdle is usually affected first (glutei,
hamstrings, and quadriceps), with involvement of the shoulder
LGMD 2A girdle 2-10 years later. Mild scapular winging may be evident
Clinical Features. Fardeau and colleagues outlined the at any stage of the disease. Calf hypertrophy is rare. Some pa-
major features of this dystrophy in affected families on Reunion tients have early involvement of the gastrocnemius and soleus
Island in the Indian Ocean.3073 Subsequently, this dystrophy has muscles with contractures at the ankles. This is particularly in-
been reported throughout the world.142 510-790-802a-963 The mean age teresting, given the recent co-localization of LGMD 2B and
Miyoshi myopathy to the same gene on chromosome 2pl3. may also to overlap with myosin. The interaction of telethonin
Miyoshi myopathy, as discussed in the section on distal my- with titin appears to be important in myofibrillogenesis.626-700
opathies, has an early predilection for the posterior compart-
ment of the distal lower limbs. Still other patients have early, LGMD 2H
prominent involvement of the anterior tibial muscles. Of note, Clinical Features. This genetically distinct LGMD has been
there is intra- and interfamilial variability in disease progression described in 15 individuals from four related families of
and pattern of muscle involvement. Manitoba Hutterite origin. Age of onset of weakness ranges
Laboratory Features. Serum CK levels are markedly ele- from 8 to 27 years." 07 The majority of affected individuals are
vated (usually 35-200 times normal) in early stages of the dis- still walking without assistance in the fourth decade of life; one
ease similar to Miyoshi myopathy. patient was in a wheelchair at the age of 61 years.
Molecular Genetics and Pathogenesis. LGMD 2B localizes Laboratory Features. Serum CKs range from 250 to 3130
to chromosome 2pl3. As noted above, Miyoshi-type distal my- IU/L. Electromyography was reported as "myopathic."
opathy was also found to localize to the same area, which raised Histopathology. Muscle biopsies demonstrate typical dys-
the possibility that these two phenotypically different disorders trophic features. Dystrophin and sarcoglycan staining is normal.
might be caused by allelic mutations in the same gene. Mutations Molecular Genetics and Pathogenesis. The disorder is
within the dysferlin gene have been identified in patients with linked to chromosome 9q31-q33, but the gene has yet to be
Miyoshi myopathy, LGMD 2B, and distal myopathy with ante- identified. Although the gene maps close to that of Fukutin
rior tibial weakness linked to chromosome 2pl3, thus proving (Fukuyama type CMD), it appears to be genetically distinct.
that these phenotypically different disorders are indeed al-
lelic.68-588 In a study of 407 muscle biopsies from patients with un- LGMD 21
classified myopathies (normal dystrophin and sarcoglycan), 6.5% Clinical Features. A large consanguineous Tunisian family
had abnormal dysferlin by Western blot and immunostaining.30'3 with 13 affected members was recently described. The age of
This accounted for 1 % of patients with an unknown limb-girdle onset ranged from 1.5 to 27 years (mean 11.6 years), and the
syndrome and 60% of patients with a distal myopathy. In the pa- course was likewise variable.257 Affected individuals had proxi-
tients with proven dysferlinopathy, 80% manifested with distal mal weakness, worse in the pelvic muscles. Some, but not all, pa-
weakness, 8% had a LGMD phenotype, and 6% presented with tients became wheelchair-dependent in their 30s. Overall, the
asymptomatic hyper-CK-emia. severity was believed to be milder than most sarcoglycanopathies.
Dysferlin shares amino acid sequence homology with C. ele- Laboratory Features. Serum CK levels were increased up to
gans spermatogenesis factor FER-1; thus, the origin of its name. 5696 IU/1 but was normal in some of the older affected patients.
Dysferlin is localized to the sarcolemma (Fig. 27-1) and is Histopathology. Non-specific dystrophic features were evi-
absent on immunohistochemistry in patients with LGMD dent on muscle biopsy. Dystrophin, dystroglycan, sarcoglycan,
2B/Miyoshi myopathy. Dysferlin does not appear to have a sig- and sarcospan staining was normal.257
nificant interaction with the dystrophin-glycoprotein complex, Molecular Genetics and Pathogenesis. The muscular dys-
and immunostaining for dystrophin, dystroglycans, merosin, trophy in this kinship linked to chromosome 19q 13.3, but the
and the sarcoglycans are normal. Mutations in dysferlin result gene has yet to be identified.257
in disruption in the sarcolemmal membrane and basement mem- Autosomal Dominant Limb-Girdle Muscular
brane. Subsarcolemmal vesicles and non-rimmed vacuoles may
be appreciated.7983-9203 Dystrophies (Table 27-2)
LGMD IA
LGMD 2G Clinical Features. Gilchrist and colleagues described a
Clinical Features. This rare disorder was initially reported large kindred (144 patients over seven generations) with an au-
in an Italian family that failed to link to other known genetic tosomal dominant inherited LGMD. 370 Sixty-one patients were
loci of LGMD. 684 The presumed inheritance was autosomal re- available for examination. Age of onset ranged from 18 to 35
cessive, as the parents were not affected, but six of eight chil- years (mean 24.8 years). Proximal greater than distal weakness
dren had the myopathy. The mean age of onset of muscle affecting the legs more than the arms was apparent. Distal leg
weakness was 12.5 years. The presenting symptoms included and occasionally arm weakness was also evident in a few pa-
difficulty walking, running, and climbing stairs. However, they tients. Rarely, dysarthria secondary to palatal muscle involve-
also had significant distal weakness, legs worse than arms. All ment and mild facial weakness was observed. Tight heal cords
had significant ankle dorsiflexion weakness at the time of pre- and reduced ankle deep tendon reflexes were noted in some pa-
sentation. Of note, the quadriceps muscles were quite weak, tients. Smaller kinships with a similar pattern of weakness and
unlike autosomal recessive hereditary inclusion body myopathy associated clinical features with onset in the late teens to sixth
(h-IBM), which can have a similar phenotype. decade of life have been reported by others.173 608
Laboratory Features. Serum CKs are elevated 3-17 fold. Laboratory Features. Serum CK levels are normal or ele-
Electrodiagnostic studies are not well described. vated up to 9 times normal. Muscle biopsies are notable for the
Histopathology. Besides the usual dystrophic features, frequent occurrence of rimmed vacuoles.173-370
many muscle fibers had one or more rimmed vacuoles. Dys- Molecular Genetics and Pathogenesis. LGMD 1A is caused
trophin and sarcoglycan staining were normal. by mutations in the gene that encodes for myotilin located on chro-
Molecular Genetics and Pathogenesis. LGMD 2G has been mosome 5q22.3-31.3.428a-889%1 Myotilin is a sarcomeric protein that
linked to mutations in the telethonin gene on chromosome co-localizes with a-actinin at the Z-disk.889 Some of the clinical,
17q 1 1-12.684-685 Telethonin is a 19-kD sarcomeric protein present laboratory, and histologic features are similar to those described in
in skeletal and cardiac muscles. It is among the most abundant autosomal dominant hereditary inclusion body myopathy (h-IBM)
proteins in muscle. By immunofluorescent staining, the protein and myofibrillar myopathy (see below). Whether or not these are
localizes along with titin to the Z-disk of human myotubes.700 It synonymous disorders awaits further genetic localization.
LGMD IB with Cardiopathy one type of LGMD from another or even from one of the other
Clinical Features. The non-chromosome 5q-linked autoso- forms of muscular dystrophy. A whole host of nonspecific findings
mal dominant LGMD represents a heterogeneous group of dis- such as prominent muscle fiber size variation, fiber atrophy, hyper-
orders. One subgroup is associated with severe cardiac trophy, and splitting can be prominent in some patients. Muscle
conduction defects leading to sudden death and often requiring fiber degeneration, phagocytosis, and regeneration vary from pa-
pacemaker insertion.301-10721073 Affected members of these kin- tient to patient An occasional mononuclear inflammatory infiltrate
ships have onset of proximal weakness in childhood or early is seen in some patients. An increase in connective tissue is also a
adult life. Small patients have early contractures and predilec- common finding, particularly as the disease progresses. In the latter
tion for the humeral-peroneal muscle weakness. In this regard, stages of the disease, all of the above-noted pathologic findings
the myopathy has also been termed autosomal dominant become more pronounced. Muscle fibers with rimmed vacuoles
Emery-Dreifuss muscular dystrophy (AD-EDMD) until the have been noted in LGMD 1A and 1B and other LGMD syn-
two disorders were found to be allelic.97-981073 dromes. 173.301,370.684 Rimmed vacuoles are a non-specific myopathic
Laboratory Features. Serum CK levels can be normal or feature but are characteristically present in inclusion body myositis,
elevated up to 25 times normal. h-IBM, oculopharyngeal dystrophy, several of the distal my-
Histopathology. Muscle biopsies demonstrate variation in opathies, and myofibrillar myopathy. However, there have not been
fiber size, increased endomysial connective tissue, normal dys- detailed studies of electron microscopic or immunocytochemistry
trophin, sarcoglycan, and emerin staining. Occasionally, rimmed findings to determine the relationship, if any, of the LGMDs with
vacuoles are evident on muscle biopsy similar to that seen in rimmed vacuoles to h-IBM and myofibrillar myopathy (these dis-
other autosomal dominant LGMDs.301 However, van der Kooi et orders are discussed in detail later). Dystrophin is usually normal,
al demonstrated rimmed vacuoles in only one out of eight pa- although a mild reduction may occasionally be seen in the sarco-
tients who were biopsied and thought this was a non-specific glycanopathies (see above).759-778 The sarcoglycan proteins are
finding.1072 Importantly, it is expressed on nuclear membranes, absent or diminished in the sarcoglycanopathies, which may distin-
but lamin A/C expression may be reduced in AD-EDMD. guish them from other forms of dystrophy (Fig. 27-5).
However, immunostaining with lamin A/C antibodies is some-
times normal.647 On electron microscopy, there are alterations in Electrophysiologic Findings in LGMD
approximately 10% of myonuclei. 88 ' 3 The major abnormalities Because the molecular advances are so recent, most of the pub-
are the loss of peripheral heterochromatin, altered interchro- lished literature regarding the electrophysiologic abnormalities of
matin texture, and fewer nuclear pores than normal. the different LGMDs have been "lumped" together. Nevertheless,
Pathogenesis. LGMD 1B with cardiopathy has been linked it is apparent that the electrophysiologic features of the different
to mutations in lamin A/C on chromosome lqll-21. 1 0 7 3 types of LGMD, including SCARMD, resemble one another and
Therefore, LGMD 2B is the same disorder as so-called autoso- those of the dystrophinopathies.261-262 The electrophysiologic find-
mal dominant EDMD, which independently linked to mutations ings can be anticipated given the above-noted histologic alter-
in lamin A/C.97 ations. Motor and sensory nerve conduction studies are normal.767
Needle electromyographic examination demonstrates an increase
LGMD IC in insertional activity in some but not all patients.939 With disease
Clinical Features. This is a rare autosomal dominant progression, increase in physical resistance to needle insertion
LGMD recently described and genetically localized in two fam- may be appreciated as a result of the connective tissue prolifera-
ilies.662 The affected patients met early motor milestones, but tion. Positive sharp waves and fibrillation potentials may be absent
noticeable weakness occurred around 5 years of age. Weakness in some patients and prominent in others. A characteristic pattern
primarily affected the proximal muscles, while some patients of short-duration, small-amplitude MUAPs with an increase in the
also complained of exercise induced myalgias. Calf hypertro- number of polyphasic potentials is also observed.180-370-437 Use of a
phy was usually evident. The rate of progression was variable. trigger and delay line can reveal satellite potentials and large-am-
Two sporadic cases of LGMD IC have also been reported. 155 plitude, long-duration MUAPs, giving the false impression of a
These children (ages 4 and 6 years) had asymptomatic mild so-called neurogenic disorder.952 As with most muscular dystro-
hyper-CK-emia without objective weakness on examination at phies, a mixed pattern of small- and large- amplitude potentials
the time of their evaluations. can be observed and should not serve as the basis of designating a
Laboratory Features. Serum CK is elevated 3-25 fold. disease as neuropathic or myopathic. The recruitment pattern is
Histopathology. Muscle biopsies demonstrated non-specific typically full at minimal effort but can be considerably reduced in
myopathic features with normal dystrophin, sarcoglycan, and the latter stages of the disease when profound muscle atrophy is
merosin staining. In contrast, there is reduced caveolin-3 stain- present. Both fiber density and jitter can be elevated.441-966 Macro
ing along the sarcolemma.155-661 EMG and scanning EMG reveal a decrease in the MUAP ampli-
Pathogenesis. LGMD 1C links to mutations in the caveolin- tude and an increase in the number of silent areas, suggesting a net
3 gene located on chromosome 3p25.155-661 Caveolins are loss of muscle fibers from the motor units.
thought to play a role in the formation of caveola membranes,
where they act as scaffolding proteins to organize and concen- Treatment
trate caveolin-interacting lipids and proteins. 661 Caveolin-3 is Treatment is largely supportive. Physical and occupational
localized by immunostaining to the sarcolemma (Fig. 27-1). It therapy is important to prevent contractures and improve func-
co-fractionates with the dystrophin-glycoprotein complex, but tion. Whether or not corticosteroids can improve strength and
is thought to be part of a discrete complex. delay progression similar to that observed in DMD is not
known, although some patients with LGMD reported benefit
Histopathology of the LGMD from such treatment. 186 Modest improvement in strength has
Unfortunately, there are no specific muscle biopsy findings been reported in a small number of patients with LGMD treated
suggestive of LGMD or histologic abnormalities that distinguish with short courses of creatine monohydrate (5-10 gm/day). 1100
Figure 27-8. (A), Congenital muscular dystrophy.T2-weighted MRI of brain of an infant with merosin-negative congenital muscular dystro-
phy reveals increased signal of the subcortical white matter consistent with hypomyelination. (B), Muscle biopsy demonstrates fiber size variability
and increased endomysial and perimysial connective tissue consistent with a dystrophic process, modified Gomori trichrome.
Advances in molecular genetics may lead to better forms of well. Affected children are considered to have normal intelli-
treatment in the future. Currently, gene therapy trials are being gence, despite abnormal white matter changes apparent on MRI
conducted in some forms of LGMD. in merosin-negative patients (see below).187 However, there is a
high incidence of epilepsy (12-20%) as well as a few reported
CONGENITAL MUSCULAR DYSTROPHY cases of occipital dysplasia in merosin-deficient CMD. 182 7,1786
Merosin-negative CMD is associated with more severe weak-
The congenital muscular dystrophies (CMDs) are a heteroge- ness and poorer prognosis than merosin-positive CMD.797-931
neous group of autosomal recessive inherited disorders charac- Calf hypertrophy may be appreciated in merosin-deficient chil-
terized by perinatal onset of hypotonia with proximal weakness; dren. Affected children typically never ambulate independently,
joint contractures affecting the elbows, hips, knees, and ankles although they may be able to stand and occasionally walk with
(arthrogryposis); dystrophic appearing muscle biopsies; and ex- assistance. In contrast, although motor milestones are delayed,
clusion of other recognizable causes of myopathy of the new- most children who are merosin-positive are eventually able to
born (Table 27-2).52-324-573 The CMDs are classified according to walk independently.797-931 As noted above, recent cases with par-
clinical, ophthalmologic, radiologic, and pathologic features. tial merosin deficiency have been identified.182-439-679-683-711-721-9311003
The major categories of CMDs are (1) the classic or Occiden- These patients have a more milder course and can present in
tal/Western type; (2) Fukuyama-type characterized by defects childhood with a DMD phenotype or in early adulthood similar
in neuronal migration (i.e., polymicrogyria) with severe mental to BMD or LGMD. Some patients with merosin-negative CMD
retardation, seizures, and a progressively deteriorating course; develop a cardiomyopathy.710
(3) Walker-Warburg or the cerebral-ocular dysplasia syndrome; Laboratory Features. Serum CK levels are elevated, usu-
and (4) the Santivouri-type or muscle-eye-brain disease. ally over 2000 IU/L in the merosin-negative infants. In contrast,
most infants with merosin-positive CMD have normal or mildly
Classic or Occidental Type elevated serum CKs, typically less than 1000 IU/L. Inter-
The absence of clinical CNS abnormalities and ophthalmo- estingly, MRIs demonstrate diffuse white matter abnormalities
logic disorders distinguishes the classic type of CMD from the suggestive of dysmyelination in most infants with merosin-neg-
other forms of CMD. The classic type of CMD is divided into ative CMD (Fig. 27-8A). MRI in merosin-positive patients is
the merosin-negative and merosin-positive subgroups. typically normal. Patients with partial merosin deficiency may
Remember, merosin or a-2 laminin is connected to the dys- or may not have cerebral hypomyelination on MRI.
trophin-glycoprotein complex (Fig. 27-1). At least 40-50% of Molecular Genetics and Pathogenesis. As noted above,
patients with CMD have absent or decreased merosin.797-930 recent studies have demonstrated that the classic type CMD
Recently, it has been appreciated that there are patients with with cerebral hypomyelination is associated with a merosin de-
partial merosin deficiency, analogous to the dystrophinopathies ficiency.797-93010-36 Merosin-negative CMD families were local-
and sarcoglycanopathies. 1 n.721.931.1003 ized to chromosome 6q21-22, where the a-2 subchain of
Clinical Features. Infants with classic CMD are character- merosin was also mapped.440 1088 Shortly thereafter, mutations in
istically hypotonic and weak at birth. Weakness is generalized the a-2 subchain of merosin were identified.786-930 The gene
with a predilection for proximal shoulder and hip-girdle mus- codes for a 390-kD protein that is synthesized as one chain but
cles. Neck flexors and extensors as well as facial musculature processed into two fragments. On immunoblot, these two frag-
are affected. Sensation appears normal, although motor and sen- ments have molecular masses of approximately 80 kD (C-termi-
sory conduction velocities can be mildly slow in merosin-nega- nal) and 300 kD (N-terminal). 931 Merosin deficiency may be
tive patients (see below). Deep tendon reflexes are diminished identified by Western blot analysis and by immunohistochem-
or absent. Arthrogryposis may or may not be present. Cerebral istry of muscle biopsies. Some patients with merosin deficiency
function is usually normal, and patients develop mentally quite have normal appearing or only minimally reduced merosin
staining with commercially available antibodies that recognize brain and EEG. Serum CK was only mildly elevated (less than 5
only the 80-kD fragment.683-931 Antibodies recognizing the 300- times normal). Electrodiagnostic features were not described.
kD fragment may be more sensitive in detecting merosin defi- The decreased expression of a7piD integrin is believed to di-
ciency, but these antibodies are not as yet commercially minish the structural integrity of the cytoskeleton.
available.182-711 However, other patients have normal staining
with antibodies directed against this 300-kD amino-terminal Merosin-Positive Classic CMD with Loss of a-Actinin
fragment but demonstrate deficiency utilizing antibodies di- A deficiency of a-actinin-3 has been demonstrated in other
rected against the 80-kD carboxy-terminus. 683 Some cases of families with merosin-positive CMD. 742 The a-actinins are
partial merosin deficiency may account for the few reports of actin-binding proteins related to dystrophin, utrophin, and spec-
cerebral hypomyelination believed to have occurred in trin. Alpha-actinin-3 is localized to the Z-disks, where it proba-
"merosin-positive" patients. 267 Thus, similar to the dystro- bly plays a role in anchoring actin-containing thin filaments.
phinopathies, it is important to study the expression of merosin Whether merosin-positive CMD is caused by a primary defect
with more than one antibody. However, there does not appear to in a-actinin-3 in these kinships or if the deficiency is a sec-
be a direct correlation between the severity of the clinical phe- ondary phenomena remains to be determined.
notype and the amount of carboxy- and amino-terminal antibod-
ies detected on immunohistochemical staining of muscle Fukuyama-Type CMD
biopsies.182-711 Also, merosin-negative CMD can be diagnosed Clinical Features. This form of CMD has been primarily but
on skin biopsies, because the protein is normally present in not exclusively localized to Japan, where it is the most common
skin.683-930 The diagnosis of merosin-negative CMD can be made form of muscular dystrophy with an incidence of 6.9-11.9 per
prenatally on chorionic villus sampling.398-720 100,000 births.353-354-478-1031 Mothers often note decreased fetal
Merosin binds to a-dystroglycan of the DGC and a 7 p l D in- movements, and there is an increased frequency of spontaneous
tegrin (Fig. 27-1). As with primary dystrophinopathies and ad- abortions. Affected infants are born hypotonic and weak.
halinopathies, merosinopathies may result in a disruption and Weakness is generalized, but proximal muscles are affected
loss of integrity of the DGC.149-641 However, other lines of evi- more than distal muscles. Pseudohypertrophy of the calves is ev-
dence suggest the binding of merosin to integrin plays a more ident in approximately half the children. Contractures are
pivotal role in the pathogenesis of merosin-negative CMD than common and progressive throughout the child's life. Tendon re-
any disruption of the dystrophin and sarcoglycan interac- flexes are often diminished. Approximately 30% have a funnel
tions.1064 First, mutations in the a-2 subchain of merosin result chest deformity. In addition to profound weakness, intellectual
in a markedly diminished expression of a 7 p i D integrin, but a function is markedly compromised. The disorder is associated
normal or only mildly decreased expression of components of with severe structural abnormalities of the brain, including mi-
the dystroglycan or sarcoglycan complexes on the sarcolemma. crocephaly, cortical dysplasia, lissencephaly, pachygyria,
Second, the merosin and a 7 p l D integrin are expressed in skele- polymicrogyria, and hydrocephalus.353-354 Seizures occur in ap-
tal muscle in the dystroglycanopathies and the sarcogly- proximately half the cases. Both physical and mental develop-
canopathies. Third, mutations involving the a 7 subunit of ment are slow, with few children standing or ambulating
integrin that binds to merosin also result in a form of CMD (see independently. Most children expire by 10-12 years of age sec-
below). 43 ' ondary to respiratory failure, although some live to adulthood.
Merosin is also present in the basal lamina of myelinated Laboratory Features. The serum CK level is usually ele-
nerves. Abnormal expression of merosin may interfere with vated 10-50 times normal values. Electroencephalography is
myelinogenesis and may account for the hypomyelination evi- abnormal, demonstrating diffuse slowing and epileptiform ac-
dent in the central and peripheral nervous system. tivity.917 In addition, low-amplitude fast activity and extreme
spindling have been reported. MRI or CT scans of the brain
Classic Type CMD Associated reveal structural abnormalities as noted above. Further, evi-
with Mutations in Integrin dence of hypomyelination may be apparent on CT or MRI
As discussed above, merosin-positive forms of classic CMD scans.
are clinically more benign than merosin-negative CMD. Molecular Genetics and Pathogenesis. Fukuyama-type
Merosin-positive CMD is likely to be genetically heterogeneic, CMD is linked to chromosome 9q31-33, and recently mutations
and only recently have mutations been identified in the gene that have been identified in the gene encoding for a protein named
encodes for the a7 subunit of integrin located on chromosome fukutin.528-1029-1031 The function of this protein is unknown. Any
12ql3. 431 Because of the relationship of merosin and integrin, theory regarding the pathogenesis of the disorder needs to take
Hayashi and colleagues addressed the role of a 7 p l D integrin in into account both the typical CNS abnormalities and the muscu-
117 muscle biopsies of patients with previously unclassified lar dystrophy. The central nervous system abnormalities suggest
form of CMD or congenital myopathy.431 Seven of the 177 biop- a defect in neuronal migration and differentiation probably
sies demonstrated decreased immunoreactivity for the a7 sub- manifesting after the second trimester. Immunolabeling studies
unit of integrin. Four of these seven were subsequently found to indicate that fukutin is not localized to the sarcolemma; rather,
be merosin-deficient and have mutations in the gene for the a-2 it appears to be a secreted protein or perhaps is an extracelluar
chain of merosin. The deficiency of integrin was believed to be matrix protein.528-1031 Whether as a secreted protein, fukutin in-
secondary to the primary loss of merosin in these four patients. teracts with proteins of the extracellular matrix (e.g., merosin)
The remaining three patients had normal expression of merosin, and/or the dystrophin-glycoprotein complex, or if fukutin has
dystrophin, p-dystroglycan, and a-sarcoglycan. A mutation in some other function, remains to be determined. Reduced im-
the a7 subunit of integrin was demonstrated in these 3 patients, munohistochemical staining to a-2 laminin has been demon-
who presented with congenital onset of generalized weakness strated in muscle tissue, although abnormalities are not
and hypotonia. Motor milestones were delayed. Mental retarda- exclusive to this extracellular matrix protein. 430 Other laminin
tion was evident in one patient who had a normal MRI of the subunits, including pi and P2, are deficient, as is P-dystroglycan.
Muscle fibers may also demonstrate reduced immunostaining Histopathology of the CMDs
for dystrophin.35 The muscle biopsy findings in CMDs are essentially similar to
one another and other forms of muscular dystrophy (see Fig. 27-
Walker-Warburg Syndrome 8B). A striking inflammatory infiltrate is occasionally present,
Clinical Features. Infants with Walker-Warburg syn- especially in merosin-negative and occasionally Fukuyama-type
drome (WWS), also known as cerebro-ocular dysplasia, are CMD. This has led to the erroneous diagnosis of a congenital in-
born hypotonic and with severe generalized weakness. 188aJ 093 flammatory myopathy or polymyositis in some reported cases
There is little spontaneous movement. The infants are born (see inflammatory myopathy section). Immunostains for dys-
blind secondary to numerous ocular malformations, including trophin, the dystroglycans, and the sarcoglycans are normal. As
fixed pupils, hypoplasia of the optic nerves, micro-ophthalmia, noted above, decreased expression of merosin or a 7 p i D integrin
corneal opacities, cataracts, shallow anterior chambers, ciliary are evident in some forms of classic CMD.
body abnormalities, iridolental synechiae, and retinal dysplasia
and detachment. Similar to Fukuyama-type CMD, WWS is as- Electrophysiologic Findings in CMD
sociated with developmental abnormalities of the brain. There is As expected, the motor and sensory nerve conduction studies
lissencephaly, polymicrogyria, hydrocephalus, hypomyelina- are normal in merosin-positive CMD, WWS, MEB, and the
tion of the subcortical white matter, and hypoplasia of the brain Fukuyama type of CMD.87-324-498-917 However, mildly prolonged
stem and vermis. Seizures are frequent. There is little psy- distal latencies and slow motor and sensory conduction veloci-
chomotor development, and infants with WWS rarely survive ties as well as abnormal somatosensory and visual evoked po-
past 4 months of age. tentials have been described in some, but not all, patients with
Laboratory Features. Structural abnormalities are evident merosin-negative CMD.645-646-797-931-943 The slowing of conduc-
on imaging of the brain.1883 Electroencephalography is often ab- tion is most likely related to the impaired myelination of central
normal, revealing slowing of the background and epileptiform and peripheral nerves described above. Needle electromyo-
activity. Serum CK levels are elevated. graphic examination essentially demonstrates nonspecific find-
Molecular Genetics and Pathogenesis. WWS was linked ings of MUAPs with decreased duration and amplitude as well
to chromosome 9q31-33 in a single sibship and possibly repre- as an increase in the number of polyphasic potentials.596 Positive
sents an allelic disorder with Fukuyama-type CMD.1031 Whether sharp waves and fibrillation potentials are usually not detected,
or not mutations occur in the fukutin gene remains to be deter- and if present are rather sparse.
mined. Alpha-sarcoglycan and laminin p2 chain are deficient in
muscle biopsies in WWS. 1110 These are secondary deficiencies Treatment
because the genes for a-sarcoglycan are on chromosome 17q Treatment of the CMD is supportive. The use of corticos-
and for laminin p2 chain are on chromosome 3p21. The devel- teroids has not been studied in a prospective, placebo-con-
opmental anomalies in the brain suggests an arrest in neuronal trolled, double-blind fashion as in DMD, but corticosteroids do
migration in the second trimester continuing into the third not appear to be of significant benefit even in those cases with
trimester, while the eye malformations point to a developmental associated significant inflammation on muscle biopsy. Physical
defect in the second or third month of gestation. therapy is important to prevent contractures. Antiepileptic med-
ications are used for control of seizures.
Santavouri-type or Muscle-Eye-Brain Disease
Clinical Features. The clinical features of this form of Comment
CMD were described in Finnish patients by Santavouri and col- It is apparent that normal dystrophin, sarcoglycans, integrins,
leagues.896-897 The disorder is commonly referred to as either merosin, and perhaps the other laminins are important for the
Santavouri-type CMD or muscle-eye-brain disease (MEB). proper function of the dystrophin-glycoprotein complex.
The disorder is similar to WWS in that brain and eye abnormal- Mutations in the genes responsible for the dystroglycans, syn-
ities accompany the muscle weakness, although MEB is less trophins, and other laminin and integrin chains may subse-
severe. Infants are hypotonic and weak. Although motor devel- quently be found to be responsible for other forms muscular
opment is slow, most children are eventually able to sit and dystrophy. In this regards, p-dystroglycan deficiency was re-
stand, and some can walk. There are significant structural ab- ported in a 4-year-old child with muscular dystrophy character-
normalities in the brain, including pachygyria, polymicrogyria, ized by an early onset of mild proximal weakness and slightly
abnormal midline structures, and hypoplasia of the vermis and elevated serum CKs; however, it remains to be proven whether
pons.188a Not surprisingly, affected children have severe intellec- the deficiency was a primary or secondary event.888
tual impairment. Progressive myopia, glaucoma, and late
cataracts secondary to structural weakness of the eyes are typi- OTHER REGIONAL FORMS OF
cal of MEB. ,88a - 897 This is in contrast to the developmental MUSCULAR DYSTROPHY
ocular malformations seen in WWS.
Laboratory Features. Serum CK levels are elevated. Facioscapulohumeral Muscular Dystrophy
Imaging studies of the brain demonstrate polymicrogyria, ab- Clinical Features. The incidence of facioscapulohumeral
normal midline structures, and hypoplastic vermis and pons. I88a muscular dystrophy (FSHD) approximates 4 per million popu-
Giant visual evoked potentials are evident in most patients with lation with a prevalence of roughly 50 per million popula-
MEB but not in patients with Fukuyama-type CMD or WWS. tion.346-692-693 The disease is inherited in an autosomal dominant
Molecular Genetics and Pathogenesis. Families with this fashion. However, there is a variable degree of penetrance of
form of CMD do not link to chromosome 9q31-33; thus, this clinical findings within families. Approximately 30% of af-
disorder is not allelic with Fukuyama-type CMD and WWS.188-831 fected family members are unaware of their deficits. Thus, it is
Recently, linkage to chromosome Ip32-p34 was established in very important to examine family members of patients sus-
several families with MEB.,88-,88a-799 pected of having FSHD.
Figure 21-9. Facioscapulohumeral muscular

dystrophy (FSHD). Characteristic appearance of a pa-
tient diagnosed with FSHD. On attempted abduction of
the arms, the scapulae progress superiorly beneath the
upper trapezius muscle, giving the false impression of
well-developed musculature. Palpation reveals the bone
underlying the muscle tissue. Observing the patient
from behind reveals the prominent scapular winging and
abnormal position. (From Brooke MH:A Clinician's View
of Neuromuscular Diseases, 2nd ed. Baltimore,Williams
&Wilkins, 1986, with permission.)
The age of onset is usually between 3 and 44 years but has been patients with FSHD experience a late exacerbation of muscle
described as late as 75 years.76,•,008•,0l2•,058•,073a•,,0, FSHD is charac- weakness. They may only have mild weakness for years, then
terized by muscle weakness and wasting in a rather specific distrib- there is a marked increase of weakness in the typical distribution
ution.346•522•705-707'^0, The muscles of facial expression, particularly over the course of several years. Approximately 20% of FSHD
the orbicularis oculi, zygomaticus, and orbicularis oris muscles, are patients eventually will require wheelchairs. Abdominal muscles
typically affected early. Patients are unable to fully close their eyes may also be involved, producing a positive Beevor's sign (the
against resistance and sleep with incomplete eyelid closure. They umbilicus typically moves up when the patient is supine and at-
demonstrate a prominent Bell's phenomena (visible sclera with tempts to flex the head). Sensation is intact to all modalities, and
eye closure). Bilateral facial muscle weakness results in a smooth, the reflexes are usually absent or diminished commensurate with
expressionless face. Facial weakness may be strikingly asymmet- the degree of muscle wasting. Individuals with this disorder usu-
ric, mimicking a seventh nerve palsy. The muscles of mastication ally have a normal life-span. Rare patents develop cardiac in-
and the external ocular muscles are typically spared. In addition to volvement manifesting as conduction defects or arrhythmias that
facial weakness, those muscles serving to fixate and rotate the may require pacemaker implantation.548
scapula (serratus anterior, rhomboid, middle trapezius, and to some A particularly devastating form of FSHD is the infantile-
degree latissimus dorsi muscles) weaken and atrophy. Weakness of onset form with presentation of the clinical abnormalities within
the scapula stabilizer muscles leads to upward and lateral rotation the first 2 years. Significant muscle weakness of the face and
of the shoulder blades with scapular winging (Fig. 27-9). pelvic muscles requires one of the most exaggerated hyperlor-
Although the deltoids are relatively spared during the early course dotic gaits compatible with ambulation. A wheelchair is re-
of the disease, the sternocostal head of the pectoralis major is espe- quired to maintain mobility by the time the patient is 9 or 10
cially affected. This results in the appearance of a "trapezius years of age. Another form of FSHD involves a combination of
hump" that often is mistaken for muscle hypertrophy. The clavi- facioscapulohumeral weakness, profound sensorineural hearing
cles are displaced more horizontal and may angle downward from loss, and retinal telangiectasias (Coats' disease).
the sternum to the upper arm. In addition, there is lateral rotation of Laboratory Features. Serum CK levels may be only mildly
the upper arms giving rise to a rather prominent indentation in the to moderately elevated, and normal in some persons.
anterior axillary folds, which are horizontally displaced. There is Histopathology. The muscle biopsy demonstrates only
also significant weakness and atrophy of the biceps brachii and tri- moderate muscle involvement, when compared with patients
ceps with relatively normal bulk of the forearm muscles producing with DMD for example.522-705-707 907 There is variation in muscle
the so-called Popeye arms. Wrist extensors are weaker than wrist fiber size with occasional necrotic and regenerating fibers.
flexors. The characteristic facial and upper torso appearance led to Internal nuclei can be seen, and there are prominent regions of
the designation of "facioscapulohumeral" muscular dystrophy. very small muscle fibers. A number of hypertrophied and split
Some patients with FSHD manifest only with scapular winging.320 muscle fibers can also be detected. With disease progression,
The tibialis anterior is the earliest lower limb muscle to mani- significant fibrosis can be observed. Of interest, a number of pa-
fest weakness and occasionally patients present with foot- tients can demonstrate a prominent mononuclear inflammatory
drop. ,073a The gastrocnemius muscle usually maintains a infiltrate, which can lead to confusion with polymyositis (Fig.
relatively good grade of strength throughout the disease, although 27-10). These patients do not improve with steroids.
rare patients manifest with difficulty walking on their toes. l073a Molecular Genetics and Pathogenesis. The pathogenesis
The muscle involvement may progress to the pelvic musculature, of FSHD is unknown. FSHD is an autosomal dominant disorder
producing a hyperlordotic posture and a waddling gait. As in the linked to the telomerie region of chromosome 4q35 (Table 27-
face, weakness in the arms and legs is often asymmetric. Some 2 ) . 5 2 2 . ! O I I . Ii o 6 . l i i 4 , i i i s However, approximately 10% of kinships do
The needle electromyographic examination can reveal an in-
crease in insertional activity with a few sustained positive sharp
waves and fibrillation potentials. The degree of membrane in-
stability is quite variable from patient to patient and muscle to
muscle in the same patient.322-7051138 Fibrillation potentials and
positive sharp waves are less prominent than in the inflamma-
tory myopathies. Some patients may demonstrate no membrane
instability. Occasional complex repetitive discharges can be de-
tected. There is a preponderance of short-duration, small-ampli-
tude, polyphasic MUAPs with early recruitment at minimal
levels of force production. As with any chronic myopathy, large-
duration, large-amplitude, polyphasic MUAPs can occasionally
be seen. The refractory period of muscle tissue is increased in
this disorder.164
Single-fiber electromyography reveals both an increase in
fiber density and upper limits of normal to slightly increased
Figure 27-/0. Facioscapulohumeral muscular dystrophy.
jitter.31I-441-1 049 These increases, however, are considerably less
Muscle biopsy demonstrates prominent inflammation (H&E).
than those observed in DMD. The findings are consistent with
Physicians need to be aware that such prominent inflammation can be
the biopsy findings of degeneration and regeneration as well as
present in muscular dystrophies and can occasionally be misdiagnosed
fiber hypertrophy and fiber splitting. Less profound motor unit
as an inflammatory myopathies (e.g., polymyositis).The inflammatory
remodeling occurs in FSHD than in DMD. Essentially the same
cells present in the dystrophic muscle usually do not invade non-
processes causing increased fiber density and jitter values are
necrotic muscle fibers, in contrast to the invasion of non-necrotic
operative in FSHD as DMD, only to a lesser degree (see above).
muscle fibers seen in polymyositis and inclusion body myositis.
Macro EMG demonstrates a slight reduction in the MUAP am-
plitude, implying random dropout of muscle fibers from indi-
vidual motor units. Also, scanning EMG shows an increase in
not map to this area, suggesting genetic heterogeneity. 389 The the number of silent regions within a motor unit. This suggests
gene has not yet been isolated, but an EcoRl polymorphism in that there are regions within the motor unit where muscle fibers
this region is present in the majority of FSHD patients on chro- have either degenerated and were not replaced or reinnervated
mosome 4q35 as noted above.389 This EcoRl polymorphism is by collateral sprouts from other motor units.
variable in size but is reduced compared with normals (FSHD Treatment. A small open-label pilot study of prednisone 1.5
10-30 kb; normals 50-300 kb). A tandem array of 3.3-kb re- mg/kg/day for 12 weeks produced no significant improvement
peats is present within this EcoRl polymorphism. Normally in strength or muscle mass estimations. 1012 The study was not
there are 12-96 copies of this repeat, but in FSHD there are less double blinded, placebo controlled, sufficiently powered, or of
than 8 copies. It is this decrease in the number of these 3.3-kb long enough duration to assess whether steroids may slow the
repeats that result in a decreased size of the FSHD-associated rate of deterioration. An open-label trial of albuterol in 15 pa-
polymorphism. Of note, these repeats do not lie within the tients with FSHD for 3 months demonstrated increased lean
FSHD gene but are closely linked and are positioned telomeric body mass and muscle strength. 521 However, a subsequent 1-
to the actual gene. There is an inverse correlation between the year, double-blinded, placebo-controlled study of albuterol re-
size of the 4q35-associated deletion and the severity of the dis- vealed no clear benefit. Modest improvement in strength has
ease.840-101 1 Anticipation phenomena may occur in some fami- been reported in a small number of patients with FSHD treated
lies, although the size of the mutation appears stable. 1011 The with short courses of creatine monohydrate (5-10 gm/day). 1100
mutation in FSHD is unlike other described genetic disorders in Based on a prospective, quantitative study of the natural history
which anticipation is associated with an increased size of a of FSHD using manual muscle testing and maximum voluntary
polymorphic trinucleotide repeat mutation. Because the 3.3-kb contraction testing, the FSHD-DY Group suggested that a two-
repeats are associated with telomeric heterochromatin, the armed clinical trial involving 160 patients per group and a 1-
FSHD gene may be subject to position effect variega- year follow-up would provide 80% power to detect a complete
tion. 3 4 6 . i o i i . i o 7 4 Deletions involving these repeats result in the arrest of progression of the disease. 346 None of the studies to
FSHD gene lying closer to the telomere, a process that may date have enrolled a sufficient number of patients to determine
cause altered transcription of the nearby gene(s). It may be that if the specific medication studies slowed the progression of the
there is not one particular gene that is affected in FSHD but disease. Surgery may be beneficial in some patients by fixing
rather a host of genes lying close to the telemerc whose tran- the scapula to the thorax, thereby increasing the range of
sciptions are altered by position effect variegation. Rare patients motion.20-515-576 Ankle-foot orthotics are useful in patients with
with the classic FSHD clinical phenotype do not have the char- foot-drop secondary to tibialis anterior and peroneal muscle
acteristic mutation in chromosome 4q35, suggesting that there weakness.
may be some genetic heterogeneity in the disorder.
Electrophysiologic Findings. The relative rarity of this dis- Facioscapulohumeral Spinal Muscular Atrophy
ease combined with little in the way of detailed quantitative A controversial form of spinal muscular atrophy with in-
electrophysiologic analysis limits the amount of information volvement of the anterior horn cells producing a pattern of
available regarding expected findings. As with other primary weakness similar to that found in FSHD has been proposed to
muscle disorders, nerve conduction studies can be anticipated to exist based on clinical, electrophysiologic, and histologic
be normal. The gross muscle wasting of the humeral and tibialis data.215-322-356-357-480 However, the description of many patients in
anterior muscles generates quite small evoked CMAPs. the reports suggests the possibility of an alternative diagnosis
(e.g., mild dystrophinopathy, LGMD, or Kugelberg-Welander life 167,706,707.1001 j n e tibialis anterior muscle is particularly af-
disease). One reported patient had severe generalized weakness fected, causing obvious wasting and associated foot-drop. It is
and an elevated CSF protein of 130 mg/dl, suggesting the possi- not uncommon for slight asymmetry in strength to be evident,
bility of chronic inflammatory demyelinating polyneuropa- and some are misdiagnosed as having a peroneal neuropathy. A
thy.511 However, nerve conduction studies were not done in the few patients may demonstrate a compensatory hypertrophy of
patient. Unlike FSHD, facial muscles were of normal strength the extensor digitorum brevis, perhaps because of attempting to
or were only mildly affected in other reported patients. In addi- dorsiflex the foot with this muscle. Ankle contractures are
tion, proximal legs were typically much more severely involved prominent features of the disease secondary to the weak ante-
than the distal lower limb muscles (peroneal group), a finding rior compartment muscles. The weak scapular muscles result in
not seen in FSHD. In the upper limbs, there was prominent in- scapular winging, and a similar hypertrophic appearance to the
volvement of the deltoid muscles, which are relatively spared in trapezius muscles may occur as seen in FSHD. In contrast to
FSHD compared with other proximal and scapula stabilizer FSHD, the humeral musculature (elbow flexors and extensors)
muscles. Deep tendon reflexes were reduced. The serum CK is usually relatively spared, although a few patients eventually
levels were either normal or only mildly elevated up to two develop weakness in these muscles. Rarely, some patients may
times normal. manifest mild weakness of the facial muscles creating a diag-
A major reason patients were considered to have a form of nostic confusion with FSHD. However, facial muscle weakness
spinal muscular atrophy was because some were believed to is usually much less prominent than that seen in FSHD. In con-
have "fasciculations" on clinical examination. However, fascic- trast, the peroneal muscles are affected more severely in scapu-
ulation potentials were not reported on electromyography. loperoneal muscular dystrophy than in FSHD. Muscle weakness
Insertional activity was noted to be increased, but fibrillation progresses at a relatively slow rate, with years of quiescence
potentials and positive sharp waves were either absent or not being common.
prominent. Needle electromyography often demonstrated a Laboratory Features. The serum CK levels can be normal
mixture of "neurogenic" (large-amplitude, long-duration) and or moderately abnormal.
"myopathic" (small-amplitude, short-duration) MUAPs. Histopathology. There are only a few detailed descriptions
Quantitative EMG of the quadriceps muscle in one patient was of muscle histopathology in this disorder. Non-specific myo-
clearly myopathic.511 As previously discussed, it is not uncom- pathic features including fiber size variation with both hyper-
mon for chronic myopathies to generate a mixture of large and trophic fibers, split fibers, and abundant small atrophic fibers
small MUAPs and occasionally decreased recruitment (in addi- are evident.707-907 Also, muscle fiber degeneration and regenera-
tion to early recruitment) in severely affected muscle groups. tion with increase in endomysial connective tissue may be
Nerve conduction studies were not done or were normal. found.
Histologically, a diagnostic impression of neurogenic atrophy Molecular Genetics and Pathogenesis. Scapuloperoneal
was based on the presence of a few small angular fibers and muscular dystrophy is an autosomal dominant disorder, which,
small groups of atrophic fibers. These are non-specific histo- as noted above, can resemble FSHD clinically. DNA studies
logic features that can be seen in myopathies. Large group atro- have demonstrated no linkage to chromosome 4q35 in scapu-
phy and fiber type grouping, which are specific for neurogenic loperoneal muscular dystrophy; therefore, the disorder is not al-
atrophy, were not described. There is a lack of autopsy material lelic to FSHD. 1010 One kinship with a scapuloperoneal
confirming the loss of anterior horn cells in the spinal cord. The syndrome and cardiomyopathy was recently linked to chromo-
above-mentioned clinical, laboratory, electrophysiologic, and some 12. 11,5 This kinship also had clinical and histologic fea-
histologic features cast doubt on the existence of a neurogenic tures suggestive of myofibrillar myopathy (discussed later).
form of FSHD, and those reported patients may just have typi- Electrophysiologic Findings. The motor and sensory nerve
cal FSHD or another neuromuscular disorder. conductions are normal aside from a reduced CMAP in the more
severely affected muscles.313-494-511-1021 Needle electromyography
Scapuloperoneal Syndromes typically does not reveal significant degrees of positive sharp
The term scapuloperoneal syndrome is sometimes used as waves or fibrillation potentials. The MUAPs are of a reduced du-
opposed to "dystrophy" because there are a number of disorders ration and amplitude with early recruitment in affected muscles.
with different modes of inheritance as well as primary sites of A increase in the degree of polyphasicity can also be noted.
pathology that can have similar clinical presentations. The com- Treatment. There are no reported studies regarding medical
monality among these syndromes is the location of muscle therapy in scapuloperoneal muscular dystrophy. It is hoped that
weakness. As the name implies, the scapular fixators and per- studies being performed on patients with DMD and FSHD will
oneal muscles are particularly affected. Proximal muscles flex- apply to those with scapuloperoneal muscular dystrophy. Ankle-
ing and extending the elbow are also involved, and thus an foot orthoses are beneficial in patients with ankle dorsiflexor
equally effective designation might be scapulohumeroper- weakness. Surgery to stabilize the scapula may improve arm
oneal syndromes. This group of disorders is somewhat confus- function in some patients.
ing because there are insufficient number of patients of any one
type as well as few detailed necropsy studies investigating the Spinal Scapuloperoneal Atrophy
central nervous system's involvement. It is hoped that with the Clinical Features. There are a few reports of a scapuloper-
recent advances in genetic detection, a better understanding of oneal syndrome believed to be secondary to a motor neuronopa-
these diseases can be accomplished. thy or spinal muscular atrophy.224-279-494-724-843 An autosomal
dominant inheritance is suspected in some kinships. The pattern
Scapuloperoneal Muscular Dystrophy of muscle involvement is similar, but not identical, to that de-
Clinical Features. Individuals with this type of muscular scribed for scapuloperoneal muscular dystrophy. Onset is usu-
dystrophy usually manifest symptoms of peroneal muscle fol- ally between the ages of 30 and 50 years and begins in the distal
lowed by scapular weakness within the first two decades of legs. However, onset in infancy has been reported.224 The kinship
paralysis, which shares many of the clinical features reported
with neurogenic scapuloperoneal syndrome, has also been lo-
calized the same area.1025 Thus, these disorders may be allelic.
Electrophysiologic Findings. The motor and sensory stud-
ies are normal.224-279-494-724-843 Needle electromyographic exami-
nation demonstrates a reduced recruitment pattern of few
MUAPs firing at high rates in affected muscles. Additionally,
large-amplitude, long-duration MUAPs are documented.
Membrane instability in the form of positive sharp waves and
fibrillation potentials can be observed and at times can be quite
florid.
Scapuloperoneal Neuropathy (Davidenkow Syndrome)
Clinical Features. This rare autosomal dominant disorder in-
volves a scapuloperoneal type of muscle weakness combined with
a glove-and-stocking distribution of sensory loss.494-673-706-9111032
Onset can occur in childhood or adult life. Weakness begins in the
Figure 27-11. Emery-Dreifuss muscular dystrophy (EDMD). distal lower limbs and subsequently involves the scapula stabilizer
Patients with EDMD demonstrate early contractures of the elbows muscles. Progression is generally slow but can eventually lead to
(shown), ankles, and neck prior to significant muscle weakness and wheelchair dependence. Pes cavus is common. Reflexes are di-
atrophy.This patient was unable to fully extend his elbows secondary minished throughout and absent at the ankles.
to contractures. Histopathology. Sural nerve biopsies demonstrate axon loss
with secondary demyelination 470
Molecular Genetics and Pathogenesis. Inheritance is usu-
reported by DeLong and Siddique demonstrated anticipation ally autosomal dominant, but sporadic cases also occur.
phenomena (the earlier onset and increasing severity over suc- Genetic localization has not been described, and the pathogen-
cessive generations). 224 Kaeser's series also demonstrated in- esis is unknown.
creasing severity in the fifth generation of that large family.494 Electrophysiologic Findings. Sensory nerve conduction
All the muscles below the knee are severely affected, both the studies reveal reduced or absent amplitudes and mild to moder-
anterior and posterior compartments, which is different than ate slowing of conduction velocities. Motor conduction studies
that found in the dystrophic form of the disease (see above). The demonstrate mild or moderately slow nerve conduction veloci-
disorder is slowly progressive, and eventually weakness is evi- ties and reduced amplitudes. On needle electromyography, a re-
dent in the pelvic girdle. Although shoulder girdle muscle wast- duced number of large-amplitude, long-duration MUAPs firing
ing and weakness are present, involvement is less severe than at rapid rates is evident. Complex repetitive discharges, fibrilla-
that found in the distal lower limbs. There may be preservation tion potentials, and positive sharp waves can also be found in
of the scapular stabilizers, which is also different from the dys- multiple muscles.
trophic form. Extension to the bulbar muscles is sometimes
seen. Of note, the kinship described by DeLong and Siddique X-linked Emery-Dreifuss Muscular Dystrophy
was associated with laryngeal palsies often requiring tra- Clinical Features. Emery-Dreifuss muscular dystrophy
cheotomy, and two patients had limited abduction of the eyes.224 (EDMD) is characterized by the triad of (1) early contractures
Fasciculations are variable. Deep tendon reflexes are absent, but of the Achilles tendons, elbows, and posterior cervical muscles;
there is sparing of sensation throughout. Patients displaying (2) slowly progressive muscle atrophy and weakness with a pre-
similar clinical features but with autosomal recessive inheri- dominantly humeroperoneal distribution in early stages; and (3)
tance or sporadic occurrence have also been described. An ear- cardiomyopathy with conduction defects.274-276-278-454-456-87310201133
lier onset and more profound weakness were seen in these cases Prominent contractures are evident in early childhood or in the
compared with the autosomal dominant cases. teenage years. There is an inability to fully extend the elbows
Histopathology. The muscle biopsies have demonstrated secondary to elbow flexion contractures (Fig. 27-11). Heel cord
fiber type grouping consistent with a chronic neurogenic contractures are also an early feature, resulting in toe walking.
process. Sensory nerve biopsies are normal. Kaiser reported au- Spine mobility can be extremely limited with an appearance
topsy findings in one case that demonstrated degeneration of an- suggestive of a rigid spine syndrome. 539 Patients have difficulty
terior horn cells in the spinal cord and of the motor nuclei of flexing their neck and trunk. Notably, the contractures are ap-
cranial nerves 7, 9, and 10.494 An autopsy on another member of parent prior to any significant weakness, a finding that helps
the same family revealed a normal number of anterior horn distinguish EDMD from other types of dystrophies in which
cells; however, there was extensive gliosis with adjacent cor- contractures can also develop.
pora amylacea as well as axonal spheroids.812 Patients with EDMD usually have minimal muscle weakness
Molecular Genetics and Pathogenesis. The kinship de- at birth.274-276-278-454-456 Some are noted to have mild weakness in
scribed by DeLong and Siddique was subsequently linked to the early childhood years by particularly milestone-oriented
chromosome 12q24.1-q24.31, 479 The exact genetic defect has parents or those patients with siblings or friends of similar age.
not been identified. It will be interesting to see if there is a ex- There is a characteristic pattern of muscle involvement that also
panded triplet repeat as seen in other disorders associated with helps distinguish EDMD from other forms of dystrophy.
anticipation phenomena (e.g., Kennedy's disease, Huntington's Weakness and atrophy are first apparent in the humeroperoneal
disease, the various spinocerebellar ataxias, and myotonic dys- distribution affecting the biceps brachii, triceps, anterior tibial,
trophy). Of note, distal spinal muscular atrophy with vocal cord and peroneal muscles. Some patients have pes cavus deformities.
As the disorder slowly progresses, the shoulder and pelvic gir- the needle electromyographic findings. 197.454^56.625,649.873,1021.1105.1142
dles can become involved, giving rise to a so-called scapulo- Insertional activity can be increased with or without sustained
humeropelviperoneal pattern of weakness. The disorder is trains of positive sharp waves and fibrillation potentials. MUAPs
slowly progressive, and even severely affected patients are usu- are usually of short duration, decreased amplitude, and polypha-
ally able to ambulate into the third decade. There is a distinct sic and demonstrate early recruitment. However, large-amplitude,
lack of calf hypertrophy. The deep tendon reflexes are dimin- long-duration polyphasic MUAPs may also be seen. When the
ished or absent early in the disease. muscle is severely atrophic with only a few muscle fibers remain-
Of particular importance is the development of profound and ing, the recruitment pattern can resemble that seen in a neuro-
potentially lethal cardiac abnormalities by the end of the second genic process, i.e., reduced number firing at high rates. The
or beginning of the third decade. Conduction defects range from so-called mixed (myopathic and neuropathic) needle electromyo-
first-degree AV block to complete heart block. As with the mus- graphic pattern is not uncommon in chronic myopathies. 232
cular weakness, cardiac involvement is highly individualized Single-fiber electromyography demonstrates a mild increase in
and may arrest at a mild stage or progress. Syncopal events and fiber density with normal or only mildly abnormal jitter.
sudden cardiac death can occur. Pacemaker administration may Treatment. It is important to monitor cardiac function be-
be required in order to decrease the threat of early mortality (see cause of the risk of arrhythmias and sudden death. The authors
treatment). Although female carriers do not manifest muscle obtain yearly electrocardiograms on all their patients (as well as
weakness or contractures, the may develop the cardiopathy.276-278 on possible female carriers) and cardiology consultations on
Laboratory Features. The serum CK levels are either patients with significant abnormalities. Patients may require
normal or only mildly to moderately elevated. Electro- pacemakers, and some authorities have even recommended pro-
cardiograms frequently reveal sinus bradycardia, prolongation phylactic pacemakers.276-278 Stretching exercises are indicated to
of the PR interval, or more severe degrees of conduction block. minimize contractures.
Histopathology. The muscle biopsy findings vary depending
upon the degree of disease involvement.278 There is usually muscle Autosomal Dominant Emery-Dreifuss Muscular DystrophyILGMD18
fiber size variation. Type 1 fibers are frequently atrophic. There The features of this rare disorder are identical to those described
can be a predominance of either type 1 or type 2 muscle fibers. above for typical X-linked EDMD except for autosomal dominant
Muscle fiber splitting, increased central nuclei, and endomysial fi- inheritance and equal frequency of affected females. Mutations in
brosis can be evident. Immunocytochemistry reveals the absence the lamin A/C gene (LMNA) located on chromosome lql 1-23
of emerin on the nuclear membrane.278-715-749 Further, there is ab- cause the autosomal dominant variant of EDMD (Table 27-
normal immunostaining with lamin A/C and B2 antibodies on the 2).97.98.32.T h u S i a s n o t e d previously, AD-EDMD and LGMD1B
nuclear membrane. EM demonstrates nuclear abnormalities in- are allelic disorders.1073 Further mutations in the rod domain are a
cluding the focal absence of peripheral heterochromatin in areas cause of hereditary dilated cardiopathy and conduction defects
between the nuclear pores, irregular and uniform thickening of the with or without a underlying skeletal muscle involve-
nuclear lamina, compaction of heterochromatin in areas of irregu- ment.98-308-321-323-656 Mutations arise de novo in 76% of cases; there-
lar thickening of the nuclear lamina, and areas where the periph- fore, mutations in LMNA should be considered in familial and
eral heterochromatin does not adhere to the nuclear lamina.749 sporadic cases of EDMD and familial dilated cardiopathy.98 There
Histologic studies of the spinal cord and peripheral nerves are can be marked inter- and intra-familial variability in the clinical
normal. Definitive diagnosis in affected males and identification expression associated with specific mutations in the LMNA gene.
of carrier females can be made by immunostaining muscle or skin Lamins A and C are produced by alternative splicing of the lamin
tissue for emerin or by immunoblot analysis of leukocytes.605 A/C RNA transcript. As discussed in the Pathogenesis discussion
Molecular Genetics and Pathogenesis. EDMD is caused regarding X-linked EDMD, these lamins are important in the or-
by mutations in a gene (STA) located on chromosome Xq28 that ganization and integrity of the nuclear membrane. Muscle biop-
encodes for the protein emerin (Table 27-2).88-278 Emerin is a sies demonstrate variation in fiber size, increased endomysial
254-amino-acid protein with one transmembrane spanning connective tissue, normal dystrophin, and sarcoglycan staining.
domain that immunolocalizes to the inner nuclear membranes Importantly, emerin is expressed on nuclear membranes, but lamin
of skeletal, cardiac, and smooth muscle fibers as well as skin A/C expression may be reduced in AD-EDMD. However, im-
cells.715 Emerin has a carboxy-terminal tail that anchors the pro- munostaining with lamin A/C antibodies is sometimes normal.647
tein to the inner nuclear membrane while the remainder of the Electron microscopy reveals nuclear alterations similar to X-
protein projects into the nucleoplasm. The function of emerin is linked EDMD in 10% of muscle fibers.881a There is loss of periph-
currently unknown. Emerin is a member of the nuclear eral heterochromatin or detachment from the nuclear envelope,
lamina-associated protein (LAP) family; specifically, emerin alterations in interchromatin texture, and fewer nuclear pores.
is an LAP2-related protein.749 The nuclear lamina is a complex
of intermediate-sized filaments (e.g., lamins A-, -B, and C) as- Autosomal Recessive Emery-Dreifuss Muscular Dystrophy
sociated with the nucleoplasm^ surface of the inner nuclear Clinical Features. An early-onset, autosomal recessive
membrane. These lamins bind to the inner nuclear membrane muscular dystrophy with contractures and severe rigidity of the
by interacting with various LAPs, including LAP1 and LAP2, spine was described in five unrelated children (three boys and
as well as lamin B receptor. LAP2, lamin B receptor, and the two girls).1015 Patients manifested their disease within the first 2
lamins are known to bind to chromatin and promote its attach- years of life, and all lost the ability to ambulate by the age of 8
ment to the nuclear membrane. Thus, mutations in emerin could years. Cardiac function was normal.
explain the disorganization of the nuclear lamina and hete- Laboratory Features. Serum CK was moderately elevated.
rochromatin apparent on EM and immunohistochemistry.749 Cardiac evaluation (e.g., EKG, echocardiogram) was normal.
Electrophysiologic Findings. Motor and sensory nerve con- Histopathology. Muscle biopsies revealed non-specific dys-
duction studies are typically normal in these patients. Of interest trophic changes with normal expression of emerin, dystrophin,
is the wide disparity of findings reported in the literature regarding the sarcoglycans, and laminins a2, a5, pi, yl chains.1015
Molecular Genetics and Pathogenesis. The pathogenic Rigid Spine Syndrome
basis of the disorder is unknown. Clinical Features. Phenotypically, these patients share many
Electrophysiologic Findings. Electrodiagnostic features features with EDMD and Bethlem myopathy. The rigid spine
have not been described. syndrome manifests in infancy with hypotonia, proximal weak-
ness, and delayed motor milestones and probably represents a
Bethlem Myopathy form of congenital muscular dystrophy. 339 - 539 - 596 ^
Clinical Features. The clinical features are very similar to The hallmark of this disorder, as the name implies, is the pro-
EDMD except for the absence of cardiac abnormalities and gressive development of severe limitation of spine mobility.
the autosomal dominant inheritance.85-488-675 Onset is usually There are typically knee and elbow contractures. Scoliosis also
at birth or early childhood, but the disorder may not present develops in all patients. Deep tendon reflexes are normal, as is
until early adulthood. There may also be variability in the age sensation. The spinal deformities continue until about 7-13
of onset and clinical features within affected family members. years, at which time the disease appears to stabilize.
Decreased fetal movements may be noted in utero, and Laboratory Features. Serum CK levels may be mild to
neonates may demonstrate generalized hypotonia. Motor moderately elevated. Electrocardiograms demonstrate cardiac
milestones are often delayed but are reached. Proximal mus- conduction defects in some patients.
cles are affected more than distal muscles, and the legs are Histopathology. Muscle biopsies reveal non-specific myo-
more involved than the arms. Extensor muscles are weaker pathic features including variability in fiber size, increased cen-
than flexor muscles (except at the hips). There can be mild tral nuclei, type 1 fiber predominance, and motheaten fibers and
neck and trunk involvement, but cranial muscles are spared. lobulated fibers on NADH dehydrogenase stains. Cytoplasmic
Rarely, muscle strength is asymmetric. Some patients can bodies, increased desmin expression, and sarcoplasmic and in-
have hypertrophy of their calves or extensor digitorum brevis tranuclear tubulofilamentous inclusions may also be present.836
muscles. Notably, contractures are evident early in the course Immunostains for dystrophin, sarcoglycans, and p-dystroglycan
at the elbows and ankles prior to any significant weakness are normal. However, a deficiency of the pi laminin chain of
similar to EDMD. Eventually, contractures develop in the skeletal muscle fibers has been demonstrated in older patients
wrists and fingers. There is also limited range of motion in but not younger members of affected kinships. 1015 The other
the hips, knees, and shoulders. Sensation is normal. Deep laminin chains a l , a2, and yl are normal. This age-related defi-
tendon reflexes can be normal or reduced. Progressive respi- ciency is restricted to skeletal muscle fibers and is not seen in
ratory muscle weakness, particularly of the diaphragm, may vascular tissue. Thus, the deficiency of the pi laminin chain
be seen. 416 Some patients manifest with only proximal hip and may just be an epiphenomenon.
shoulder girdle weakness without evidence of contractures. Molecular Genetics and Pathogenesis. Congenital muscu-
Thus, the disorder may be mistaken for one of the autosomal lar dystrophy with rigid spine syndrome has been linked in
dominant LGMDs. 983 some autosomal recessive kinships to chromosome lp35-
Laboratory Features. Serum CK is normal or mildly ele- 35 339,673.674 ^ s noted above, there is clinical overlap with EDMD
vated (< 6 times normal). Cardiac evaluation (e.g., EKG, Holter and rare cases of rigid spine syndrome have been linked to mu-
monitor, and echocardiogram) is normal. tations in the emerin gene.539
Histopathology. Muscle biopsies demonstrate non-specific Electrophysiologic Findings. Nerve conduction studies are
myopathic features. There is variability in fiber size, increased normal. Electromyography descriptions are limited, but short-
splitting and central nuclei, and mild endomysial fibrosis. duration polyphasic MUAPs have been described.
Lobulated type 1 fibers and motheaten fibers are apparent on Treatment. Physical therapy is indicated to improve range
NADH dehydrogenase stains. of motion about the spine and prevent progressive contractures.
Molecular Genetics and Pathogenesis. Bethlem myopathy
is a disorder of type VI collagen (Table 27-2). There is evi- Bent Spine/Dropped Head Syndrome
dence for genetic heterogeneity with different kinships linked to Clinical Features. Neck extensor weakness can be an early
mutations of the genes encoding for the a l and a2 subunits of and prominent manifestation of several disorders, specifically
collagen VI located on chromosome 21q 488 and ot3 subunit of myasthenia gravis, amyotrophic lateral sclerosis, and focal
collagen VI located on 2q37. 764962 Collagen VI is believed to myositis. Many patients who initially manifest with head-drop
play a role in bridging cells within the extracellular matrix. are eventually diagnosed with these other disorders.507 However,
Mutations of the subunits of this protein may impair fixation of there are rare reports of patients who develop weakness re-
merosin of the dystrophin-glycoprotein complex to the sur- stricted to the cervical, and sometimes also the thoracic and
rounding endomysial connective tissue. paraspinal muscles.89-507-864-903-923 Most patients develop symp-
Electrophysiologic Findings. Motor and sensory nerve con- toms over the age of 60 years. Over the period of several weeks
duction studies are normal. There is no or only rare abnormal to months, these patients develop head-drop secondary to neck
spontaneous activity (e.g., fibrillation potentials, PSWs) on extensor weakness. Slowly progressive involvement of the tho-
electromyography. Often a mixture of small-amplitude, short- racic paraspinal muscles often occurs over time, resulting in
duration polyphasic MUAPs with large-amplitude, long-dura- severe kyphosis or the bent spine posture upon standing. When
tion MUAPs can be seen.85-416-675-983 The electromyographic the patients are supine, their posture is normal, in contrast to pa-
interpretation was a neurogenic process in three of nine origi- tients with fixed contractures of the spine. In some patients,
nally described cases.85 However, there is no histopathologic ev- weakness clinically remains fairly isolated to the neck extensors
idence that this disorder has a neurogenic basis, and these even for several years, although there may be subclinical (radi-
electromyographic abnormalities are now appreciated to be ographic or electromyographic) evidence of disease in the
common in chronic myopathic conditions. upper thoracic paraspinal muscles. 507 Mild shoulder girdle in-
Treatment. Physical therapy is indicated to prevent progres- volvement can also occur. A family history of bent spine syn-
sive contractures that can impair mobility and function. drome has been described in two distinct kinships. 923 Both
cases involved a mother and a daughter (in one case, two daugh- usually does not alter the patient's life span provided adequate
ters were affected). medical attention is sought with regard to the nutritional aspect
Laboratory Features. Serum CK is usually normal or only of this disease.
mildly elevated. CT and MRI of the low cervical and upper tho- Laboratory Features. Serum CK levels are normal or only
racic spine reveals atrophy and fatty or edematous changes in mildly elevated. Swallowing studies demonstrate impaired pha-
the paraspinal muscles. ryngeal and esophageal motility.
Histopathology. Muscle biopsies of the cervical paraspinal Histopathology. The muscles most severely involved are the
muscles demonstrate non-specific myopathic features including extraocular and pharyngeal muscles, although minor abnormali-
variability in fiber size with atrophic and hypertrophic muscle ties may be detectable in the limb muscles in advanced
fibers, increased central nuclei, fiber splitting, motheaten fibers, cases.4393*8741035 There is noted to be prominent muscle fiber size
fibers with rimmed vacuoles and increased endomysial connec- variation with both degenerating and regenerating muscle fibers.
tive tissue. Endomysial inflammation with invasion of non- Internal nuclei and an increase in adipose and connective tissue
necrotic fibers is unusual but has been reported. 89 Biopsies of are also noted. Rimmed vacuoles similar to those found in inclu-
proximal limb muscles may be normal or demonstrate similar, sion body myositis/myopathy and some of the distal myopathies
but less prominent, non-specific myopathic abnormalities. Type are often, though not universally, observed (Fig. 27-12). Im-
2 muscle fiber atrophy has been reported, which may be sec- portantly, 8.5 nm tubulofilaments can be demonstrated in muscle
ondary to disuse. Ragged red fibers and cytochrome C oxidase nuclei on EM. In addition, 15-18 nm tubulofilaments may be evi-
(COX)-negative fibers have also been described, but these mi- dent in the cytoplasm as seen in inclusion body myositis, heredi-
tochondrial abnormalities may be age related. Immunostains for tary inclusion body myopathy, and some of the distal myopathies.
dystrophin, sarcoglycans, and merosin are normal. OPMD can be distinguished from various mitochondrial my-
Pathogenesis. The pathogenesis is unknown. In some pa- opathies, which can also cause ptosis and ophthalmoparesis, by
tients, the disorder may represent a monophasic inflammatory the lack of ragged red fibers. However, there have been a few cases
process restricted to the paraspinal muscles.89-864 Alternatively, of abnormal mitochondrial structure and quantity on EM, al-
this disorder may represent a form of muscular dystrophy that though these findings for the most part are suspected to be age re-
predominantly affects the paraspinal muscles. Isolated neck ex- lated.1123 Some have suggested a neurogenic etiology for OPMD
tensor myopathy may just represent a forme fruste of the bent based on muscle and sural nerve histology.418 However, the re-
spine syndrome. ported muscle histology demonstrated non-specific myopathic
Electrophysiologic Findings. Motor and sensory nerve con- features and not grouped atrophy or fiber type grouping, which
duction studies are normal for age. Electromyography reveals would be expected in a chronic neuropathic disorder. Sural nerve
fibrillation potentials and positive sharp waves in cervical and biopsy in a few patients revealed a mild reduction in myelinated
thoracic paraspinals.507-923 Short-duration, small-amplitude and unmyelinated nerve fibers; however, this could have been
MUAPs with early recruitment have been described in the cer- normal, given the patients' advanced ages.
vical and thoracic paraspinal muscles. Thoracic paraspinal mus- Molecular Genetics and Pathogenesis. Expansions of a
cles may be involved by electromyography in some patients short GCG repeat within the poly(A) binding protein 2 gene
who clinically only have isolated neck extensor weakness. 507 (PABP2) on chromosome 14ql 1 have been identified as the
Electromyography of limb muscles is usually normal. cause of OPMD (Table 27 - 2).91-111-4393-577 Normally, there are
Treatment. Immunosuppressive therapy and pyridostigmine six GCG repeats encoding for a polyalanine tract at the N-ter-
are not typically beneficial. However, improvement with corti- minus of the protein. Approximately 2% of the population
costeroid and azthioprine treatment has been reported in rare have polymorphism with seven GCG repeats (GCG) 7 . In
patients.89-864 Cervical collars are used to treat the head-drop. OPMD, there is an expansion to 8-13 repeats (GCG) 8 . 13 . These
expansions are meiotically stable; thus, there is no apparent
Oculopharyngeal Muscular Dystrophy anticipation phenomena noticeable in affected kinships. Patients
Clinical Features. Oculopharyngeal muscular dystrophy
(OPMD) is an autosomal dominant trait, thereby affecting men
and women equally. The majority of patients with OPMD mani-
fest in the fourth to sixth decade of life with increasing
ptosis.4393-874-1035 As many as 23% first note difficulty swallowing.
The ptosis is always bilateral; however, it can be asymmetric. A
number of patients adopt a backward tilting of the head in order
to see, but this can worsen the dysphagia. The external ocular
muscles are also involved in 50% of patients, but diplopia is not
a common symptom. 4393 The pupils are spared. There is mild
weakness of facial and masticatory muscles. Difficulty swallow-
ing solid food becomes more of a problem with time, and dys-
phagia can be so severe that caloric consumption is limited and
patients become emaciated. The gag reflex is impaired.
Laryngeal involvement can also develop, resulting in dysphonia.
Weakness slowly progresses. Mild weakness of the neck and
proximal limbs can be detected in some patients. Involvement
of distal muscles may also occur, particularly in the oculopha-
ryngeal distal variant (see below). Sensation is normal, but deep Figure 27-12. Oculopharyngeal muscular dystrophy (OPMD).
tendon reflexes can be reduced or absent. Fortunately, the late onset Muscle biopsies in patients with OPMD occasionally demonstrate
of the disease in most patients combined with slow progression rimmed vacuoles. Modified Gomori-trichrome.
who are homoygotes for (GCG) expansions have more severe Treatment. Eyelid crutches on glasses or even taping the
phenotypes. 91 •••• Patients who are heterozygous for (GCG) 813 eyelids open can be used to treat the ptosis. Ptosis surgery can
and the (GCG) 7 polymorphism are more severely affected. A also be performed if patients have sufficient orbicularis oculi
late-onset, autosomal recessive form of OPMD can develop in strength to allow complete closure of the eyelids postoperatively.
patients who are homozygous for the (GCG) 7 polymorphism. Patients with severe dysphagia may benefit from cricopharyn-
Thus, the PABP2 (GCG) 7 allele is the first example of a poly- geal myotomy. Some patients will require percutaneous endo-
morphism that can act as a modifier of a dominant phenotype or gastric (PEG) tube placement secondary to severe dysphagia.
as a recessive mutation.
The function of PABP2 and how the mutation in the gene leads Variants of Oculopharyngeal Muscular Dystrophy
to muscle degeneration are unknown. PABP2 is found mostly in A few variants of OPMD may represent distinct disorders. A
the dimeric and oligomeric form in the nuclei. The expansion of severe early-onset form with ptosis, ophthalmoparesis, and gen-
the GCG repeats probably results in a gain of function of PABP2. eralized weakness with onset in infancy or early childhood has
It is thought that the pathologic expansions of the GCG repeats been described.4393*546'863-1034 These cases were associated with
may cause mutated PABP2 oligomers to accumulate as the 8.5 severe respiratory failure eventually requiring mechanical ventila-
nm intranuclear tubulofilamentous inclusions apparent on EM.111 tion. Another possible variant of OPMD is oculopharyngodistal
The more severe clinical phenotypes are associated with a large myopathy. Most of the reports of oculopharyngodistal myopathy
number of myonuclei containing intranuclear inclusions.91 have come from Japan,350-381 but the myopathy has been described
Electrophysiologic Findings. As with the other muscular in other ethnic groups. 119101085 Weakness seems to occur earlier
dystrophies noted above, both motor and sensory nerve conduc- than classic OPMD onset, in the first decade of life in some cases.
tion studies are normal.104-2l2-866-908-,°82 Needle electromyographic Chronic intestinal pseudo-obstruction was reported in one case.11
findings vary depending upon the muscle studied and progres- The laboratory, histologic, and electrodiagnostic features of these
sion of the disease at the time of the examination. If the external variants are for the most part indistinguishable features from
ocular muscles and frontalis/orbicularis oculi muscles are ex- OPMD. The characteristic 8.5-nm intranuclear tubulofilaments of
amined, small-amplitude, short-duration MUAPs displaying an OPMD have not been identified in the severe, early-onset form.
early recruitment pattern can be recorded. Insertional activity is However, Rose et al demonstrated cytoplasmic and intranuclear
usually normal and spontaneous activity is typically absent, but tubulofilaments measuring 25 nm in diameter in one patient.863
rare positive sharp waves and fibrillation potentials may be Although initially it was reported that 8.5-nm tubulofilaments
found in some cases in the facial and proximal muscles. There were not evident in one case of oculopharyngodistal myopathy,11
are reports of "neuropathic" features in OPMD based on the subsequently we were able to document these intranuclear fila-
finding of positive sharp waves and fibrillation potentials and ments. Whether or not these variants have mutations in the PABP2
large polyphasic MUAPs. 418 Some large-amplitude, long-dura- gene similar to OPMD remains to be determined. In a single kin-
tion polyphasic MUAPs as well as positive sharp waves and fib- ship of atypical OPMD (early onset in the 2nd to 3rd decade, mod-
rillation potentials can be observed in myopathic conditions and erately elevated serum CK, and profound ophthalmoplegia),
do not in themselves constitute a neurogenic etiology. mutations in the PABP2 gene were not identified.4393
It is important to keep in mind that the facial muscles typi-
cally have shorter duration MUAPs than are found in the limbs. Distal Myopathy/Muscular Dystrophy
Care must be exercised when attempting to quantify these po- A number of diseases must be kept in mind when considering
tentials in so far as normative data for facial muscle MUAP du- the diagnosis of distal myopathy (Table 27-3). 63 The distal my-
ration should be used. Also, patient cooperation is necessary opathies refer to a group of inherited muscular disorders charac-
when attempting to analyze recruitment with respect to judging terized clinically by progressive atrophy and weakness of distal
early or reduced recruitment. Some patients have a tendency to arm or leg muscles and histologically by non-specific myo-
contract the orbicularis oculi fully, and it must be stressed that pathic features on muscle biopsy. The authors consider the
only a minimal amount of eye closure is desired. distal myopathies to be forms of muscular dystrophy. Based
Table 27-3. Distal Myopathies

Type Inheritance Gene Localization Initial Weakness Creatine Kinase Muscle Biopsy
Welander type Autosomal 2pl3 Hands: finger/wrist Normal or slightly Myopathic with
Late adult type 1 dominant extensors increased rimmed vacuoles
Markesbery-Griggs-Udd type Autosomal 2q3l-33 (? titin) Legs: anterior Normal or slightly Myopathic with
Late adult type II dominant compartment increased rimmed vacuoles
Nonaka/h-IBM type Autosomal 2pl-ql Legs: anterior Slightly increased, Myopathic with
Early adult-onset type 1 recessive compartment usually < 5 x normal rimmed vacuoles
Miyoshl/LGMD 2B Autosomal 2pl2-l3 Legs: posterior Increased Myopathic with
Early adult-onset type II recessive (Dysferlin) compartment; 10-150 x normal non-rimmed
occasionally the vacuoles and
anterior compart- vessicles
ment or hip girdle
is affected initially
LaingType Autosomal I4ql 1 Legs: anterior compart- Slightly increased Myopathic
Early adult-onset type III dominant ment, neck flexors < 3 x normal
Modified from Barohn RJ, Amato AA, Griggs RC: Overview of the distal myopathies: From the molecular to the clinical. Neuromuscul Disord 1998, with permission.
upon the clinical features, age of onset, CK levels, muscle his- short-duration MUAPs.63-64 - - - 7 9 The more proximally
101102 205 268 5
tology, and mode of inheritance, the distal myopathies can be located muscles about the shoulder and pelvic girdles may reveal
subdivided into (1) Welander myopathy (late adult-onset type 1) only a mild increase in the number of short-duration MUAPs or
with autosomal dominant inheritance; (2) Markesbery-Griggs- can be completely normal, especially during the initial stages of
Udd myopathy (adult-onset type 2) with autosomal dominant the disease. Quantitative electromyography using interference
inheritance linked to chromosome 2q31-33; (3) Nonaka myopa- pattern analysis has been consistent with a myopathic process.102
thy (early adult-onset type 1) with autosomal recessive inheri- Positive sharp waves and fibrillation potentials are not prominent
tance localized to chromosome 9pl-ql; (4) Miyoshi myopathy features but can present in some persons. Some studies have re-
(early adult-onset type 2) with autosomal recessive inheritance ported normal jitter and fiber density,102 while others have noted
and localization to chromosome 2pl2-14; and (5) Laing myopa- increase in jitter values reaching 280 ps. 965
thy (early adult-onset type 3) with autosomal dominant inheri-
tance and linkage to chromosome 14ql l.63 Markesbery-Griggs-Udd Distal Myopathy (Late Adult-Onset Type 2)
Clinical Features. This late adult-onset distal myopathy was
Welander Distal Myopathy (Late Adult-Onset Type I) initially reported in English and French-English families.610-988
Clinical Features. Welander reported 249 cases from 72 Recently, several large kinships and sporadic cases also have been
families with this peculiar form of distal myopathy.1108 The dis- described in Finland.63-226-417-77,-,059'106°-1062 Patients begin to notice
order usually occurs in persons of Scandinavian descent. Most weakness of the anterior compartment of the lower legs resulting
patients develop symptoms in the fifth decade of life (mean 47 in unilateral or bilateral foot-drop after the age of 35 years. As the
years, range 20-77 years); onset before 30 years is very uncom- disease slowly progresses, the distal upper limbs (hand intrinsics
mon. Patients initially manifest with weakness of the distal and wrist extensors) and rarely proximal arm and leg muscles can
upper limbs, primarily the wrist and finger extensors. 63 ' 3901108 become involved. Facial muscles are spared. Sensation is normal.
The disease slowly progresses. Eventually, weakness affecting A few patients have diminished ankle tendon reflexes.
the distal lower limbs, ankle dorsiflexors more than the plantar Cardiomyopathy has been reported in some patients.536-610
flexors, is noted. In about 10% of cases, weakness is first noted Laboratory Features. Serum CK is normal or only slightly
in the legs or there is simultaneous involvement of the distal elevated (mean approximately 3 times normal). 1060
arms and legs. Although the extensor muscle groups are more Histopathology. Non-specific myopathic features similar to
severely affected, the flexor groups are involved in over 40% of that described above for Welander myopathy are evident, although
cases. Rarely, proximal muscles become weak. rimmed vacuoles are much more frequent in the Markesbery-
Sensation is usually normal, although quantitative sensory Griggs-Udd and the Nonaka forms of distal myopathy.611 A sec-
testing can demonstrate mild impairment in vibratory and tem- ondary loss of calpain 3 may be noted on immunoblots 417
perature perception. 100101 During the initial presentation, the Molecular Genetics and Pathogenesis. The genetic defect
deep tendon reflexes are clearly preserved, but the brachioradi- localizes to chromosome 2q31-33, although the altered gene
alis and Achilles reflexes begin to diminish or disappear during product has yet to be identified.417-1060 The giant protein titin
the later stages of the disease. (connectin), which is present in cardiac and skeletal muscle, lo-
Laboratory Features. The CK is usually normal or only calizes to this region and is a candidate gene. Calpain 3 is a
minimally elevated up to three times the normal limit.63 ligand for titin, which may explain the secondary loss of calpain
Histopathology. Muscle biopsies demonstrate significant 3 in this myopathy. Titin plays an important role in myofibrillo-
fiber size variability, increased central nuclei, split fibers, and genesis. It has been speculated that the secondary loss of cal-
increased connective tissue and adipose cells in long-standing pain 3 may perturb gene regulatory pathways, leading to
disease.7-631011021108 A few muscle fibers with rimmed vacuoles apoptosis of myonuclei.417
are frequently evident in biopsies of weak muscles. Electron mi- Electrophysiologic Findings. Motor and sensory nerve con-
croscopy reveals 15-18 nm cytoplasmic and nuclear filaments duction studies are normal. Electromyography of affected mus-
similar to those observed with IBM, h-IBM, and OPMD. 579 cles reveals fibrillation potentials and positive sharp waves as
Myofibrillar disruption and plaques of Z-disk-derived material well as small-amplitude, brief-duration MUAPs that recruit
similar to that found in myofibrillar myopathy have also been early.771-1059-1060
noted.101 A moderate reduction of mainly small-diameter,
myelinated fibers has been described in sural nerve biopsies.101 Nonaka Distal Myopathy (Early Adult-Onset Type I)
There was no evidence of axonal degeneration or segmental de- Clinical Features. This early adult-onset autosomal reces-
myelination/remyelination. sive distal myopathy was initially reported in Japan670-737-738,991
Molecular Genetics and Pathogenesis. The pathogenesis is but has since been described elsewhere.33-45-655-914 Weakness
unknown. The disorder is believed to be genetically distinct from begins in the anterior compartment of the distal lower limb with
other forms of distal myopathy because it does not link to chro- toe extensor and ankle dorsiflexor weakness in the second or
mosomes 2q (Markesbery-Griggs-Udd myopathy), 9pl-ql third decade of life.63 The posterior compartment of the legs and
(Nonaka myopathy), or 14q (Laing myopathy). 67 Recently, link- distal upper limb muscles are also affected early, but to a milder
age to chromosome 2pl3, the locus of Miyoshi myop- degree. Over time, there is progression with involvement of
athy/LGMD2B, has been demonstrated.6-7-8 However, the genetic proximal arm and leg muscles as well as neck flexors. Notably,
defect is not believed to lie in the dysferlin gene. the quadriceps remain strong or are relatively spared compared
Electrophysiologic Findings. Motor and sensory nerve con- with other muscle groups. Cranial nerve-innervated muscles are
duction studies should be normal compared with age matched spared. There is no evidence of sensory loss. Deep tendon re-
controls. However, quantitative sensory testing has demon- flexes can be normal or absent. Cardiopathy with syncope due
strated diminished temperature and vibratory perception in to complete heart block has been reported.991
some patients as noted above. 100102 Needle electromyographic Laboratory Features. Serum CK is normal or only mildly
evaluation demonstrates early recruitment of small-amplitude, elevated, usually less than five times normal.
Histopathology. Muscle biopsies demonstrate non-specific and distal upper limb weakness can develop in a few patients
myopathic features as described with the other forms of distal my- over time. Progression is variable, but as many as one third of
opathy as well as prominent rimmed vacuoles.617-670-671'1130 patients require wheelchairs for transportation outside the home
Inflammation is absent. In addition, EM demonstrates the non- after 10 years of symptoms. 583 Sensation is normal. Ankle deep
specific IBM type of 15-18 nm intranuclear and cytoplasmic tendon reflexes are lost early, while the others are preserved.
tubulofilaments.617-670 Further subsarcolemmal vesicles and non- Laboratory Features. The characteristic laboratory fea-
rimmed vacuoles appear to be common on EM beneath disrupted ture is the markedly elevated serum CK levels, usually 20-150
sarcolemmal membrane.798a-920a times normal. The elevated serum CK levels can be detected
Molecular Genetics and Pathogenesis. Nonaka distal my- prior to the patient being symptomatic.360-583 MRI confirms that
opathy links to chromosome 9pl-ql. 4 7 i Autosomal recessive the posterior compartment muscles are more severely affected
hereditary inclusion body myopathy (h-IBM) localizes to the than anterior compartment muscles.643
same genetic area; therefore, these disorders may in fact be iden- Histopathology. Muscle biopsies demonstrate a variety of
tical (see Familial Inclusion Body Myopathies in this chapter).33-45 non-specific myopathic features including variability in fiber
The actual gene product and pathogenesis are still unknown. size, increased central nuclei, scattered necrotic and regenerat-
Electrophysiologic Findings. Motor and sensory nerve con- ing fibers, as well as split fibers. There is increased endomysial
duction studies are usually normal, but the peroneal CMAPs connective tissue and fatty replacement as the muscles become
may demonstrate reduced amplitudes. 63 Electromyography may more severely affected. Biopsy of the gastrocnemius usually
be normal or reveal small-amplitude, brief-duration MUAPs demonstrates severe end-stage muscle changes with extensive
that recruit early.63 Positive sharp waves and fibrillation poten- fatty tissue replacement and fibrosis; therefore, this muscle
tials may also be evident. should be avoided. In contrast, biopsy of normal proximal leg
(e.g., quadriceps) or arm muscles (biceps brachii, deltoid) may
Miyoshi Distal Myopathy (Early Adult-Onset Type 2) be uninformative. The biceps femoris is an excellent muscle to
Clinical Features. Similar to the Nonaka type of distal my- biopsy, because it is usually involved clinically and histologi-
opathy, Miyoshi distal myopathy is autosomal recessive with cally, yet is not end-stage. Unlike the other distal myopathies,
onset usually between the ages of 15 and 30 years.34-59-360-543-583-667 rimmed vacuoles are uncommon. However, the authors have
However, in Miyoshi myopathy, weakness begins in the poste- found rare rimmed vacuoles on muscle biopsies of patients with
rior compartment of the distal lower limbs. The gastrocnemius Miyoshi myopathy,932 further illustrating the non-specificity of
muscles become very atrophic and weak (Fig. 27-13). Patients this histologic abnormality. Immunostaining reveals diminished
have great difficulty standing on their tiptoes. Climbing stairs or absent dysferlin on the sarcolemma, while dystrophin,
can become a problem. One large series of 24 patients reported utrophin, and the sarcoglycans are normally expressed.618-1130
nearly half the patients had asymmetric involvement of their Molecular Genetics and Pathogenesis. Miyoshi myopathy
calves at initial presentation. 583 In roughly 17% (4 of 24 pa- has been linked to chromosome 2pl2-14, 73 and interestingly,
tients), the signs and symptoms remained asymmetric; in 3 pa- LGMD 2B was previously linked to the same locus.67 In addi-
tients, weakness and atrophy stayed confined to one leg. The tion, a large Spanish family with distal lower limb weakness
anterior compartment of the distal lower limbs can also become with onset in the anterior compartment was also linked to the
affected with time but not to the same degree of weakness as ev- same chromosomal region.67 These findings suggested that
ident in the calves. Weakness can spread to the proximal legs, Miyoshi myopathy, LGMD 2B, and this distal myopathy with
again affecting the posterior muscles (i.e., hamstrings) more anterior tibial weakness of the legs could be allelic disorders. In
than the anterior muscles (i.e., quadriceps). Moderate proximal this regards, Illarioshkin et al described a large kinship in which
seven family members had a typical LGMD phenotype, while
three family members had a distal myopathy.473 The distal my-
opathy in these patients was different than typical Miyoshi distal ,
myopathy in that the anterior and posterior compartments of the j
lower limbs appeared to equally affected. Members of the family
with the LGMD phenotype and those with the distal myopathy
mapped to chromosome 2pl2. Another large kindred whose
family members included both Miyoshi myopathy and LGMD
2B patients linking to chromosome 2pl2 was also described.473
Subsequently, the laboratory of Brown and colleagues cloned
and identified mutations within the dysferlin gene in patients
with Miyoshi myopathy, LGMD 2B, and distal myopathy with
anterior tibial weakness linked to chromosome 2pl3. 588 Thus,
there is a broad clinical spectrum of myopathies linked to muta-
tions in dysferlin. In a study of 407 muscle biopsies from pa-
tients with unclassified myopathies, 6.5% had abnormal
dysferlin by Western blot and immunostaining.27-301a The dysfer-
linopathies accounted for 1 % of patients with a limb-girdle syn-
drome and 60% of patients with a distal myopathy. Of the
dysferlinopathies, 80% of patients manifested with distal weak-
ness, 8% had a LGMD phenotype, and 6% had asymptomatic
hyper-CK-emia.27-30,a Dysferlin is a cytoskeletal protein located
Figure 27-/3. Miyoshi myopathy. N o t e the marked atrophy of predominantly on the subsarcolemmal surface on the muscle
the calves in a patient with Miyoshi myopathy. membrane of skeletal and cardiac muscle, but it has a small
transmembrane tail (see Fig. 27-1). The protein does not appear Molecular Genetics and Pathogenesis. The myopathy lo-
to be an integral component of the dystrophin-glycoprotein calized in this family to chromosome 5q31. 315 Myotilin, a sar-
complex because dystrophin and the sarcoglycans are normally comeric protein that co-localizes with oc-actinin, is a candidate
expressed in patients with dysferlinopathies. The function of gene.889 Of note, LGMD 1A localizes to the same region. There
dysferlin is not known. Bashir suggested dysferlin may have a is overlap between the clinical features of this disorder and those
role in membrane fusion. 68 Others have posited that dysferlin of myofibrillar myopathy (MFM) (see below in Congenital
may bind calcium and mediate signaling events.618 Myopathy section). MFM is genetically and clinically hetero-
There also appears to be genetic heterogeneity in the Miyoshi geneic, and it is possible that previous cases of MFM with vocal
type of distal myopathy. Linssen et al recently reported three cord and pharyngeal involvement may be one in the same.
families with Miyoshi myopathy who failed to show linkage to Electrophysiologic Findings. Motor and sensory nerve con-
chromosome 2pl2-14. 584 In two of these kinships, there was pu- duction studies are usually normal but may revel mild slowing
tative linkage to chromosome 10. The other family failed to link of conduction velocities. Needle electromyography revealed
to either chromosome 2p 12-14 or chromosome 10. mixed neurogenic and myopathic features.315
Electrophysiologic Findings. Motor and sensory nerve con-
duction studies are normal.34-59-583-667 Positive sharp waves and Myofibrillar Myopathy
fibrillation potentials can be seen in distal muscles in the arms Myofibrillar myopathy (MFM) is actually a clinically and ge-
and legs on electromyography, and may be present but less netically heterogeneous group of disorders that may present
abundant in the proximal muscles.34-59-583-667 Electromyography with distal, proximal, or generalized weakness. It is discussed in
also reveals small-amplitude, brief-duration MUAPs that recruit greater detail in the section regarding congenital myopathies.
early. In extremely weak and atrophic muscles, insertional ac-
tivity may be diminished secondary to replacement of muscle Treatment of the Distal Myopathies
fibers with connective and adipose tissue, and MUAPs may be There is no medical treatment available for the distal my-
difficult to identify and recruit. Further, large-amplitude, long- opathies. Braces for the lower limb weakness and other orthotic
duration MUAPs with decreased recruitment may be identified devices may improve gait and functional abilities.
in severely affected muscles.
HEREDITARY INCLUSION BODY MYOPATHIES
Laing Distal Myopathy (Early Adult-Onset Type 3)
Clinical Features. Laing and colleagues recently described Clinical Features. There are autosomal dominant725-953 and re-
an Australian family (nine affected members over four genera- cessive32-613,884 forms of hereditary inclusion body myopathy (h-
tions) in which weakness of the anterior compartment of the IBM). Histologically, the h-IBMs resemble sporadic inclusion
distal lower limbs and neck flexors developed between the ages body myositis (s-IBM), except for the absence of inflammation in
of 4 and 25 years.549 Eventually the finger extensors become in- h-IBM.44-45-854 Autosomal recessive h-IBM was initially reported in
volved and there can be mild weakness of the shoulder and hip Iranian-Jewish families but was subsequently described in Iranian-
girdle. Finger flexors and hand intrinsic muscles are spared. Kurd, Afghani-Jewish, and North American families. The age of
Laboratory Features. Serum CK was normal or slightly el- onset and pattern of weakness in h-IBM are different than that of s-
evated, usually less than 3 times normal. IBM. Most patients with s-IBM present over the age of 50 years
Histopathology. Muscle biopsies demonstrated non-specific with prominent quadriceps and volar forearm weakness. In con-
myopathic features. Rimmed vacuoles were not noted. Im- trast, most autosomal recessive h-IBM patients present in the
munostaining for dystrophin and desmin were normal. second or third decade of life. Patients with h-IBM have preferen-
Molecular Genetics and Pathogenesis. The family de- tial involvement of distal lower limb weakness and frequently pre-
scribed by Laing et al was linked to chromosome 14ql 1,549 The sent with foot-drop. There is insidious progression with gradual
gene has not yet been cloned. involvement of the iliopsoas, thigh adductors, and to a lesser extent
Electrophysiologic Findings. Motor and sensory nerve con- the glutei muscles. Notably, the quadriceps are normal or relatively
duction studies were normal. Electromyography demonstrated spared even when more proximal muscles are significantly in-
occasional fibrillation potentials and positive sharp waves and volved. The proximal arms and neck flexors can also become af-
small-amplitude, short-duration, polyphasic MUAPs in distal fected. There can be asymmetry of muscle weakness. Progression
more than proximal muscles.549 is variable, with some patients becoming wheelchair-dependent
within 4 years of onset, while others are ambulatory 18 years after
OTHER DISTAL MYOPATHIES onset. Extraocular and bulbar muscles are normal, as is sensation.
Deep tendon reflexes are normal early, but diminish later in the
Distal Myopathy with Vocal Cord Paralysis course. As noted above, some forms of autosomal recessive h-IBM
and Pharyngeal Weakness and Nonaka distal myopathy could be allelic disorders.
Clinical Features. A single large kinship with an autosomal Autosomal dominant forms of h-IBM are much less common
dominant transmission of distal limb weakness, vocal cord paral- than the recessive forms.725-953 Although the pattern of weakness
ysis, and pharyngeal weakness has been described.315 Weakness is variable in autosomal dominant h-IBM, most patients have a
usually began in the anterior tibial muscles during the 4th to 6th limb-girdle distribution of muscle involvement. Distal muscles
decade and can be asymmetric. Vocal cord and pharyngeal in- can occasionally be involved. Extraocular and bulbar muscles are
volvement developed after the limb weakness manifested. spared. Sensation and deep tendon reflexes are usually normal.
Laboratory Features. Serum CK levels were normal to There are a few reports of familial cases of s-IBM in which
moderately elevated. siblings, even twins, had the characteristic clinical phenotype
Histopathology. Muscle biopsies demonstrated non-specific and histologic features of s-IBM.12a-953 These cases do not repre-
myopathic features along with rimmed vacuoles. EM did not sent h-IBM but a familial predisposition for development of s-
reveal filamentous inclusions. IBM, similar to that described for other autoimmune disorders.
discharges.32-884 There is a mixture of small-amplitude, short-du-
ration polyphasic MUAPs with large-amplitude, long-duration
polyphasic MUAPs. Argov et al initially suspected a neurogenic
etiology based on these features. 32 However, it is now com-
monly appreciated that these findings are common in chronic
myopathic disorders. Quantitative electromyography and
macro-EMG support a myopathic process.884 Single-fiber elec-
tromyography reveals increased jitter and fiber density.884
Treatment. There is no medical treatment available for h-
IBM. Patients with distal lower limb weakness may benefit
from bracing.
Hereditary Inclusion Body Myopathy
with Cerebral Hypomyelination
There is a another form of autosomal recessive h-IBM that is
associated with marked cerebral white matter abnormalities on
Figure 27-/4. Hereditary inclusion body myopathy (h-IBM). CT and MRI.183-438 Cole and colleagues reported five of six male
Muscle biopsies in patients with h-IBM demonstrate rimmed vacuoles siblings with an infantile onset of progressive proximal greater
and the accumulation of tubulofilaments characteristic of biopsies than distal weakness, legs worse than arms.183 Calf hypertrophy
from patients with sporadic inclusion body myositis (s-IBM). In con- was noted on examination. Sensation was normal. Deep tendon
trast to s-IBM, there is no invasion of non-necrotic muscle fibers by in- reflexes are normal at the ankles but were diminished or absent
flammatory cells in h-IBM. Modified Gomori trichrome. elsewhere. The pattern of weakness was apparently similar in
cases described in abstract form by Hentati et al.438 Despite the
white matter changes on CT and MRI, intellectual function was
Laboratory Features. Serum CK levels are normal or only normal in all the cases. Motor nerve conduction studies were
mildly elevated in the various forms of h-IBM. Some autosomal mildly slow. The clinical, laboratory, and electrodiagnostic fea-
recessive kinships are associated with a severe leukoen- tures are similar to classic CMD with merosin deficiency, except
cephalopathy apparent on MRU 83 438 rimmed vacuoles are not a prominent feature of merosinopathy.
Histopathology. Muscle biopsies of the autosomal recessive The cases were reported before the discovery of merosin and its
and dominant h-IBMs are similar to s-IBM except for the lack of role in CMD, and it would be interesting to know if these kin-
endomysial inflammation and invasion of non-necrotic muscle ships are deficient in merosin or some other laminin.
fibers.44-45 Fiber size variability, split fibers, increased central
nuclei, and, importantly, numerous fibers with rimmed vacuoles DYSTROPHIC MYOTONIAS
are evident (Fig. 27-14). As in s-IBM, EM demonstrates the ab-
normal accumulation of 15-18 nm tubulofilaments in the cyto- This group of disorders refers to the more common distally
plasm and nuclei of muscle fibers. In addition, amyloid and other predominant myotonic dystrophy (DM1), a phenotypically sim-
"Alzheimer characteristic proteins" can be identified in vacuo- ilar but genetically distinct disorder (DM2), and proximal my-
lated muscle fibers. Congo red positivity is present but much less otonic myopathy/dystrophy or PROMM. 475 664a Of note, DM2
frequent in vacuolated muscle fibers of h-IBM compared with s- and PROMM appear to be allelic disorders.
IBM. There is also a difference in expression of phosphorylated
tau epitopes between s-IBM and h-IBM. 663 Nitrotyrosine, in- Myotonic Dystrophy (DM I)
ducible nitric oxidase, and neuronal nitric oxidase have been Clinical Features. There are a number of disorders associated
demonstrated in vacuolated muscle fibers in h-IBM.1131 These with clinical and/or electrical myotonia, of which myotonic dys-
findings suggest that nitric oxide-induced oxidative stress may trophy (DM1) is the most common (see Table 27-4). DM1 is in-
play a pathogenic role in h-IBM. herited in an autosomal dominant manner. The incidence of this
Molecular Genetics and Pathogenesis. Autosomal reces- disorder is 13.5 per 100,000 live births, and the prevalence is 3-5
sive h-IBM kinships from Iraqi-Jewish and Afghani-Jewish per 100,000.277-391 DM1 can present at any age; onset in infancy is
kinships as well as from a non-Jewish family originating from known as congenital myotonic dystrophy. DM 1 produces a char-
India were mapped to chromosome 9pl-ql. 3 3 Interestingly, at acteristic pattern of muscle involvement. Frontal balding, ptosis,
the same time, Nonaka distal myopathy was linked to the and wasting of the facial and masseter/temporalis muscles are
same genetic locus, suggesting these are allelic disorders. 471 characteristic. The muscle wasting gives rise to the so-called
The gene has not been isolated. When the gene is identified, it hatchet face appearance. Temporomandibular joint dislocation can
may provide insight not only into the pathogenesis of this be quite problematic in some patients. Involvement of the pharyn-
form of h-IBM but also perhaps into that of s-IBM and the geal and lingual muscles can produce dysarthria and dysphagia.
other distal myopathies, which share similar histologic fea- An early manifestation of the disease, and helpful clinical clue, is
tures. An autosomal recessive h-IBM family with severe a complaint of trouble lifting the head off a pillow signifying neck
white matter abnormalities did not map to chromosome 9pl- flexor and sternocleidomastoid weakness. Limb weakness begins
ql. 33 Autosomal dominant h-IBM has been localized to chro- distally and progresses rather slowly to affect proximal muscles.
mosome 17pl3.1 in some kinships. Myotonia is described by patients as muscle "stiffness."
Electrophysiologic Findings. Motor and sensory nerve con- Many patients do not complain or are not aware of their myoto-
duction studies are usually normal, except for the families with nia or stiffness. The myotonia is most prominent in the hands.
leukoencephalopathy. Electromyography demonstrates fibrilla- There is a delay in relaxation of the fingers following a forceful
tion potentials, positive sharp waves, and complex repetitive hand grip (action myotonia). Repeated muscle contractions
result in reduced myotonia, a so-called warm-up phenomenon. Histopathology. The most characteristic feature on biopsy
Percussion of muscle groups, in particular the thenar eminence is the excessive number of central nuclei in the muscle fibers.
and the tongue, produces myotonia (percussion myotonia). Type 1 fiber atrophy is evident in 50% of cases.391 Hypertrophic
Deep tendon reflexes are depressed or absent, while sensory type 2 fibers, ring fibers, small angulated fibers, and sarcoplas-
testing is normal.631 Adult patients with DM1 may have a mild mic masses are also frequently observed. In contrast to other
reduction in cognitive abilities.90,807 More severe mental retarda- muscular dystrophies, necrotic fibers and increased connective
tion is associated with the congenital form of the disease. tissue are less commonly appreciated.
Congenital myotonic dystrophy is considerably more dis- Molecular Genetics and Pathogenesis. DM1 is caused by an
abling than adult-onset DM 1. Affected infants are invariably born expansion of unstable polymorphic cytosine-thymine-guanine
to mothers with myotonic dystrophy.403,835 Mothers may not even (CTG) trinucleotide repeats in the 3' untranslated region of the
be aware that they have the disorder; thus the necessity of exam- gene on chromosome 19ql3.2 (Table 27-2).114-336358-359'424.60°.644^8'9.
ining the mother of floppy infants. On questioning, the mother 830.934 Tj^g CTG repeat is copied in the gene up to 27 times in nor-
may recall decreased fetal movement. Pregnancy can be compli- mals, but 50 or more times in affected patients. The gene, dys-
cated by polyhydramnios. Infants present with severe generalized trophia myotonica-protein kinase (DMPK), encodes for a protein
weakness and hypotonia. The upper lip has a "tented" appearance named myotonin protein kinase. The severity of myotonic dys-
or inverted "V" shape. Ventilatory assistance is usually necessary trophy directly correlates with the size of the CTG repeat. The size
and is associated with a poor prognosis, particularly if it is re- of the repeat is unstable and typically expands from one genera-
quired for more than 4 weeks. The disorder is fatal in approxi- tion to the next, which accounts for the anticipation phenome-
mately 25% of affected infants. Both mental and physical non (i.e., the earlier presentation and/or more severe disease in
milestones are abnormal, and nearly 75% of surviving children each generation). Marked expansion of the CTG repeat usually
have subnormal intelligence. Associated abnormalities include occurs in children of mothers with myotonic dystrophy, account-
club feet and arthrogryposis. Clinical myotonia is not apparent in ing for the severe phenotype of congenital myotonic dystrophy.
the neonatal period and may not be noticeable until about 5 years How the mutation results in an abnormal expression of myotonin
of age. However, myotonic discharges can be appreciated on elec- protein kinase and the function of this protein is unclear.
tromyography before the appearance of clinical myotonia. Myodegeneration may be due to a toxic gain of function of the
Associated Manifestations. There are a number of systemic mutant mRNA retained in the myonuclei.1024a The expanded
abnormalities associated with DM1. The smooth muscles of the mRNA may be unable to be exported out of the nuclei or may
gasfrointestinal tract are also involved. Besides dysphagia, reduced impair the transcription of the genes or transportation of other
motility can lead to chronic pseudo-obstructions.457,745 Involvement mRNA species. Studies have demonstrated that the large CTG re-
of the diaphragm and intercostal muscles is common, leading to peats may be associated with a chromatin environment that re-
alveolar hypoventilation. Respiratory insufficiency is more severe presses local gene expression. An enhancer element that regulates
in congenital myotonic dystrophy.'59,835 Controversy exists over the expression of the adjacent dystrophia myotonica-associated
whether or not decreased central drive contributes to hypoventila- homeobox protein (DMAHP) gene is located near the CTG re-
tion.72,415 Regardless, patients develop symptoms suggestive of peats array of the myotonin protein kinase (DMPK) gene.
sleep apnea: frequent nocturnal arousals, excessive daytime hyper- DMAHP expression is decreased in patients with myotonic dys-
somnolence, and morning headaches. Pulmonary hypertension can trophy, implicating this protein into the possible pathogenesis of
result, leading to cor pulmonale. Cardiac abnormalities are myotonic dystrophy. Transgenic animal models containing ex-
common, with approximately 90% of patients having conduction panded CTG repeats in muscle-specific actin gene reproduce the
defects on electrocardiograms.695 Sudden cardiac death secondary clinical, histologic, and electrophysiologic features of myotonic
to arrhythmia is well documented. Life expectancy is greatly re- dystrophy.606 This suggests that DM1 may be the result of nuclear
duced in DM1 patients, particularly those with early onset of the retention of mutant mRNA containing expanded CTG repeats
disease and significant proximal weakness in addition to distal rather than a specific function of the DMPK protein.
weakness.218,616 The higher mortality is reflective of death from the Recently, a second myotonic dystrophy locus (DM2) was
associated respiratory weakness and cardiomyopathy. However, the mapped to chromosome 3q21.3 in a five-generation family with
severity of the cardiomyopathy does not necessarily correlate with clinical features similar to the more common chromosome 19q-
the severity of skeletal muscle weakness. linked disorder.6440,832 Patients had facial weakness, distal
Neurobehavioral abnormalities are common in patients with greater than proximal weakness, myotonia, frontal balding,
DM 1,223 Neuropsychologic testing demonstrates elements of cataracts, and cardiac arrhythmias. They did not demonstrate
obsessive-compulsive, passive-aggressive, dependent, and hyperglycemia, hypersomnia, or gonadal failure that are occa-
avoidant personality traits in many patients. Apathy and depres- sionally seen in classic myotonic dystrophy. Subsequently, it
sion are also frequent. Cognitive impairment, particularly in was demonstrated that this disorder is allelic to proximal my-
memory and spatial orientation, may be evident, although these otonic myopathy/dystrophy or PROMM (discussed below).
abnormalities are not as severe in adult-onset cases as they are Electrophysiologic Findings. Motor and sensory nerve con-
in the congenital form of the disorder. duction studies are usually normal.651 There have been patients
Posterior subscapular cataracts are common, although a care- reported with myotonic dystrophy demonstrating mild prolon-
ful slit lamp examination may be required to identify them. gation of the distal motor latency and slowing of nerve conduc-
Testicular atrophy and impotence can occur in males. A high tion velocity with F-wave prolongation. 766 These findings are
rate of fetal loss and complications of pregnancy are noted in the exception and not the rule in this disorder. It can be antici-
women.943 Hyperinsulinemia is common following glucose tol- pated that because of the distal wasting of muscle tissue, routine
erance tests; however, the frequency of overt diabetes mellitus CMAPs obtained from the distal hand muscles can be reduced
is not increased.696 in magnitude, particularly in those persons with long-standing
Laboratory Features. Serum CK may be normal or mildly disease. Motor unit counting techniques have revealed de-
increased. creased numbers of motor units in the extensor digitorum
brevis, suggesting a peripheral nerve etiology to the disease. 766 even in a limb that does not have overt manifestations of clinical
However, detailed morphologic analysis of nerve biopsies has myotonia. In congenital myotonic dystrophy, electrical myoto-
been normal. 803 It is unlikely that any mild abnormalities pre- nia may be observed as early as 5 days to 3 weeks following
sent in patients with DM1 are clinically significant. birth and increases with age.253*998 Not all muscles examined
A unique type of decrementing response can be observed in may reveal myotonic potentials. Therefore, it is important to
patients with DM1. Unlike a neuromuscular junction's decre- sample multiple muscles, especially those located distally that
ment in which there is an immediate decline in CMAP magni- are usually clinically affected.975 The documentation of electri-
tude following the first response with a 2-3 Hz stimulus rate (see cal myotonia was in the past a sensitive technique for diagnos-
Chapter 25), in DM1 repetitive stimulation at 1-3 Hz does not ing patients with only subtle clinical abnormalities.34-802-814-989
elicit a decrementing CMAP.15'651 A minimal stimulus delivery at The most sensitive and specific test for myotonic dystrophy is
5 Hz and preferably 10 Hz is required to generate a decrement- DNA analysis for the mutation.
ing response. Higher rates of stimuli generally produce compar- During rest, a myotonic muscle may be electrically silent or
atively greater CMAP decrements. Also, a continuous train demonstrate single muscle fiber discharges similar in appear-
applied for up to 3 minutes may be required to show the decre- ance to fibrillation potentials and positive sharp waves. These
ment. There is usually a steady decline in CMAP amplitude potentials may be difficult to appreciate in patients with promi-
throughout the stimulus period starting after about 4-30 seconds nent electrical myotonia. The apparent fibrillation potentials
depending upon the rate of stimuli, less time for faster stimulus and positive sharp waves are the result of spontaneous depolar-
rates. A few patients may demonstrate a CMAP decline and then izations of the muscle fibers secondary to intrinsic muscle
leveling off of the response. Following cessation of repetitive membrane instability rather than denervation. Single-fiber elec-
stimulation, it may take between 10 seconds and 1 minute for the tromyography reveals an increase in both jitter and fiber den-
CMAP again to return to baseline values. Of interest, delivering sity, suggesting remodeling of the motor unit most likely as a
a second train of stimuli as soon as the CMAP has returned to result of a myogenic and not neurogenic process.
normal after the first decrementing responses results in little, if Treatment. There is no treatment available clearly shown to
any, decrement. Stimulation or exercise appears to repair any improve muscle strength. A small pilot study of dehy-
further decrement once the initial decrement is expressed and re- droepiandrosterone sulfate (DHEAS) in 11 patients with DM1
covered. The above findings may be duplicated by asking the pa- seemed to be beneficial in a few patients. 985 Obviously, larger,
tient to maximally contract a muscle for about 10 seconds and prospective, blinded, controlled trials are necessary before com-
then eliciting a single supramaximal CMAP and comparing it menting on the possible efficacy of DHEAS. Myotonia rarely
with a pre-exercise stimulus.974 Patients with DM1 may have a warrants treatment. In fact, some drugs that improve myotonia
smaller CMAP after the exercise.327 The short exercise test635 on such as quinine, procainamide, and tocainide can potentiate car-
patients with DM1 usually demonstrates a smaller than normal diac arrhythmias and should be avoided. If myotonia is severe
increase in CMAP amplitude during and after exercise.545 enough to require treatment, phenytoin or mexiletene.391-393-6443
The needle electromyographic examination reveals two The authors obtain yearly electrocardiograms to monitor for
major abnormalities. The MUAPs in the distal and some proxi- evidence of conduction defects/arrhythmias and right-sided heart
mal muscles in long-standing disease demonstrate reduced du- failure due to pulmonary hypertension. Cardiology consultation,
ration and amplitude as well as increased polyphasia. Also, 24-hour Holter monitoring, and echocardiograms are ordered in
large action potentials can occasionally be found in severely af- patients with significant EKG abnormalities. Some patients will
fected muscles. 719 Recruitment is usually early in that a small ultimately require anti-arrhythmic medication or pacemaker in-
amount of force production results in multiple small-duration sertion. Patients with myotonic dystrophy are at risk for pul-
MUAPs being generated. These findings can certainly be ex- monary and cardiac complications from general anesthesia and
pected given both the muscle fiber atrophy and increase in fiber neuromuscular blocking medications.10-110-422'423-615 These agents
size variation documented on muscle biopsy. should be avoided if possible. Pulmonary function tests are rou-
The second major finding is the observation of trains of my- tinely performed. The authors obtain overnight polysomnogra-
otonic potentials (Fig. 27-15). Insertion of the needle, tapping phy in patients with symptoms and signs of cor pulmonale or
the skin adjacent to the needle insertion point, asking the patient sleep apnea. Patients with significant hypoventilation or sleep
to voluntarily contract the examined muscle, or stimulating the apnea may benefit from non-invasive ventilatory assistance with
muscle's nerve electrically with a brief pulse all can produce a BIPAP. Some patients require excision of their cataracts. Braces
sustained run of single muscle fiber activity outlasting the incit- are indicated in patients with foot-drop to assist their gait.
ing stimulus. In myotonic dystrophy, lowering the limb temper- One of the most important services clinicians can provide is
ature does not serve to enhance one's ability to detect these genetic counseling. Patients need to know that the risk of pass-
potentials. It is possible to observe this "electrical" myotonia ing the disease on to their children is 50% with each pregnancy.
Further, the disease severity is generally worse from one gener-
ation to the next, especially in children born to mothers with
myotonic dystrophy. Prenatal diagnosis is possible via amnio-
centesis or chorionic villus sampling.
Proximal Myotonic Myopathy
Clinical Features. Proximal myotonic myopathy
(PROMM) is a multisystem, autosomal dominant disorder
characterized by proximal muscle weakness, myotonia, myal-
Figure 27-/5. Myotonic discharge. A single myotonic discharge is gias, and cataracts.644-697-698-850-852-909-1022 These features can occur
depicted. Note the waxing and waxing characteristics of the wave- singly or in various combinations. Onset of symptoms usually
form's amplitude and discharge rate. develops between 20 and 60 years of age, although childhood
onset has been noted. The initial complaint is often intermittent Histopathology. Muscle biopsy reveals non-specific myopathic
stiffness of the thigh muscles of one or both legs and of grip my- features. There is a mild to moderate increase in central nuclei.
otonia. In contrast to patients with myotonic dystrophy, patients Variability of fiber size with hypertrophy of type 2 fibers is seen. In
with PROMM complain of myotonia or "stiffness." Some pa- contrast to myotonic dystrophy, selective type 1 fiber atrophy, sar-
tients notice myotonia in the muscles of mastication or in the coplasmic masses, and ringed fibers are not usually present.
neck. Myotonia can also be demonstrated in the eyelids with a Molecular Genetics and Pathogenesis. Early linkage stud-
lid lag following forced eye closure. Brief generalized myotonia ies established that PROMM is not caused by mutations in the
may develop after performing a quick strenuous activity, i.e., myotonin protein kinase gene on chromosome 19, the sodium
following jumping exercises. The myotonia is variable and not channel on chromosome 17, or the chloride channel on chromo-
always present. Myotonia can initially present or exacerbate some 7.851 Subsequently, PROMM was linked to chromosome
during pregnancy. 7253 There is an associated "warm-up" phe- 3q21.3.644a-852-909 DM2 was previously localized to the same
nomenon with decreased myotonia following repeated muscle region, suggesting that these two disorders are allelic or caused
contractions. The myotonia does not exacerbate with cold tem- by closely linked genes. 8321023 There is evidence of genetic het-
perature, although a few patients have described worsening of erogeneity as not all kinships with PROMM/DM2 have linked to
symptoms with warm temperatures.891 the 3q21.3 locus.6443-11133
Many patients describe occasional disabling burning, tearing, In vitro analysis of muscle fibers in two patients with PROMM
or jabbing pains in the thighs, shoulders, and upper arms. The demonstrated normal resting membrane potentials and normal chlo-
pain is not related to the myotonic stiffness of the muscles. ride conductance.344-850 These findings contrast with the decreased
Some patients describe peculiar chest pains. These muscle pains resting membrane potential seen in myotonic dystrophy and the re-
usually develop later in the course of the illness but can be the duced chloride conductance evident in myotonia congenita.
initial complaint. The muscle pains are variable and can be Lowering the extracellular potassium concentrations increased the
severe one day then absent for several weeks. myotonic discharges of these muscle fibers, and vice versa.850
Slowly progressive proximal weakness develops in the major- Electrophysiologic Findings. Routine motor and sensory
ity of patients. Weakness begins in the legs but can later involve nerve conduction studies are normal. In contrast to myotonic dy-
the neck and upper arms. The distal limb and facial muscles are strophy, immediately following 1 minute of exercise, baseline
normal or only mildly affected. A few patients describe fluctua- amplitude and area of CMAPs in PROMM mildly increase
tions of their weakness.851 Episodes of increased weakness last- rather than transiently decrease.892 However, the exercise test has
ing hours or weeks can occur. During these periods of increased been described only in two patients with PROMM and the data
weakness, repeated activity can lead to transient improvement in are insufficient to allow discrimination from normals, much less
strength. Most patients do not have significant atrophy early in other myotonic disorders. Repetitive stimulation of distal limb
the illness. However, a few patients develop considerable atro- muscles at low and high frequencies has demonstrated no signif-
phy of proximal muscles late in life. Calf hypertrophy has been icant increment or decrement.892 However, repetitive stimulation
noted in some patients, which was asymmetric in a few cases. A at Erb's point recording from the deltoid muscle revealed a
few patients have had episodes suggestive of myoglobinuria. decrementing response in one patient at low and fast rates of
Symptoms and severity can vary within families. It is unclear stimulation. The short exercise test635 on patients with PROMM
whether or not anticipation is a feature of PROMM. In 27 may demonstrate a normal increase in CMAP amplitude during
living parent-offspring pairs from 10 families observed, a dis- exercise but an abnormal decrement following exercise.545
ease-onset age difference of 18.8 years was noted. 851909 The Needle electromyography can reveal myotonic discharges in
mean disease onset interval was greater in father-offspring com- all muscles even in patients without clinical myotonia.5333 These
pared with mother-offspring pairs. However, in contrast to myotonic discharges, however, can be difficult to detect in some
DM1, anticipation in PROMM is much milder and a congenital patients. Despite the prominent proximal muscle involvement
form does not seem to occur.909 clinically, electrical myotonia is often more easily detected in
Associated Manifestations. Cataracts indistinguishable from distal muscles. Warming the limbs induced frequent myotonic
those in myotonic dystrophy are common in PROMM. These discharges and fibrillation potentials in the deltoid of two pa-
cataracts appear usually before the age of 50 years and have even tients.891 In contrast, the prominent myotonic discharges and fib-
developed in patients in their late childhood. Testicular atrophy rillation potentials present at baseline in the first dorsal interossei
with gonadal insufficiency has been reported in a few males. abated with cooling. Complex repetitive discharges and brief runs
Likewise, cardiac arrhythmias have also been described in a few (up to 1 second) of very high frequency (180-250 Hz) single-
patients. Unlike myotonic dystrophy, most series have not reported spike discharges similar to neuromyotonia have also been de-
an increased incidence of alveolar hypoventilation in patients with scribed.851 MUAPs have been reported as showing "mild
PROMM. However, there are a few patients described with clini- myopathic changes."8511061 Quantitative electromyography in two
cal features of sleep apnea.891 There does not appear to be a signif- patients revealed small-duration MUAPs in the first dorsal in-
icant association with mental retardation. However, Hund and terossei but normal MUAPs in the deltoid muscles.891
colleagues described three families with PROMM-associated MRI Treatment. There is no specific treatment for the muscle
white matter abnormalities in some patients.4673 In addition, some pain, myotonia, or weakness associated with PROMM. The
of the affected individuals had stroke-like symptoms, seizures, muscle pain occasionally improves with carbamazepine. 698
parkinsonian features, and hypersomnia. None of the reported pa- There are insufficient data available to comment on the utility of
tients have had gastrointestinal hypomotility. Late-onset deafness antimyotonia agents, but trials of mexiletine, phenytoin, and ac-
was described in one kinship with atypical PROMM.1061 etazolamide deserve consideration. 698891 Cataracts may need
Laboratory Features. Serum CK levels are often mildly el- surgical excision. It seems prudent to monitor patients carefully
evated. White matter abnormalities on MRI have been described during surgery and the postoperative period. One patient with
in one reported series involving three distinct kinships, albeit PROMM developed increased muscle pain, myoglobinuria, and
with atypical clinical features. transient renal insufficiency after minor surgery.851
Table 27-4. Clinical Features of the Non-Dystrophic Myotonias
Unknown Mechanism Chloride Channel Sodium Channel Myotonia Sodium Channel Myotonia
for Myotonia Myotonia w i t h Periodic Paralysis w i t h o u t Periodic Paralysis
Paramyotonia Acetazolamide
Congenita with Hyperkalemic Responsive
Proximal Myotoniia Recessive Hyperkalemia Periodic Sodium
Clinical Myotonic Myotonic Congenita Generalized Paramyotonia Periodic Paralysis Channel Myotonia
Features Dystrophy Myopathy of Thomsen Myotonia Congenita Paralysis with Myotonia Myotonia Fluctuans
Inheritance Dominant Dominant Dominant Recessive Dominant Dominant Dominant Dominant Dominant
Gene C h r o m o s o m e 19; Unknown Chromosome Chromosome Chromosome Chromosome Chromosome Chromosome Chromosome
defect C T G expansion 7; a f f e c t s 7; a f f e c t s 17; affects 17; a f f e c t s 17; a f f e c t s 17; a f f e c t s 1 I7;affectsl
affecting a skeletal muscle skeletal m u s c l e skeletal skeletal skeletal skeletal skeletal
protein kinase; chloride chloride muscle muscle muscle muscle muscle
repeat size channel channel sodium sodium sodium sodium sodium
ranges from chennel channel channel channel channel
50 to > 2000;
normal 5-37
repeats
Myopathy Face, eyes, Mild; thighs, Muscle Occasional Very rare Rare Infrequent Rare Rare; muscle
forearm, hands, hips, n e c k , hypertrophy muscle wasting hypertrophy
a n d legs, w i t h flexors; frequent; no and weakness common
generalized occasional myopathy can occur
weakness and calf m u s c l e although late; hyper-
h y p o t o n i a in hypertrophy variants un- trophy of
affected commonly muscles fre-
infants develop quently o c c u r s
weakness in legs
Myotonia Primarily affects M a i n l y in Generalized Generalized Especially Especially Especially Face, paraspinal Face, limbs,
hand and f o r e - hands and stiffness, e s - stiffness, e s - paradoxical paradoxical paradoxical muscles, para- eyelids;
arm muscles. thighs; varies; pecially after pecially after myotonia of myotonia of myotonia of doxical myo- frequently
and tongue; frequently rest; improves rest; transient the eyelids, t h e eyelids, the eyelids tonia of f l u c t u a t e s in
occasionally hard to with exercise; w e a k n e s s is and grip and grip . eyelids, grip. severity.
affects r e s p i r a - d e t e c t ; pain prominent prominent limbs; varies especially
tory muscles occurs some- myotonia of after c o m p l e t e in s e v e r i t y after
and s m o o t h times with eye closure, relaxation for and often exercise
muscle, s u c h as and w i t h o u t but n o t several minutes; t h e r e is p a i n
intestine o r myotonia paradoxical myotonia occurs with myotonia
uterus myotonia in e y e s ; n o p a r a -
doxical myotonia
Provocative Myotonia Myotonia Prolonged rest Prolonged rest o r Cold exposure Oral potassium Rest after Fasting, c o l d , Exercise-rest-
stimuli w o r s e n e d by w o r s e n e d by o r mainten- maintenance of f o l l o w e d by load, rest after exercise, cold. oral potassium. exercise, oral
rest and cold; rest, but varies ance of the the s a m e posture e x e r c i s e leads exercise mainly oral potassium infection potassium
m y o t o n i a is in s e v e r i t y . same posture t o local paraly- in m o r n i n g
relatively occasionally sis; occasionally (hyperkalemic
c o n s t a n t in being a b s e n t exercise pro- weakness), cold
severity and o n clinical v o k e s stiffness, exposure
muscles examination. but cold does f o l l o w e d by
affected H a n d grip a n d not cause exercise
thigh s t i f f n e s s weakness (focal paralysis)
are usual sites
Therapy Bracing; cataract Cataract re- Exercise; Exercise, especially Mexiletine, mild Mild e x e r c i s e , Thiazides, - Acetazolamide, Mexilitine,
for removal; moni- moval; o c c a - antimyotonia avoiding p r o - exercise, keep thiazides. acetazolamide. mexiletine, avoid high
symptoms toring arrhyth- sional n e e d t h e r a p y , e.g., longed rest; patient w a r m mexiletine, sodium m o n i t o r during potassium
. mias and for p a c e m a k e r ; mexiletine; antimyotonia tocainide restriction and after diet, m o n i t o r
respiratory anti m y o t o n i a Achilles t h e r a p y , e.g.. s u r g e r y for during and
insufficiency; therapy often tendon mexiletine; rigidity a n d after s u r g e r y
pacemaker; not necessi- stretching transient rhabdomyolysis f o r rigidity
antimytonia sary (pheny- helps pre- weakness does and r h a b d o -
therapy (phenytoin, mexiletine, vent n e e d for not improve myolysis
toin, mexiletine); acetazolamide); heal cord- after mexiletine
avoid depolar- monitor care- lengthening
izing m u s c l e fully d u r i n g a n d surgery
relaxants and after s u r g e r y
barbiturates, for m u s c l e
with surgery rigidity a n d
f o r all o f rhabdomyo-
these myotonic lysis
disorders
M o d i f i e d f r o m M o x l e y R T III: M y o t o n i c d i s o r d e r s in c h i l d h o o d . D i a g n o s i s a n d t r e a t m e n t . J C h i l d N e u r o l 1997; 12:116-129, w i t h permission.
NON-DYSTROPHIC MYOTONIAS AND sodium channel (paramyotonia congenita, hyperkalemic and

CHANNELOPATHIES normal kalemic periodic paralysis, myotonia fluctuans, and so-
called acetazolamide-responsive myotonia congenita). Hyper-
kalemic and normal kalemic periodic paralysis as well as
There are several inherited myopathic disorders associated paramyotonia congenita is associated with episodes of tran-
with clinical or electrical myotonia in which muscle tissue is sient generalized or focal weakness. Hypokalemic periodic
not dystrophic. These disorders have been found to be caused paralysis is not associated with myotonia clinically or electri-
by mutations in the chloride channel (myotonia congenita) or cally but is also a "channelopathy," being caused by mutations
in the dihydropyridine receptor (a type of calcium channel) of vary in their firing rates, amplitudes, and rise times. The typical
muscle cells. Thus, it is reasonable to discuss these disorders to- pattern is for a single muscle fiber to begin firing at a high rate
gether (Table 27-4). with a relatively large amplitude and over the course of seconds
to minutes decrease in amplitude and slow in its rate of firing.
CHLORIDE CHANNELOPATHIES Additionally, it is not unusual for the morphology of the poten-
tial to change from a triphasic spike potential to one that resem-
Myotonia Congenita (Autosomal Dominant Form: bles at least superficially a positive sharp wave. These potentials
Thomsen's Disease) can be found in any limb muscle, although some muscles may
Clinical Features. Autosomal dominant myotonia con- demonstrate a lower threshold for this type of irritability than
genita is an inherited disease of muscle that was initially de- other muscles. Axial muscles can also reveal myotonic bursts,
scribed by Dr. Asmus Julius Thomsen, a Danish physician with but the degree and amount of electrical myotonia are less than
the disease.55-421-425-569-822 Symptoms usually occur in the first 2 those encountered in the limbs. Reducing the muscle's tempera-
years of life. Infants are noted to have difficulty opening their ture does not result in an exacerbation of the clinical or electri-
eyes as well as facial distortion after a crying spell. The legs cal myotonia or the production of weakness.844-979-981
appear stiff during the first few steps, causing the affected chil- Needle electromyographic examination demonstrates normal
dren to occasionally fall. As patients become older, they com- MUAP morphology and recruitment as expected given the
plain of muscle stiffness or myotonia of the upper or lower above-noted mild histologic changes.979 It may be quite hard to
limbs as well as facial muscles, particularly the eyelids and lips. critically evaluate MUAP characteristics in some individuals
Unlike patients with PROMM, patients with myotonia con- secondary to the action myotonia, which can be rather signifi-
genita do not complain of muscle pain. In patients with severe cant. Even attempts at mild voluntary contraction can result in
myotonia, impaired mastication and swallowing of food may be the production of florid myotonic discharges. Occasionally, fib-
noted. Myotonia diminishes with repeated contractions, the so- rillation potentials and positive sharp waves can be appreciated
called warm-up phenomenon. A typical example is when a pa- when the electrical myotonia abates. Single-fiber electromyo-
tient with myotonia congenita attempts to walk or run. At first, graphic recordings reveal a normal fiber density with a mild in-
the patient has some difficulty with a lack of lower limb mobil- crease in jitter and occasional blocking.
ity secondary to muscle tightness; however, within a short time,
walking becomes easier and the patient can eventually run with- Myotonia Congenita (Autosomal
out any problems. After rest, the same stereotypical pattern re- Recessive Form: Becker Type)
turns on attempted running. Clinical Features. There is considerable overlap between
Physical examination often reveals an individual with consid- the autosomal recessive form of myotonia congenita and the au-
erable muscle bulk appearing as someone who regularly lifts tosomal dominant form as well as distinct differences. The age
weights. Aside from the myotonia elicited through the percus- of onset in patients with the autosomal recessive or Becker type
sion with a reflex hammer (percussion myotonia), or sec- of myotonia congenita is between the ages of 4 and 12 years of
ondary to voluntary muscle contraction (action myotonia), the age, somewhat later than that seen in the autosomal dominant
physical examination including muscle strength, sensation, and form.569-822 However, the severity of the myotonia is worse in the
deep tendon reflexes is normal. The life span is not adversely recessive form and gradually increases during the first two
affected, and unlike myotonic dystrophy, there are no systemic decades of life. Patients note a profound stiffness in the lower
disorders associated with the disease. The severity of the my- compared with upper limbs especially involving the proximal
otonia can vary within family members and may even fluctuate more so than distal muscles. Transient muscle weakness may
in affected individuals.1092 occur following rest. Patients often use tricks, e.g., shuffling
Laboratory Features. Serum CK is normal or only slightly around with the legs before standing up after a long rest.
elevated. Repetitive contractions improve this phase of transient pare-
Histopathology. Muscle biopsies demonstrate mildly in- sis.1155 The gluteal and leg muscles often appear hypertrophic,
creased variability in fiber size, increased central nuclei, and while the neck, shoulder, and arm muscles are less well devel-
absent type 2B muscle fibers.739 Scattered tubular aggregates are oped. Some patients develop mild fixed muscle weakness and
occasionally noted. atrophy of distal limb and occasionally proximal muscles in-
Electrophysiologic Findings. As one might expect, routine cluding neck flexors. A hyperlordotic posture is evident in some
motor and sensory nerve conduction studies are normal. The individuals. Sensation is normal. The deep tendon reflexes may
short exercise test may demonstrate a mild increase in CMAP be mildly depressed, particularly at the ankles. Systemic com-
amplitude during exercise and a reduction of the CMAP ampli- plications (e.g., cataracts, endocrinopathies, cardiopathy, pul-
tude following exercise of the muscle.545-635 Of note, repetitive monary abnormalities) similar to those of myotonic dystrophy
nerve stimulation results in a decrement similar to that de- are not evident in the recessive form of myotonia congenita.
scribed above in persons with myotonic dystrophy. However, Laboratory Features. Serum CK level is usually increased
the decrement is not usually observed until a prolonged train of two to four times normal.542
stimuli is delivered at 10 Hz or more. In these cases, a maximal Histopathology. The muscle biopsy in the recessive form of
CMAP decrement may reach 65%. 1 5 1 , 9 The decrement is myotonia congenita demonstrates features similar to those seen
greater at higher frequencies. in the autosomal dominant form.70-739
The most prominent electrophysiologic abnormalities are my- Electrophysiologic Findings. Routine motor and sensory
otonic discharges at rest and during volitional activity. Both the nerve conduction studies are normal. Significant decrement of
routine needle examination and single-fiber recordings demon- the CMAP can be demonstrated on repetitive stimulation even
strate single muscle fiber action potentials firing repetitively. at 2 Hz. The decrementing response is apparently easier to
This repetitive firing is thought to be a result of abnormal chlo- obtain in the autosomal recessive compared with dominant form
ride ion conductance in the muscle membrane. These potentials of myotonia congenita and may worsen with time.15-974 The
short exercise test may demonstrate a mild increase in CMAP from inactivation. Thus, despite the fact that the muscle mem-
amplitude during exercise and a reduction of the CMAP ampli- brane may still be partially depolarized, uncontrolled bursts
tude following exercise of the muscle.545-635 Surface EMG of action potentials or myotonia occur. 448 The use-dependent
recording during volumtary contractions showed a strong de- potassium accumulation in the T-tubule is required to gener-
cline in force and EMG amplitude that was accompanied by a ate these myotonic discharges.
sharp fall in the muscle fiber conduction velocity pointing to a Treatment. Most patients with myotonia congenita do not
failing membrane conduction as the cause of the transient pare- require medical treatment. When the myotonia is severe and
sis. These phenomena improved with successive contrac- limits function, antiarrhythmic and antiepileptic medications,
tions. 1155 Needle electromyography of essentially all muscles which interfere with the muscle sodium channel, can be benefi-
reveals profound myotonic discharges.70-990 The pathophysiol- cial. Mexiletine, tocainide, quinine, procainamide, phenytoin,
ogy of these potentials is similar to the autosomal dominant and carbamazepine have all been used successfully to treat my-
form in that an abnormality in chloride conductance is pre- otonia. Tocainide can cause bone marrow suppression and inter-
sent.345 Given the above-noted muscle histopathology, it is not stitial lung disease and, therefore, is no longer recommended.
surprising that short-duration, small-amplitude MUAPs can be Dantrolene blocks the release of calcium from the sarcoplasmic
detected in the muscles of the upper and lower limbs, with a reticulum and reduces muscle stiffness associated with myoto-
variable prominence in proximal versus distal muscles from pa- nia. The authors have found the most success with mexiletine,
tient to patient. It is particularly difficult to quantitatively evalu- which reduces not only the myotonia, but also, to a lesser
ate MUAPs in patients with this form of myotonia congenita degree, the transient weakness that can occur in autosomal re-
because of the propensity to develop florid myotonic potentials cessive myotonia congenita. We obtain a baseline electrocardio-
with insertion and movement of the needle electrode. Detecting gram and a cardiology consultation, if there are conduction
myotonic discharges in family members of known patients with abnormalities prior to starting mexiletine. Treatment is initiated
the disease may be of benefit in identifying persons who are as with mexiletine 150 mg daily and gradually increased as toler-
yet asymptomatic. 1144 ated and as necessary to control the symptoms to a maximum of
Molecular Genetics and Pathogenesis of Myotonia 300 mg TID. The major side effects of mexiletine are lighthead-
Congenita. Both the autosomal dominant form (Thomsen) edness, diarrhea, and dyspepsia.
and recessive form (Becker) of myotonia congenita have been
linked to mutations in the muscle chloride channel gene SODIUM CHANNELOPATHIES
(CLCN1) on chromosome 7q35 (Fig. 27-1 6).368-530-569-593-822
There is an atypical painful variant of "myotonia congenita" Potassium-sensitive or hyperkalemic periodic paralysis,
that is clinically and genetically distinct and caused by muta- paramyotonia congenita, and the potassium-aggravated myotonias
tions in the muscle sodium channel (discussed later). The (e.g., myotonia fluctuans, myotonia permanens, and acetazo-
muscle chloride ion channel is responsible for the high rest- lamide-responsive myotonia) are autosomal dominant myopathies
ing membrane conductance of skeletal muscle cells. 448 with clinical similarities as well as important clinical differ-
Structurally, the chloride ion channel is thought to be a ho- ences (Table 27-4).'53-393-568-569-819 In the past few years, these dis-
motetramer with each subunit having approximately 1000 orders have been demonstrated to be allelic and caused by
amino acids and encoded by the CLCN1 gene.569-593 Mutations mutations within the a subunit of the voltage-dependent
of the CLCN1 gene result in the loss of function of the chlo- sodium channel (SCN4A) encoded on chromosome 17q23-25
ride ion channel and reduction in chloride conductance. (Fig. 27-17). 153 - 3 ' 2 . 340 ^ In addition, familial hy-
Because chloride ions are responsible for 70% of the skeletal pokalemic periodic paralysis, a myopathy usually the result of
muscle resting membrane potential, defects of the chloride mutations in the dihydropyridine receptor gene (CACNLIA3) of
channel reduce the rate of action potential repolarization. the calcium channel, may also be caused by mutations in
This allows sufficient time for sodium channels to recover SCNA4.l34-492a-970
C00H
Figure 27-/6. Chloride channel and mutations.The voltage-gated chloride channel is shown and contains 12 hydrophobic segments.These
proteins are thought to form homodimers.The locations of recognized mutations causing myotonia congenital are shown. (From Ptacek LJ:The fa-
milial periodic paralyses and nondystrophic myotonias. Am J Med 1998; 105:58-70, with permission.)
Q hyper KPP
: • Paramyotonia congenita
Q Potassium aggravated myotonia
O Other
Figure 27-17. Sodium channel and mutations.The recognized sodium channel mutations resulting in hyperkalemic periodic paralysis,
paramyotonia congenita, and potassium-aggravated myotonia are shown. (From Ptacek LJ:The familial periodic paralyses and nondystrophic my-
otonias. Am J Med 1998; 105:58-70, with permission.)
Potassium-Sensitive or Hyperkalemic Periodic affect swallowing and coughing. As with all periodic paralyses,
Paralysis (Adynamia Episodica Hereditaria) the sphincter muscles are well preserved during attacks.
Between attacks, sensation and deep tendon reflexes are normal.
Clinical Features. Primary hyperkalemic periodic paraly- During attacks, the reflexes are diminished or absent, whereas
sis is transmitted in an autosomal dominant fashion, and there sensation remains normal. Some patients develop fixed weak-
is a high degree of penetrance in both females and ness usually involving the more proximal muscles after many
m a l e s 109.153.163.362,391-393,568.569,629,819,877,878,906 The authors prefer the
recurrent attacks of weakness.
Hyperkalemic periodic paralysis can occur in three forms: (1)
term potassium-sensitive periodic paralysis, because attacks without myotonia, (2) with clinical or electrical myotonia, or (3)
of weakness are not necessarily associated with hyperkalemia associated with paramyotonia congenita (also called paralysis pe-
in all patients. However, all patients are sensitive to potassium, riodica paramyotonica). The course of the attacks of weakness is
as they can become weak when given potassium. In the majority the same in all three forms, except that cooling more commonly
of patients, symptoms manifest within the first decade of life. provokes weakness in patients with paramyotonia congenita.
Attacks of weakness usually develop in the morning but can Clinical myotonia is usually mild. Myotonia can be elicited in the
occur at any time and are precipitated by rest following exercise face/eyelids, tongue, finger extensors, and the thenar eminence
or fasting. Paresthesia and a sense of heaviness in the legs or with percussion or activity. Patients with paramyotonia congenita
small of the back herald the onset of an attack in some individu- exhibit paradoxical myotonia in which muscle stiffness is induced
als. The weakness then manifests in the thighs and calves to or worsened by exercise or cold temperature.
progress and involve multiple other muscles. Weakness can also Provocative testing can be performed when the diagnosis is not
be focal. Unlike hypokalemic periodic paralysis (discussed clear. Provided the patient has no significant underlying cardiac
later), there is rarely generalized flaccid paralysis. Attacks of or renal disease, a potassium load can be administered in order to
weakness can be mild or severe, with the latter more common increase the serum potassium levels to see if an attack can be pro-
following strenuous activity. Sustained mild exercise after a voked.393 The patient's strength, electrolytes, and cardiac function
period of strenuous activity may postpone or prevent weakness (EKG) need to be closely monitored during the study. With ge-
from developing in the exercising muscles, while resting muscle netic testing now commercially available, provocative testing
groups become weak. The duration of weakness is usually less usually is not necessary to confirm a diagnosis.
than 2 hours, although mild weakness can persist for a few days. Secondary hyperkalemia can cause generalized weakness
The frequency of attacks is highly variable, with some persons mimicking primary hyperkalemic periodic paralysis and must
afflicted several times a day, whereas others experience diffi- be excluded particularly in patients with no family history
culty once a year. In addition, there is great variation of attack (Table 27-5). Generalized weakness is usually associated with
severity and frequency within and between families. The fre- serum potassium levels greater than 7 mEq/L. Patients with sec-
quency of paretic attacks often decreases with age. Pregnancy, ondary causes of hyperkalemia do not exhibit clinical or electri-
stress, and corticosteroids can provoke or worsen an attack. cal myotonia.
Following a bout of weakness, it is not uncommon for pain to Laboratory Features. Between attacks of weakness, serum
be experienced in the affected muscles up to several days. In potassium levels are normal. The attacks of weakness are usually
some persons, the degree of weakness may be severe enough to
Table 27-5. Etiologies of Secondary Hypokalemic and mildly elevated in patients even between attacks of weakness.
Hyperkalemic Paralysis Increased amplitudes of the precordial T waves are occasionally
Hypokalemic Paralysis noted on the EKG secondary to hyperkalemia.
Thyrotoxic periodic paralysis Histopathology. Muscle biopsy in patients with hyper-
Renal tubular acidosis kalemic periodic paralysis frequently reveals vacuoles.653-9701033
Villous adenoma Molecular Genetics and Pathogenesis. Potassium-sensitive pe-
Banter's syndrome riodic paralysis is caused by mutations in the a subunit of the volt-
Hyperaldosteronism age-dependent sodium channel (SCN4A) (Fig. 27-17).569-815-818-822
Chronic or excessive use of diuretics, corticosteroids, licorice Electrophysiologic Findings. Both motor and sensory nerve
Amphotericin B toxicity conduction studies are normal between and during attacks of
Alcoholism weakness. 1061l8-,29-459-56K635-691 The exception is a reduction in the
Toluene toxicity CMAP magnitude during an attack of weakness. Abnormalities
Barium poisoning are apparent during the exercise test (Fig. 27-18).545-635 The test
Hyperkalemic Paralysis is performed by having the patient isometrically exercise a
Addison's disease muscle (e.g., adductor digiti minimi) for 5 minutes while
Hypoaldosteronism (hyporenemic) recording CMAPs every minute during the exercise period and
Isolated aldosterone deficiency for 20 minutes after exercise. During exercise, an increase
Excessive potassium supplementation CMAP amplitude from baseline is usually observed (mean in-
Potassium-sparing diuretics (e.g., spironolactone, triamterene)
crease 35%, range 0-300%) in severely affected persons.635 This
Chronic renal failure
CMAP facilitation is followed by a progressive decline in am-
Rhabdomyolysis
plitude over the subsequent 20 minutes (mean decrease of 48%
from baseline). In normal patients, CMAP amplitudes only
Modified from Griggs RC: Periodic paralyses. Sem Neurol 1983;3:285-292. mildly increase during exercise (mean 11%, range 0-27%) and
mildly decrease within 5 minutes of the recovery period (mean
associated with an increase in serum potassium levels (up to 5-6 15%, range 0-30%).
mmol/L). However, serum potassium levels can remain within The needle electromyographic examination findings are quite
normal limits during bouts of paralysis as noted above. During interesting and depend on the form of the disease, i.e., with or
the attacks, urinary excretion of potassium increases. In contrast without myotonia. In patients with clinical myotonia, examina-
to serum potassium levels, serum sodium levels decrease during tion of muscle between attacks of weakness reveals an increase
the attacks. At the end of an attack, diuresis and transient hy- in insertional activity with mild to moderate amounts of sponta-
pokalemia commonly occur. Serum C K levels can be normal or neous potentials provoked by needle movement or voluntary
contractions. The spontaneous potentials consist of the antici-
pated runs of myotonic potentials. Myotonic discharges can also
15 be seen in patients without apparent clinical myotonia. A few
patients may have minimal myotonic findings except for a short
period prior to developing weakness and the ensuing reduction
39% in electrical activity. There are also "fibrillation potentials" and
> increase
"positive sharp" waves noted in these patients. It is important to
62% decrease keep in mind that these spontaneous single-fiber discharges
(fibrillation potentials and positive sharp waves) are not indica-
tive of denervation in these individuals. Rather, they merely re-
flect the underlying hyperexcitability or instability of the
/ muscle membrane. A reduction in limb temperature may exac-
erbate the runs of myotonic potentials, and the positive sharp
5 minutes
exercise waves and fibrillation potentials do not disappear. Analysis of
1 1 i i i i i i i i MUAP parameters may reveal either normal potentials or a
0 5 15 25 35 45 55 slight increase in the percentage of small-duration, polyphasic
Minutes after exercise
potentials. If an attack of weakness is provoked during the ex-
amination, there may be a slight initial increase in spontaneous
Figure 27-/8. The exercise test. The hand is immobilized, and activity followed by a reduction in all electrical activity includ-
ulnar CMAPs are recorded following stimulation at the wrist. Several ing both spontaneous and voluntary. The number of MUAPs
baseline CMAPs are obtained.The patient is then asked to isometri- detected decreases, and the recruitment pattern may be reduced to
cally exercise the muscle for 5 minutes with brief rest periods (about just a few motor units of normal or short duration firing rapidly.
5 seconds) every 20 seconds. Ulnar CMAPs are recorded every In patients with hyperkalemic periodic paralysis without my-
minute during the exercise period and then for 20-25 minutes after otonia, the insertional activity is normal. Specifically, needle
exercise. Normal patients may have a mild increase in amplitude (mean movement or voluntary contraction does not provoke the ap-
I I %) during exercise and a slight decrease in amplitude following ex- pearance of fibrillation potentials, positive sharp waves, or my-
ercise (mean 15%). Patients with various forms of periodic paralysis otonic potentials. During an attack of weakness, instead of even
demonstrate exaggerated increase in amplitude during exercise and a transitory increase in membrane excitability, there is a pro-
decrementing amplitude following exercise.The figure demonstrates gressive reduction in the electrical activity detected. Not only
the abnormal exercise test in a patient with periodic paralysis. (From do the MUAPs decrease in numbers, but also the MUAP dura-
McManis PG, Lambert EH, Daube JR:The exercise test in periodic tion and amplitude decrease. There may be a transitory increase
paralysis. Muscle Nerve 1986;9:704-710, with permission.) in the number of polyphasic potentials observed. In patients
with profound weakness, complete electrical silence may be ob- also results in the overt myotonia, which in some patients devel-
served in some muscles with respect to voluntary MUAPs. If a ops into either focal or a more generalized weakness. The facial,
needle is located in the end-plate zone, end-plate noise and hand, pharyngeal, and tongue muscles are most sensitive to this
spikes should still be observed, although the amplitude of the phenomenon. Patients who live in cold climates may note an in-
spike may be somewhat decreased secondary to a limited crease in exercise-induced muscle contraction leading to weak-
amount of excitable membrane. In some patients, there may be ness during the shoveling of snow, for example. There may be
a mild increase in the number of short-duration, polyphasic an occasional patient who complains of hand weakness when
MUAPs with a decreased duration suggesting a mild and persis- shopping in the frozen food section of the supermarket.
tent myopathy. Occasionally, this weakness may progress to flaccid paralysis of
Treatment. Preventive therapy with a low-potassium, high- the muscle or of a larger body segment. A cold-induced attack
carbohydrate diet and avoidance of fasting, strenuous activity, can last for several hours even after return to a warm environ-
and cold is recommended. The acute attacks of weakness are ment. Weakness can be induced in some cases by potassium
often mild in severity, short lasting, and do not require treat- intake.
ment. Ingestion of simple carbohydrates (e.g., fruit juices, glu- Percussion myotonia can be demonstrated, though usually is
cose-containing candies) result in insulin excretion, which not prominent. Paramyotonia, particularly of the eyelids, is typ-
diminishes serum potassium levels and can improve strength. ically evident in most patients. Myalgias are not a common
Beta-adrenergic agonists (e.g., metaproterenol, albuterol, salbu- complaint. Muscle strength is normal in patients between at-
tamol) can be effective in improving strength and used safely tacks of paralysis and in those with pure paramyotonia con-
provided there are no associated cardiac arrhythmias. The effect genita, as are the deep tendon reflexes and sensory examination.
of beta-adrenergic agents is probably mediated via the sodium- Laboratory Features. Serum CK levels can be mildly to
potassium pump. Only rarely with severe attacks is treatment moderately elevated. Serum potassium levels may be elevated
with intravenous glucose, insulin, or calcium carbonate indi- in some patients during an attack of paralysis.
cated. Prophylactic treatment with acetazolamide (125-1000 Histopathology. Minimal changes are noted on muscle
mg per day), chlorothiazide (250-1000 mg per day), and biopsy. There may be mild fiber size variation with a mixture of
dichlorphenamide (50-150 mg per day) may be beneficial in re- normal, atrophic, and hypertrophic fibers.7391024 There is usually
ducing the frequency of attacks and may help with myotonia as normal fiber type differentiation, although a few reports have
w e jj Mexiletine has been used to prevent weakness and
393.698.ioi3 suggested a poor degree of muscle fiber type differentiation. A
myotonia induced by cold in patients with associated paramy- few patients may display intracytoplasmic vacuoles, particularly
otonia congenita. those with superimposed periodic paralysis. EM can reveal my-
ofibrillar disarray and intracytoplasmic tubular aggregates.
Normokalemic Periodic Paralysis Molecular Genetics and Pathogenesis. Paramyotonia con-
As noted above, some patients develop weakness during genita with and without episodes of periodic paralysis is caused
which time the serum potassium levels remain normal.653-808 by mutations in the a subunit of the voltage-gated sodium chan-
However, most of the patients develop weakness when given nel (SCN4A) (Fig. 27-17).63,-816-8,8-82° (See below for more de-
potassium. The clinical and electrophysiologic features are sim- tailed discussion regarding the pathophysiology.)
ilar to those observed with hyperkalemic periodic paralysis. Electrophysiologic Findings. Routine sensory and motor
Further, mutations in the muscle sodium channel gene have nerve conduction studies are normal. 976 Prolonged repetitive
been demonstrated in families with normal kalemic periodic stimulation, or repetitive stimulation following a minute or
paralysis. For the reasons discussed above, the authors prefer more of exercise, can induce a decrement in the CMAP in some
the term potassium-sensitive periodic paralysis to hyperkalemic patients at rates exceeding 5 Hz.15-976 Further, if the muscle is
or normal kalemic periodic paralysis. cooled and the patient asked to exercise the muscle, a pro-
nounced (50% or more) decrement in the CMAP can be docu-
Paramyotonia Congenita (Eulenburg Disease) mented in most patients with paramyotonia. If the patient
Clinical Features. Paramyotonia congenita is an autosomal forcefully contracts the hand intrinsic muscles for several min-
dominant disorder with high penetrance, which as noted above utes, the CMAP during and after exercise is often markedly re-
is allelic to hyperkalemic periodic paralysis.153-393-568-569-819-877- duced from baseline and can remain so for prolonged periods,
87H.976.98o j n facti s o r n e kinships have clinical features of both hy- sometimes exceeding an hour.635-730-974-976'977-981
perkalemic periodic paralysis and paramyotonia congenita Needle electromyography reveals normal MUAPs; however,
(paralysis periodica paramyotonica), also as described above. this may be quite difficult to observe secondary to the overt in-
The name derives from the "para"-doxic reaction to exercise. duction of profuse trains of myotonic potentials. 550 The myoto-
In contrast to the warm-up phenomenon observed in the other nia is usually worse in the distal compared with proximal
myotonic syndromes, repeated exercise worsens the muscle aspects of the limbs. In patients with pure paramyotonia con-
stiffness in patients with paramyotonia congenita. Cold temper- genita, cooling the muscle results in increased myotonic dis-
ature also precipitates myotonia and occasionally weakness in charges. However, muscle strength remains normal, as does
individuals with paramyotonia congenita. MUAP morphology and recruitment.
Patients usually display evidence of the disease within the In patients with paramyotonia congenita and periodic paraly-
first decade of life. Infants may be noted to have the disease sis, local cooling of a muscle results in dense fibrillation-like po-
during a crying spell, when they are unable to open the eyes sec- tentials and the gradual reduction in MUAP activity. Electrical
ondary to the "exercise"-induced myotonia of the orbicularis myotonia vanishes, as the muscle becomes flaccid. Complete
oculi muscles. Washing the infant's face with a cold washcloth electrical silence associated with paralysis of the cooled muscle
may result in a cold-induced myotonic spasm of the facial mus- is observed. In contrast, persons with pure paramyotonia con-
cles.55 Symptoms are nonprogressive, and patients either remain genita and myotonia congenita continue to generate a maximal
stable or improve slightly with aging. Decrease in temperature interference pattern with cooling of the muscle.402
Single-fiber electromyography demonstrates a mild increase Myotonia Permanens
in jitter with occasional potential blocking. 597 Also, the fiber Clinical Features. Myotonia permanens is a more severe
density is slightly increased compared with normal. These find- form of myotonia fluctuans.153 878 The myotonia is almost con-
ings indicate a mild remodeling of the motor unit, which is sub- stantly present, although it may exacerbate following exercise.
stantiated by the above-noted histopathologic findings. Patients can develop dyspnea, acidosis, and hypoxia secondary
Treatment. Tocainide and mexiletine prevent the muscle to myotonia of respiratory muscles. Myotonia is aggravated by
stiffness and weakness associated with cold. Mexiletine is the potassium. There are no episodes of weakness or exacerbation
preferred medication because of the side effects associated with of myotonia with cold.
tocainide.483 846 Mexiletine has been demonstrated to correct the Laboratory Features. Serum CK levels are normal or only
cold-induced decrements of baseline CMAPs following exer- mildly elevated.
cise or repetitive stimulation correlating with the observed clin- Histopathology. There are too few reports of myotonia per-
ical improvement. 483 Hydrochlorothiazide is also sometimes manens to comment on the histopathology.
effective in relieving the myotonia.978 Molecular Genetics and Pathogenesis. Myotonia perma-
nens is caused by mutations in the a subunit of the voltage-
Potassium Aggravated Myotonias (Myotonia gated sodium channel (SCN4A). 153
Fluctuans, Myotonia Permanens, and Electrophysiologic Findings. Nerve conduction studies and
Acetazolamide-Responsive Myotonia) electromyography demonstrate features similar to those of my-
The potassium-aggravated myotonias (PAM) are also caused otonia fluctuans.
by mutations in the muscle sodium channel gene and are allelic Treatment. Mexiletine can be tried to ease the myotonia,
to the above described hyperkalemic periodic paralysis and although there is little literature regarding its use.
paramyotonia congenita (Table 27-5). Patients with these disor-
ders have myotonia without episodes of weakness. Acetazolamide-Responsive Myotonia
Myotonia Fluctuans Clinical Features. This disorder was previously known as "ac-
etazolamide-responsive myotonia congenita."820 822 1050 However,
Clinical Features. Myotonia fluctuans is a rare disorder char- this term is a misnomer because the disorder is now known also to
acterized by (1) fluctuating myotonia of varying severity; (2) in- be caused by mutations in the a subunit of the voltage-gated
creased myotonia of delayed onset (several minutes) following sodium channel and not the chloride channel as in myotonia con-
exercise; (3) paramyotonia of eyelids in some patients; (4) warm- genita. Patients develop painful muscle stiffness/myotonia in child-
up phenomenon of myotonia in the limbs; (5) no episodes of hood that is most severe in the face and hands. Severity and
weakness nor weakness following potassium loading, exercise, or frequency increase with age, at least into early adulthood.
cold; and (6) increased myotonia with potassium but not with ex- Myotonia is provoked by fasting, potassium, and to a lesser extent
posure to cold.574-819-822-847-849 The fluctuating nature of the myoto- by exercise. Myotonia is eased by ingestion of high-carbohydrate
nia, and hence the name, is unlike that of myotonia congenita, meals. Examination reveals normal muscle strength. Action myoto-
potassium-sensitive periodic paralysis with myotonia, or paramy- nia of the extraocular muscles, muscles of mastication, and the
otonia congenita. On "good days," patients describe no symptoms. proximal limbs can be observed. Percussion myotonia is evident in
On "bad days," patients have marked stiffness of the extraocular the thenar eminence, more proximal upper limb muscles, and the
muscles, the muscles of mastication and swallowing, and in the tongue. Paradoxic myotonia may be found in the eyelids.
limbs. Exercise can induce such severe myotonia that the patients Laboratory features. Serum CK can be normal or mildly
are immobilized. Administering a potassium load to patients with elevated.
myotonia fluctuans dramatically exacerbates both the clinical and Histopathology. Muscle biopsies have been performed in
electrical myotonia, a finding that does not occur in myotonia con- only a few patients and have been normal or revealed general-
genita, fin contrast to potassium-sensitive periodic paralysis, a ized muscle fiber hypertrophy.
potassium load does not result in weakness in myotonia fluctuans. Molecular Genetics and Pathogenesis. Acetazolamide-re-
Myotonia fluctuans is also unlike the other myotonic disorders in sponsive myotonia has been linked to gene coding for the a sub-
that exercise induces myotonia, which is delayed in onset. Unlike unit of the voltage-gated sodium channel.817-820*822
paramyotonia congenita, patients with myotonia fluctuans are rel- Electrophysiologic Findings. Routine motor and sensory
atively unaffected by the lowering of muscle temperature. studies are normal. Needle electromyographic examination
Laboratory Features. Serum CK levels are normal or only demonstrates significant runs of myotonic potentials, but MUAP
mildly elevated (2-3 times normal). morphology and recruitment are normal.
Histopathology. Muscle biopsies are normal or reveal only Treatment. Acetazolamide is effective in reducing myoto-
mild non-specific abnormalities such as increased central nuclei nia and associated muscle pain. Acetazolamide is started at 125
and fiber size variability.848 EM demonstrated a few subsar- mg per day and titrated as tolerated to 250 mg TID. Mexiletine
colemmal vacuoles in one patient.847 is also affective in some patients.
Molecular Genetics and Pathogenesis. Myotonia fluctuans is
caused by mutations in the a subunit of the voltage-gated sodium Familial Hypokalemic Periodic Paralysis Type 2
channel (SCN4A)819-822-848 (see below for more detailed discussion). Most cases of familial hypokalemic periodic paralysis
Electrophysiologic Findings. Routine motor and sensory (hypoKPP type 1) are caused by mutations in the skeletal muscle
studies are normal. Needle electromyographic examination voltage-gated calcium channel a-1 subunit (CACL1 A3) gene.970
demonstrates significant runs of myotonic potentials in all mus- Several kinships have been identified with mutations in SCN4A,
cles tested. MUAP morphology and recruitment are normal. so-called hypoKPP type 2.,34-492a-970 In a recent series of 45 families
Treatment. Mexiletine is useful in reducing the myotonia with hypoKPP, 40 were linked to mutations in the CACNL1 A3
associated with myotonia fluctuans. Prophylactic treatment in- gene, while 5 had mutations in the SCN4A gene.970 These patients
cludes avoiding high-potassium diet. had an early age of onset (mean 10 ± 3 years), complete penetrance
Figure 27-/9. Cation channel model.Voltage-gated sodium and calcium channels are believed to have similar structures and physiology.
These cation channels have four domains (DI-D4), each containing six transmembrane segments (also see Fig. 27-17).The four domains are
arranged around the ion pore of the membrane.The S4 segments of cation channels contain a repeating motif of positively charged amino acids
(arginine or lysine) at every third position separated by two neutral amino acids. (A) In the closed state the pore is closed and the inactivation
gate is opened. (B) In response to depolarization, the S4 segments move under the influence of electrostatic forces.This conformational shift re-
sults in the opening of the ion pore. (C) Channel closing is thought to result from a "ball-valve" mechanism where the cytoplasmic loop between
domains D3 and D4 (also see Fig. 27-17) falls into the the ion pore, thus blocking it. (D) Upon repolarization, the channel assumes its closed con-
formation and release of the inactivation gate.The channel is now in the closed state (A) and ready to open in response to the next depolariza-
tion. (From Ptacek LJ:The familial periodic paralyses and nondystrophic myotonias. Am J Med 1998; 105:58-70, with permission.)
in men and women by the age of 20 years, and myalgias following tively charged amino acids at every third position, suggesting that
attacks of weakness lasting one to several days. One family had this region serves as the voltage sensor.819 Studies have suggested
heat-induced myotonia and cold-induced paralysis with hy- that the S4 segment is critical for inactivation of the open channel,
pokalemia.986 Unlike hypoKPP type 1 in which muscle biopsies while the S3 segment plays a role in the recovery of inactivated
demonstrate vacuoles, muscle biopsies in patients with hypoKPP channels.878 The S3 and S4 segments interact during the transition
type 2 contain tubular aggregates without vacuoles. Patients with to and from inactivation states. Over 19 different point mutations
hypoKPP type 2 may worsen with acetazolamide treatment, in SCN4A have been described (5 for potassium-sensitive periodic
unlike patients with hypoKPP typel or the postassium-sensitive paralysis, 8 for paramyotonia congenita, and 6 for the various
periodic paralysis caused by SCNA4 mutations.970 potassium-aggravated myotonias). At least 4 distinct mutations (3
potassium-aggravated myotonias and 1 paramyotonia congenita)
Molecular Genetics and Pathogenesis/Pathophysiology are located in the S3 or S4 segments. Seven mutations, including
of the Sodium Channelopathies the two most commonly associated with potassium-sensitive peri-
The voltage-gated muscle sodium channel is a heterodimer con- odic paralysis, are located in the cytoplasmic regions of the S5 or
sisting of a and p subunits that are encoded on chromosomes S6 segments.822 Three mutations associated with paramyotonia
17q23-25 and 19q 13.1, respectively.569-822 Point mutations in the a congenita involve a positively charged amino acid, arginine 1448,
subunit gene, SCN4A, are responsible for hyperkalemic periodic which may serve as part of the voltage sensor that couples activa-
paralysis, paramyotonia congenita, the potassium-aggravated my- tion to inactivation. Thus, 14 of the 19 known mutations are lo-
otonias (Fig. 27-17) and some forms of hypokalemic periodic cated in regions of the a subunit critical for fast inactivation. The p
paralysis. No human diseases have been linked to mutations in the subunit is non-covalently linked to the a subunit and functions to
P subunit. The a subunit is a 260-kD glycoprotein that has four increase the amplitude of the current and speed of inactivation.
homologous domains (I to IV), each containing 225-325 amino Normally, the voltage-gated sodium channels open (activate)
acids (Fig. 27-19).448-819-822 Each of the four domains have six hy- quickly in response to depolarization then close to a fast-inacti-
drophobic segments (S1-S6) that transverse the plasma mem- vated state from which further openings are rare (Fig. 27¬
brane. An extracellular loop dips within the plasma membrane 19).i53.569.822 Upon depolarization to the threshold potential, the
between S5 and S6 of each domain and participates in the forma- inward sodium current peaks within a millisecond and the re-
tion of the pore. The S4 helix contains a repeating motif of posi- laxes back to zero as the channel inactivates. In order for the
Trecovery
Figure 27-20. Gating defects in mutant sodium channels revealed by macroscopic currents from whole cell recordings. (A) Super-
imposition of amplitude-normalized current tracings shows a slowed rate of fast activation for a potassium-associated myotonia (PAM) mutation
9Glyl306Glu. (B) A depolarized shift in sodium channel availability (open symbols) occurs with this PAM mutation. Availability is measured as the
relative peak elicited at -10 mV, after a 300-ms conditioning pulse at potentials ranging from -120 to -10 mV.Thr704Met mutations result in channel
activation at milder depolarizations than normal, as shown by the hyperpolarized shift in the relative conductance (filled symbols). (C) Recovery
from fast activation is accelerated for paramyotonia congenita mutation Thr 1313Met.The initial step depolarization allows fast inactivation to occur,
and the time course of recovery is assayed as the relative peak current elicited after a variable recovery interval (repeated trials are superimposed).
(From Cannon SC: From mutation to myotonia in sodium channel disorders. Neuromusc Disord 1997;7:241 —249, with permission.)
sodium channels to recover from the inactivated state, the muscle seconds to minutes, thereby influencing muscle membrane ex-
membrane must become hyperpolarized by the influx of potas- citability. Rare cases have also been reported in patients with
sium. Once reprimed, the sodium channels are again available to SCN4A mutations manifesting as potassium-sensitive periodic
open with subsequent depolarizations. The fast inactivation of paralysis and paramyotonia congenita who had impaired slow
the channels limits the duration of the action potential and initi- inactivation as opposed to defective fast inactivation.433
ates repolarization of the muscle membrane. Inactivation also Paramyotonia congenita mutations result in the most dramat-
regulates the number of sodium channels that are available to ically prolonged % (producing sodium channel inactivation that
open (those channels not inactivated, but in a resting, closed is two to three times slower than normal), reduced voltage de-
state). Recovery from the fast-inactivated state ranges from 5 to pendence of steady-state availability, accelerated recovery from
10 msec near the resting membrane potential of -90 mV and is inactivation, and mildly persistent currents secondary to fre-
responsible for the refractory period and limits the firing rate of quent late re-openings of the sodium channels (Fig. 27-20). 153
the muscle fibers. These abnormalities may explain the paradoxic myotonia ob-
Electrophysiologic evaluations of various mutant sodium served with repetitive muscle activity. In vitro studies using
channels has demonstrated that the primary pathophysiologic ab- patch clamp techniques of intercostal muscles of patients with
normality is an alteration of channel inactivation. In contrast, ac- paramyotonia demonstrated normal resting membrane poten-
tivation of the sodium channel is not altered by the majority of tials at 37°C.564-565 However, reducing the temperature to 27°C
known mutations. In patch clamp experiments, PAM-mutant increases sodium conductance by opening voltage-gated so-
sodium channels conduct sodium currents that showed abnormal dium channels, producing a depolarization of the muscle mem-
inactivation.153-575-878 Compared with controls, the decay towards brane to approximately -40 mV. Spontaneous action potentials
baseline is mildly slowed (long xh), the non-inactivating compo- generate secondary to the approximation of the resting mem-
nent is increased, there is a two- to fourfold increase in persistent brane and threshold potentials. In patients with paramyotonia
current, and the position of the steady-state inactivating curve (h) congenita associated with periodic paralysis, the muscle mem-
was shifted towards the less negative potentials (more channels brane maintains a prolonged depolarized state that is no longer
available to activate) (Fig. 27-20). 153 These changes increase capable of generating further action potentials, and therefore,
muscle membrane excitability and lead to myotonia. Distinct the muscles becomes weak.153-564'565
from fast inactivation is a process called "slow inactivation" that In potassium-sensitive periodic paralysis, mutant sodium
limits the availability of sodium channels on a time scale of channels result in the largest persistent currents, have minimal
Normal Muscle Met1592Val
Figure 27-2 f. Disrupted fast inactivation of —yyr—
sodium channels in hyperkalemic periodic paralysis. —

Tracings show unitary sodium currents recorded from
human myotubes in culture. Sodium channels normally
open within milliseconds after depolarization (down-
ward deflections) and then close to an inactive confor-
mation from which further openings do not occur. In
a
consecutive tracings, failure of fast inactivation produces
bursts with prolonged openings in mutant channels.
Ensemble averages (below tracings) show that mutant
channels inactivate for the majority of trials (rapid de-
cline in P en)» but that intermittent bursts cause a small
op
s
persistent current (From Cannon SC: From mutation to
myotonia in sodium channel disorders. Neuromusc -*0 Vm
Disord 1997;7:241-249, with permission.)
m*©c
10 20
0 0
I0'
o- 02
03
slowing of i h , and have no change in availability and recovery prevalence of l/i00,000.'47-386'393-556'568-569-822-906 It is an autosomal
(Fig. 27-21).153 The ratio of steady-state to peak open channels dominant disorder, with reduced penetrance in women (a male
increases threefold when extracellular potassium is increased in to female ratio of 3 or 4 to 1). Symptom onset is usually in the
vitro from 0 to 10 mM.878 In normal sodium channels, this ratio first two decades when patients note the development of
does not significantly change in relation to extracellular potas- episodic weakness. Myotonia or paramyotonia are not seen in
sium. Increased extracellular potassium results in depolariza- hypokalemic periodic paralysis.
tion of the muscle membrane and increased late openings of the Most patients note that some form of atypical strenuous exer-
non-inactivated sodium channels. 878 The continued sodium cise or exertion followed by rest or sleep usually precipitates an
influx sustains the depolarization of the membrane, which in attack. Other aggravating factors include heavy meals rich in
turn leads to inactivation of normal sodium channels and subse- carbohydrates and sodium, alcohol consumption, exposure to
quent muscle fiber inexcitability. cold, and emotional stress. The bouts of weakness can occur at
The main effect of the prolonged xh and reduced rate of fast- any time of day, although early morning hours appear to have a
inactivation is an increased duration of the action potential. This slightly higher propensity for being associated with weakness.
in turn increases the amount of potassium that flows into the T- If the patient notes the above-described prodrome, mild exercise
tubule per discharge. The generation of myotonic discharges in may stave off the full-blown attack of weakness; however, this
the various sodium channelopathies is dependent on extracellu- is not always successful.
lar potassium accumulation in the T-tubules. Depolarization of Severity of an attack can range from mild weakness of an iso-
the muscle membrane produces a small elevation in extracellu- lated muscle group to severe generalized paralysis. The fre-
lar potassium as a result of the outward current of potassium at quency of these attacks of weakness is also highly variable and
the end of each action potential. The normally high chloride can occur several times per week or once per year. The fre-
conductance of muscle membranes attenuates the depolariza- quency of attacks generally decreases after the age of 30 years,
tion of the T-tubules resulting from this potassium accumula- and some patients become free of attacks in their 40s or 50s.
tion. De-tubulization abolishes after-discharges in animal The episodes of periodic weakness are often preceded by a
models of sodium channelopathy-associated myotonia.153 Thus, vague sensation of heaviness in the lumbosacral region, thighs,
use-dependent potassium accumulation in the T-tubules is re- and calves that spreads to involve other muscle groups, primar-
quired to generate myotonic discharges in the chloride chan- ily those in the proximal upper limbs. Weakness follows the
nelopathies and sodium channelopathies (see Chapter 26). heavy sensations and can be of such a degree as to render the
patient completely incapacitated and confined to a bed. The
CALCIUM CHANNELOPATHIES facial and respiratory muscles as well as the sphincter muscles
are typically spared or only minimally involved during particu-
Primary Hypokalemic Periodic Paralysis Type I larly severe attacks. However, death from respiratory muscle in-
Clinical Features. Hypokalemic periodic paralysis is the volvement and cardiac arrhythmia secondary to hypokalemia
most frequent form of periodic paralysis with an estimated have been reported. 556 During peak weakness, reflexes are
also required to lower the potassium sufficiently. The patient's
strength, electrocardiogram, and electrolytes need to be care-
fully monitored during such testing. Now, provocative testing is
necessary only if genetic testing does not confirm a diagnosis,
which is in about 50% of the cases at the moment.
Laboratory Features. Attacks of weakness are associated
wjth decreased serum potassium levels, usually below 3.0
mEq/1. Serum phosphate levels also decrease. Between bouts of
weakness, the serum potassium is normal. During severe attacks
of weakness, there is oliguria with urinary retention of sodium,
potassium, chloride, and water. Obstipation and diaphoresis
may also occur. The EKG may demonstrate bradycardia, flat-
tened T waves, prolonged PR and QT intervals, and notably U
waves secondary to the hypokalemia. Serum CK levels are
normal or only mildly elevated between attacks and increased
during an attack of weakness.
Histopathology. The muscle biopsy may demonstrate multi-
Figure 27-22. Familial hypokalemic periodic paralysis. EM of ple or single intracellular vacuoles, tubular aggregates, and dila-
muscle biopsies demonstrates dilated sarcoplasmic reticulum vesicles tion of the sarcoplasmic reticulum (Fig. 27-22). 2841033 A recent
and T-tubules. study demonstrated that patients with the typical CACNL1A
mutation had vacuoles in their muscle fibers, while tubular ag-
absent and the muscle is electrically unexcitable. Profound gregates were documented in patients with SCNA4 mutation.970
weakness may last for several hours to more than a day in some Muscle fiber size variation, split fibers, hypertrophic and some
instances. Characteristically, those muscles affected last are the atrophic fibers can also be present. Rarely, necrotic and degen-
first to return to normal strength. Some patients may note a erating muscle fibers are noted.
.residual weakness for several days following an attack. Many Molecular Genetics and Pathogenesis. Primary hy-
patients eventually develop permanent fixed weakness after pokalemic periodic paralysis type 1 is caused by mutations in
multiple attacks of paralysis.568-784 However, the relation be- the muscle calcium channel gene, specifically in the oc-1 sub-
tween attack frequency and later permanent weakness has been unit (CACNLIA3), which is encoded on chromosome 1 q31 -32
questioned since the description of several patients with a defi- (Fig. 27-23).492-821-822-970 This calcium channel is voltage-depen-
nite myopathy who never experienced any paralytic at- dent and composed of five subunits (cc-1, a - 2 , 5, p, and y). The
tacks.580,581 The proximal muscles, especially in the legs, are oc-1 subunit contains the dihydropyridine (DHP) receptor
more prone to developing fixed weakness. and forms the pore, which conducts calcium ions in the T-tubule
Provocative testing was used in the past, when the diagnosis of skeletal muscle (see Figs. 27-2 and 27-19). The DHP recep-
was not clear.393 The goal of provocative testing was to reduce tor is responsible for the slow L-type calcium current that is im-
serum potassium levels in order to see if this causes a typical portant in regulating excitation-contraction coupling. 448 The
attack of weakness. Hypokalemia can be accomplished with an other subunits of this calcium channel serve to regulate the func-
oral or intravenous glucose load, although sometimes insulin is tion of the oc-1 subunit. The oc-1 subunit of the voltage-gated
Figure 27-23. Calcium channel and ryanodine

CaCh RM48H receptor model showing the location of hy-
pokalemic periodic paralysis mutations. Calcium
channel depicted shares significant homology with the
sodium channel a-subunit (see Figs. 27-17 and 27-19).
Three are four homologous domains each containing six
putative membrane spanning segments (SI-S6). The
fourth segment in each domain has a number of posi-
tively charged arginine or lysine residues, which are
C00H
thought to serve as a voltage sensor for the protein.The
location of the three recognized hypokalemic periodic
paralysis mutations are shown—all involve the S4 argi-
nine residue.This skeletal muscle calcium channel (CaCh
or the dihydropyridine receptor; DHP) located on the
sarcolemma interacts with the ryanodine receptor
(RyR) that resides in the sarcoplasmic reticulum (SR).
The contribution of calcium influx across the CaCh or
DHP into the sarcoplasm is small. However, the depolar-
izing of the muscle membrane is sensed by the DHP,
which interacts with the RyR leading to opening of the
calcium slow release channel in the SR. (From Ptacek LJ:
The familial periodic paralyses and nondystrophic my-
otonias. Am J Med 1998; 105:58-70, with permission.)
Control D
HypoPP (R528H) ^ HypoPP (R1239H)
-60 -40 -20 0 20 40 60 -60 -40 -20 0 20 40 60 -60 -40 -20 0 20 40 60

Membrane potential (mV) Membrane potential (mV) Membrane potential (mV)
Figure 27-24. Voltage-dependent activation of calcium inward currents in normal and hypokalemic periodic paralysis myotubes.Voltage
steps were applied from a holding potential of -90 mV to various membrane voltages (Vm, -60 to + 50 mV). Selected current traces (upper panels)
and current density-voltage relations (lower panels) are illustrated. Symbols represent • , peaks of the rapid currents (T-type);0, maximum ampli-
tudes of the slow (L-type) current. (A), controls (n = 47). (B), Mutation R528H (n = 15). (C), Mutation R1239H (n = 28).The density of the DHP-
sensitive L-type current is significantly reduced in the 0 to +50 mV range for the RI239H mutation, while it is unaltered in R528H.The amplitudes
of theT-type current are increased for both mutations.The differences between controls and hypokalemic periodic paralysis are significant in the
+ 10 to +30 mV range. (From Sipos l,Jurkat-Rott K, Harasztosi C, et al: Skeletal muscle DHP receptor mutations alter calcium currents in human
hypokalaemic periodic paralysis myotubes. J Physiol 1995;483:299-306, with permission.)
calcium channel is similar to the a subunit or the voltage-gated appear to be influenced by mutations involving the DHP re-
sodium channel in that it is composed of four transmembrane do- ceptor. There is a depolarization of the resting membrane po-
mains, each of which contains six transmembrane segments (S1 tential from about - 8 0 mV to around - 5 0 mV. The sodium
to S6). Mutations involving highly conserved amino acids have conductance is increased in the resting state, accounting for
been identified in the S4 segments of the second and fourth do- the depolarized resting membrane potential. The shift in
mains of the a-1 subunit of the voltage-dependent calcium chan- potassium from the extra- to intracellular space further en-
nel in patients with hypokalemic periodic paralysis.492 821822 This hances the sodium conductance, which in turn destabilizes
segment is important in conferring the voltage-sensing properties the membrane. Reduced extracellular potassium concentra-
to the channel, which are apparently altered by the mutations. tion results in an abnormal ratio of gated sodium channels in
The exact mechanism whereby the muscle membrane is ren- the active compared with inactive state. In this partially depo-
dered inexcitable by the mutation involving the DHP receptor is larized state, the number of sodium channels available to acti-
not known.384-449-556-569-822-875-952 The DHP receptor has the dual vate is likely reduced, thus creating an inexcitable membrane.
function of a calcium channel and a voltage sensor for excita- So-called hypokalemic periodic paralysis type 2 is associ-
tion-contraction coupling (Figs. 27-2 and 27-23). Electro- ated with mutations in SCNA4.I34-492a-970 Mutations in SCNA4
physiologic recordings of myotubes expressing mutant account for approximately 10% of familial hypokalemic peri-
calcium channels have demonstrated a reduction of calcium odic paralysis. 970 The onset of symptoms is earlier, penetrance
current and a negative shift of the steady-state inactivation is more complete in both men and women, and myalgias are
current (Figs. 27-24 and 27-25). 556 The reduced calcium more severe and longer lasting with the attacks of weakness.
influx through the T-tubule may impair excitation-contraction The mutations in SCNA4 result in an enhanced inactivation
coupling. Somehow, the kinetics of the sodium channel also and reduced current through the muscle sodium channel.4923
15 ms
- 9 0 mV 1 U
200 ms
Control B
- HypoPP (R528H) C
HypoPP (R1239H)
— i — , — i — i — i — i — r —1 — . — \ — i — r — • » — i I—i—i—i—i—i—i—«—r »" 1—«—i » i I—•—r—•—i—•—i—•—r—'—i—•

1 r
~~l
-100 -80 -60 -40 -20 0 20 40 -100 - 8 0 -60 -40 -20 0 20 40 -100 - 8 0 -60 -40 -20 0 20 40
Prepulse potential (mV) Prepulse potential (mV) Prepulse potential (mV)
Figure 27-25. Voltage dependence of steady-state inactivation of calcium currents in normal and hypokalemic periodic paralysis my-
otubes. For inactivation curves, the current values obtained at the test pulses with a conditioning prepulse (l ) were normalized by the test pulse
TP
response with a prepulse (lT). Note the scheme at the top that shows the pulse protocol for the L-type current. Symbols represent: B.T-type cur-
rent; O , L-type current. (A) Normal controls. (B) The steady-state inactivation curve for the L-type current was shifted to he more negative po-
tentials by 40 mV for the R528H mutation. (C) The steady-state inactivation currents for the R1239H mutation are not significantly different from
the normal controls. (From Sipos l,Jurkat-Rott K, Harasztosi C, et al: Skeletal muscle DHP receptor mutations alter calcium currents in human hy-
pokalemic periodic paralysis myotubes. J Physiol 1995;483:299-306, with permission.)
Electrophysiologic Findings. Sensory and motor nerve con- during voluntary activity. Rarely, sparse fibrillation potentials
duction studies are normal between attacks of weakness.266-280*378-580 may be observed. Early in an attack of weakness, a slight in-
Sensory studies remain normal during the paralytic attacks. The crease in spontaneous potentials (fibrillation potentials and pos-
motor responses continue to demonstrate a normal conduction ve- itive sharp waves) and insertional activity may be noted. The
locity for as long as the response can be obtained. Obviously, fibrillation potentials and positive sharp waves are merely re-
during the paralytic attack, the CMAP amplitude declines precipi- flections of hyperirritable muscle membranes and do not indi-
tously secondary to muscle membrane inexcitability. Repetitive cate muscle denervation. As the paralytic attack progresses, one
stimulation during a paralytic attack can maintain the CMAP am- observes a decrease in the amplitude and duration of voluntary |
plitude to some degree, supporting the clinical impression that MUAPs as well as an overall decrease in the number of MUAPs
mild exercise can stave off an attack. Between attacks, prolonged contributing to the interference pattern. When the paralytic
voluntary muscular activity (5 minutes) may result in an initial attack is maximal, there are minimal, if any, voluntary MUAPs
slight facilitation of the CMAP, which is then followed by a de- and a marked reduction or complete absence of insertional ac-
crease in the CMAP magnitude near the end of the exercise tivity. A careful search usually demonstrates end-plate activity,
period. Surface recordings demonstrate reduced muscle fiber con- although it is reduced in amplitude and more difficult to find.
duction velocity between paralytic attacks.1154 Once an attack of Recovery from muscle paralysis essentially displays the above-
weakness is underway, it is possible to reverse the decreased noted needle electromyographic changes in reverse.
CMAP amplitude and associated weakness by delivering four Single-fiber electromyography during an attack reveals a de-
trains of stimuli (each train lasting 2 minutes) at a rate of 10 Hz crease in fiber density and a slight increase in jitter with occa-
with a 1-minute rest interval between trains. sional potential blocking. 219 Between attacks, the fiber density
The needle electromyographic examination reveals a number is slightly increased, while the jitter is normal. The increased
of interesting findings both during and between bouts of weak- fiber density between attacks is likely a result of a mild myo-
ness.378 Needle evaluation between attacks of muscle paralysis pathic process, as noted in the histopathology section. The re-
reveals there is usually no detectable abnormality in the major- duction in muscle membrane excitability during an attack of
ity of patients. However, in those persons who appear to develop weakness causes a dropout of single muscle fibers, thus result-
a myopathy characterized by persistent muscle weakness, there ing in the observed decrease in fiber density compared with
is noted to be MUAPs with decreased amplitudes and durations both normal values and the patient's interattack values.
as well as an increase in the number of polyphasic potentials. Treatment. Preventive measures include avoidance of
There is also some indication of an early recruitment pattern provocative factors (e.g., ingestion of high-carbohydrate meals,
strenuous exercise). Acetazolamide (125-1500 mg/d) and potas- of myotonia or paramyotonia. Of note, there can be intrafamilial
sium salts (0.25-0.5 mEq/kg) can also be prophylactically ad- variability of the severity of the clinical phenotype.
ministered to prevent hypokalemia and attacks of weakness. Laboratory Features. Serum CK is normal or only mildly
Acetazolamide may exacerbate attacks of weakness in patients elevated (less than 5 times normal). Serum potassium levels can
with hypokalemic periodic paralysis type 2 caused by SCNA4 be normal, elevated, or decreased during attacks of weakness. A
mutations.970 Dichlorphenamide (50-150 mg/d) appears to be ef- prolonged QT interval is present in 80% of patients, while some
fective in reducing attack frequency and severity.1013 Triamterene have even more ominous ventricular tachyarrhythmias.
(25-100 mg/day) and spironolactone (25-100 mg/day) may also Histopathology. Muscle biopsies frequently reveal tubular
be used to prevent attacks and improve interattack weakness, aggregates similar to those observed in other forms of periodic
when acetazolamide and dichlorphenamide are not effective. The paralysis.
authors treat acute attacks with oral potassium salts (0.25 Molecular Genetics and Pathogenesis. The molecular basis
mEq/kg body wt) every 30 minutes until strength improves.393 If and pathophysiology of the myopathy are unknown. The disorder
the patient's condition precludes oral potassium, intravenous has not been linked to the SCNA4 gene (hyperkalemic periodic
potassium (KCL bolus 0.05-0.1 mEq/kg body wt or 20-40 paralysis and related sodium channelopathies), the DHP receptor
mEq/1 of KCL in 5% mannitol) may be administered.393 Cardiac (hypokalemic periodic paralysis), or one of the prolonged QT loci
monitoring is essential throughout treatment. (the cardiac potassium channel on chromosome 11).895
Secondary Hypokalemic Paralysis duction studies are normal. Likewise, electromyography is normal
Secondary hypokalemic periodic paralysis can occur from a interictally. Importantly, there are no myotonic discharges.
number of causes (Table 27-5). Urinary or gastrointestinal Treatment. Early recognition of the potential cardiac con-
wastage of potassium may precipitate a bout of weakness as duction abnormalities are important, because they may be
well as cause a necrotizing myopathy. Muscle weakness re- treated with antiarrhythmic agents or pacemaker insertion.
solves with correction of the electrolyte imbalance. Secondary Provocative testing to induce hypokalemia or hyperkalemia
causes of hypokalemia need to be excluded prior to concluding should be avoided, because of risk of arrhythmia. Small doses of
a patient has the familial form of hypokalemic periodic paraly- acetazolamide may prevent paralytic attacks in some patients.
sis, especially when there is no family history.
OTHER CHANNELOPATHIES
Thyrotoxic Periodic Paralysis
Thyrotoxic periodic paralysis resembles hypokalemic peri- Cardiac Sodium Channelopathies
odic paralysis, except that it is sporadic in occurrence (see Some families with autosomal dominant "long-QT syndrome"
Thyrotoxic Myopathies; chapter 28). It is possible that these pa- associated with cardiac arrhythmias have been linked to muta-
tients have a mutation in a channel gene, which clinically mani- tions in the cardiac sodium channel a subunit gene (SCN5A) lo-
fests only if the patient becomes hyperthyroid. The disorder is cated on chromosome 3p21-24.569 n03 However, these patients do
most prevalent in Asian adults, but has been described in all not typically manifest neuromuscular symptoms or signs.
races. Although hyperthyroidism is more common in women,
the majority of cases of thyrotoxic periodic paralysis occur in Muscle Potassium Channel Diseases
males. Patients can develop progressive muscle weakness sec- Most families with autosomal dominant "long-QT syn-
ondary to hyperthyroidism. Attacks of weakness resolve with drome" associated with cardiac arrhythmias have been linked to
treatment of the thyrotoxicosis but can recur with exacerbation mutations in a subunit of the cardiac potassium channel located
of the hyperthyroid state. Unlike the familial forms of hy- on chromosome 7q35-q36 (LQT2). 5691,03 Mutations of other
pokalemic and hyperkalemic periodic paralysis, acetazolamide subunits of the cardiac potassium channel have also been re-
does not appear to have any significant benefit. However, (3- ported in other families with prolonged QT syndrome.203 In ad-
blockers may be effective in reducing the frequently and sever- dition, although not a muscle-specific channelopathy per se,
ity of the paralytic attacks in thyrotoxic patients. autosomal dominant episodic ataxia has been linked to a potas-
sium channel.122
OTHER FORMS OF PERIODIC PARALYSIS
Other Calcium Channelopathies
Klein-Lisak-Andersen Syndrome Central core disease and malignant hyperthermia are caused
Clinical Features. Klein-Lisak-Andersen syndrome is a dis- by mutations in the ryanodine receptor encoded on chromosome
tinct autosomal dominant disorder characterized by the triad of 19q 13.1. 569823 The ryanodine receptor is responsible for the re-
periodic paralysis, ventricular dysrhythmias, and dysmorphic fea- lease of calcium from the sarcoplasmic reticulum (see Fig. 27¬
tures.525-583-8951009 Contrary to most of the earlier reports noting the 2). Central core disease is discussed in the congenital myopathy
attacks of weakness were associated with hyperkalemia, Sansone section. Rippling muscle disease and Brody's disease are be-
and coworkers demonstrated that this form of periodic paralysis lieved to be secondary to abnormalities of calcium channels lo-
could be associated with hypokalemia, normal kalemia, or hyper- cated on the sarcoplasmic reticulum.
kalemia.895 The cardiopathy ranges from an asymptomatic long
QT interval to potentially fatal ventricular tachyarrhythmias. The Malignant Hyperthermia
major dysmorphic features described include short stature, Clinical Features. Malignant hyperthermia (MH) is an au-
scaphocephaly, hypertelorism, low-set ears, broad nose, microg- tosomal dominant disorder characterized by severe muscle
nathia, high-arched palate, clindactyly and short fingers, syn- rigidity, myoglobinuria, fever, tachycardia, cyanosis, and car-
dactyly, and scoliosis. The episodes of periodic weakness and diac arrhythmias precipitated by depolarizing muscle relaxants
cardiac arrhythmia can manifest in early childhood. Some pa- (e.g., succinylcholine) and inhalational anesthetic agents (e.g.,
tients have mild fixed proximal weakness. There is no evidence halothane). The incidence of MH in patients exposed to general
anesthesia varies from 0.5 to 0.0005%. 83a At least 50% of pa- are stimulated at 0.1-0.2 Hz for 1-5 seconds, and tension is
tients with MH have had previous anesthesia without clinically measured by a stain gauge. Varying concentrations of halothane
manifesting the disorder. 39,-393 MH usually occurs during and caffeine are applied, and the resultant tension produced by
surgery, but it can manifest in the postoperative period. Rarely, muscle stimulation is recorded. In patients with MH, much
attacks of MH have developed following exercise, ingestion of lower concentrations of caffeine and halothane produce muscle
caffeine, or triggered by stress. contractions than needed in normal muscle tissue.
Laboratory Features. Serum CK can be normal or mildly Treatment. Patients at risk for MH should not be given
elevated interictally in patients susceptible to MH. During at- known triggering anesthetic agents. MH is a medical emergency
tacks of MH, serum CK levels are markedly elevated and myo- requiring several therapeutic steps.833 The anesthetic agent must
globinuria can develop. Hyperkalemia is also usually present. be discontinued, while 100% oxygen is delivered. Dantrolene
Metabolic and respiratory acidosis is evident with lactic acido- 2-3 mg/kg every 5 minutes for a total of 10 mg/kg should be ad-
sis, hyopoxia, and hypercapnia. ministered. The stomach, bladder, and lower gastrointestinal
Histopathology. Muscle biopsies demonstrate non-specific tract are lavaged with iced saline solution, and cooling blankets
myopathic features including fiber size variability, increased in- are applied. Acidosis and hyperkalemia are treated with sodium
ternal nuclei, motheaten fibers, and necrotic fibers after an bicarbonate, hyperventilation, dextrose, insulin, and occasion-
attack of MH. ally calcium chloride. Urinary output must be maintained with
Pathogenesis and Molecular Genetics. MH is believed to hydration, furosemide, or mannitol. The patient must be moni-
arise secondary to excessive calcium release by the sarcoplas- tored and treated for cardiac arrhythmias.
mic reticulum calcium channel, the ryanodine receptor (Fig. 27¬
2). This receptor bridges the gap between the sarcoplasmic Rippling Muscle Disease
reticulum and the T-tubule. Increased intracytoplasmic calcium Clinical Features. Rippling muscle disease is an autosomal
leads to excessive muscle contraction, increased utilization of dominant disorder characterized by localized transient swelling
oxygen and ATP, and overproduction of heat. The reason vari- of muscle induced by percussion (muscle mounding or my-
ous anesthetic agents and depolarizing muscle relaxants trigger oedema) and the rhythmic waves of muscle contraction (rip-
this exaggerated release of calcium from the sarcoplasmic retic- pling muscles) following volitional activity.9-,37-469-493-845 l039-,°86
ulum in predisposed individuals is not known. Onset of the muscle mounding and rippling is usually in the
MH susceptibility is genetically very heterogeneic and has second decade of life. Patients often complain of a tight or a
been designated as MHS1, MHS2, etc., as families have been mild aching sensation in their thighs, upper arms, and trunk.
linked to different chromosomes and genes. The first mutations Their "stiffness" seems to correlate with the rippling waves of
were discovered in the ryanodine receptor gene located on chro- muscle contraction induced by volitional muscle activity or pas-
mosome 19q 13.1 (MHS 1).823 These mutations may result in a sive stretching. Percussion of the muscle results in mounding
functional alteration of the associated calcium channel such that and rippling of the muscle. This muscle mounding/rippling may
there is an excessive release of calcium into the cytoplasm upon or may not be painful. Muscle strength is normal, as are sensa-
activation. Of note, mutations in this gene are also responsible tion and deep tendon reflexes. Of note, acquired forms of rip-
for the congenital myopathy central core disease. However, mu- pling muscle disease may also occur in the setting of
tations in the ryanodine receptor gene have been identified in myasthenia gravis and thymoma.1-701-7141079
only a minority of patients with MH. Subsequently, other ge- Laboratory Features. Serum CK is usually mildly elevated.
netic loci associated with susceptibility to MH have been identi- Serum electrolytes and thyroid function tests are normal.
fied. MHS2 localizes to chromosome 17ql 1.2-q24 (possibly the Histopathology. Muscle biopsies are normal or reveal only
gene for the a subunit of the sodium channel). Thus, MHS2 mild non-specific myopathic features such as variability in fiber
may be allelic to potassium-sensitive periodic paralysis, size and increased central nuclei.
paramyotonia congenita, and related disorders. MHS3 has been Molecular Genetics and Pathogenesis. One large autoso-
linked to chromosome 7q21-q22 (possibly to a gene encoding mal dominant pedigree has been localized to chromosome
the subunit calcium channel). MHS4 localizes to chromosome jq41 969 other kinships have not been localized to this area, sug-
3q 13.1, but the gene has yet to be identified. Mutations in the gesting genetic heterogeneity. The physiologic basis for the ab-
dihydroperidine receptor gene on chromosome 1 q31 (allelic to normal muscle activity is not known. In vitro electrophysiologic
hypokalemic periodic paralysis) are the cause of MHS5. recordings of intercostal muscles demonstrated normal resting
Linkage to chromosome 5p has been demonstrated in still other membrane potentials. Muscle contraction and relaxation in all
families (MHS6). Besides these disorders, it is well known that isometric and most isotonic recordings were normal. 137
patients with dystrophinopathies are susceptible to developing However, occasional secondary contractions developed during
MH. Thus, it appears that MH may occur in various myopathic or immediately after relaxation. In response to maintained con-
disorders affecting the structural proteins of the muscle mem- stant-current stimulation at low threshold (< 75 nA), a pro-
brane or ion channels. longed latency (approximately three times normal) to the
Electrophysiologic Findings. Nerve conduction studies and production of action potentials was demonstrated. In addition,
electromyography are usually normal interictally unless the pa- many fibers fired repetitively. It has been hypothesized that the
tient has a predisposing myopathic disorder, e.g., muscular dys- rippling muscles and mounding result from a secondary slow
trophy. Therefore, routine electrodiagnostic studies are not release of calcium from the sarcoplasmic reticulum, perhaps be-
helpful in distinguishing who may be at risk for developing cause of a calcium channelopathy.137
MH. Electromyography shortly after an attack of MH would be Electrophysiologic Findings. Routine nerve conduction stud-
expected to demonstrate increased spontaneous activity and, ies are normal, and electromyography reveals no abnormal inser-
perhaps, small polyphasic MUAPs recruiting early. tional or spontaneous activity.9137-469-493-834-845 10391086 Likewise, motor
The diagnosis of individuals susceptible to MH is accom- unit morphology and recruitment are normal. Interestingly, the
plished by the in vitro muscle contracture test.83a Strips of muscle muscle mounds and rippling muscle activity are not associated
with abnormal electrical activity. The velocity of the rippling Electrophysiologic Findings. Motor and sensory nerve con-
wave of muscle contraction is approximately 0.6 m/s.845 Of note, duction studies are normal.75-2,0-503-8()1-1014 Repetitive stimulation
myotonic discharges are not present. at 2 Hz demonstrates no decrement, and there is no change in
Treatment. Because of the rarity of the disorder, there are CMAP amplitude following 1 minute of sustained muscle con-
little data regarding treatment. One patient was treated with to- traction. Electromyography is normal, including insertional ac-
cainide without benefit, whereas dantrolene seemed to reduce tivity, MUAP morphology, and recruitment. There is no
the muscle stiffness.845 abnormal spontaneous activity, including fibrillation potentials,
positive sharp waves, myotonia, or neuromyotonia. Importantly,
Brody's Disease electrical silence is apparent on needle electromyography in
Clinical Features. Brody reported an unusual disorder char- muscles exhibiting impaired relaxation.
acterized by impaired skeletal muscle relaxation that markedly Treatment. Dantrolene was tried without success in one pa-
increased with exercise.113 Subsequently, other patients with sim- tient,503 although other studies reported improvement in muscle
ilar features have been reported.75-210'503-801,1014 Patients usually de- relaxation and pain. 801 Verapamil may also improve muscle
scribe onset of exercise-induced cramping and stiffness in the symptoms. 1014 Dantrolene and verapamil were also demon-
arms and legs after brief exercise. Rare cases with recurrent strated to improve muscle function in vitro in muscle biopsy
myoglobinuria have been reported.801 Opening and closing one's specimens from patients with Brody's disease. 75
fists or performing deep knee bends for less than 1 minute in-
duces severe impairment of muscle relaxation that can be painful OTHER POSSIBLE CHANNELOPATHIES
in affected patients. The impaired relaxation after forced eyelid
closure can be demonstrated in some individuals. The muscle Diffuse Abnormal Insertional Activity
stiffness resembles myotonia or, more appropriately, paramyoto- An interesting and primarily electrical disorder characterized
nia, as the stiffness worsens with activity. However, there is no by brief decrescendo runs of positive sharp wave potentials to
percussion myotonia. Mild proximal weakness may be apparent needle insertion will occasionally be encountered. 74611,211131,26
on examination. Sensation and deep tendon reflexes are normal. There is a distinct lack of any additional electrical abnormalities
Laboratory Features. Serum CK is normal or only slightly aside from the positive sharp waves, and rarely a few fibrillation
elevated. The exercise forearm test reveals a normal rise in potentials may be detected. Fasciculation potentials, complex
lactic acid and ammonia, distinguishing the disorder from some repetitive discharges, or myokymia is not typically detected as a
of the dynamic glycogen storage disorders (e.g., phosphorylase result of this disease process. The positive sharp waves dp not
deficiency; see below). wax and wane and, therefore, do not constitute myotonic poten-
Histopathology. Muscle biopsies demonstrate type 2 tials. These potentials can be found in essentially any skeletal
milscle fiber atrophy with some angularity in appearance. Many muscle examined including those innervated by the cranial
of the type 2 fibers contain internal nuclei. Immunocyto- nerves (personal observation). Additionally, the degree of posi-
chemistry reveals markedly diminished calcium-ATPase in type tive sharp waves recorded varies from muscle to muscle, and
2 muscle fibers. Swollen mitochondria with crystalline inclu- examining the patient on different days results in varying de-
sions have been noted in some cases,801 but the majority of stud- grees of positive sharp waves in the same muscles. Voluntary
ies report no significant abnormalities present on EM. Skeletal MUAP parameters are normal, as is their recruitment.
muscle fibers demonstrate enhanced caffeine sensitivity similar The electrical abnormalities are emphasized because there is
to malignant hyperthermia. little in the way of clinical findings to hint at the electrical ab-
Molecular Genetics and Pathogenesis. The disorder is normalities. A distinct lack of any type of clinical myotonia is
usually inherited in an autosomal recessive or perhaps X- noted. Temperature reduction neither produces myotonia nor
linked recessive pattern. 503 Mutations in the ATP2A1 gene lo- does it reduce or increase the above-noted membrane instability
cated on chromosome 16p 12.2-12.2 have been identified in (personal observation). Manual muscle testing is normal, as is
some autosomal recessive cases. 747 This gene encodes for sar- the remainder of the neurologic examination. Histologic exami-
coplasmic reticulum calcium-ATPase (SERCA 1), a calcium nation of muscle tissue is normal, as is the serum CK levels. The
channel present on the sarcoplasmic reticulum of type 2 authors have had the opportunity to investigate several families
muscle fibers. The mutations result in a reduction of calcium- and confirm the previously noted autosomal dominant nature of
ATPase activity in the sarcoplasmic reticulum of type 2 the disorder.
muscle fibers with a corresponding decreased rate of ATP-de- This benign disorder is possibly a result of some muscle
pendent calcium transport in particulate membrane fractions membrane ionic abnormality resulting in provocation of posi-
of skeletal muscle. 75 - 503 - 80U014 Normally, upon depolarization tive sharp waves and rare fibrillation potentials. Insufficient data
of the T tubules, calcium ions are released from the lateral cis- are available regarding the kinetics of various ion-gated chan-
terns of the sarcoplasmic reticulum into the sarcoplasm lead- nels in this disorder, and one can only speculate as to whether
ing to sliding of the myofilaments and muscle contraction. sodium, chloride, potassium, or some other genetic ion-gate ab-
Relaxation requires that the calcium levels in the sarcoplasm normality is present. Voltage clamp investigations are necessary
return to baseline. This is accomplished by calcium-ATPase to elucidate the underlying membrane defect.
located in the sarcoplasmic reticulum membrane, which The practitioner must be aware of this genetic muscle mem-
pumps calcium back into the sarcoplasmic reticulum. The re- brane disorder not because of any symptoms or signs on the pa-
duction of calcium ATPase activity in type 2 muscle fibers tient's part, but because of diagnostic difficulties, and saving the
leads to a cumulative increase in myofibrillar calcium and im- patient expensive and potentially invasive diagnostic proce-
paired relaxation following phasic (fast-twitch) activity. Not dures. The syndrome of diffuse insertional activity is also
all patients with Brody's disease have been found to have mu- known as "EMG disease" because the only abnormalities are
tations in the ATP2A1 gene; thus, the disorder is genetically electrical. As a result, it is essentially impossible to evaluate
heterogeneic. 1148 the patient with this disorder for any type of nerve or muscle
disease with the needle electrode portion of the electrodiagnos- Molecular Genetics and Pathogenesis. SJS has been local-
tic medicine consultation. The patient is usually referred for ized to chromosome lp34-36.1, but the gene has not yet been
some type of musculoskeletal complaint such as a radiculopathy identified.728
or peripheral nerve entrapment. If the nerve conduction studies Electrophysiologic Findings. Routine motor and sensory
are abnormal, this may be the only reliable method of diagnos- studies are usually normal.775 It is unknown whether prolonged
ing a peripheral nerve injury. When the needle electromyo- repetitive stimulation results in a decrementing CMAP. Needle
graphic examination demonstrates positive sharp waves in all electromyography reveals continuous electrical activity.154-330-341-
muscles tested, localizing a focal lesion to a root or nerve is 478X1016 j n e electrical activity is most likely spontaneous depo-
quite difficult. One may use the fact that fibrillation potentials larizations of single muscle fibers, as the amplitudes are usually
are not usually found in the syndrome of diffuse insertional ac- too small to represent MUAPs. These recorded potentials may
tivity. However, this approach can be fraught with error, as it is be ephaptically driven by neighboring single muscle fibers.
possible for some nerve or muscle diseases to primarily display Curare may or may not abolish the activity, suggesting that in
positive sharp waves. In some of these patients, it may simply those patients with cessation of activity following the applica-
be impossible to unquestionably localize a focal lesion. It is im- tion of curare, a neurogenic cause for the spontaneous firings
portant, however, to recognize this syndrome for what it is, a may be responsible. The continuous electrical activity makes it
benign muscle membrane disorder, and spare the patient exten- impossible to ascertain if there are any fibrillation potentials or
sive and costly medical work-ups simply to purse the finding of positive sharp waves originating from muscle fibers deprived of
diffuse positive sharp waves. their innervation. Complex repetitive discharges have also been
documented in some patients. 960 In addition, myokymic dis-
Schwartz-Jampel Syndrome charges can be observed, again emphasizing the possible neural
(Chondrodystrophic Myotonia) etiology for some patients.773-774
The disorder known as Schwartz-Jampel syndrome (SJS) The continuous electrical activity may or may not display a
is classified with the myotonias in this discussion; however, it crescendo/decrescendo (waxing/waning) character.4-12U43-196-468-
is not entirely clear if this is appropriate. Clinically, the pa- 48i.782.io76 j n s o m e patients, there is simply continuous firing of
tients appear to demonstrate myotonia, but the associated single-fiber potentials. Other patients have not only this type of
electrical discharges are not the typically described waxing- activity, but also a somewhat atypical waxing and waning of
and-waning potentials. The rare occurrence of this disorder MUAPs during the course of their spontaneous firing. The ac-
necessarily limits the number of patients examined clinically, tivity can be intensified by voluntary activity, percussion, or
electrophysiologically, as well as through microelectrophysi- needle movement. It is obvious that considerably more detailed
ologic means. electrical recordings on both a routine and single fiber level are
Clinical Features. The disorder is usually inherited in an au- required.
tosomal recessive manner, although a few cases of autosomal There is some evidence to suggest that the primary defect in
dominant inheritance are known.818 Individuals with SJS have a SJS is an alteration in the muscle membrane's sodium channel
rather characteristic appearance; thus, they are often diagnosed kinetics. 566 Specifically, there is a synchronous opening of
on the basis of the physical examination. 55 Infants present at sodium channels following a stimulus to the muscle membrane
birth with dysmorphic facies denoted by micrognathia, narrowed after repolarization of the membrane. Sodium channel activa-
palpebral fissures, and rather low-set ears. They often have a de- tion is also delayed. Following normal sodium inactivation, the
creased suck and a weak, high-pitched cry. During crying, the abnormal reopening of multiple sodium channels in a synchro-
muscle contractions induce myotonic contractions of the facial nized manner is a possible cause of the continuous muscle fiber
muscles such that the eyelids close and the lips are pursed with activity. A mild chloride channel abnormality may also be pre-
dimpling of the chin. There is rather striking muscle develop- sent in some persons with the disorder, thus possibly accounting
ment with relatively little subcutaneous fat, which accentuates for the variable myotonic discharges superimposed on the con-
the muscular hypertrophy. Although the disease is essentially tinuous firing of the muscle membrane.
nonprogressive, children display delayed developmental mile- Treatment. Procainamide is effective in SJS in suppressing
stones. Movement is best characterized as somewhat stiff and continuous activity, but not tocainide. This suggests that there is
slow. Occasional joint contractures can be found. There is usu- a difference in the defect regarding the manner in which the
ally associated epiphysial dysplasia, shortened stature, and sodium channel is altered in this disorder compared with other
pectus carinatum that are particularly noticeable as the child myotonias.
ages. A number of children with this disorder have decreased
cognitive function, while others have normal or above-average Toxin/Drug-Induced Myotonic Syndromes
intelligence. Hyporeflexia may be observed in some patients. Both toxins and drugs have the ability to produce clinical and
Laboratory Features. Serum CK levels may be normal or electrical myotonia in humans and animals. The exact manner
mildly elevated. in which these substances produce these effects is not entirely
Histopathology. Muscle fiber size variation with both hyper- understood, although evidence appears to implicate the chloride
trophic and atrophic fibers are usually found in most pa- channel. Continued work is required to more fully appreciate
tients.739-960 Both type 1 and type 2 fiber predominance may the generation of myotonic potentials with an associated insight
occur in different persons. Rarely, fiber type grouping may be into the various diseases producing myotonia.
observed suggesting some type of neurogenic abnormality. Fiber Toxin-Induced Myotonia. The best studied toxins capable
degeneration and regeneration have been described, but these are of generating clinical and electrical myotonia are the aromatic
not commonly observed. During the course of the disease, monocarboxylic acids.762 Examples of these substances include
muscle tissue is replaced to some degree by fat and connective 2,4-dichlorophenoxyacetic acid and anthracene-9-carboxylic
tissues. Mild and nonspecific ultrastructural abnormalities can acid. The toxin-induced myotonia is dose-dependent and wors-
be found. ens for any given concentration and an elevation in temperature.
Convincing evidence exists that the location of toxin action CENTRAL CORE DISEASE
is within the sarcolemma directly affecting the chloride chan-
nel's ability to passively transmit chloride ions across the cell Clinical Features. Central core disease usually manifests as
membrane. In the resting state, the muscle membrane's major hypotonia and weakness at birth or early childhood.95-305-373-392-946
ion channel capable of mediating an ionic current flow is chlo- The muscle weakness is predominantly proximal and symmet-
ride. In this regard, the chloride current accounts for 85% of ric with the lower limbs affected more than the upper limbs.
the membrane's conductance with the remainder being medi- Despite this weakness, the infants and children have sufficient
ated by potassium (a small fraction of the current flow in the strength to overcome gravity and variable amounts of resis-
resting state is also through sodium ions leaking into the cell). tance. The muscle weakness leads to delayed motor milestones.
Blocking chloride's ability to passively "clamp" the resting Independent ambulation is sometimes not achieved until after 3
membrane potential removes the stabilizing effect chloride has years of age. Patients walk with a waddling hyperlordotic gait.
on maintaining the resting membrane potential at about -80 A prominent Gower's sign can be present. There may be mild
mV. Depolarization of the cell leads to an accumulation of facial and neck flexor weakness. However, ptosis is not evident
potassium ions in the transverse tubules, where 80% of the and extraocular movements are intact, findings that can help
membrane's chloride channels are located. The combination of distinguish central core myopathy clinically from central nu-
increasing extracellular potassium concentration in the trans- clear and nemaline myopathies. Muscle atrophy is not a promi-
verse tubules and a reduced chloride conductance in this small nent feature of the disease but may be observed in some family
region results in the repetitive activation of the muscle mem- members. Rarely, major joint contractures are noted. The clini-
brane, i.e., myotonia. cal course is stable or only slowly progressive. Deep tendon re-
Drug-Induced Myotonia. In patients or animals given the flexes are normal or reduced. Sensation is normal. Intellectual
anticholesterolemic medication 20,25-diazacholesterol or ani- capacity is believed to be normal in these patients. There are
mals subjected to similar drugs, both clinical and electrical my- usually a number of mild to moderate skeletal deformities pre-
otonia develops. These drugs prevent the conversion of sent such as pes planus, pes cavus, kyphoscoliosis, and congen-
desmosterol to cholesterol. The development of myotonia is ac- ital hip dislocation.
companied by a buildup in the sarcolemma of desmosterol, the Laboratory Features. The serum CK levels are typically
precursor to cholesterol. The desmosterol is not directly respon- normal or only mildly elevated.
sible for an alteration in the membrane conductance. Histopathology. As the name implies, there are gross struc-
Investigations in animals have clearly identified a small reduc- tural alterations within the center of muscle fibers that appear as
tion (10%) in chloride conductance in resting skeletal muscle, distinct round areas on cross-section.305 The central cores extend
but this is insufficient to generate myotonia. The exact mecha- along the length of the muscle fibers on longitudinal section. The
nism whereby these medications result in myotonia remains to cores can occasionally be eccentric and multiple within a given
be elucidated. muscle fiber. These cores appear only in type 1 muscle fibers and
are particularly noticeable on oxidative enzyme stains where
these regions are devoid of stain (Fig. 27-26). Muscle fiber size
CONGENITAL MYOPATHIES variation can be prominent, and there is a predominance of type
1 fibers. Increased central nuclei are often appreciated. However,
The term "congenital myopathy" refers to myopathic dis- increased endomysial connective tissue, necrosis, and inflamma-
orders presenting preferentially, but not exclusively, at birth tion are not prominent features. On EM, the cores may be
(Table 27 - 6).95-305-373-392 Some congenital myopathies can pre- "structured" or "unstructured." In structured cores, there is Z-
sent later in childhood or even in early adulthood. The congen- band streaming and irregularity but the sarcomeres are pre-
ital myopathies were initially considered as non-progressive, served. In unstructured cores, there is severe myofibrillar
although it is now clear that progressive weakness can occur, disruption and loss of the normal sarcomere organization.
making the clinical distinction between some of the congenital Mitochondria and glycogen granules are reduced or absent in the
myopathies and muscular dystrophies sometimes difficult. structured and unstructured cores. Immunocytochemistry
Affected infants are usually hypotonic and display delayed demonstrates that the area of the cores react strongly to desmin,
motor development. Congenital myopathies can be inherited dystrophin, actin, cc-actinin, gelsolin, nebulin, p-amyloid precur-
in an autosomal dominant, autosomal recessive, or X-linked sor protein, NCAM, and various cyclin-dependent kinases. 217
pattern. Within families, there can be considerable variation The cores are also variably congophilic.
with respect to disease presentation and degree of muscle in- Molecular Genetics and Pathogenesis. The disorder is in-
volvement. The serum CK level is either normal or only herited in an autosomal dominant fashion. Mutations have been
mildly elevated. With respect to the electrodiagnostic medi- identified on chromosome 19q 13.1 in the ryanodine receptor
cine aspects of congenital myopathies, only a few of the con- gene (RYR1), the same gene that is abnormal in familial malig-
genital myopathies have been investigated in detail. nant hyperthermia (Table 27-6). 823 Thus, patients with central
Electrophysiologic studies reveal normal nerve conduction core myopathy are at risk for malignant hyperthermia. The
studies and normal or mild abnormalities regarding voluntary mechanism for core formation is unknown. The ryanodine re-
MUAP parameters. ceptor is formed by a tetrameric arrangement of RYR1 proteins
The classification of congenital myopathies is continually and acts as both a calcium-release channel and a "foot" struc-
changing and expanding. Initial categorizations of different ture bridging the gap between the sarcoplasmic reticulum and
types of congenital myopathies were based almost exclusively the T-tubules in skeletal muscle (Fig. 27-2). 823 The ryanodyne
on clinical presentation and light/electron microscopic struc- receptor is believed to play a central role in excitation-contrac-
tural alterations of the muscle biopsy specimen. Advances in tion coupling. The exact pathogenic mechanism by which muta-
molecular genetics will continue to provide better insight into tions in the ryanodine receptor lead to the formation of the
classification of these myopathies. central cores in muscle fibers and weakness is not known.
Table 27-6. Congenital Myopathies

Disease Inheritance Gene/Chromosome Clinical Features Electrodiagnostic Finding
Central core myopathy AD Ryanodine receptor Onset Infancy or childhood, NCS: Normal
(RYRI)/l9qI3.l occasionally adulthood; proximal EMG: Often normal. May
limbs and mild fecial weakness; have fibs/PSWs and BSAPPs
skeletal anomalies; risk for MH in severely weak muscles
Multicore/minicore AD,AR, Unknown Onset: Infancy or childhood;
myopathy sporadic Proximal and facial muscles; rare NCS: Normal
EOM weak; cardiomyopathy and EMG: Normal insertional and
respiratory weakness; skeletal spontaneous activity: normal
anomalies; risk for MH MUAPs or BSAPPs
Nemaline myopathy
Severe infantile form AR/AD Nebulin/2q2l.2-q22; Infantile onset: Severe generalized NCS: Usually normal
a-actin/1 q42 hypotonia/weakness; respiratory EMG: May have prominent
weakness; skeletal anomalies; Fibs/PSWs; BSAPPs
usually fetal in first year of life
Nemaline myopathy
Rare: a-tropomyosin Most common subtype. NCS: Normal
Mild early-onset form AD (TMP3)/lq2l-q23; Onset: Infancy or childhood; EMG: Rare Fibs/PSW; BSAPPs
NOTE: Most AD mild generalized hypotonia and
kinships do not map weakness; fecial muscles; rare
to this locus ptosis, EOM weak; dysmorphic
fades and skeletal anomalies
Nemaline myopathy
Adult-onset form Sporadic Unknown Onset in adult life; mild proximal NCS: Normal
and occasionally distal weakness;
no fecial or skeletal anomalies EMG: Rare Fibs/PSW; BSAPPs
Centronuclear/myotubular
myopathy
Severe neonatal type X-linked Myotubularin/Xp28 Severe neonatal hypotonia and NCS: Normal
weakness; respiratory weakness; EMG: Prominent fibs, PSWs, .
ptosis and EOM weak; poor CRDs, myotonic discharges;
prognosis in most BSAPPs
Centronuclear myopathy
Late infantile type AR, perhaps Unknown Most common subtype. NCS: Normal
AD Onset Late infancy or early EMG: Fibs, PSWs, CRDs,
myotonic discharges are
childhood; generalized weakness less common but can be
and hypotonia; facial and EOM seen; BSAPPs
weakness, ptosis; fecial anomalies
Centronuclear myopathy
Late childhood/adult AD Unknown Onset in late childhood or adult- NCS: Normal
type hood; mild proximal and/or distal EMG: Fibs, PSWs, CRDs,
weakness predominance;fecialand myotonic discharges are
EOM muscles variably involved: no less common but can be
skeletal or facial anomalies seen; BSAPPs
Congenital fiber type Sporadic Unknown Onset in infancy; generalized non- NCS: Normal
disproportion progressive weakness; occasional EMG: usually normal; rare fibs,
respiratory weakness; skeletal PSWs, CRDs; MUAPs are
and facial anomalies often normal but can have
BSAPPs
Reducing body myopathy Majority appear Unknown Onset in infancy to adulthood; NCS: Normal
sporadic; generalized or proximal weak- EMG: Usually normal insertional
? AR in some ness; may have fecial, respiratory and spontaneous activity;
or asymmetric weakness; rare fibs/PSWs; BSAPPs
skeletal anomalies
Fingerprint body Most sporadic Unknown Infantile onset; slowly or non- NCS; Normal
myopathy progressive proximal weakness EMG: N o abnormal insertional
or spontaneous activity;
BSAPPs
(Table continued on next page.)
Table 27-6. Congenita! Myopathies (Continued)
Disease Inheritance Gene/Chromosome Clinical Features Electrodiagnostic Finding
Sarcotubular myopathy Unknown; Unknown Onset: Infancy; slow progressive NCS: Normal
single report proximal +/- distal weakness EMG: Normal MUAPs or
in two EBSAPPs
brothers
Trilaminar myopathy Unknown; Unknown Infantile onset'generalized NCS: Normal
single case weakness; skeletal anomalies EMG: Normal
Hyaline body myopathy Sporadic or AR Unknown Onset in infancy or early childhood; NCS: Normal
proximal or scapuloperoneal EMG: Normal or BSAPPs
weakness
Cap myopathy Unknown Unknown Onset in infancy; generalized weak- NCS: Normal
ness; skeletal anomalies EMG: BSAPPs
Zebra body myopathy Unknown Unknown Onset in infancy or childhood; NCS: Normal
generalized weakness- may be EMG: BSAPPs
asymmetric and worse in arms
Myofibrillar myopathy AD Desmin/2q35 Onset in infancy or late adulthood; NCS: Usually normal; some
(Desmin myopathy, ctB-crystallin/l Iq2l distal, scapuloperoneal, or gener- infantile onset forms with
cytoplasmic or spheroid ?/ chromosome 12 alized weakness; cardiomyopathy axonal sensorimotor
body myopathy) neuropathy
AR Desmin/2q35 EMG: Prominent fibs, PSWs,
CRDs, "myotonic"
Sporadic Unknown discharges; BSAPPs
Tubular aggregate myopathy
Type 1 AD Unknown Onset: Childhood or early NCS: Normal except in
adulthood; limb-girdle weakness type 2 which is associated
with decrement on
Type 2 AR Unknown Onset Infancy; congenital repetitive stimulation
myasthenia; fatigable weakness EMG: Occasional fibs/PSWs;
Type 3 Sporadic Unknown Adult onset myalgia normal or BSAPPs
AD: autosomal dominant; AR: autosomal recessive; EOM weakness: ophthalmoparesis; BSAPPs: brief-duration, small-amplitude, polyphasic potentials.
Electrophysiologic Findings. Motor and sensory nerve con- period because the jitter is normal despite a concomitant fiber
duction studies are usually normal. One case has been reported density increase, implying that newly formed neuromuscular
of slowed peripheral nerve conduction; however, this finding is junctions are relatively rare events and have time to mature
exceptional.452 fully.
The needle electromyographic examination demonstrates Treatment. One of most important aspects in the care of pa-
a spectrum of findings depending upon the disease's severity. tients with central core disease and their families is to counsel them
Insertional activity is typically normal with an absence of ab-
normal spontaneous activity. A few patients, usually with
long-standing disease, have been reported with scattered fib-
rillation potentials and positive sharp waves. 37 Voluntary
MUAPs are typically reduced in amplitude and duration
while increased in the number of phases.84-258-699 When a trig-
ger-and-delay line are utilized, exceptionally long duration
MUAPs accompanied by satellite potentials may be
noted.476-592 In most patients, a careful quantitative assess-
ment of MUAPs reveals not only normal appearing MUAPs,
but also ones with both long and short durations. Using the
recommended guidelines of measuring nonpolyphasic
MUAP durations, however, results in a number of muscles
having reduced mean MUAP durations consistent with a dis-
ease process intrinsic to muscle. An early recruitment pattern
is evident in weak muscles.
Single-fiber electromyography reveals an increase in fiber
density without a concomitant increase in the jitter or percent of
potential blockings. 195 The increased fiber density correlates Figure 27-26. Central core myopathy. Muscle biopsy reveals
with a finding of an increase in the terminal innervation ratio.181 central and eccentric areas devoid of oxidative enzyme staining.These
These two findings suggest that there is a mild degree of motor cores occur predominantly in type I muscle fibers (darker staining
unit remodeling. This process also occurs over a prolonged time fibers), NADH-tetrazolium reductase.
regarding the risk of malignant hyperthermia. 343 Appropriate NEMALINE MYOPATHY

precautions and avoidance of certain anesthetic agents (e.g.,
halothane) and neuromuscular blocking agents (succinyl- Clinical Features. There are three major clinical presentations
choline) need to be taken during surgical procedures. There is of nemaline myopathy: (1) a severe infantile form; (2) a static or
no available medical treatment. Patients may benefit from phys- slowly progressive form; and (3) an adult-onset form.95-281-355-373-392-
ical therapy and orthotic devices. 947.IO94.IO98 The severe infantile form is characterized by significant
hypotonia and generalized weakness at birth. This severe form of
MULTICORE/MINICORE MYOPATHY trie disease has an autosomal recessive inheritance. The infants ex-
hibit a weak cry and suck and frequently need to be placed on a
Clinical Features. The clinical presentation of persons with ventilator. There is a lack of spontaneous movements. The deep
multicore or minicore myopathy is quite similar to those tendon and Moro reflexes are usually absent. Respiratory muscle
noted above with central core disease.95-285-305-373-491'944'995'n45 The weakness combined with inability to handle secretions and feed-
myopathy may present in infancy or adulthood. Affected infants ing difficulties combine to result in death often within the first year
are usually hypotonic and weak, resulting in slow motor devel- of life. The presence of intranuclear rods may be a marker for this
opment. Weakness is greater in the proximal muscles and some- severe form of nemaline myopathy.62-743-853
times affects the upper limbs more than the lower limbs. Facial The most frequent form of the disease is the mild, non-pro-
muscle weakness, ptosis, and occasionally ophthalmoparesis gressive or slowly progressive type. Mild hypotonia and
can been seen. Muscle contractures and multiple skeletal defor- muscle weakness are usually noted in infancy or early child-
mities such as kyphoscoliosis, high-arched palate, and club feet hood. Most cases are believed to be inherited in an autosomal
are common findings. Cardiomyopathy and respiratory muscle dominant pattern, although penetrance may be reduced. This
involvement can also develop.491-944-1145 In approximately 50% of weakness is diffuse, affecting proximal and distal muscles.
cases, the muscle weakness is not progressive, but a slow pro- Some patients have a facioscapuloperoneal distribution of
gression of muscular function over the course of years occurs in weakness. Motor milestones are delayed, and ambulation may
some individuals. be marked by a waddling hyperlordotic gait. There is a general-
Laboratory Features. Serum CK is usually normal or only ized reduction in muscle bulk compared with similarly aged
slightly elevated. children. Facial and masticatory muscles are also affected.
Histopathology. As the name implies, there are multiple However, ptosis and extraocular weakness are only rarely en-
small regions within muscle fibers of variable size (minicores) countered. Dysmorphic narrow facies with high-arched palate,
formed by disorganization of the myofibrils. These minicores micrognathia, and prognathism are characteristically seen. In
are similar to central cores described in the previous section but addition, multiple skeletal deformities such as pectus excava-
are much smaller and do not extend the entire length of the tum, kyphoscoliosis, pes cavus, or club feet are common. Deep
muscle fiber as do central cores. In addition, minicores can tendon reflexes are reduced or absent.
occur in either type 1 or 2 muscle fibers. Type 1 fiber predomi- The adult-onset type of nemaline rod myopathy is somewhat
nance and atrophy as well as fiber size variation are also noted. controversial as to whether it represents a distinct disorder or a
EM demonstrates myofibrillar disruption similar to that seen in milder, allelic variant of the early-onset forms of the disease.
central cores. The muscle biopsy is crucial for distinguishing The adult-onset form is not associated with dysmorphic facial
this myopathy from other congenital myopathies with similar features or skeletal deformities typical of the early-onset forms.
clinical presentations. Also, familial cases of adult-onset nemaline myopathy have not
Molecular Genetics and Pathogenesis. The pattern of in- been described. These patients have a relatively normal child-
heritance is unclear. Autosomal dominant and recessive inheri- hood and adolescence; mild proximal and occasionally distal
tance has been reported, as have sporadic cases. Chromosome muscle weakness are not noted until later in adulthood. Some
linkage has not been demonstrated in any of these familial patients have minimal skeletal muscle weakness but manifest
cases. Multicores have been reported on muscle biopsy in one with a cardiomyopathy.638
child with short chain acyl-CoA dehydrogenase deficiency Laboratory Features. The serum CK level is normal or
(SCAD).1018 slightly elevated.
Electrophysiologic Findings. Needle electromyographic in- Histopathology. On modified Gomori trichrome stain, the
vestigation demonstrates normal insertional activity with an ab- rods appear as small, red-staining bodies in the subsarcolemma
sence of any type of membrane instability or abnormal and occasionally perinuclear regions (Fig. 21-21 A). Type 1
spontaneous activity.491-789"5-1145 There is a mixture of both fiber predominance is found in the congenital forms but not in
normal appearing and short-duration, low-amplitude polyphasic the adult-onset form of the disease. The rods appear mainly in
MUAPs. In the proximal muscles, quantitative electromyogra- type 1 fibers that are often also hypotrophic. The percentage of
phy^ reveals abnormally short mean MUAP durations. The re- muscle fibers containing rods varies widely even within fami-
cruitment pattern is consistent with an intrinsic muscle disease, lies, ranging from 7 to 100%. 1099 The frequency of the rod
i.e., early recruitment. Some patients with mild disease may not bodies does not correlate with the severity of muscle weakness.
reveal gross electrophysiologic abnormalities and require care- On EM, the typical "rod bodies" measure 3-6 pm in length and
ful quantitative measurement of MUAP durations before any 1-3 pm in diameter, giving the appearance of threads (nema-
abnormality is noted. Single-fiber electromyographic analysis line: Greek for "thread-like").305-373 On EM, nemaline rods have
demonstrates an increase in the fiber density with about half of a density similar to the Z-disk (Fig. 27-27B). Intranuclear
potential pairs revealing a jitter elevation. Potential pair block- rods have been identified in several cases of severe infantile ne-
ing is not noted. maline myopathy and have been suggested to represent a
Treatment. No medical treatment is available. Patients marker for this severe form of the disease (Fig. 27-27C).62-743-853
may be at risk for malignant hyperthermia (see Central Core However, intranuclear rods are not demonstrated in all severe
Disease). 529 infantile cases, while they have also been identified in a few
Figure 27-27. Nemaline Myopathy. (A) Muscle biopsy of an infant

with nemaline myopathy reveals the accumulation of rods at the pe-
riphery of most muscle fibers. Gomori trichrome. (B) On electron mi-
croscopy, the rods are electron-dense and appear to originate from the
Z-disks. Most rods are beneath the sarcolemma or within myofibrils,
but (C) can be evident within myonuclei, so-called intranuclear rods.
adult-onset cases of nemaline myopathy. 288 Immunohisto- sporadic in the past, may represent spontaneous mutations or au-
chemistry reveals the rods and Z-disk are strongly immunoreac- tosomal recessive inheritance of the mutation. Nebulin is a giant
tive for a-actinin. 1097 A slightly decreased amount but normal protein (800 kD) found in the thin filaments and Z-disk of striated
size of nebulin may be seen in some forms of nemaline myopa- muscle. Mutations in the nebulin gene apparently lead to a loss of
thy.474 Rods are not specific for nemaline myopathy and have the structural integrity of the Z-disks and the formation of the
been reported following tenotomy, in HIV-associated myopathy, rods. A severe neonatal form of autosomal recessive nemaline
polymyositis, hypothyroidism, and in biopsies from schizo- myopathy has been linked to mutations in the oc-actin gene
phrenic patients. (ACTA1) located on chromosome lq42 in 13 families.744 In ad-
Molecular Genetics and Pathogenesis. Nemaline rod for- dition, another family apparently had autosomal dominant inheri-
mation is thought to be secondary to a derangement of proteins tance. Mutations in ACTA1 gene are also responsible for
necessary to maintain normal Z-disk structure. There are at least previously reported cases of "congenital myopathy with excess of
three genetically distinct forms of nemaline myopathy (Table thin filaments."744
27-7). One kinship with autosomal dominant nemaline my- Electrophysiologic Findings. The needle electromyo-
opathy has been linked to a missense mutation in the a- graphic examination in nemaline myopathy may demonstrate a
tropomyosin gene (TMP3) on chromosome Iq21-q23. 549a wide spectrum of findings, especially if followed over time in
Subsequently, over 50 unrelated families with nemaline myopa- the same patients. The general dynamics of the needle elec-
thy have been tested with only one other patient having a muta- tromyographic findings in this disease usually demonstrate little
tion in the TMP3 gene.1099 This patient had severe disease, dying in the way of abnormalities in children with the slowly progres-
at the age of 21 months, and was believed to have autosomal re- sive or static form of the disease. A small proportion of these in-
cessive inheritance. The patient's parents were first cousins, and dividuals may have muscles demonstrating abnormally short,
the child had homozygosity for a nonsense mutation in TMP3. mean MUAP durations with decreased amplitudes and in-
Thus, it would appear that missense mutations of the TMP3 creased numbers of polyphasic potentials. Abnormal sponta-
gene may cause the mild autosomal dominant form of the dis- neous potentials in the way of fibrillation potentials and positive
ease, while nonsense mutations of the same gene can cause a sharp waves are very rare.
severe autosomal recessive variant. Because most of the autoso- Between the ages of 4 and 10 years, there is a dramatic in-
mal dominant forms do not have mutations in TMP3, this form crease in the electrical abnormalities. A few patients may
of the disease is genetically heterogeneous. demonstrate an increase in abnormal insertional activity; how-
Most of the autosomal recessive cases are caused by mutations ever, this is a rare finding. More commonly, patients demon-
in the nebulin gene (NEM2), which is located on chromosome strate significant numbers of abnormal MUAPs with short
2q21.2-q22.787-10961099 Some cases, which have been considered durations, decreased amplitudes, and a higher percentage of
polyphasic potentials.38-295-453-500-534 The recruitment pattern is myopathy from most other forms of congenital myopathy. Deep
also usually early in nature with more MUAPs than anticipated tendon reflexes are depressed or absent, but sensation is com-
for the given amount of force production. There are still easily pletely normal. Some children have mental retardation and
detected normal MUAPs, but these are in the minority com- seizures.
pared with the above-described abnormal potentials. A few The X-linked recessive neonatal form of the disease presents at
long-duration, large-amplitude MUAPs can be observed, but not birth with severe hypotonia and weakness. Infants typically have
necessarily greater than normally expected. respiratory insufficiency and difficulty swallowing, requiring
After the age of about 11 years, MUAPs with abnormally ventilatory support and feeding tubes. Polyhydramnios frequently
long durations and large amplitudes can also be observed.743-827 is noted in later stages of the mother's pregnancy. Ptosis and oph-
A reduced recruitment pattern can occasionally be seen in thalmoparesis become more prominent after the newborn period.
which there are fewer than anticipated MUAPs firing at high Hip and knee contractures are evident in some. The neonatal form
rates. With increasing age, single-fiber electromyography of centronuclear myopathy is usually fatal in infancy. However,
demonstrates an increase in fiber density into the abnormal the prognosis is not invariably poor. In a review of 40 reported
range. Occasional single fiber pairs have an increase in the jitter cases, six boys were alive at ages of 6 months to 27 years (mean
with rare blocking, but this is not a prominent finding. Despite 10 years).1095 All but one had respiratory difficulties at birth, and
the clinical impression of preferential proximal weakness, ab- two still needed mechanical ventilation at the ages of 8 and 10
normalities can also be found in the distal limb muscles, partic- years. Four of the children learned to walk, albeit delayed, and
ularly the tibialis anterior muscle. three had no significant disabilities at the ages of 6 months, 5
The above continuum of electrophysiologic findings suggests years, and 7 years. Interestingly, there has been one well-de-
that there is significant motor unit remodeling occurring over time scribed case of a manifesting female with proven X-linked (my-
in these patients. It is doubtful that these "neurogenic findings" are otubularin deficiency) centronuclear myopathy who began having
a result of a peripheral neuropathy or motor neuron disorder, as weakness after the age of 5 years 414 The mechanism may be akin
neither peripheral nerve conduction nor histologic evaluation sup- to skewed inactivation as sometimes seen in manifesting female
port a peripheral neuropathy or anterior horn cell loss. carriers of dystrophin mutations.
In those individuals with the aggressive infantile form, mem- In addition, a form of the disorder can manifest in late child-
brane instability in the form of fibrillation potentials and posi- hood or adulthood. At least some of these cases are believed to
tive sharp waves can be rather prominent. Both short- and be autosomal dominantly inherited. The pattern of muscle
long-duration MUAPs may be observed. These findings are weakness is quite variable. Some patients have predominantly
compatible with a much more aggressive form of the disease proximal weakness, while others have more distal limb involve-
creating a rapid progression through the above-noted stages of ment. A facioscapulohumeral pattern of weakness has also been
muscle fiber loss. described.319 Weakness is usually mild and only slowly progres-
Treatment. No specific medical treatment is available. sive if at all. Facial and neck flexor muscle weakness can be ev-
Patients may benefit from physical therapy and bracing. ident; however, ptosis and ophthalmoparesis are variable in
occurrence. Dysmorphic facial features and skeletal anomalies
CENTRONUCLEAR MYOPATHY are not associated with the adult-onset form of centronuclear
myopathy.
Clinical Features. Spiro and colleagues introduced the term Laboratory Features. Serum CK is normal or slightly elevated.
myotubular myopathy to the first reported cases because the Histopathology. Muscle biopsies demonstrate centrally lo-
histologic features of this congenital myopathy resemble my- cated myonuclei often forming chains along the longitudinal
otubes. 964 However, it is now clear that this myopathy is not aspect of the muscle fiber.305 In transverse section, the number
caused by an arrest of myotubes and the most appropriate desig- of muscle fibers with central nuclei range from 25 to 95% (Fig.
nation for this disorder is centronuclear myopathy. At least 27-28). 307 Occasionally, the nuclei cluster in the center of the
three clinically different forms of the disease are recognized: (1) fiber rather than forming longitudinal chains. The central nuclei |
a slowly progressive, late infantile-early childhood type; (2) a appear in both fiber types and are surrounded by a small perinu-
severe X-linked neonatal type; and (3) a late childhood or adult- clear halo devoid of ATPase activity. Oxidative enzyme stains
onset type.95-305-373-392'095 reveal the center of muscle fibers to be dark with a radial
The most common form of centronuclear myopathy is the arrangement of the intermyofibrillar network giving the appear-
slowly progressive, late infantile-early childhood type. The mode ance of spokes on a wheel. The central areas immunostain for
of inheritance is still debatable. Autosomal recessive inheritance desmin and vimentin. 899 The type 1 fibers are smaller than
is suspected in most kinships, although the appearance of mild normal and are the predominant fiber type, whereas the type 2
histologic abnormalities in maternal muscle biopsies has sug- fibers appear rather normal in size. On EM, there is reduced my-
gested autosomal dominant inheritance with incomplete pene- ofibrillar elements and an excess of mitochondria and glycogen
trance in other families. Affected children are usually the product granules in the center of muscle fibers not occupied by nuclei.
of a normal pregnancy and delivery, although there may be mild In a review of muscle biopsies performed on female obligate
hypotonia and generalized weakness. Motor milestones are typi- carriers of X-linked centronuclear myopathy, 6 out of the 14
cally delayed. When ambulation is finally achieved, a lordotic carriers showed fibers with central nuclei resembling fetal my-
waddling gait with prominent scapulae are noted. The weakness otubes, 3 showed other abnormalities, and 5 were normal. 1095
is slowly progressive, and a wheelchair may be required by the Finally, some infants have a severe clinical phenotype resem-
second or third decade. Children have a slender appearance with bling the X-linked recessive neonatal form of the centronuclear
reduced muscle bulk diffusely. Many of the children are noted to myopathy but have only type 1 fiber hypotrophy without central
have weak facial muscles, elongated narrow facies, and high- nuclei on biopsy.
arched palate similar to that seen in nemaline myopathy. Ptosis Molecular Genetics and Pathogenesis. As noted above,
and ophthalmoparesis are common, distinguishing centronuclear there is genetic heterogeneity among the different forms of
Figure 27-28. Myotubular or centronuclear myopathy. (A) Biopsy of an infant with severe X-linked myotubular myopathy reveals hy-
potrophic muscle fibers that demonstrate intense oxidative enzyme staining (NADH-reductase) in the center of the fibers. (B) Central nuclei are
also evident in the majority of muscle fibers in a patient with adult-onset centronuclear myopathy. Gomori trichrome stain.
centronuclear myopathy (Table 27-6). The severe neonatal CONGENITAL FIBER TYPE DISPROPORTION
form has been linked to mutations in the myotubularin gene
located on chromosome Xp28 (MTM1 ).467 557 Myotubularin is a Clinical Features. Patients with congenital fiber type dis-
dual-specificity phosphatase important in the signal pathways proportion present during the neonatal period with generalized
involved in muscle cell growth and differentiation. Terminal hypotonia and weakness, weak cry and suck, and multiple joint
muscle fiber differentiation requires the hypophosphorylation contractures.3'-95-305-373-395-915 Muscle weakness is usually nonpro-
of gene regulating proteins that contain a characteristic motif gressive, and many patients improve their functional status with
of unknown function termed "SET."198 Myotubularin is thought age. Motor milestones are delayed but are eventually reached.
to dephosphorylate these SET domain-containing regulating However, there are cases with a progressive and sometimes fatal
proteins. Mutations in myotubularin result in the loss of func- course secondary to respiratory muscle insufficiency. The my-
tion of this phosphatase activity leading to maturational distur- opathy is associated with dysmorphic facial features with a
bances of muscle. The autosomal recessive and dominant high-arched palate, congenital hip dislocations, kyphoscoliosis,
forms of centronuclear myopathy have not been genetically club foot, and a possible relationship to the rigid spine syn-
linked. Perhaps the mutations in these disorders involve prodrome. Deep tendon reflexes are diminished, and sensation is
teins that interact with myotubularin or with other cell cycle normal. Approximately one third of patients have some type of
regulating proteins. CNS dysfunction.
Electrophysiologic Findings. This form of congenital Laboratory Features. The serum CK is normal or mildly
myopathy is associated with the most abnormal electromyo- elevated.
graphic findings, particularly in regards to muscle membrane Histopathology. The characteristic feature of this disorder,
instability.85-272-435-783-9381152 Motor and sensory nerve conduc- as the name implies, is a disproportion in the size of type 1
tion studies are normal. Patients typically display prominent versus type 2 fibers.305 The type 1 fibers are more numerous but
electromyographic abnormalities. There is usually increased are more than 15% smaller than the type 2 fibers which are
insertional activity accompanied by positive sharp waves and normal or slightly hypertrophic in diameter (Fig. 27-29).
fibrillation potentials. These findings vary from muscle to However, these histologic abnormalities are not specific and are
muscle and can be demonstrated even in clinically strong also evident in centronuclear myopathy, nemaline myopathy,
muscles. Besides positive sharp waves and fibrillation poten- spinal muscular atrophy, congenital muscular dystrophy, and
tials, varying degrees of complex repetitive discharges can be central nervous system disorders. Sequential muscle biopsies
seen.78-371-429-664 In addition, myotonic discharges have been re- sometimes demonstrate changes consistent with nemaline or
ported in some patients, although clinical myotonia is central nuclear myopathy. 211 No consistent ultrastructural ab-
absent.371429-704-828 The MUAPs are usually abnormal in that normalities have been noted.
the duration and amplitude are reduced while the recruitment Molecular Genetics and Pathogenesis. Most cases are spo-
pattern is usually early and full. In some individuals with radic in occurrence, although there are some cases that appear
mild disease, either a normal electrophysiologic evaluation is to be inherited in an autosomal dominant and others in an auto-
found or there are a few small MUAPs with early recruit- somal recessive fashion. No linkage to specific chromosomes
ment.319-922 Occasionally, patients have only a few fibrillation have been identified.
potentials with normal appearing MUAPs, but this is not a Electrophysiologic Findings. The needle electromyo-
common finding.964 graphic examination reported in a small number of patients with
Treatment. Infants with the X-linked form of the disease congenital fiber type disproportion failed to reveal any abnor-
usually require mechanical ventilation and gastric tube feedings malities.201 There was normal insertional activity accompanied
to support life. No other medical therapy is available. Patients by an absence of abnormal spontaneous activity, and voluntary
with less severe disease may benefit from physical therapy and MUAPs displayed normal parameters. However, a few patients
orthotic devices. demonstrated short-duration, low-amplitude voluntary MUAPs
the reducing bodies are evident in both fiber types. EM reveals
these reducing bodies are composed of electron-dense granules
and 12-17 nm tubulofilaments.
Molecular Genetics and Pathogenesis. The majority of
cases appear to be sporadic in nature, although two sisters were
involved in one report. The pathogenesis is unknown.
duction studies are normal. The needle electromyographic ex-
amination can be expected to reveal a prominence of voluntary
MUAPs with short durations, low amplitudes, and an increased
number of phases. 115J36- 750 These potentials recruit in an early
manner at low levels of force. Abnormal spontaneous activity is
not commonly encountered; however, one patient did demon-
strate significant degrees of positive sharp waves and fibrillation
potentials. Additional studies are required to more fully appreci-
ate the possible patterns of abnormality in this disease.
Figure 27-29. Congenital fiber type disproportion. The mean Treatment. No specific treatment is available.
diameter of type I muscle fibers is significantly lower (< 12%) than the
mean diameter of type 2 fibers. In addition, there is a predominance of FINGERPRINT BODY MYOPATHY
these darker staining small type I muscle fibers. ATPase, pH 4.3.
Clinical Features. There are only a few reports of fingerprint
body myopathy.95-202-287-303-305-392 Infants have proximal weakness
with early recruitment. 117 ' 166544 Several patients have been re- and atrophy and are hypotonic. Weakness is nonprogressive or only
ported with high degrees of fibrillation potentials and positive slowly progressive. Reflexes are absent. Intelligence is subnormal,
sharp waves.166-572-987 Complex repetitive discharges may also be and a few patients have had febrile seizures. Kyphoscoliosis and
found in abundance in various muscles. Based on the limited pectus excavatum have been observed in some cases.
number of electrophysiologic reports, there appears to be some Laboratory Features. Serum CKs are normal or slightly
suggestion of a correlation between the clinical severity of the elevated.
disease and the degree of abnormalities detected on electrodiag- Histopathology. Muscle biopsy demonstrates type I fiber
nostic testing. However, more reports are required to establish predominance with type 1 fiber hypotrophy and type 2 fiber hy-.
an unquestionable relationship. pertrophy. Oxidative enzyme stains reveal reduced activity in
Treatment. Supportive measures in regards to mechanical the subsarcolemma in perinuclear regions in type 1 fibers. On
ventilation and tube feeding may be temporarily required in EM and phase-contrast microscopy, a complex lamellar pattern
some patients. Physical therapy and orthotic devices may be resembling fingerprints are evident in these areas. The finger-
beneficial. print bodies may be composed of cytoskeletal proteins.
Fingerprint bodies have also been described in myotonic dystro-
REDUCING BODY MYOPATHY phy, distal myopathies, nemaline myopathy, dermatomyositis,
oculopharyngeal dystrophy, and muscle biopsies from patients
Clinical Features. Only a few patients with reducing body with uremia and chronic pulmonary disease.
myopathy have been reported, and the clinical presentation of Molecular Genetics and Pathogenesis. Most of the cases
patients with reducing body myopathy appears quite have been sporadic, although the disease was reported in a pair
varie4.95;,,5^-334-373-3^5,2-7M-750 Two patients reported in the liter- of male identical twins202 and in two siblings.303 The pathogenic
ature presented as floppy infants. One child had slight facial mechanism for the formation of the fingerprint bodies is not j
weakness and ptosis. Muscle weakness was generalized and ac- known.
companied by multiple joint contractures. The infants died of Electrophysiologic Findings. Nerve conduction studies are
complications related to severe respiratory muscle weakness. normal.202-287-303 Electromyography demonstrates either
There are also a few patients described who had normal neona- normal202-303 or short-duration, low-amplitude MUAPs 287 with
tal periods but developed muscle weakness later in childhood or no abnormal spontaneous activity.
in adulthood. Some had mild proximal weakness, whereas Treatment. There is no specific medical treatment.
others had asymmetric involvement of the arms. The course
varied from static and benign weakness to progressive deterio- SARCOTUBULAR MYOPATHY
ration of strength leading to death.
Laboratory Features. Serum CK levels are usually normal, Clinical Features. There has been only one report of this
although a few patients have demonstrated mild elevations. disorder that occurred in two brothers of a consanguineous mar-
Histopathology. The distinctive features of this myopathy riage.485 The brothers presented with predominantly proximal,
are "reducing bodies" within the muscle fibers as demonstrated nonprogressive muscle weakness since infancy. One brother had
by their unique ability to reduce nitroblue tetrazolium when me- ankle dorsiflexor weakness as well. Attainment of motor mile-
diated by menadione.305-373 The reducing bodies stain purple stones was delayed. Deep tendon reflexes were diminished.
with modified Gomori trichrome stain, pink on H&E stain, and Intelligence was normal.
are devoid of oxidative enzyme staining. Desmin immunoreac- Laboratory Features. Serum CK was normal in one boy
tivity may be increased at the periphery of some reducing and slightly elevated in the other.
bodies, but aB crystallin, a-actinin, titin, and nebulin stains are Histopathology. Small vacuoles were evident in 20-30% of
normal.334 In most cases, there is type 1 fiber predominance, but type 2 muscle fibers but in less than 4% of type 1 fibers. On
EM, these vacuoles were membrane bound and appeared empty Molecular Genetics and Pathogenesis. The mode of inher-
or contained a small amount of amorphous debri. T-tubules itance and cause for this rare myopathy are unknown.
were seen to abut many of these vacuoles. The vacuoles im- Electrophysiologic Findings. Electromyography has been
munostained for sarcoplasmic reticulum-associated ATPase. In reported as normal or showing an increased number of small-
addition, there was an increase in internal nuclei and muscle duration, low-amplitude, polyphasic MUAPs.61-151-614-885
fiber splitting. Treatment. There is no specific medical treatment available.
Molecular Genetics and Pathogenesis. The cause for the
selective segmental vacuolization is not known, but the histo- CAP DISEASE
logic abnormalities are believed to represent an abnormality in
the sarcotubular system. Clinical Features. This rare myopathy is associated with
Electrophysiologic Findings. Nerve conduction studies generalized muscle weakness and hypotonia from birth. 331
were normal.485 Electromyography was normal in one child but Marked skeletal anomalies were reported. Tendon reflexes were
revealed low-amplitude, short-duration MUAPs in the other absent.
sibling.485 Laboratory Features. Serum CK is normal.
Treatment. There is no specific medical treatment. Histopathology. The majority of muscle fibers demonstrate
a peripheral crescent that reacts strongly to NADH dehydroge-
TRILAMINAR MYOPATHY nase, PAS, and phosphorylase but not to SDH or myofibrillar
ATPase. On EM, there is widened Z-bands, disarray of the my-
Clinical Features. There is a single reported case of this dis- ofibrils, and lack of thick filaments.
order.856 The infant had rigidity of her trunk and limbs, de- Molecular Genetics and Pathogenesis. The pathogenesis is
creased spontaneous movements, and numerous joint unknown.
contractures. Suck and swallowing were also noted to be weak. Electrophysiologic Findings. Nerve conduction studies are
Sensation appeared normal, and deep tendon reflexes were normal. Electromyography demonstrates myopathic MUAPs.331
intact. By 10 months of age, the infant had some head control Treatment. There is no specific medical treatment available.
but was still unable to sit. Subsequently, the patient was able to
ambulate, albeit with difficulty. ZEBRA BODY MYOPATHY
Laboratory Features. Serum CK was markedly elevated at
birth (approximately 40 times normal). Clinical Features. Only a couple of cases of Zebra body
Histopathology. Muscle biopsy demonstrated variability in myopathy have been reported. 551838 One child presented with
fiber size. Approximately 25% of fibers were large and had three generalized weakness and thin muscles from birth.551 The
concentric zones that displayed a differential staining pattern. second report involved a child with severe hypotonia, dyspha-
The inner and outer zones stained intensely with Gomori gia, and asymmetric weakness of the upper limbs.838 The
trichrome and NADH stains, while the inverse pattern was seen courses were nonprogressive or only slowly progressive.
on ATPase staining. On EM, the innermost zone demonstrated Laboratory Features. Serum CK is two to three times normal.
myofibrillar disarray and densely packed mitochondria, glyco- Histopathology. Muscle biopsies demonstrate variability in
gen granules, and myofilaments. The intermediate zone revealed muscle fiber size, increased internal nuclei, and occasional vac-
Z-band streaming. The outer zone was composed of disorga- uoles. The Z-bodies are evident only on EM, where there is 270-
nized myofibrils, mitochondria, lipid droplets, and vesicles. nm zebra-like periodicity of osmiophilic stria resembling
Molecular Genetics and Pathogenesis. The pathogenesis is Z-disks and measuring up to 2 nm in length. Streaming of the Z-
unknown. bands and nemaline rods are also present.
Electrophysiologic Findings. Nerve conduction studies and Molecular Genetics and Pathogenesis. Zebra bodies are
electromyography were normal.856 found normally at myotendonous junctions, in muscle spindles
Treatment. No specific medical treatment is available. in extraocular muscles, and in cardiac muscles. They may also
be found in other pathologic conditions (e.g., myofibrillar my-
HYALINE BODY MYOPATHY/FAMILIAL MYOPATHY
opathy). The pathogenic basis for the disease is not known.
Electrophysiologic Evaluation and Findings. Electro-
WITH LYSIS OF MYOFIBRILS myography is reported as showing myopathic units without ab-
normal spontanenous activity.551-838
Clinical Features. This is a rare myopathy presenting in in- Treatment. There is no specific medical treatment available.
fancy or early childhood with hypotonia and weakness. Muscle
weakness has been described as predominantly proximal in TUBULAR AGGREGATE MYOPATHY
some and scapuloperoneal in other cases.61-151-614-885 The myopa-
thy is nonprogressive, although motor milestones are delayed. Clinical Features. Tubular aggregates are a non-specific
Deep tendon reflexes are preserved. histologic abnormality that has been demonstrated in several
Laboratory Features. Serum CK levels are normal. disorders including periodic paralysis, hyperthyroidism, con-
Histopathology. Muscle biopsies demonstrate subsar- genital myasthenia (slow channel syndrome), hypoxia, and
colemmal "hyaline" bodies. These lesions stain pale green on toxic myopathies. Normal patients can also have tubular aggre-
modified trichrome and pale pink on H&E stains. The hyaline gates on muscle biopsy. However, there are three clinical syn-
bodies occur in type 1 fibers, which are hypotrophic. The hya- dromes in which the primary pathologic feature is tubular
line bodies lack oxidative enzyme and PAS staining but aggregates on muscle biopsy.95-220-392,6863 The first condition man-
demonstrate intense ATPase activity. On EM, the hyaline ifests as a slowly progressive limb-girdle syndrome with onset
bodies are devoid of myofibrils and are composed of gran- in childhood or early adulthood.220-861 The second syndrome
ulofilamentous debris. should be considered as a form of congenital myasthenia and is
Figure 27-30. Tubular aggregates. (A) Tubular aggregates stain

bright red on Gomori trichrome and (B) intensely dark with NADH
dehydrogenase. (C) They are usually evident in only type 2 muscle
fibers (the lighter staining fibers on NADH dehydrogenase), staining in
patients with periodic paralysis and muscle/cramp syndromes. Electron
microscopy demonstrates that these aggregates are composed of
groups of dilated tubules coursing in different directions.
associated with slowly progressive muscle weakness from involuntary MUAPs with short durations and low ampli-
fancy.252489 These patients demonstrate fatigable weakness that tudes. 22o.6i2.686a Positive sharp waves and fibrillation potentials
improves with anticholinesterase medications. The third clinical are occasionally found. Routine motor and sensory nerve con-
group consists of patients with diffuse myalgias.124 612-678 Muscle duction studies are normal. Patients with the myasthenic syn-
pain is worse with exertion, but there is no myoglobinuria. drome demonstrate a decremental response on repetitive
Muscle tone, bulk, and strength are normal, as is the rest of the stimulation that improves with pyridostigmine. Patients with the
physical examination. muscle-pain syndrome typically have completely normal elec-
Laboratory Features. Serum CK is normal or mildly trodiagnostic findings.678
increased. Treatment. Patients with the congenital myasthenic syn-
Histopathology. Tubular aggregates appear as subsarcolem- drome may benefit from pyridostigmine. Some patients with the
mal or intracytoplasmic irregularly shaped lesions, which stain muscle-pain syndrome improve with dantrolene or tricyclic an-
basophilic on H&E and are red on modified Gomori trichrome tidepressant medications.
(Fig. 27-30A). They show intense reactivity to NADH-TR (Fig.
27-30R) but do not stain for SDH. Tubular aggregates are pre- MYOFIBRILLAR MYOPATHY
sent only in type 2 muscle fibers in the syndromes associated
with periodic paralysis and muscle pain but are evident in both Myofibrillar myopathy (MFM) is a rare but frequently misdi-
fiber types in the limb-girdle syndrome. On EM, the tubular ag- agnosed disorder characterized by the pathologic finding of my-
gregates are composed of bundles of tubules 60-80 nm in diam- ofibrillar disruption on EM and excessive desmin accumulation
eter that course in various directions with respect to the long in muscle fibers on immunostains.1213-208-216-293-436-640-717 Desmin
axis of the muscle fibers (Fig. 27-30C). is not the only protein that accumulates in this disorder; thus,
Molecular Genetics and Pathogenesis. The limb-girdle syn- Nakano et al recommend the term "myofibrillar myopathy," as
drome may be inherited in an autosomal dominant861 or recessive this may be a more accurate description of the spectrum of the
manner.220 The congenital myasthenic syndrome is inherited in an histologic abnormalities.717 This myopathy has been reported as
autosomal recessive pattern. Most cases of the muscle-pain syn- desmin storage myopathy, 307 desmin myopathy,!46-208 familial
drome are sporadic in occurrence. None of the disorders have been desminopathy, 1067 spheroid body myopathy,372-375 cytoplasmic
linked to specific chromosomes. The pathogenic basis for the for- body myopathy,3-80-156-485-668-777-919 Mai lory body myopathy,332 fa-
mation of tubular aggregates is not known but has been postulated milial cardiomyopathy with subsarcolemmal vermiform de-
to represent an adaptive response of muscle fibers to injury. posits,145 and myopathy with intrasarcoplasmic accumulation of
Electrophysiologic Findings. The electrophysiologic find- dense granulofilamentous material and hereditary EBM with
ings vary depending upon the subtype but usually demonstrate early respiratory failure.172-304 In addition, some patients previously
Figure 27-31. Myofibrillar myopathy. (A) Muscle biopsy demon-

strates hyaline lesions composed of compacted myofilaments.These le-
sions stain reddish-purple or dark green on Gomori trichrome. (B)
Non-hyaline lesions appear as amorphous lobulated areas within the
muscle fibers and result from degeneration of myofibrils. Gomori
trichrome. (C) Electron microscopy of the non-hyaline lesions reveals
scattered dappled disk structures of the same density as the Z-disks.
(D) Both the hyaline and, (E) non-hyaline lesions immunostain to
desmin (shown) and to other myofibrillar proteins. (From Amato AA,
Kagan Hallett K, Jackson CE, et ahWide spectrum of myofibrillar my-
opathy suggests a multifactorial etiology and pathogenesis. Neurology
1998;51:1646-1655, with permission.)
diagnosed with other forms of distal myopathy may actually Some patients have a facio-scapulo-humeral or scapuloperoneal
have MFM. The clinical features of MFM are to some extent distribution of weakness.
heterogeneous. The cardiomyopathy may manifest as arrhythmias or conduc-
Clinical Features. There is a wide spectrum of clinical phe- tion defects as well as congestive heart failure.12-146-208-458-640-717
notypes associated with MFM.12-208-717 Most reported patients Pacemaker insertion or cardiac transplantation may be required.
developed weakness between 25 and 45 years of age, although Severe respiratory muscle weakness can also complicate
there are reports of onset in infancy, early childhood, and later MFM.12-208-7271127 In addition, there are rare reports of smooth
in adulthood.12-13-208 Either cardiac or skeletal muscles can be in- muscle involvement leading to intestinal pseudo-obstruction.
volved and dominate the clinical picture. Limb weakness can be Laboratory Features. Serum CK is normal or usually only
predominantly distal and affect either the arms or the legs. In slightly increased in MFM.12-208-717 The EKG may demonstrate
other cases, proximal muscles are involved more than distal conduction defects or arrhythmia. An echocardiogram may
muscles. Facial and pharyngeal muscles can also be affected. reveal a dilated or hypertrophic cardiomyopathy.
Histopathology. Muscle biopsies demonstrate variability in demonstrated linkage to chromosome 12 in another family with
fiber size, increased central nuclei, and occasionally type 1 fiber an autosomal dominant scapuloperoneal syndrome and car-
predominance. Muscle fibers with rimmed vacuoles may also diomyopathy that had histologic features of MFM on muscle
be evident. Nakano et al define two major types of lesions on biopsy.1115 Linkage to chromosome 2q24-31 was demonstrated
light and electron microscopy: hyaline structures and non-hya- in Swedish families and to chromosome 2q2 1 727 and in French
line lesions.717 The hyaline structures are cytoplasmic granular families with an autosomal dominant myopathy with features of
inclusions that are typically eosinophilic on H&E and dark MFM. 1127 In addition, a large autosomal kinship of MFM with
blue-green or occasionally red on modified Gomori trichrome cardiomyopathy was linked to chromosome lOq.640 The respon-
stains (Fig. 27-31 A). They appear as cytoplasmic bodies, spher- sible gene defects in these kinships have not been identified.
oid bodies, or Mallory bodies on EM. The non-hyaline lesions The pathogenic basis of how abnormal desmin or aB-crys-
appear as dark green areas of amorphous material on Gomori tallin leads to muscle cell destruction is not known. Desmin is
trichrome stains (Fig. 27-3IB). On EM, these non-hyaline lean intermediate filament protein of skeletal, cardiac, and some
sions correspond to foci of myofibrillar destruction and consist smooth muscle cells. This cytoskeletal protein links Z-bands
of disrupted myofilaments, Z-disk-derived bodies, dappled with the sarcolemma and the nucleus. The intermediate filament
dense structures of Z-disk origin, and streaming of the Z-disk network is important in the stability of the muscle fiber and
(Fig. 27-3IC). 717 Although some have demonstrated the accu- during mitosis/regeneration of muscle cells. Transgenic studies
mulation of 8-10 nm filaments,146-332 others have not found have demonstrated that cultured cells harboring the mutation do
these intermediate-sized filaments despite extensive search- not form proper intermediate filament networks in vitro.208-703
ing.146-717 In addition, some authors have also reported the accu- Mutated desmin filaments form insoluble aggregates that pre-
mulation of larger size tubulofilaments (14-20 nm) typical of vent the formation of the normal filamentous network.576a
the inclusion body myopathies.146-332-372 Abnormal accumulation of desmin is not specific for MFM
Immunohistochemistry reveals both the hyaline (Fig. 27-3ID) and can be seen in a variety of neuromuscular conditions includ-
and non-hyaline lesions (Fig. 27-3IE) contain desmin and nu- ing X-linked myotubular myopathy, congenital myotonic dystro-
merous other proteins.172 216717 Excessive desmin accumulation phy, spinal muscular atrophy, nemaline rod myopathy, fetal
has also been shown in cardiac muscles in patients with car- myotubes, IBM, and in regenerating muscle fibers of any etiol-
diomyopathy 1 2.709.805.972 immunohistochemistry also reveals that ogy.374 Thus, focal accumulation of desmin is a non-specific find-
the non-hyaline lesions react strongly for desmin, dystrophin, ing. However, abnormally phosphorylated desmin has been
gelsolin, N-terminus of (3-amyloid precursor protein, and reported in some familial and sporadic cases of MFM, 81 -82-217,833 a
NCAM. However, the non-hyaline lesions are depleted of actin, finding that has not been not described in other disorders.
oc-actinin, myosin, and less consistently of titin and nebulin.216 In Phosphorylation of desmin in vitro inhibits the formation of inter-
contrast, the hyaline structures are composed of compacted and mediate filaments.366 The mutated desmin protein may be more
degraded remnants of thick and thin filaments and react to actin, susceptible to phosphorylation and its consequences. Abnormal
cc-actinin, myosin in addition to dystrophin, gelsolin, and the N- muscle fibers in MFM immunoreact strongly for (1) CDC2
terminus of p-amyloid precursor protein; they do not react to kinase, which phosphorylates and disassembles intermediate fila-
NCAM and react variably to desmin. Both types of lesions also ments; and (2) several cyclin-dependent kinases important in cell
react for ocB-crystallin, a-1 antichymotrypsin, ubiquitin, and can cycle regulation.127,8 Further, lamin B and nuclear matrix protein
be congophilic. Interestingly, abnormal muscle fibers also abnor- are ectopically expressed in the cytoplasm in patients with
mally express several cyclin-dependent kinases in the cytoplasm, MFM.718 Abnormal expression of the CDKs, which normally are
including CDC2, CDK2, CDK 4, and CDK7.12-718 not activated in post-mitotic muscle, may lead to hyperphospho-
Molecular Genetics and Pathogenesis. The pathogenesis rylation of structural proteins and dissolution of myofibrils. The
of MFM is likely multifactorial, given the heterogeneous nature inappropriate activation of the cell cycle could lead to apoptosis
of the disorder. Most familial cases demonstrate autosomal or mitotic catastrophe.718 However, the authors found no evidence
dominant inheritance, although autosomal recessive or X-linked of apoptosis in their patients with MFM. 12 The trigger for the in-
inheritance is possible in some families. 12 Mutations in the appropriate activation of these cell cycle regulating kinases or
desmin gene located on chromosome 2q35 have been identified how these abnormalities relate to the recently identified mutations
in several families with autosomal dominant myofibrillar my- in the desmin and aB-crystallin genes is not known.
opathy as well as in a few sporadic cases.208-377-703 One family Electrophysiologic Findings. Increased insertional and
with a heterozygous A337P mutation had autosomal dominant spontaneous activity with fibrillation potentials, positive sharp
inheritance of an adult-onset skeletal myopathy with mild car- waves, pseudomyotonic potentials, and complex repetitive dis-
diac involvement.377 In addition, a homozygous or hemizygous charges are common.12-269-304 374-375-458-71711,3 MUAPs are typically
mutation involving a 21 base pair deletion in the first exon of polyphasic and of short duration and diminished amplitude.
the desmin gene was reported in a patient with presumed auto- Some investigators reported "mixed myopathic-neurogenic"
somal recessive inheritance of MFM. 703 MUAPs.270-374-375 The long-duration polyphasic MUAPs, reported
As suggested on the basis of the wide clinical spectrum of in some cases, can be demonstrated in chronic myopathies and
MFM, 12 there is significant genetic heterogeneity of MFM. do not necessarily imply a superimposed neuropathy.
Mutation in the desmin gene was excluded in one large autoso- Nonetheless, there are well-documented cases of MFM with
mal dominant kinship that eventually linked to mutations in the neuropathy.81-587-717-881 Nerve conduction studies are usually
aB-crystallin gene on chromosome 1 lq21-23. 1081 ccB-crystallin normal, although low amplitudes of SNAPs and CMAPs and
possesses "molecular chaperone" activity and is believed to in- slowing of conduction velocities have been reported in some
teract with desmin in the assembly of the intermediate filament cases.587-881 Nerve and intramuscular nerve biopsies have
network. demonstrated enlarged axons with accumulation of intermedi-
Some patients have no identifiable mutations in either the ate-sized neurofilaments and formation of axonal spheroids in
desmin or aB-crystallin genes. In this regard, Wilhelmsen et al. some patients.81-587-881
Table 27-7. Glycogen Storage Disorders

Type Associated Name Enzyme Deficiency Clinical Features EDM
I von Gierke's disease Glucose-6-phosphate No neuromuscular signs or symptoms
Autosomal recessive
II Pompe's disease Acid maltase Infantile: Profound weakness; fatal Myotonia, CRD, Fibs, PSW,
(a1,4- glucosidase) Childhood/adult: Limb-girdle or BSAPP
scapuloperoneal weakness
Autosomal recessive
III Cori-Forbes disease Debrancher Infantile: Hypotonia Myotonia, CRD, Fibs, rare
Adult: Proximal or distal weakness, fascics, BSAPP
(amylo-1,6-glucosidase) dementia, UMN and LMN NCS: superimposed axonal
involvement, incontinence; sensorimotor neuropathy
Autosomal recessive
IV Anderson's disease Branching Infantile: generalized weakness Rare myotonia, BSAPP
Adults: proximal or distal weakness
(amylo-1,4-1,6-transglucosidase) Autosomal recessive
V McArdle's disease Infantile: Profound weakness Rare fibs, PSW, CRD, silent
Myophosphorylase Adult Exercise intolerance, cramps, contractures, rare BSAPP,
fatigue decremement of CMAP
Autosomal Recessive on 20 Hz stimulation
VI Liver phosphorylase N o neuromuscular signs or symptoms
Autosomal recessive
VII Tarui's disease Phosphofructokinase Childhood: Cramps, fatigue, exercise Same as McArdle's disease
intolerance
Autosomal recessive
VIII — Phosphorylase B kinase Infancy to adulthood: Exercise intol- Rare Fibs, PSW, BSAPP
erance, myoglobinuria, weakness
Autosomal recessive
IX — Phosphoglycerate kinase Childhood: Myoglobinuria, cramps, Normal
exercise intolerance, rare weakness,
CNS dysfunction, hemolytic anemia
X-linked
Phosphoglycerate mutase Childhood or adolescence: Exercise Normal
intolerance, cramps, myoglobinuria
Autosomal recessive
XI Lactate dehydrogenase Childhood to adulthood: Exercise Normal
intolerance, cramps, myoglobinuria
Autosomal recessive
XII p-Enolase Childhood to adult; exercise Not described
intolerance, myalgias
Autosomal recessive
EDM: electrodiagnostic medicine findings; Ml: membrane instability referring to positive sharp waves and fibrillation potentials; Fascic = fasciculations; CRD: complex
repetitive discharge; BSAPP: brief small abundant polyphasic potentials; NCS: nerve conduction studies; UMN: uper motor neuron; LMN: lower motor neuron.
Treatment. There is no proven medical therapy to improve GLYCOGEN METABOLISM DISORDERS

skeletal muscle weakness. Antiarrhythmic and cardiotropic
medications are sometimes necessary in patients with cardiopa- There are 12 recognized disorders affecting glycogen metabo-
thy. Cardiac transplantation can be life-saving in patients with lism (Fig. 27-32).245-246-248-290The universal scheme of designating
severe cardiomyopathy. individual disorders assigns each glycogen storage disease
(GSD) a Roman numeral. Specific disorders may be referred to
simply by naming the enzymatic deficiency or designating the
METABOLIC DISORDERS OF MUSCLE disease by the name of the person who discovered the defect
(Table 27-7). The majority of these metabolic myopathies are
The metabolic disorders of muscle can be considered to be dynamic, in that the major neuromuscular complaints are exer-
divided into four major categories. The first involves abnormal- cise-induced muscle pain/cramps and myoglobinuria. Other
ities of various enzymes in the metabolism of glucose/glycogen. types of metabolic myopathies are considered static, in that they
Disturbances in the metabolism of lipids constitute a second are associated with fixed weakness, rather than symptoms/signs
major category of muscle disorders. Abnormalities affecting the associated with exercise intolerance. Types I (von Gierke's dis-
intricate aspects of mitochondrial functioning constitute a cate- ease) and VI do not have significant neuromuscular symptoms
gory referred to as mitochondrial myopathies. Finally, derange- and are not discussed further.
ments in the metabolic pathways governing the utilization of The inability to metabolize a substrate secondary an enzyme
adenine nucleotides can also lead to muscle fiber dysfunction. defect results in accumulation of that substrate, unless it can be
Metabolic Myopalhies deficiency; however, the frequency of GSD II is low, occurring
{Lysosome) Epinephrine
in less than 1 in 100,000 newborns. 93
Exercise I Clinical Features. The infantile form of acid maltase defi-
l ! ciency is also referred to as Pompe's disease after the original
( Acid Maltase -W- n descriptor of the disorder.804 The cardinal features of the disease
Cyclic AMP ! include profound cardiomegaly, macroglossia, and mild to mod-
Protein Kinase I
erate hepatomegaly.288'29U450-591'804 In addition, infants demon-
strate progressive weakness and hypotonia within the first 3
Glucose Glycogen
I ! months of life. Feeding difficulties and respiratory muscle weak-
IV
Phosphorylase b Kinase — ness are common. The disease is progressive and invariably fatal
l-^—vrn by 2 years of age secondary to cardiorespiratory failure.
^ Glucose 1-P The juvenile form of the disease usually presents in the first
I #-V-VI
Phosphorylase a •*- Phosphorylase 6
decade of Iife. ' '. 64- 56.957.994.ii4! M o t o r milestones are often
288 29 4 9
Glucose ^-Blood Glucose delayed as a result of proximal greater than distal weakness.
V I
PLD
Children demonstrate Gower's maneuver, waddling gait, and
significant lumbar lordosis. Some patients also have hypertro-
ATP-
ADP-* 3| —V I I phy of the calf muscles; thus, they can easily be misdiagnosed
Fructose 1,6-P as having a dystrophinopathy or sarcoglycanopathy. In contrast
to the infantile form, cardiomegaly, hepatomegaly, and
\ macroglossia are uncommon. 291 However, muscle weakness is
Glyceraldehyde 3-P (2)
slowly progressive. In particular, the respiratory muscles are es-
2ADP- \ pecially affected, leading to death in the second or third decade
2ATP« -IX of life. Rare cases of rigid spine syndrome may be due to acid
\ maltase deficiency.299
3-P-Glyeeroyl Phosphate
3-Phosphoglycerate (2) (2)
— x The adult-onset form of acid maltase deficiency manifests at

2-Phosphoglycerate (2)
J XII
variable ages but usually begins in the third or fourth
decade. 60 - 282 - 28 ^ The patient's presentation may
2ADP-
Phosphoenol Pyruvate (2)
appear clinically quite similar to polymyositis or a type of limb-
2ATP-
Pyruvate (2} girdle dystrophy with generalized proximal greater than distal
-XI muscle weakness. Rare patients have a scapuloperoneal distrib-
Lactate (2) ution of weakness. 60 Weakness is asymmetric in approximately !
8% of cases.317 Muscle atrophy is proportionate to the degree of
Figure 27-32. Glycogen metabolism.The Roman numerals refer muscle weakness and has been noted in approximately 20% of
to the various disorders of glycogen metabolism. Disorders I and VI patients. 3 ' 7 Facial or tongue weakness occurs in 13%, while
are not listed, as they do not produce neuromuscular symptoms. macroglossia is apparent in 8%. 3,7 Deep tendon reflexes have
Roman numerals and associated enzymatic deficiencies are as follows: been reported as normal in 62%, diminished in 31%, and absent
I: glucose-6-phosphate; II: acid maltase; III: debrancher; IV: brancher;V: in 8% of patients. 317 Liver and cardiac enlargement does not
muscle phosphorylase;VI: liver phosphorylase;VII: phosphofructokinase typically occur in the adult form of acid maltase deficiency.
(PFK); VIII: phosphorylase b kinase; IX: phosphoglycerate kinase; X: However, electrocardiographic abnormalities and arrhythmias
phosphoglycerate mutase;XI: lactate dehydrogenase (LDH); XII: p eno- can be seen. As in the infantile and juvenile forms of the dis-
lase. (From DiMauro S, Miranda AF, Sakoda S: Metabolic myopathies. ease, the respiratory muscles are particularly affected. In fact,
AmJ Med Genet 1986;25:635-651, with permission.) 16-33% of patients present with symptoms related to respira-
tory insufficiency (e.g., dyspnea, frequent nocturnal arousals, j
converted to some other substance through an alternate pathway morning headaches, excessive daytime sleepiness).291317
or degraded into usable metabolites. Enzymatic deficiencies in Laboratory Features. Deficiency of a-glucosidase activity
the metabolism of glycogen can result in the reduction of avail- can be demonstrated in muscle fibers, fibroblasts, leukocytes,
able energy, i.e., ATP. This lack of energy leads to exercise in- lymphocytes, and in the urine. The infantile form is usually asso-
tolerance, fatigue, and possibly weakness. The exact manner in ciated a severe deficiency of a-glucosidase activity, while the less
which the buildup of metabolic substrates leads to muscle dys- severe adult onset form has residual activity, up to 30% in muscle
function is not fully known. Further investigations into the and 53% in lymphocytes. 1121 Serum CK levels are elevated to
metabolic aspects of muscle physiology should result in a more variable degrees in all forms of the disease. The infantile form is
clear understanding of how these disorders produce not only the associated with the highest CK levels, but these are still usually
clinical and histologic alterations in patients, but also the elec- less than 10 times the upper limit of normal. In adults with acid
trophysiologic consequences of these diseases. maltase deficiency, the CK can be normal. Electrocardiograms
can demonstrate left-axis deviation, a short PR interval, large
Type II Glycogenosis (Acid Maltase Deficiency) QRS complexes, inverted T waves, ST depression, and persistent
GSD II is an autosomal recessive disorder caused by defects sinus tachycardia in the severe and mild forms of GSD II.291317
in the lysosomal acid maltase (a-glucosidase) pathway. There Wolff-Parkinson-White syndrome has been reported in infantile
are three recognized clinical subtypes of GSD II or acid maltase and adult forms of the disease.133 342 Echocardiograms can show
deficiency: (1) a severe infantile form (also known as Pompe's progressive hypertrophic cardiomyopathy. Pulmonary function
disease), (2) a juvenile-onset type, and (3) an adult-onset variant tests show a restrictive defect with decreased forced vital capac-
(Table 27-7, Fig. 27 - 32).60-237-248-249-283^ Fifteen ity, reduced maximal inspiratory and expiratory pressures, and
percent of patients with glycogen storage disease have acid maltase early fatigue of the diaphragm. 925 Computed tomography has
Figure 27-33. Acid maltase deficiency. (A) Muscle biopsy in a patient with adult-onset acid maltase deficiency reveals one or more vacuoles
within many muscle fibers. H&E. (B) These vacuoles are filled with glycogen that stain intensely red on PAS.
demonstrated early and severe involvement of the trunk and Acid maltase is a lysosomal enzyme with the capability of
thighs, with selective sparing of the tensor facia lata, short head cleaving a-1,4 and a-1,6 linkages in glycogen, maltose, and
of the biceps femoris, gracilis, and sartorius muscles in adults.221 isomaltose. When engulfed by lysosomes, glycogen is degraded
Shoulder and distal lower limb muscles were less affected. to glucose by acid maltase cleaving the a-1,4 and a-1,6 bonds.
Histopathology. The characteristic light microscopic fea- When acid maltase is deficient, glycogen accumulates within
ture is the formation of vacuoles within both type 1 and 2 fibers lysosomal vacuoles and in the cytoplasm. The reason muscle
(Fig. 27-33A).60'249-282-283-288'291-502 The vacuoles are very promi- fibers become dysfunctional as a result of acid maltase defi-
nent in the infantile form, occurring in most, if not, all the ciency is unclear. Progressive loss of muscle function may be
muscle fibers. In the childhood and adult forms, vacuoles are the result of the accumulation of glycogen displacing or replac-
apparent in only 25-75% of fibers in clinically affected muscles ing normal cellular organelles. Alternatively, the secondary
and may be absent in clinically unaffected muscle groups. 291 lysosomes can rupture, releasing potentially toxic lysosomal en-
The vacuoles react strongly to periodic acid-Schiff (PAS), and zymes that breakdown muscle. Some studies have demonstrated
this staining is sensitive to diastase. These vacuoles also stain that muscle breakdown is increased by 3 1 % compared with
intensely to acid phosphatase, confirming that the vacuoles normal controls and mean protein balance is reduced. 93
filled with glycogen are secondary lysosomes (Fig. 27-33B). Furthermore, there is an increase in resting energy expenditure
Glycogen can also be found free in the cytoplasm. Electron mi- in GSD II.93 Utilization of non-membrane-bound glycogen and
croscopy also demonstrates the abnormal accumulation of glucose for energy metabolism is not impaired; therefore, pa-
glycogen not only within lysosomes but also free in the cyto- tients do not exhibit exercise intolerance of myoglobinuria (dy-
plasm. Necrotic and regenerating fibers are not prominent but namic symptoms or signs). The accumulation of glycogen in
can be seen. Fiber size variation is common, as well as fiber anterior horn cells may be responsible for loss of motor neurons
splitting. In severe disease, muscle fiber atrophy and connective and some superimposed neurogenic features on muscle biopsy
tissue proliferation in the endomysial regions may be present. and electrophysiologic testing.
Fiber type grouping and group atrophy have rarely been noted Electrophysiologic Findings. Sensory and motor nerve con-
in adult acid maltase deficiency.291-502 Glycogen accumulations duction are typically normal in the infantile, childhood, and
can also be observed in anterior horn cells and bulbar nuclei as adult forms of acid maltase deficiency.60-237-283-317-450-464-865-870-957
well as in Schwann cells, accounting for the superimposed neu- However, with advanced disease, the CMAP amplitude may be
rogenic findings in some patients.291-361*450-602 reduced secondary to muscle fiber destruction. Needle elec-
Molecular Genetics and Pathogenesis. The gene encoding tromyography reveals a wide spectrum of abnormalities de-
for acid maltase (a-glucosidase) is located on chromosome pending upon the muscles examined. Minimally affected
17q21-23. The gene contains 20 exons and is approximately 20 muscles on clinical examination may demonstrate little in the
kilobases in length.466-837 Missense, nonsense, and frame-shift way of abnormalities, whereas those significantly affected con-
mutations have been identified in the a-glucosidase gene in tain quite varied pathologic findings. Needle insertions induce
cases of infantile-, childhood-, and adult-onset acid maltase de- abundant fibrillation potentials and positive sharp waves that
ficiency.466-837 These mutations lead to a decrease in a-glucosi- persist after cessation of needle movement. Occasionally, fasci-
dase activity, and there is usually an inverse correlation between culation potentials can be observed. Additionally, profuse com-
residual acid maltase activity and the clinical severity.466-837 plex repetitive discharges are common. Of interest, myotonic or
However, there are cases associated with an adult-onset GSD II pseudomyotonic potentials can be quite prominent and have
that may have very little residual enzyme activity, so the rela- been reported in nearly 30% of patients.317 Importantly, there is
tionship between disease activity and clinical severity is not no evidence of clinical myotonia. These abnormal spontaneous
100% accurate. 60 Interestingly, there have been reports of phe- potentials are especially prominent in the paraspinal muscles,
notypic variability in severity within families.60-538-591 Im- reinforcing that these muscle groups should always be exam-
portantly, prenatal diagnosis is possible with amniocentesis or ined in suspected myopathies of any etiology, particularly when
chorionic villus sampling.524-837 acid maltase deficiency is in the differential diagnosis.
Voluntary motor unit action potentials (MUAPs) demonstrate or lymphocytes. Serum CK levels are elevated 2-20 times
the typical alterations noted in chronic myopathic disor¬ normal. Exercise forearm testing shows a normal increase in
60,237,283,317.450,464,865,870.957 X n e MUAP durations and amplitudes serum ammonia but not in lactate levels. Electrocardiograms
are reduced, while the number of polyphasic potentials is in- can reveal conduction defects and arrhythmias. 204 1000 Echo-
d e r s
creased. An early recruitment pattern can be documented in coop- cardiograms may reveal findings suggestive of hypertrophic
erative individuals, especially in the weaker muscles. In adults obstructive cardiomyopathy in most patients with GSD
with slowly progressive disease, needle investigation can display !IIa. 125,204
long-duration, large-amplitude polyphasic MUAPs, suggesting Histopathology. Muscle biopsies demonstrate a vacuolar my-
significant motor unit remodeling from chronic muscle fiber de- opathy with abnormal accumulation of glycogen in the subsar-
struction and subsequent regeneration or reinnervation.317 502 colemmal and intermyofibrillar regions of muscle fibers.248-427-607
Treatment. Unfortunately, there is no specific treatment of These vacuoles stain intensely with PAS but are partially dias-
acid maltase deficiency other than supportive therapy for associ- tase-resistant. Further, in contrast to acid maltase deficiency,
ated cardiorespiratory complications. Low carbohydrate and ke- these vacuoles do not stain with acid phosphatase, suggesting the
togenic diets are ineffective. Studies evaluating the benefits of a glycogen does not primarily accumulate in lysosomes. By elec-
high-protein diet have produced contradictory results. A recent tron microscopy, the vacuoles correspond to free pools of glyco-
study and review reported that 4 of 16 patients treated with a gen. Some glycogen may be apparent in lysosymes, but not to the
high-protein diet demonstrated improvement in muscle and res- same extent as evident in acid maltase deficiency. Skin, Schwann
piratory function. 93 A small, open-label study of albuterol and cells, and intramuscular nerves, and the sural nerve may also
branched-chain amino acids in 4 patients with late-onset acid mal- demonstrate excess glycogen accumulation.810-890 1063
tase deficiency revealed some improvement in patient function.25 Molecular Genetics and Pathogenesis. The debranching
Using recombinant DNA techniques with adenovirus and retro- enzyme has been cloned and localized to chromosome 1 p21. M32
virus vectors, a-glucosidase activity was restored in vitro in fi- Mutations in the gene have recently been identified in both GSD
broblasts, myoblasts, and myotubes.729-779'1139 In addition, enzyme Ilia and GSD nib.754-780-935-936 Prenatal diagnosis is possible. 937
replacement with intravenous injections of recombinant human a- The molecular basis for the differential expression of the
glucosidase resulted in clinical improvement in acid maltase-defi- enzyme between the two subtypes of GSD III has not been fully
cient quails.517 Further, heart, muscle, and liver histology and elucidated. Mutations in exon 3 appear to be specific for GSD
glycogen content appeared normal and a-glucosidase activity was Hlb, but the sensitivity is low.
increased. The debranching enzyme has two separate catalytic functions:
(1) oligo-l,4-l,4-glucanotransferase activity and (2) a-1,6 glu-
Type III Glycogenosis (Debranching cosidase activity. Both the transferase and the glucosidase activ-
Enzyme Deficiency) ity are important in metabolizing glycogen into glucose, and a
Clinical Features. The GSD III, also known as Cori-Forbes deficiency in either or both enzymatic functions results in this
disease, accounts for approximately 25% of glycogen storage disorder. Deficiency of the enzyme leads to the accumulation of
disease (Table 27-7, Fig. 27-32).,25-,84'192«248-694 There are two glycogen in muscle; however, the exact mechanism of muscle
forms of the disease. In GSD Ilia, there is deficiency of the de- weakness is not known. Similar amounts of glycogen accumula-
brancher enzyme in liver and muscle. In contrast, enzyme activ- tion in muscle can be demonstrated in patients who do not mani-
ity is normal in the muscle in GSD Hlb; thus, muscle weakness fest weakness. Accumulation of glycogen in peripheral nerves
does not occur in this form of the disease. GSD Hlb generally may account for some degree of weakness and atrophy, particu-
presents in infancy or early childhood with hepatomegaly, re- larly of the distal muscles.
duced rate of growth, failure to thrive, and fasting hypoglycemia. Electrophysiologic Findings. Motor and sensory nerve con-
Occasionally, hypoglycemia-related seizures occur. GSD Hlb is duction studies can demonstrate mixed findings.125-184192-694
usually a benign disease because often these symptoms resolve Specifically, some patients may have completely normal nerve
spontaneously around puberty and most patients live a normal conduction studies with respect to distal latencies, conduction
adult life. However, some patients develop liver failure (cirrho- velocities, and CMAP/SNAP amplitudes. On the other hand, a
sis) or hepatocellular carcinoma in the future.401 few patients may demonstrate all or some of the following ab-
Deficiency of the debrancher enzyme in muscle does lead to normal findings: prolonged distal motor latencies, prolonged or
weakness in patients with GSD Ilia. Onset of muscle weakness is absent distal sensory responses, reduced motor nerve conduc-
usually in the third to fourth decade of life and is slowly progres- tion velocities, and borderline CMAP amplitudes. Some pa-
sive J25.i84.i92.239,248,348.427.607.694.7i2,758.954 Approximately one third of the tients develop a superimposed mild to moderate peripheral
cases begin in infancy or early childhood, and motor milestones neuropathy, as supported by nerve biopsies, which can add to
can be delayed.191 There is prominent atrophy and weakness of the diagnostic confusion.
distal limb muscles in about 50% patients; thus, the myopathy can The needle electromyographic abnormalities can be rather
easily be mistaken for motor neuron disease or a peripheral neu- pronounced in some muscles, while documenting only minimal
ropathy.192 However, some patients have pseudohypertrophy, partic- findings in other muscles.125-184192-694 Generally, there is some
ularly of the more proximal muscle groups.607 There are rare degree of positive sharp waves and fibrillation potentials in all
reports of exercise intolerance with fatigue, cramping, or myoglo- muscles examined with an occasional muscle having florid
binuria.192427JI2758 Cardiomyopathy can also complicate debrancher membrane instability. Complex repetitive discharges provoked
deficiency, again usually in adulthood.204-3481000 However, clini- by minimal needle movement can be rather prominent in some
cally significant cardiomyopathy can also develop in children.654 patients. Rarely, fasciculation potentials have been observed.
Some patients have a superimposed mild sensorimotor polyneu- There is an abnormal increase in the number of polyphasic
ropathy. Deep tendon reflexes can be normal or diminished. MUAPs with decreased amplitudes and durations. Normal- and
Laboratory Features. Debranching enzyme deficiency can large-amplitude MUAPs can also be found; however, these do
be demonstrated with biochemical assay of muscle, fibroblasts, not constitute the predominant MUAPs recorded. Although
there is no apparent clinical myotonia, electromyography IV, including adult polygiucosan body disease.53-595-1149 The phe-
may detect myotonic or pseudomyotonic potentials in weak notypic variability and differential expression of branching
muscles.428-723 enzyme activity most likely result from allelic mutations in the
Treatment Patients are best managed by preventing fasting hy- same gene. The mechanism by which the abnormal accumula-
poglycemia through frequent low-carbohydrate feedings and main- tion of polysaccharide results in muscle damage is not known.
taining a high protein intake. There is no specific medical therapy Electrophysiologic Findings. Most of the reported patients
for the muscle weakness. Supportive therapy is required for pa- with myopathies studied in detail had normal motor and sensory
tients with clinically manifesting congestive heart failure. Liver nerve conduction studies. 3281,43 However, slight decreased con-
transplantation has been performed on patients with cirrhosis and duction velocities have been described in some adults with a
hepatocellular carcinoma 401 However, debranching enzyme activ- proximal myopathy and cardiopathy.722 Needle electromyogra-
ity has remained absent in leukocytes after transplantation and is phy reveals early recruitment of polyphasic, short-duration, and
not likely to normalize the enzyme activity in the muscle. small-amplitude MUAPs. Membrane instability characterized
by fibrillation potentials, positive sharp waves, and pseudomy-
Type IV Glycogenosis (Branching Enzyme Deficiency) otonic potentials has been noted in some individuals.722 In adult
Clinical Features. GSD IV, also known as Andersen's dis- polygiucosan body disease affecting the CNS and PNS, nerve
ease and polygiucosan body disease, is caused by the defi- conduction studies have revealed an axonal sensorimotor neu-
ciency of the enzyme capable of creating the branched glycogen ropathy, while electromyography demonstrated evidence of
molecule that results in an accumulation of polysaccharide in active denervation and reinnervation.126*144-594
the liver, central nervous system, and skeletal and cardiac Treatment. Liver transplantation has been performed in
muscle (Table 27-7, Fig. 27 - 32). 103-126-144-248-w^ some children with GSD IV.868-920-968 Long-term follow-up
There are several forms of branching enzyme deficiency. The (mean 42 months) has shown that most of the patients became
classic and most common type of GSD IV manifests in infants free of liver, neuromuscular, and cardiac dysfunction. A reduc-
as progressive liver dysfunction with hepatomegaly, spleno- tion of glycogen accumulation in cardiac and skeletal muscle
megaly, and failure to thrive. The severe liver disease overshad- with normal growth and development was evident. However, at
ows neuromuscular involvement; however, muscular weakness, least one child has died from cardiomyopathy as a result of mas-
atrophy, hypotonia, hyporeflexia, and contractures can also sive deposition of polysaccharide material in the heart 2V2 years
occur.3281143 Most children succumb to severe liver failure by 5 after transplantation. 868 No other medical therapies have been
years of age. There is also a benign hepatic form of GSD IV in demonstrated to be affective.
which the liver disease does not progress.53-634
In addition, there is a neuromuscular form of the disease in Type V Glycogenosis (Myophosphorylase Deficiency)
which patients manifest primarily with muscle weakness and Clinical Features. The type V glycogenosis (myophospho-
cardiomyopathy.53*103-722-924 Weakness and atrophy can be pre- rylase deficiency) is more commonly known as McArdle's dis-
dominantly proximal or distal. ease and is a rare disorder (Table 27-8, Fig. 27-32).'89-222-248-250*628
Finally, there is a form of branching enzyme deficiency, often The major symptom is exercise intolerance, which usually starts
referred to as polygiucosan body disease, that manifests mainly in childhood. Exertional muscle pain, cramps, and myoglobin-
in adults as progressive upper and lower motor neuron loss, sen- uria develop later, and the diagnosis is usually made by the
sory nerve involvement, cerebellar ataxia, neurogenic bladder, second or third decade of life. Patients describe pain, cramps,
and dementia. ,26144594 - 595J149 Occasionally, CNS involvement stiffness, and fatigue in the exercised muscle. If patients ignore
can begin in children.318 the above warning signs and continue to exercise at a high level,
Laboratory Features. Depending on the subtype of GSD IV, the muscle pain and cramping can become quite intense and
deficiency of branching enzyme may be demonstrated in muscle, electrically silent contractures may develop. Subsequently,
peripheral nerve, fibroblasts, and leukocytes. 103.126.144.594.595.1149 j n muscle swelling can be noted for several hours. These symp-
patients with primary neuromuscular involvement, the defi- toms are more likely to be induced by brief, but very intense,
ciency may be noted only in muscle.103 Branching enzyme activ- activities (e.g., weight lifting, sprinting) but can also occur fol-
ity can be normal in the muscle in patients with adult lowing prolonged low-intensity exercises (e.g., swimming, jog-
polygiucosan body disease manifested by CNS and PNS dys- ging). Some patients note a second wind phenomenon in
function.I26-144 The serum CK may be normal or slightly elevated. which after the onset of mild exertional myalgias or cramps, the
Electrocardiogram can demonstrate progressive conduction de- individual is able to continue with the exercise at the previous or
fects leading to complete A-V block.722 Echocardiogram may a slightly reduced level without complaints.582 The second wind
reveal a dilated cardiomyopathy.722 phenomenon is thought to be more related to the ability to me-
Histopathology. Routine light and electron microscopy re- tabolize free glucose than fatty acids.4113 Overt myoglobinuria is
veals deposition of varying amounts of finely granular and fila- rarely noted in children and primarily manifests in the second or
mentous polysaccharide (polygiucosan bodies) in the CNS, third decades. The earliest appearance of myoglobinuria in a pa-
peripheral nerves (axons and Schwann cells), skin, liver, cardiac tient with McArdle's disease was 8 years of age.537 Roughly half
and skeletal muscle and so 0n.103-144-249-318-636-722-924 These poly- of patients experience myoglobinuria related to exercise, while
giucosan bodies are PAS-positive and diastase-resistant. This a third of these individuals have various degrees of renal failure.
polysaccharide resembles amylopectin in that it has longer than The majority of patients essentially have normal physical exam-
normal peripheral chains and few branch points. inations between attacks of muscle cramping. However, as
Molecular Genetics and Pathogenesis. The disease is in- many as one third of patients develop mild, fixed proximal
herited in an autosomal recessive manner. The gene for the weakness as a result of recurrent bouts of rhabdomyolysis.
glycogen branching enzyme has been localized to chromosome There is some heterogeneity in regards to clinical presenta-
3. Mutations within this gene have been identified in the severe tion. Some patients present with fatigue following exercise
hepatic, benign hepatic, and the neuromuscular forms of GSD without associated cramps or muscle pain.294 Still other patients
manifest with progressive proximal muscle atrophy and weak- ATP. However, studies have demonstrated that ATP is not de-
ness in late adult life.1122 Weakness may involve the arms more pleted during exercise in McArdle's disease, Tauri disease, or in
than the legs and can be quite asymmetric. Rare cases have been the other disorders of glycogenolysis and glycolysis.880 In animal
reported with congenital weakness, some of which was rapidly models of glycolysis deficiency that were ischemically exercised
progressive leading to respiratory failure within the first year of to the point of contracture formation, the following biochemical
life.1052 features were noted: (1) an increase in adenosine diphosphate
Interestingly, there have been rare reports of patients mani- (ADP), (2) intracellular pH did not acidify in response to exer-
festing the combination of two inherited metabolic deficiencies. cise, (3) inorganic phosphate levels in muscle were 50% lower
One boy had both myophosphorylase deficiency and myoad- than normal muscle tissue ischemically exercised; and (4) intra-
enylate diaminase deficiency.1056 This child had congenital hy- cellular calcium at the onset of contracture was more than 10-
potonia and weakness and experienced his first bout of clinical fold greater than that found in normal control muscle
myoglobinuria at the age of 2 years. ischemically exercised. 879 These observations suggest that the
Laboratory Features. Serum CK levels are invariably ele- combination of increased intracellular ADP, reduced inorganic
vated in patients with myophosphorylase deficiency; however, phosphate, and lack of acidification with impaired glycolysis in-
there is a wide range of elevation among individuals. The exer- creases calcium sensitivity of the muscle fiber contractile appa-
cise forearm test can be used to diagnose various disorders of ratus. The increased intracellular ADP may cause contractures
glycolysis. The test can be adequately performed without blood by inhibiting ADP dissociation from actin-myosin cross-bridges,
pressure cuff insufflation. In fact, performing this test with the thereby increasing the time spent in contraction.
limb ischemic may be hazardous to the patient, because it can In addition, patients with McArdle's disease have reduced
induce profound muscle damage and myoglobinuria.639 The au- concentrations of the sodium-potassium ATPase pump, higher
thors place a butterfly needle in the antecubital fossa and draw exercise-induced serum potassium concentrations, and a greater
baseline lactate and ammonia levels. The forearm muscles are ex- increase in heart rate during exercise 410 The reduced concentra-
ercised by having the patient rapidly and strenuously open and tion of sodium-potassium ATPase may contribute to the exercise-
close the hand for 1 minute. Immediately after exercise and then induced increase in extracellular potassium because of impaired
1, 2, 4, 6, and 10 minutes post exercise, blood samples are again reuptake of potassium released during muscle contraction.
taken and analyzed for lactate and ammonia. The normal re- Further, decreased physical activity may result in down-regula-
sponse is for lactate and ammonia levels to rise three to four times tion of the pump. Increased ADP may decrease the transport rate
the baseline levels. If neither the lactate nor ammonia levels in- of the remaining pumps. The increased concentration of extra-
crease, the test is inconclusive and implies that the muscles were cellular potassium results in depolarization of the muscle mem-
not sufficiently exercised. A rise in lactate levels but not ammonia brane thereby inactivating sodium channels and reducing
is diagnostic for myoadenylate deaminase deficiency (see below). membrane excitability.409-410 This reduction of muscle membrane
In myophosphorylase, phosphofructokinase, phosphoglycerase excitability explains the observed decrement of CMAP on nerve
mutase, phosphoglycerase kinase, phosphorylase b kinase, de- conduction studies following exercise or repetitive stimulation
brancher, enolase, and lactate dehydrogenase deficiencies, the (see below). Also, patients with McArdle's disease develop
ammonia levels rise appropriately, but the lactic acid does not. higher heart rates in response to exertion. 410 This exaggerated
Histopathology. Excessive accumulation of glycogen in the cardiorespiratory response can limit the exercise capacity of af-
subsarcolemmal and intermyofibrillar areas are usually ob- fected individuals. The cause of the low sodium-potassium pump
served on light microscopy and EM. Variability in fiber size concentrations in skeletal muscle in patients with McArdle's dis-
and scattered necrotic and regenerating fibers may also be ap- ease is not known. Reduced physical activity due to exercise in-
parent. 112 - m396 Several regions of muscle may need to be exam- tolerance may diminish the number of sodium-potassium
ined prior to finding these histologic abnormalities. Staining ATPase pumps. Alternatively, myophosphorylase deficiency
for myophosphorylase is absent, and biochemical assay may promote down-regulation of normal pump numbers by dis-,
myophosphorylase activity reveals absent or significantly re- rupting the normal coupling of muscle glycogenolysis and pump !
duced activity. activity.410
Molecular Genetics and Pathogenesis. This disorder is in- Electrophysiologic Findings. Routine motor and sensory
herited in an autosomal recessive fashion and is caused by mu- nerve conduction velocities are normal in patients with
tations in the gene encoding for myophosphorylase localized McArdle's disease. However, delivering single nerve stimuli
to chromosome 1 lql 3.86-329-1052 Myophosphorylase initiates following a short period of maximal voluntary muscle contrac-
glycogen breakdown by phosphorylytically lysing a-1,4 gluco- tion or performing repetitive nerve stimulation techniques re-
syl residues from the outer branches of glycogen, thus, liberat- veals several interesting findings.112!78-265-809 After obtaining a
ing glucose-1-phosphate. A variety of different types of baseline supramaximal CMAP amplitude, 30-60 seconds of
mutations have been identified, but the resulting biologic effect maximal voluntary contraction is performed and followed im-
is the same: there is usually little detectable protein or enzyme mediately by a second supramaximal stimulation. The CMAP
activity. Interestingly, the mutation associated with some of the amplitude is compared with that prior to exercise. If good pa-
rare cases of fatal infantile myopathy is the same as evident in tient cooperation is achieved, a significant reduction in the
the more common clinical presentation of McArdle's dis- CMAP should be observed in most patients with McArdle's dis-
ease.1052 Some families experience a pseudodominant pattern of ease. With repetitive stimulation at low rates of 2-A Hz, a decre-
transmission. This may arise secondary to heterozygotes mani- ment is not usually observed. But following several seconds of
festing secondary to low levels of residual myophosphory- repetitive stimulation at 5 Hz, or more commonly at 20 Hz, a
lase.604 Another mechanism is the mating of a homozygote (or progressive decline in the CMAP is observed in some patients
compound heterozygote) with a heterozygote. 86 with McArdle's disease. This exceeds the CMAP decrement or
Previously, it was believed that premature muscle fatigue and increment in normal individuals. When a decrement is ob-
contractures were the result of an inability to generate enough served, a 30-second period of maximal voluntary contraction
exacerbates the CMAP decrement. Within 5 minutes or so of but branched chain amino acid supplementation may actually
complete rest, an additional volley of stimuli results in achiev- lower exercise capacity.411 In fact, surplus calories may lead to
ing the baseline CMAP decrement noted prior to exercise. Of weight gain and subsequent decline in cardiovascular fitness.
note, not all patients demonstrate a CMAP decrement at 20 Hz Some small studies have suggested that vitamin B 6 supplementa-
with only a few stimuli, and 20-40 seconds of continuous stim- tion (50 mg/day) can reduce exercise intolerance and enhance
ulation may be required. However, this is very painful and never performance.86 In a small double-blind, placebo-controlled cross-
necessary to make the diagnosis. over study of oral creatine monohydrate supplementation (150
The needle electromyographic findings are somewhat vari- mg/kg/day for 5 days followed by 60 mg/kg/day), 5 of 9 patients
able depending upon the severity of the disease process. In most had statistically significant improvement in ischemic isometric
patients with disease for only a few years to decades and little forearm exercise capacity.1087 However, there was no improve-
permanent weakness in between exercise-induced cramping, the ment in nonischemic isometric exercise or cycle exercise capac-
needle electromyographic examination is normal. 123J78265 There ity. Muscle phosphocreatine levels determined by magnetic
is normal insertional activity and an absence of any type of ab- resonance spectroscopy were no different in treated patients com-
normal spontaneous activity. The MUAP duration, amplitude, pared with normal controls who consumed creatine monohydrate.
phases, and recruitment are also normal. In patients with long- The results suggest that creatine may benefit patients not by in-
standing disease or with fixed muscle weakness, increased increasing energy availability but by somehow permitting exercise
sertional activity is seen, as well as sustained spontaneous to continue to a level of greater energy depletion.4111087
activity comprised of positive sharp waves, fibrillation poten-
tials, and myotonic complex repetitive discharges on needle ex- Type VII Glycogenosis
ploration of weak muscles.112'238'316'396-582-809-1122 These abnormal (Phosphofructokinase Deficiency)
spontaneous discharges are best appreciated in paraspinal mus- Clinical Features. Phosphofructokinase deficiency, or
cles and may be evident even in patients with no objective Tarui's disease, is an autosomal recessive disease caused by an
! weakness.794 Voluntary MUAPs are also decreased in amplitude absence or reduction in the activity of phosphofructokinase
and duration with a higher percentage of polyphasic potentials (PFK) in both muscle tissue and erythrocytes (Table 27-7, Fig.
compared with normal. An early recruitment may be noted in 27-32). 248-250 The disorder is far less common than McArdle's
those persons with weakness. Single-fiber electromyography re- disease. The clinical features are essentially identical with
veals a slight increase in both fiber density and jitter measure- McArdle's disease with respect to exercise intolerance, muscle
ments, suggesting some remodeling of the motor unit in those pain, contractures, and relief of discomfort by rest. There is a
patients with significant disease.809 lower incidence of myoglobinuria and accompanying renal fail-
If a patient is asked to provoke an attack of muscle cramping, ure. The second-wind phenomenon is also less common in pa-
inserting a needle electrode into the muscle tissue demonstrates tients with Tarui's disease than McArdle's disease because
a series of findings.265-628-871-872 Prior to the cramp, MUAP para- patients are unable to metabolize free blood-borne glucose.4112
meters are typically normal, as is the recruitment aside from the A number of patients may suffer from jaundice (mild hemoly-
exceptions noted above. During sustained maximal contraction, sis) and gouty arthritis, which help distinguish these patients
the MUAP interference pattern begins to decline in both the from those with McArdle's disease.
number of active MUAPs and their size, and insertional activity The clinical phenotype can vary, and there are at least three
is also diminished. Within a minute or so, depending upon the unusual modes of disease presentation: (1) hemolytic anemia
severity of the patient's disease, complete electrical silence is without evidence of a myopathy; (2) late-onset permanent
noted despite evidence of continued muscle contraction, i.e., weakness432; and (3) a fatal infantile form.925 Patients with late-
flexed fingers, wrist, etc. After a few minutes of rest, the MUAP onset weakness notice only mild exercise intolerance in their
activity gradually returns to normal but may take several min- younger years, but never have a history of cramps or myoglo-
utes to an hour in profoundly affected persons. The demonstra- binuria. Weakness predominantly affects the proximal or occa-
tion of electrical silence during a muscle contraction clearly sionally the scapuloperoneal muscles. The fatal infantile form
documents a muscle contracture. This suggests that the defect in presents with severe generalized weakness and cardiomyopathy.
McArdle's disease is a disturbed muscle contraction, with pos- These children die of cardiorespiratory failure in infancy or
sibly a secondary effect on muscle membrane excitibility.582 early childhood. Of note, these infants do not exhibit features of
Treatment. Intense isometric exercises such as weight lift- hemolytic anemia. Contractures, cortical blindness, and corneal
ing and maximum aerobic exercises such as sprinting should be opacifications are evident in some infants.
avoided. However, some patients benefit from a mild to moder- Laboratory Features. Patients usually have some degree of
ate aerobic conditioning.410-411 A sedentary lifestyle leads to a serum CK elevation. Mild anemia and increased reticulocyte
decline in muscle energy resources. This results in poor cardio- count are often noted. Similar to McArdle's disease, there is a
vascular fitness and decline in the delivery of blood-borne subnormal increase in ammonia production but a blunted increase
strates necessary for muscle oxidative metabolism. A mild to in lactic acid in response to the exercise forearm test.
moderate exercise program improves exercise capacity by in- Histopathology. Light and electron microscopic analysis of
creasing cardiovascular fitness and the supply of necessary muscle tissue demonstrates abnormal accumulation of glycogen
metabolic substrates to muscle.411 Patients should be instructed similar to that found in McArdle's disease.249-250 One important
on moderating their physical activity and in obtaining a "second difference between Tarui's and McArdle's disease histologically is
wind" response. Any bout of moderate exercise should be pre- the abnormal accumulation of polysaccharide in some cases, espe-
ceded by 5-15 minutes of low-level warm-up activity to pro- cially older patients. The abnormal accumulation of polysaccha-
mote the transition to the second "wind."411 ride stains intensely with PAS but is diastase-resistant. Of note, in
Dietary modifications and supplementation have also been ad- the fatal infantile form of the disease, muscle biopsies have demon-
vocated. Oral glucose or fructose loading prior to activities has strated only non-specific myopathic features without evidence of
yielded inconsistent results. Increased protein diet may be beneficial, abnormal glycogen accumulation. Definitive diagnosis of Tarui's
disease can be made by biochemical and histochemical analyses, Fig. 27-32). However, the disorder may present in infancy or
which reveal the deficiency of PFK activity and staining. childhood with mild weakness and delay in motor milestones. In
Molecular Genetics and Pathogenesis. PFK catalyzes the addition, fatal infantile cardiomyopathy was reported in two
ATPase-dependent conversion of fructose 6-phosphate to fruc- cases. Almost half the reported cases described muscle weakness
tose 1,6-diphosphate. Human PFK is composed of three distinct that developed in childhood or later in adult life. Weakness may
isoenzyme subunits (M-muscle, L-liver, P-piatelet). Skeletal predominantly affect either proximal or distal limb muscles.
muscles contain only the M isoform, whereas erythrocytes con- Laboratory Features. Serum CK can be normal or mildly
tain a hybrid of M and L subunits. Tarui's disease is inherited in elevated. An abnormal exercise forearm test (insufficient rise in
an autosomal recessive manner, although for some unclear lactic acid) is seen in some cases.
reason there is a 9:1 male predominance. The M-fsoform of Histopathology. Muscle biopsy can be normal but may
PFK was initially linked to chromosme lq32, but subsequently, demonstrate variability in fiber size. Slight subsarcolemmal ac-
the gene was reassigned to chromosome 12q 13. Several muta- cumulation of glycogen, particularly in type 2B fibers, has also
tions have been identified in this gene. 716 825 The symptoms re- been described in some cases. Necrotic fibers were evident in a
flect inactivation of PFK in muscle and partial inactivation in patient with progressive distal muscle weakness.175
red blood cells. Different molecular defects may explain the dif- Molecular Genetics and Pathogenesis. PBK catalyzes the
ferent clinical presentations; however, the biochemical and mol- conversion of inactive myophosphorylase to the active form. In
ecular basis for clinical heterogeneity remains unknown. addition, the enzyme converts active glycogen synthetase to a
Similar to McArdle's disease, there is ADP accumulation in less active form. PBK is a multimeric enzyme composed of four
exercised muscle. Whether or not there is a reduction in sodium- different subunits. Mutations have yet to be identified within
potassium pumps in Tarui's disease, as evident in McArdle's any of the specific subunits of PBK.
disease, is not known. The normal coupling of muscle Electrophysiologic Findings. Nerve conduction studies are
glycogenolysis and sodium-potassium pump activity may be normal. Electromyography may be normal or demonstrate low-
disrupted by increased ADP or reduction in pump concentra- amplitude, short-duration polyphasic MUAPs. Fibrillation po-
tion, as described above in McArdle's disease. Further investi- tentials and positive sharp waves are infrequently noted.
gations are necessary. Treatment. There is no specific medical therapy. Patients
Electrophysiologic Findings. The limited number of case should be instructed on a mild to moderate exercise program
reports and inexperience with large numbers of patients result in and avoid vigorous activity.
minimal data available regarding the details of electrophysio-
logic findings. Patients have normal motor and sensory nerve Type IX Glycogenosis (PGK Deficiency)
conduction studies.5-4321028 The response to limited trains of Clinical Features. Phosphoglycerate kinase (PGK) deficiency
repetitive stimulation at low rates of stimulation does not reveal is an X-linked disorder that until recently was believed to most
a decrement. Prolonged repetitive stimulation delivered at vari- commonly present in male children as hemolytic anemia and CNS
ous rates combined with exercise has not been adequately inves- disturbances (e.g., mental retardation, seizures). However, there
tigated. A response similar to that found in McArdle's disease are increasing reports of myopathy as the primary manifestation of
may be present; however, definitive data are lacking. the disease (Table 27-8, Fig. 27-32).243-347-862-984-1038 1053 It now ap-
The needle electromyographic examination is likely to be pears as though hemolytic anemia, CNS disturbances, and myopa-
normal between attacks; however, patients with fixed weakness thy appear to occur in equal frequencies in patients with PGK
may display MUAPs consistent with a myopathic process, i.e., deficiency. The myopathy is characterized by exercise intolerance,
short-duration, low-amplitude, and increased polyphasic poten- cramps, and recurrent myoglobinuria. Slowly progressive proxi-
tials.4321028 The presence or absence of abnormal spontaneous ac- mal weakness has also been described.
tivity is not documented sufficiently but may consist of fibrillation Laboratory Features. Serum CK is two to three times
potentials, positive sharp waves, and complex repetitive discharges normal. Most patients with the myopathy do not have hemolytic
in those patients with significant disease. During an exercise-in- anemia, although it was reported in one case.984 Exercise fore-
duced cramp, electrical silence is likely to be observed. In short, arm tests fail to show a normal rise in lactate.
the findings are believed to be similar to McArdle's disease, al- Histopathology. Muscle biopsies have usually been normal.
though sufficient substantiation of this supposition is lacking. Mild and diffuse PAS stain is only occasionally noted, but some
Treatment. Glucose or fructose administration prior to ac- glycogen accumulation is usually suggested by EM in all pa-
tivities does not help and may be deleterious. The deficiency of tients. Reduced PGK enzyme activity is appreciated on bio-
PFK results in the abnormal accumulation of glycogen in chemical analysis.
muscle and a reliance on free fatty acids as a fuel substrate. Molecular Genetics and Pathogenesis. The disorder is
Interestingly, exercise intolerance is exacerbated if patients are caused by mutations in the PHK gene, which is located on chro-
given a glucose infusion or if they consume high-carbohydrate mosome Xql3. 1053 Thus far, the different mutations in the PGK
meals because glucose reduces the blood levels of free fatty gene do not appear to correlate with the spectrum of clinical
acids.408 This is just the opposite of the second-wind phenome- features. PGK catalyzes the transfer of the acylphosphate group
non and is sometime called the out-of-wind phenomenon. An of 1,3-diphosphoglycerate to adenosine diphosphate with the
aerobic conditioning program similar to those given to patients formation of 3-phosphoglycerate and ATP in the terminal stage
with McArdle's deficiency may improve exercise tolerance. of the glycolysis. The enzyme is monomeric, and there are no
tissue-specific isoforms, which again make it difficult to ac-
Type VIiI Glycogenosis (PBK Deficiency) count for the presence of myopathy in some patients and he-
Clinical Features. Phosphorylase b kinase (PBK) deficiency molytic anemia or CNS disturbance in others.
is an autosomal recessive disorder with heterogeneous clinical Electrodiagnostic Findings. Routine nerve conduction
manifestations.2-17510691116 Exercise intolerance with cramping studies are normal, but electromyography may reveal "myo-
and myoglobinuria is the most common presentation (Table 27-7, pathic" MUAPs. 2431038
Treatment. No specific medical therapy for the myopathy is Treatment. There is no specific medical therapy. Obste-
available. Treatment is similar to that for McArdle's disease. tricians need to be made aware of potential complications of
labor in affected pregnant females.
Type X Glycogenosis (PGAM Deficiency)
Clinical Features. Patients with phosphoglycerate mutase Type XII Glycogenosis (P-EnoSase Deficiency)
deficiency (PGAM) present with exercise intolerance, cramps, A 46-year-old man with exercise intolerance, myalgias, and
and recurrent myoglobinuria in childhood or early adult life episodic hyper-CK-emia was reported with p-enolase defi-
(Table 27-7, Fig. 27-32).1055 ,084 There have been no documented ciency.1853 No rise in lactic acid was noted on ischemic forearm
cases with muscle weakness. testing. Muscle biopsy revealed abnormal accumulation of
Laboratory Features. Serum CK is mildly elevated be- glycogen in the sarcoplasm. Electrodiagnostic features were
tween attacks. Exercise forearm test results in only a small rise not reported. Selective p-enolase deficiency was demonstrated
in lactic acid (less than the normal fourfold increase). on immunohistochemistry and immunoblot, and heterozygous
Histopathology. Increased glycogen is evident by PAS stain mutations were identified within the gene. P-enolase converts
and EM. Rare patients have tubular aggregates in type 2B fibers. catalyze the step interconverting 2-phosphoglycerate and phos-
Biochemical assay demonstrates normal or only mildly elevated phoenol pyruvate.
glycogen content and markedly diminished activity of PGAM
(less than 10% of normal). Danon Disease (X-linked Vacuolar Cardiomyopathy
Molecular Genetics and Pathogenesis. PGAM is an autoso- and Myopathy)
mal recessive disorder caused by mutations in the PGAM-M Clinical Features. Danon reported two 16-year-old boys
gene encoded on chromosome 7ql2-pl3. 1055 PGAM catalyzes who presented with hypertrophic cardiomyopathy, myopathy,
the interconversion of 2-phosphoglycerate and 3-phosphoglycer- and mental retardation.209-733a Patients are normal at birth but de-
ate. There are two subunits: a muscle-specific subunit (PGAM- velop proximal muscle weakness in early childhood or adoles-
M) and a non-muscle-specific or brain subunit (PGAM-B). cence. Hepatosplenomegaly may be noted. Patients generally
Mature muscle contains the homodimer MM form of PGAM, die of heart failure or arrhythmia in the third decade.
which has diminished enzymatic activity in type X glycogenosis. Laboratory Features. Serum CK levels are moderately ele-
Electrophysiologic Findings. Nerve conduction studies and vated. Echocardiogram reveals hypertrophic cardiomyopathy.
electromyography are normal.1084 Histopathology. Muscle biopsies demonstrate variability in
Treatment. There is no definitive medical therapy. Dantro- fiber size with autophagic vacuoles that are PAS positive.209 EM
lene improved symptoms in one patient but is not recommended reveals excess glycogen free between disorganized myofibrils
as routine therapy. Patients should avoid strenuous activity and and within membrane-bound sacs and vacuoles. Unlike acid
be placed on a mild to moderate aerobic exercise program. maltase, a-glucosidase activity is normal. Lysosome-associ-
ated membrane protein-2 is absent on immunostaining and
Type XI Glycogenosis (LDH Deficiency) there is no deposition of membrane attack complex on muscle
Clinical Features. This rare autosomal recessive disorder fibers.128
manifests as exercise intolerance, cramping, and recurrent myo- Molecular Genetics and Pathogenesis. Danon disease is
globinuria (Table 27-7, Fig. 27-32).499 Muscle strength is other- caused by mutations in the gene that encodes for lysosome-as-
wise normal between attacks of myoglobinuria. Patients who sociated membrane protein-2 (LAMP-2), which is located on
become pregnant may develop uterine stiffness in early stages the chromosome Xq24.733a LAMP-2 is a major lysosomal mem-
of delivery, which often requires cesarean section. This compli- brane protein.
cation has not been associated with other glycogenoses. Patients Electrophysiologic Findings. Nerve conduction studies are
also develop a generalized, scaly, erythematous rash, particu- normal. Electromyography reveals increased insertional and spon-
larly in the summer. Chronic renal failure can develop sec- taneous activity in the form of fibrillation potentials, PSWs, com-
ondary to recurrent myoglobinuria. plex repetitive discharges, and myotonic discharges.209 MUAPs
Laboratory Features. Serum CK levels are markedly in- are small in amplitude and duration, polyphasic, and recruit early.
creased during an episode of myoglobinuria. In contrast, serum Treatment. There is no specific medical therapy.
LDH is normal. On exercise forearm test, lactate does not rise;
however, there is a normal increase in pyruvate levels. This re- X-linked Myopathy with Excessive Autophagy (XMEA)
sults because the defect lies distal to the formation of pyruvate in Clinical Features. XMEA manifests as slowly progressive
the metabolic pathway. Electrophoretic studies demonstrate a re- proximal weakness beginning in infancy or early adult
duction in the LDH-M isoform (less than 5% of normal) in life.495a l082a ll28a They can present as a floppy infant and develop
muscle and blood. a progressive cardiomyopathy resembling Danon disease or
Histopathology. Muscle biopsies can appear normal, but acid maltase deficiency.
biochemical assays following exercise demonstrate increased Laboratory Features. Serum CK levels may be normal or
glycolytic metabolites proximal to the formation of lactic acid mildly elevated.
as well as reduced ATP and NAD levels. Histopathology. Muscle biopsies reveal muscle fiber size varia-
Molecular Genetics and Pathogenesis. LDH is separated tion and many fibers with autophagic rimmed vacuoles 495aJ082a-ll28a
into five isoenzymes that form tetramers by the random combi- These vacuoles are not PAS-positive, and immunohistochemistry
nation of two different subunits, M and H. Thus far, only muta- reveals membrane attack complex (C5b-9) deposition along the
tions involving the M subunits encoded on chromosome 11 pi5.4 sarcolemma of abnormal muscle fibers.11283 Further, LAMP-2 is
have been associated with muscle disease.499-599 LDH activity is present on the vacuoles and within the cytoplasm in XMEA.
markedly depressed in muscle (less than 5% of normal). Molecular Genetics and Pathogenesis. XMEA has been
Electrophysiologic Findings. Nerve conduction studies and mapped to chromosome Xq28 but the gene has not yet been
electromyography have not been well documented. identified.
intermembrane inner
space membrane
Figure 27-34. Mitochondrial metabolism.This scheme

Long-
Chain
may appear daunting; however, we are primarily concerned
Fatty with tatty acid (FA) transport into the mitochondria.Very long
Acids
chain and long chain FA must first be joined to coenzyme A
(CoA) using I ATP, creating FACoA, which is catalyzed by acyl-
CoA-synthetase (ACS). Carnitine palmityltransferase (CPT I),
located in the outer aspect of the inner mitochondrial mem-
brane, joins carnitine and FACoA, producing FACarn so the FA
can be transported across the mitochondrial membrane by
acylcarnitine translocase. Once inside the mitochondrial
matrix, CPTII, located on the inner aspect of the inner mem-
brane, regenerates carnitine (Cam) and FACoA.The carnitine
is exchanged across the inner membrane for FACarn, complet-
AcAcCoA
CoA
ing this cycle. FACoA is then oxidized and prepared to feed
into the Kreb's cycle. Any deficiency in carnitine, CPT, or some
other factor in the above-noted sequence results in the accu-
mulation of lipid material with the potential for a myopathy.
(From Engel AG, Franzini-Armstrong C (eds): Myology, 2nd ed.
AcAc, acetoacetate
New York, McGraw-Hill, 1994, with permission.)
AATH, acetoacelyl-CoA thielase BHB, 0-hydroxybutyrate
ACS, acyl-CoA synthetase FA, latty acid
BHB, B-hydroxybutyrate dehydrogenase Cam, carnitine
CoA, coenzyme A
CAT, carnitine acetyltranlerase
ATP. adenosine triphosphate
CPT, carnitine palmitoyltransferase
AMP, adenosine monophosphate
PDH, pyruvate dehydrogenase
PP, pyrophosphate
SCAT, succinyl-CoA acetoacetyl-CoA transferase
NAD. nicotinamide adenine dinucleotide
Electrophysiologic Findings. Routine motor and sensory physical examination in patients with primary MAD deficiency is
nerve conduction studies are normal. Electromyography demon- completely normal.
strates features similar to Danon disease and acid maltase defi- Laboratory Features. Serum CK is normal or only slightly
ciency: increased insertional and spontaneous activity with elevated. The exercise forearm test is abnormal: serum lactate
fibrillation potentials, PSWs, complex repetitive discharges, and levels rise normally with exercise; however, ammonia levels re-
myotonic discharges. 495a l082a',,28a There is early recruitment of mains relatively stable.
small-amplitude, short-duration polyphasic MUAPs. Histopathology. The muscle biopsy is usually normal in the
Treatment. There is no specific medical therapy. primary form of the disease.248 513 Specific biochemical assay or
histologic stain for MAD is essentially the only abnormality
DISORDER OF PURINE NUCLEOTIDE METABOLISM noted. In primary MAD deficiency, residual MAD activity is
less than 2% of normal with the residual activity in secondary
The only disorder of nucleotide metabolism involved in deficiencies being much higher.
muscle disorders is myoadenylate deaminase (MAD). This Molecular Genetics and Pathogenesis. The main function of
deaminase is important, because it is an enzymatic component MAD is to catalyze the removal of an ammonia group from adeno-
of the purine nucleotide cycle. sine monophosphate (AMP) and convert this substance to inosine
monophosphate (IMP). This is important because AMP inhibits the
Myoadenylate Deaminase Deficiency formation of ATP (2 ADP ^ ATP + AMP). By converting AMP to
Clinical Features. Patients with MAD deficiency can present IMP, the above reaction is favored toward the formation of ATP
with complaints of exertional muscle pain and fatigue in late ado- maintaining energy supplies. Also, the production of ammonia
lescence to middle age.248-337-338-513945 MAD deficiency may be a buffers the lactic acid formed during exercise. IMP stimulates gly-
cause of myoglobinuria.1037 The relationship between these symp- colysis by acting on PFK and helps in the formation of fumarate, a
toms is controversial, as some individuals with MAD deficiency substrate for the Kreb's cycle. As can be seen, a deficiency in
are asymptomatic. MAD deficiency has been reported in 1-2% of MAD not only may result in the inhibition of ATP formation, but
muscle biopsies, making it the most common enzyme deficiency also may have wide reaching metabolic effects in multiple energy
in muscle.1080 Muscle biopsies in patients with other types of neu- production cycles. MAD-deficient patients have been demon-
romuscular disorders such as amyotrophic lateral sclerosis, spinal strated to have reduced phosphocreatine and ADP levels compared
muscular atrophy, inflammatory myopathies, and various forms of with normal controls.882 However, a study of sustained, isometric
muscular dystrophies can have deficiencies in MAD. This sug- muscle contraction during ischemia in MAD-deficient patients and
gests that there may be primary and secondary forms of MAD de- normal controls found no difference in oxygen utilization, en-
ficiency. The frequency of MAD deficiency is increased in muscle durance time, and resting and post-exercise lactate and phospho-
biopsies performed for evaluation of exertional myalgias.513 The creatine levels, suggesting a normal exercise capacity.1083
The gene for MAD has been localized to chromosome lpl3-21, acylcarnitine translocase. Carnitine palmityltransferase 2
and point mutations have been identified in the gene in primary (CPT 2), located on the inner surface of the inner membrane,
MAD deficiency. 8831080 Some studies have suggested that as mediates the formation acyl-CoA from the acylcarnitine com-
many as 88% of individuals with this genetic defect experience plex and CoA. The acyl-CoA now within the mitochondrial
exertional myalgias. However, the association between MAD matrix can be metabolized by p-oxidation into ATP.
deficiency and exertional myalgias may be just coincidental, be- P-oxidation of fatty acid derivatives within the mitochondria
cause the frequency of the mutation is high (as much as 2%) in proceeds through a repeated series of four enzymatic steps. In
the normal population. 1080 Further, there are many reports of the first step, flavin-dependent, length-specific acyl-CoA de-
MAD-deficient patients without exertional-related symptoms. hydrogenase (note: there are short chain, medium chain, long
As noted above, secondary MAD deficiency has been associ- chain, and very long chain acyl-CoA dehydrogenases) converts
ated with a number of neuromuscular disorders. A recent study the respective lengthened acyl-CoA substrates into enoyl-CoAs
in the Dutch population revealed no significant differences in and reduced flavin adenine dinucleotide (FAD). Next, length-
frequencies of the characteristic "mutation" in the MAD gene in specific enoyl CoA hydratase catalyzes the formation of 3-hy-
patients with exercise intolerance, those with other neuromus- droxyacyl-CoA derivatives. In the third step, 3-ketoacyl-CoA
cular disorders, and in healthy volunteers.1080 Thus, the investi- esters are formed by a second dehydrogenation reaction cat-
gators concluded that "secondary MAD deficiency" in patients alyzed by length-specific NAD-dependent 3-hydroxyacyl-
with other neuromuscular disorders was in fact due to the coin- CoA dehydrogenases. In the final step, length-dependent
cidental genetic defect in the MAD gene. In addition, the study 3-ketothiolase catalyzes the conversion of the 3-ketoacyl-CoA
suggested that the MAD deficiency is due to a harmless poly- ester to acetyl-CoA and to fatty acyl-CoA, which is now two
morphism, rather than a disease-causing mutation, and that ex- carbon atoms shorter than the acyl-CoA that entered the initial
ercise intolerance is just a coincidental symptom. first step. This cycle of four steps is then repeated.
Electrophysiologic Findings. There are no detailed quanti- Electrons transferred to FADH 2 and NADH during the above
tative electrodiagnostic medicine evaluations reported in pa- series of reactions are transferred to the respiratory chain, which
tients with MAD deficiency. The few brief descriptions suggest is composed of five multimeric protein complexes embedded in
that both the nerve conduction and the needle electromyo- the inner mitochondrial membrane (Fig. 27-35). FADH trans-
graphic examinations are completely normal.240-337-338-513-945 fers its electrons to coenzyme Q through two flavoproteins:
There is some mention of "nonspecific findings" with no at- electron-transferring protein (ETF) and ETF-coenzyme Q
tempt to define what this vague term means. oxidoreductase (ETF-QO). NADH transfers its electrons to
A few reports note the presence of positive sharp waves, fibril- complex I of the respiratory chain. The electrons are transported
lation potentials, complex repetitive discharges, and fascicula- down an energy gradient form one complex to another, generat-
tions in persons with this enzyme defect. However, these patients ing a proton motive force that is necessary to produce ATP.
had a primary diagnosis of motor neuron disease or a form of Disorders of lipid metabolism can affect multiple organs; how-
muscular dystrophy that probably accounted for these electro- ever, we are primarily concerned with those producing my-
physiologic abnormalities. There are no well-documented elec- opathies. A number of lipid disorders remain poorly identified and
trophysiologic abnormalities in the primary form of the disease. are primarily recognized by the characteristic finding of lipid ac-
Treatment. There is no specific medical treatment available. cumulation in muscle. Considerable work must be done to more
fully define the various disorders affecting lipid metabolism.
LIPID METABOLISM DISORDERS
Carnitine Deficiency
Lipid metabolism as a source of energy requires the libera- Clinical Features. Carnitine deficiency is the most
tion of free fatty acids from circulating very low density common disorder of lipid metabolism. There are three major
lipoproteins in the blood or cytoplasmic fat stores. ATP is gen- carnitine deficiency syndromes: (1) primary systemic carnitine
erated from P-oxidation of fatty acids within the matrix of mito- deficiency, (2) primary muscle carnitine deficiency, and (3) a
chondria.161-756 Fatty acids are divided into short, medium, long, poorly defined secondary form with low or normal carnitine
and very long chain fatty acids, depending on their size. In order 1 e ve 1 s.21 •190-191 -241 '248-289-501 -933-1117
for p-oxidation to occur, the fatty acids must enter the inner mi- Primary systemic carnitine deficiency is a heterogeneous
tochondrial matrix. Unlike short and medium chain fatty acids, syndrome. Presumably, there is a primary reduction in the synthe-
long chain fatty acids are not readily permeable to either the sis or intracellular transport of carnitine throughout the body, i.e.,
outer or inner mitochondrial membranes. Long chain fatty acids liver, plasma, and muscle tissue. Patients with systemic carnitine
must be modified and interact with various carrier proteins in deficiency have findings resembling Reye's syndrome. The disor-
order to be transported across the mitochondrial membranes. der usually presents in young children with acute attacks of vomit-
First, the long chain fatty acids combine with coenzyme A ing, altered mental status, hypoglycemia, and hepatomegaly. Some
(CoA) in a reaction catalyzed by acyl-CoA-synthetase, creating patients have a severe cardiomyopathy.169-296-363-682-967 The systemic
a two-carbon fatty acid-derived fragment, Acyl-CoA, which manifestations tend to overshadow muscle involvement, but pro-
crosses into the outer membrane of the mitochondria (Fig. 27¬ gressive proximal weakness is evident in some patients. Death has
34). Next, acyl-CoA must cross the mitochondrial inner mem- been reported to occur at different ages depending upon the dis-
brane in order to enter the organelle's matrix. This requires the ease severity and varies from childhood to early adult life.
joining of fatty acid-CoA to carnitine, which is reversibly cat- The second form of the disease is primary muscle carnitine
alyzed by carnitine palmityltransferase 1 (CPT 1), an enzyme deficiency.22-69 160-286-426-609-813 Disease usually manifests in child-
located on the inner face of the outer mitochondrial membrane. hood or early adult life, but infantile onset has also been de-
The acyl-carnitine complex is transported across the inner mito- scribed. Progressive proximal muscle weakness and atrophy can
chondrial membrane in exchange for carnitine, which in turn is be quite profound in some patients. Not surprisingly, patients
transported in the opposite direction, in a reaction catalyzed by may ambulate with a waddling gait and have difficulty arising
Carbohytlfat&s
Cytosol
j Glycolysis
Fatty Acids
Pyruvate Amino Acids
Pyruvate "Amino-Acids
j Transaminase
Fatty Acids H Acetyl CoA |
0 -Oxidation
Mitochondrion
Complex I
FMN—FeS-*FeS
H.ft$^F»sk Complex I I I Complex IV
CoQ —HCyl b -~Cyt b.-^FeS —Cyl c,L_^ Cyt c -MCyt a—Cyt a 3 r - ^ Oj
T
Complex II 1
•* 1
— 1
-AD—F*S—F«S—F#S
1 Complex V I
AOP ATP
Pi
Figure 27-35. Mitochondrial metabolism and the respiratory chain complex.This scheme represents the mitochondrial metabolism of
carbohydrates, fatty acids, and amino acids in simplified form. Note that all three substances utilize acetyl coenzyme A to feed into the Kreb's cycle
and eventually lead to the electron transport chain. Complexes l-V utilize the Kreb's cycle products to generate ATP for cellular use. An alteration
in the biochemical steps at any location in these processes can be considered to constitute a mitochondrial myopathy. (From DiMauro S, DeVivo
DC: Diseases of carbohydrate, fatty acid, and mitochondrial metabolism. In Siegel GJ.Agranoff BW, Albers RW (eds): Basic Neurochemistry. New
York, Raven Press, 1989, pp 647-670, with permission.)
from the floor. Lumbar lordosis can be evident, and neck flexor a marked elevation in the serum CK and liver enzyme levels as |
and extensor muscle weakness can also be prominent. A few well as the potential for hypoglycemia and acidosis. However, I
cases have worsened significantly during pregnancy or in the ketones are not elevated in the urine during fasting. An echocar-
post-partum period. Mentation is normal. Cardiac involvement diogram can demonstrate dilated or hypertrophic cardiomyopa-
with ventricular hypertrophy, congestive heart failure, and ar- thy, and an EKG may show left axis deviation.
rhythmias occurs in some patients. Histopathology. Muscle fiber size can be normal, demon-
The secondary form of carnitine deficiency is less well strate regions of decreased fiber size, or have some degree of
characterized. A secondary deficiency of carnitine may result fiber size variation. Occasionally, the muscle fibers contain nu-
from a variety of disorders, including respiratory chain defects, merous vacuoles (Fig. 27-36A). Abnormal accumulation of
organic aciduria, endocrinopathies, dystrophies, renal and liver lipid material in the subsarcolemma and intermyofibrillar re-
failure, malnutrition, and as a toxic effect of certain medica- gions is evident on Oil red O stain (Fig. 27-36B). 249 Type 1
tions.236-1057 It is not clear whether or not patients with secondary fibers are preferentially affected, as would be expected given
carnitine deficiency truly develop myopathic symptoms. the type of oxidative metabolism utilized by these fibers.
Laboratory Features. Plasma and tissue carnitine levels are Muscle carnitine levels should be dramatically decreased (less
severely decreased in the primary systemic carnitine deficiency, than 2^1% of normal) in patients with primary systemic or pri-
while the deficiency is much less (25-50% normal) in sec- mary muscle carnitine deficiency (this may serve to distinguish
ondary forms of carnitine deficiency.967 Only muscle carnitine patients with secondary deficiency).
levels are decreased in primary muscle carnitine deficiency. Molecular Genetics and Pathogenesis. Most cases of pri-
Serum CK levels are normal in approximately 50% of patients mary systemic and primary muscle carnitine deficiency have
with the myopathic form of the disease but can be elevated to as been sporadic in occurrence, but an autosomal recessive inheri-
much as 15 times normal. In the systemic form of the disease, tance is suspected. Primary carnitine deficiency has been linked
liver enzymes are also elevated. When the patients fast, there is to mutations in the sodium-dependent carnitine transporter
Figure 27-36. Muscle carnitine deficiency. (A) Many vacuolated muscle fibers are apparent on this muscle biopsy. Gomori trichrome. (B)
Marked increased lipid deposits that stain red on Oil red O and are seen.
protein gene (OCTN2) located on chromosome 5q33.1. 726 One demonstrated, even in those who improved in muscle strength.967
family with autosomal dominant hypertrophic cardiomyopathy It was speculated that the intracellular (muscle) concentration of
j and muscle weakness with carnitine deficiency has also been carnitine only needs to be 2 ^ % of normal to allow for normal
described.69 lipid metabolism.
The deficiency of carnitine impairs the long chain fatty acids
from entering the inner mitochondrial matrix, thus severely af- Carnitine Palmityltransferase Deficiency
fecting energy production from these fatty acids. Carnitine is Clinical Features. This disorder is inherited in an autosomal
supplied by the diet and by endogenous synthesis. Intracellular recessive manner but manifests predominantly in males.51,225-241-249-
carnitine levels are maintained at 20-50 times the extracellular 5i6.io44.ii5i typical clinical presentation is muscular pain and
concentration by an active transport system. In patients with pri- cramping following intense or prolonged exertion. Myoglobinuria
mary systemic carnitine deficiency, a defect in carnitine uptake is a common feature of this disease, and renal failure can occur.
in fibroblasts and leukocytes was reported, thereby reducing its Fasting worsens the above-noted symptoms. Most patients
intracellular concentration.967 The defect presumably is also pre- become symptomatic by the second decade. Between attacks, the
sent in kidneys and muscle. The concentration and rate of physical examination is usually normal.
uptake of carnitine in the parents of affected children were in- Laboratory Features. Serum CK levels are usually normal,
termediate between normal adult controls and those of the af- except when the patient performs intense physical activities or
fected children, consistent with autosomal recessive fasts for prolonged periods.
inheritance.967 It was postulated that carnitine does not become Histopathology. There is no gross abnormality noted on
a rate limiting factor for fatty acid oxidation as long as its intra- light microscopic examination of muscle tissue. An increase in
cellular concentration is 30-50 prnol/1 or approximately 2-4% the lipid content of muscle is detectable in muscle tissue exam-
of normal.967 ined by EM.249
Electrophysiologic Findings. Motor and sensory nerve con- Molecular Genetics and Pathogenesis. Mutations in the
duction studies should be normal. A CMAP decrement of 28% CPT 2 gene located on chromosome 1 p32 have been identi-
by the sixth response to 5-Hz repetitive stimulation was reported fied.3351007 Deficiency of carnitine palmityltransferase impairs
in a single patient.904 After treatment with dietary carnitine sup- the transport of acylcarnitine across the inner mitochondrial
plementation, the decrement disappeared. The physiologic mech- membrane (Fig. 27-34). Thus, the generation of ATP from fatty
anism of this decrement is unclear. acid metabolism is impaired.
Needle electromyographic examination in patients with some Electrophysiologic Findings. Insufficient cases using elec-
degree of weakness usually reveals normal insertional activity trodiagnostic medicine techniques have been reported in the lit-
with an absence of positive sharp waves and fibrillation poten- erature to comment in detail on the electrophysiologic findings
tials. A few patients with profound myopathy have demon- in these patients. We have found no abnormalities between at-
strated increased insertional activity with sustained runs of tacks on either nerve conduction or needle electromyographic
positive sharp waves and fibrillation potentials.426-609-1075 evaluation. During an attack, it is not known what changes, if
Complex repetitive discharges can also be detected. There is an any, are detectable. Considerably more work is required in this
isolated report of true myotonic potentials waxing and waning disease to fully characterize the abnormalities present, if any.
in this disease. 958 Short-duration, small-amplitude, polyphasic
MUAPs that recruit early can be observed.2,-19,-289-50ul17 Very Long Chain Acyl-CoA Dehydrogenase
Treatment. Oral L-carnitine (2-6 gm/day) has benefited some (VLCAD) Deficiency
but not all patients with carnitine deficiency.2'•'91.233.236.501.813.933.958 A Clinical Features. VLCAD deficiency is a clinically hetero-
dramatic clinical response to oral L-carnitine in patients with sys- geneous disorder that manifests in early childhood with hypoke-
temic carnitine deficiency manifested by severe cardiomyopa- totic hypoglycemia and dicarboxylic aciduria.16'648-662-748-1007'"28
thy and muscle weakness has been reported.967-10171045 However, Most, if not all, of the previously described cases of long chain
only modest increases in muscle carnitine levels have been acyl-CoA deficiency (see below) may actually have had very
long chain CoA deficiency.6621007-1128 There is an early-onset but similar to that of LCAD deficiency.236-860 The course as in
fatal form of the disease associated with a severe hypertrophic LCAD deficiency is bimodal with acute metabolic attacks pre-
cardiomyopathy. A milder form characterized by Reye's syn- dominating in infancy. Later in childhood, these metabolic at-
drome-like episodes in early childhood also occurs. In addition, tacks cease and patients develop a mild myopathy.1150
rare reports of exercise-induced myoglobinuria beginning in Laboratory Features. Carnitine levels are decreased in the
early childhood to early adulthood have been reported.662-748-955 plasma, liver, and muscle. Increased urinary excretion of dicar-
Laboratory Features. Serum CK is elevated in cases of boxylic, adipic, and sebacic acids can be demonstrated. MCAD
myoglobinuria as expected. Between attacks, the CK may be activity is diminished to less than 10% in fibroblasts, lympho-
normal. Serum carnitine levels are normal, but muscle carnitine cytes, and in the liver.
levels may be reduced. There is an increase in plasma concen- Histopathology. Muscle biopsy is notable only for excess
tration of tetradecnoic acid (C14:1) with normal levels of myris- lipid.
tic acid (C !4: i) consistent with a defect in p-oxidation of long Molecular Genetics and Pathogenesis. Mutations within
chain fatty acids. Reduced VLCAD activity can be demon- the MCAD gene located on chromosome lp31 have been iden-
strated in cultured fibroblasts. tified in patients with MCAD deficiency.251 MCAD acts on fatty
Histopathology. Muscle biopsies demonstrate abnormal ac- acyl-CoA derivatives whose acyl residues contain 4-14 carbon
cumulation of lipid. atoms.
Molecular Genetics and Pathogenesis. This myopathy is Electrophysiologic Findings. Electrodiagnostic studies
caused by mutations in the VLCAD gene, which is located on have not been reported in detail to allow for sufficient comment.
chromosome 17pl 1.2-p 13.1. 1629 Patients with this enzyme defi- Treatment. Carnitine has improved the hepatomegaly, uri-
ciency have impaired ability to metabolize very long chain fatty nary organic acid profile, and prevented metabolic attacks in
acids. some patients.860-1042
Electrophysiologic Findings. Detailed descriptions of the
electrophysiologic findings are scant, but electromyography has Short Chain Acyl-CoA Dehydrogenase
been noted to show "evidence of previous muscle fiber degener- (SCAD) Deficiency
ation and regeneration."748 Clinical Features. SCAD deficiency is very rare. Some in-
Treatment. A low-fat/high-carbohydrate diet in which long fants present with failure to thrive and nonketotic hypoglycemia.
chain fatty acids are partially replaced by medium chain triglyc- A few patients have been reported with myopathy. 177-23410,81()57
erides can be very effective in preventing attacks of hypoketotic Progressive proximal weakness may be present at infancy or de-
hypoglycemia, dicarboxylic aciduria, and myoglobinuria.662-748 velop in early to mid-adulthood. Weakness can also be episodic
and made worse with exertion. Some patients describe myalgias
Long Chain Acyl-CoA Dehydrogenase with exercise. Facial weakness, ptosis, progressive external oph-
(LCAD) Deficiency thalmoplegia, respiratory weakness, and cardiomyopathy have
Clinical Features. LCAD deficiency usually presents in in- also been described.1018
fancy with failure to thrive, hepatomegaly, cardiomegaly, non- Laboratory Features. Serum CK is usually normal. There
ketotic hypoglycemia, and an encephalopathy resembling is increased urinary excretion of short chain metabolites ethyl-
Reye's syndrome.236*405 Patients who reach childhood and adult- malonate and methylsuccinate.
hood frequently develop recurrent episodes of muscle pain, Histopathology. The few reports of muscle biopsies have
cramps, and myoglobinuria along with proximal weakness.235 demonstrated excess lipid. Muscle carnitine levels may be sec-
Laboratory Features. Serum CK is elevated during attacks ondarily reduced. SCAD deficiency can be demonstrated in
of muscle pain and cramps. Total and free carnitine levels are muscle tissue. Multicore myopathy has also been reported in the
reduced in the plasma, liver, and muscle, but long chain acylcar- setting of SCAD deficiency.1018
nitine esters are increased. Diagnosis is made by demonstrating Molecular Genetics and Pathogenesis. Genetic defects
decreased LCAD activity in cultured fibroblasts. have not yet been localized. SCAD acts on fatty acyl-CoA de-
Histopathology. Muscle biopsies reveal abnormal accumu- rivatives whose acyl residues contain 4-6 carbon atoms.
lation of lipid. Electrophysiologic Findings. Electrodiagnostic studies
Molecular Genetics and Pathogenesis. Genetic defects have not been reported in detail to allow for sufficient comment.
have not been localized for LCAD. As noted above, many of the Treatment. No specific medical therapy has been shown to
reported cases of LCAD deficiency were in fact patients with be beneficial, including carnitine supplementation.
VLCAD deficiency. LCAD acts on fatty acyl-CoA derivatives
whose acyl residues contain more than 12 carbon atoms. 3-Hydroxy Acyl-CoA Dehydrogenase (HAD) Deficiency
Patients with LCAD deficiency have impaired ability to metab- Clinical Features. There are only a few reports of long
olize long chain fatty acids. chain HAD deficiency.82-406-484-859 The disorder manifests in in-
Electrophysiologic Findings. Electrodiagnostic studies fancy with Reye's-like syndrome, nausea, vomiting, seizures,
have not been reported in detail to allow for sufficient comment. hypoketotic hypoglycemia, respiratory failure, myopathy, and
Treatment. Intravenous glucose has relieved the muscle cardiomyopathy. One infant had a progressive sensorimotor
pain and lowered the serum CK levels in some patients. 405 polyneuropathy, necrotizing myopathy, and pigmentary
Carnitine can improve the cardiomyopathy but does not affect retinopathy.82
skeletal muscle strength.405 Laboratory Features. Serum CK and lactate levels are ele-
vated. Long chain HAD deficiency can be demonstrated on
Medium-Chain Acyl-CoA Dehydrogenase assay of cultured fibroblasts.
(MCAD) Deficiency Histopathology. Abnormal accumulation of lipids can be
Clinical Features. MCAD deficiency is the most common apparent in muscle biopsies, although this increase is not as
form of acyl-CoA deficiency. Clinical presentation is variable prominent as that observed in other disorders of (3-oxidation.
Nerve biopsy in one patient demonstrated marked loss of myeli- Table 27-8. Mitochondrial Myopathies:
nated nerve fibers and axonal degeneration. Biochemical Classification
Molecular Genetics and Pathogenesis. The disorder can be I. Substrate Transport Defects
inherited in an autosomal recessive pattern, but mutations in the 1. Carnitine palmityltransferase
gene have yet to be identified. Long chain HAD catalyzes the 2. Primary systemic/muscle carnitine deficiency
third step in P-oxidation, the conversion of 3-hydroxyacyl-CoA 3. Secondary carnitine deficiency
derivatives to 3-ketoacyl-CoA derivatives. Deficiency of the 4. Combined carnitine and carnitine palmityltransferase deficiency
enzyme leads to impairment in metabolism of long chain fatty
acids. II. Substrate Utilization Defects
Electrophysiologic Findings. One infant had evidence of an A. Pyruvate
axonal sensorimotor polyneuropathy on nerve conduction stud- 1. Pyruvate decarboxylase deficiency
ies, 82 but detailed electrophysiologic data on other cases are 2. Pyruvate dehydrogenase deficiency
lacking. 3. Pyruvate carboxylase deficiency
Treatment. Some improvement with a diet high in carbohy- B. Fatty Acids
drates, protein, and medium chain triglycerides in combination I. P-Oxidation defects
with carnitine supplementation has reportedly been noted in III. Kreb's Cycle Defects
some cases.484 1. Fumarase
2. a-Ketoglutarate dehydrogenase
Electron Transferring Flavoprotein (ETF) and ETF- 3. Dihydrolipoyl dehydrogenase
Coenzyme Q Oxidoreductase (ETF-QO) Deficiencies IV. Oxidation/Phosphorylation Coupling
Clinical Features. Disorders of ETF and ETF-QO result in
glutaric aciduria type II. There are several forms of glutaric I. Luft's syndrome: Loose coupling with hypermetabolism
aciduria type II, but only one form has been associated with a V. Respiratory Chain Defects
myopathy. 236 Some infants are born hypotonic and floppy, but 1. Complex I
they may appear normal until early childhood. The affected 2. Complex II
children present with progressive proximal weakness and atro- 3. Complex III
phy associated with episodes of confusion, ataxia, tremor, 4. Complex IV
nausea, vomiting, hypoketotic hypoglycemia, lethargy, and he- 5. Complex V
patomegaly.,90-236-264-839 Deep tendon reflexes are reduced. 6. Combination of l-V
Laboratory Features. Secondary carnitine deficiency is ev- Modified after DiMauro,Tonin, Servidei248, and Morgan-Hughes.689
ident in the plasma, liver, and muscle. Reduced ETF-QO activ-
ity has been demonstrated in cultured fibroblasts.236 in which to classify mitochondrial disorders according to the
Histopathology. Muscle biopsies demonstrate lipid accu- metabolic defect present: (1) transport, (2) substrate utilization,
mulation. (3) Kreb's cycle, (4) oxidation/phosphorylation coupling, and
Molecular Genetics and Pathogenesis. Genetic defects (5) respiratory chain.247-248-689J2,a As a result, the previously dis-
have not yet been localized. ETF transfers electrons from re- cussed myopathies resulting from lipid metabolic derange-
duced forms of acyl-CoA dehydrogenase to the respiratory ments could be classified as mitochondrial myopathies. One
chain via ETF-QO. 236 ETF-QO transfers electrons from ETF to major drawback of the biochemical classification scheme is
ubiquinone. Defects in these enzymes result in the inability to that the biochemical abnormalities are non-specific. For exam-
oxidize the reduced forms of various dehydrogenases including ple, cytochrome oxidase (COX) deficiency can be evident in
VLCAD, LCAD, MCAD, and SCAD. almost any type of mitochondrial myopathy and does not sug-
Electrophysiologic Findings. The rare descriptions of elec- gest a primary defect lies in COX. The rapid advances of mole-
trophysiologic data indicate nerve conduction studies are cular genetics should provide a better classification for the
normal, whereas electromyography demonstrates "non-specific mitochondrial myopathies (Table 27-9). Mitochondrial my-
myopathic features."190-236-264 opathies caused by toxic medications are discussed in chap-
Treatment. No specific medical therapy, including carnitine ter 28.
supplementation, has been proven effective.
COMPOSITION OF MITOCHONDRIAL
DNA AND PROTEINS
MITOCHONDRIAL MYOPATHIES
The mitochondrial genome is composed of 16.5 kB circular
The term "mitochondrial myopathies" refers to disorders double-stranded DNA. There are no introns, and in some re-
with identifiable structural abnormalities of muscle mitochon- gions contiguous mitochondrial genes overlap. There is a single
dria.688-689 Mitochondrial myopathies have been classified ac- promoter site, and transcription is polycistronic. That is, all the
cording to the associated biochemical defects (Table 27-8). The mitochondrial genes are transcribed as two large RNAs that are
mitochondria well deserve their nickname of the "cell's power- subsequently cleaved into respective mRNAs, rRNA, and
house," as this is the final convergence of acetyl-CoA, which tRNAs. Interestingly, the genetic code for translation of mito-
utilizes the end result of fatty acid, carbohydrate, and amino chondrial genes differs from the universal code that governs the
acid metabolism. The acetyl-CoA feeds into the Kreb's cycle translation of nuclear-encoded genes.
located exclusively in mitochondria. The electrons derived Mitochondrial DNA (mtDNA) encodes for 22 transfer RNAs
from the Kreb's cycle are then shuttled to the respiratory chain (tRNAs), two ribosomal RNAs (rRNA), and 13 messenger
and processed through complexes I-V to generate ATP mole- RNAs (mRNAs). The 13 mRNAs are translated into 13 poly-
cules. This biochemical scheme permits a convenient manner peptide subunits of the respiratory chain complexes (Table 27-10).
TABLE 27-9. Mitochondrial Myopathies: Genetic Classification
Disease Mode of Inheritance Mitochondrial D N A mutation Gene location
Kearns Say re syndrome Sporadic Single large mtDNA deletion Large area of mt genome
PEO Sporadic Single large mtDNA deletion Large area of mt genome
PEO Maternal Point mutations of mtDNA tRNA Leu, tRNA l,e, tRNA
PEO Autosomal dominant None Unknown nuclear gene
PEO Autosomal dominant Multiple mtDNA deletions Chromosome 10q23.3-24.3
Chromosome 3p 14.1 -21.4
ARCO Autosomal recessive Multiple mtDNA deletions Unknown nuclear gene
MERRF Maternal Point mutations of mtDNA tRNA Lys, tRNA Ser, tRNA Leu
MERRF Autosomal dominant Multiple mtDNA deletions Unknown nuclear gene
MELAS Maternal Point mutations of mtDNA tRNA Leu, tRNA ^ tRNA c r s , ND5, COX III
MNGIE Autosomal recessive Multiple mtDNA deletions Chromosome 22q 13.32-qter/thymidine
phosphorylase
Leigh's syndrome/NARP Maternal Point mutations of mtDNA ATPase 6, tRNA Val
Leigh's syndrome Maternal Point mutations of mtDNA tRNA Lys , tRNA Val
Leigh's syndrome Sporadic Single large deletions of mtDNA Large area of mt genome
Leigh's syndrome X-linked None El (subunit of the PDH complex
Recurrent myoglobinuria Maternal Point mutations of mtDNA tRNA Phe
Recurrent myoglobinuria Autosomal recessive Multiple mtDNA deletions Unknown nuclear gene
Fatal and benign infantile Autosomal recessive mtDNA depletion Unknown nuclear gene
myopathies
mtDNA: mitochondrial DNA; PEO: progressive external ophthalmoplegia;ARCO: autosomal recessive cardiopathy and ophthalmoplegia; MERRF: myoclonic epilepsy
and ragged red fibers; MELAS: mitochondrial encephalopathy lactic acidosis and strokes; MNGIE: myo-neuro-gastrointestional-encephalopathy; mt: mitochondrial;
NARP: neuropathy, ataxia, and retinitis pigmentosa
A mutation in a mitochondrial tRNA gene can impair the proper by mtDNA; and complex V (ATPase synthetase) is composed of
translation of the 13 mitochondrial mRNAs. Importantly, the 13 14 subunits, two encoded by mtDNA (Table 27-10).
proteins encoded by the mitochondrial genome account for less
than 5% of mitochondrial proteins. Thus, the majority of mito- GENETICS OF MITOCHONDRIAL DISORDERS
chondrial proteins are encoded by nuclear DNA and these pro-
teins are translated in the cytoplasm and subsequently are Population-based studies in northern England determined
transported into the mitochondria. Further, there appears to be that 6.57 per 100,000 adults have a mitochondrial disease and
some nuclear control of replication of the mitochondrial 12.48 per 100,000 of children and adults are at risk for develop-
genome. The respiratory chain is composed of five multienzyme ing a mitochondrial disorder on the basis of indentifiable
complexes (complexes I to V). Complex 1 (NADH-CoQ reduc- mtDNA mutations.171 During fertilization, all mitochondria are i
tase) is composed of 41 subunits, seven encoded by mtDNA; contributed by the mother. Hundreds of mitochondria are pre- |
complex II (succinate dehydrogenase-CoQ reductase) is com- sent in each cell in the body, and every mitochondria has several
posed of four subunits, each encoded nuclear; complex III copies of mtDNA. Mutations in mtDNA are more common and
(CoQH 2 -cytochrome C reductase) is composed of 11 polypep- more likely to manifest clinically than mutations in nuclear
tide units, one of which is encoded by mtDNA; complex IV (cy- genes because of the lack of introns and decreased DNA repair
tochrome C oxidase) is composed of 13 subunits, three encoded mechanisms involving the mitochondrial genome. Mutations af-
fecting mtDNA are passed on randomly to subsequent genera-
tions of somatic cells during mitosis and germ cells during
TABLE 27-10. Composition and Genetic Control of the meiosis (Fig. 27-37). Therefore, some cells will have few or no
Mitochondrial Respiratory Chain mutant genomes (normal homoplasty), some will have a mix-
Respiratory Polypeptides ture of mutant and normal or wild-type mitochondrial DNA
Chain Complex Total Number mtDNA Encoded
(heteroplasty), and some will have predominantly mutant
genomes (mutant homoplasty). Phenotypic expression is de-
1 41 7 pendent on the relative proportion of mutant and wild-type mi-
II 4 0 tochondria within each cell. When the number of mutated
III 11 1
mitochondria are above a certain threshold, impairment of mito-
chondrial function arises and clinical symptoms may manifest
IV 13 3 (threshold affect). During mitosis and meiosis, the proportion
V 14 2 of mutant mitochondria in daughter cells can shift, thus chang-
Modified from Zeviani M, Bonilla E, DeVivo DC, DiMauro S: Mitochondrial dis- ing the genotype and possibly the phenotype (mitotic/meiotic
eases. Neurol Clin 1989;7:123-156, with permission. segregation). Through a process called complementation,
nearby mutated mitochondria may utilize the mitochondrial-en-
coded mRNAs and tRNAs from neighboring normal mitochon-
dria. Thus, there can be some degree of translation of
mtDNA-encoded proteins even in mitochondria harboring large
DNA deletions. Different organs manifest varying susceptibility
for mitochondrial abnormalities depending on their energy re-
quirements. The CNS is in constant demand for energy; thus, a
small decrease in energy can be detrimental. On the other hand,
skeletal muscle has low energy demands at rest, but these de-
mands drastically increase with exercise.
It should be apparent from the above discussion that primary
mutations of mtDNA can be inherited only from the mother
(e.g., MERRF, MELAS; see below). Unlike X-linked disorders
that are also passed on from the mother, females and males
should be equally affected in mitochondrial-inherited diseases.
In addition, dependent on the degree of mitochondrial segrega-
tion and heteroplasty, all or none of the children of an affected
mother may be affected. This is distinctly different from the in-
heritance patters of autosomal dominant and recessive disor-
ders. Further, the distribution of mutant mitochondria can differ Figure 27-37. Mitotic segregation of mitochondria. Most if not
between individuals patients even in the same kinship, which all of the mitochondria in a fertilized egg are inherited from the
can account for the variable clinical phenotype and severity. mother. During mitosis, the proportion of normal (wild-type) and ab-
It is important to understand that inheritance of mitochondr- normal mitochondria in different cells and ultimately different organ
ial disorders is not strictly maternal. As over 95% of mitochon- systems can vary (mitotic segregation). Phenotypic expression of the
drial proteins are encoded from nuclear genes, it should be no mitochondrial D N A mutation arises when the relative proportion of
surprise that mitochondrial disorders can have autosomal domi- mutant to wild-type mitochondria reaches a certain threshold (i.e.,
nant (e.g., some forms of progressive external ophthalmople- threshold effect), which varies from tissue to tissue. (From DiMauro S,
gia—PEO), autosomal recessive (e.g., MNGIE syndrome), and Bonilla E, Lombes A, et al: Mitochondrial encephalomyopathies. Neurol
even X-linked (e.g., some forms of Leigh's syndrome) patterns Clin 1990;8:483-506, with permission.)
of inheritance. In addition, the presence of a mutation involving
mtDNA does not imply a maternal/mitochondrial inheritance
pattern. Keam-Sayres syndrome (see below) is associated with of abnormal mitochondria stains red and gives the abnormal
large mtDNA deletions but is sporadic in nature. Further, be- muscle fibers their characteristic appearance (ragged red
cause there appears to be some nuclear control over the mito- fibers). Oxidative enzyme stains (NADH, SDH, and COX) are
chondrial genome, mutations in nuclear genes may result in also routinely utilized to diagnose mitochondrial myopathies.
syndromes associated with depletion or multiple deletions of The ragged red fibers and small arteries intensely react to NADH
mtDNA (see below). 993 These disorders can demonstrate auto- and SDH stains. However, some patients have normal trichrome,
somal recessive or dominant inheritance patterns even though NADH, and SDH staining. COX stain is more sensitive and
there are gross abnormalities of the mitochondrial genome. demonstrates scattered unstained muscle fibers (Fig. 27-38) in
As will be apparent in the discussion of the specific mito- addition to normal or hyperintense reactivity in other fibers. The
chondrial disorders, there can be significant genetic hetero- COX-negative fibers are seen in both ragged red and otherwise
geneity even within well-defined clinical syndromes. For normal appearing fibers. The variability of COX staining in
example, progressive external ophthalmoplegia (PEO) can be
associated with multiple mtDNA deletions, point mutations in
various mitochondrial tRNA genes, or have no mitochondrial
DNA mutations. In addition, there can be clinical heterogene-
ity in the manifestations of specific mtDNA. For example, point
mutations in the mitochondrial tRNALeu can result in MELAS,
PEO, encephalomyopathy, or a generalized myopathy. Vari-
ability in clinical phenotype can also be apparent within fami-
lies with identical mtDNA mutations. The vast clinical and
genetic heterogeneity of the various mitochondrial disorders
can be explained by the different segregation patterns of mutant
mitochondria, the degree of mutant heteroplasty, tissue-specific
thresholds, and the severity of the biochemical impairment re-
lated to the specific mutations.
HISTOPATHOLOGY
The histopathologic abnormalities on muscle biopsies of the
various mitochondrial myopathies are non-specific.247-248-688-689 Figure 27-38. Mitochondrial myopathy. A muscle biopsy in a pa-
Mitochondrial abnormalities are reflected on the modified tient with MERRF demonstrates an variable reactivity to COX stain
Gomori trichrome stain in which subsarcolemmal accumulation with numerous COX-negative fibers.
variability of COX staining reflects the heteroplasmic population
of mutant and wild-type mitochondria. Ultrastructural alterations
in mitochondria are apparent on EM. These abnormalities in-
clude an increased numbers of normal appearing mitochondria,
enlarged mitochondria with abnormal cristae, and mitochondria
with paracrystalline inclusions (Fig. 27-39).
ELECTROPHYSIOLOGIC FINDINGS
The electrodiagnostic findings are not specific and do not
help distinguish one mitochondrial myopathy from another.
Unfortunately, many of the descriptions of nerve conduction
studies and electromyography occurred prior to the better mole-
cular characterization of these disorders. Patients with symp-
toms of exercise intolerance and normal or only mild weakness
can have completely normal nerve conduction and needle elec-
Figure 27-39. Mitochondrial myopathy. Electron microscopy of a tromyographic studies.686-687-7212'869 CMAP decrement on repetitive
patient with chronic progressive ophthalmoplegia demonstrates abnor- stimulation has not been appreciated in the mitochondrial my-
mally shaped mitochondria that contain paracrystalline inclusions and opathies. This is an important observation in those persons with
aberrant mitochondrial cristae. (Courtesy of Dr. Kathleen Kagan-Hallet) ptosis and facial weakness in whom a neuromuscular junction
disorder is suspected. Some individuals with mitochondrial dis-
ease can have evidence of a peripheral neuropathy, myopathy,
combination with intense SDH staining is characteristic of disor- or both on electrophysiologic studies. 165 - 256 - 496 ^^
ders with mtDNA mutations. Remember, succinate dehydroge- Spontaneous activity in the form of positive sharp waves, fib-
nase (SDH) of complex II is entirely encoded by nuclear DNA, rillation potentials, and complex repetitive discharges is not a
whereas 3 of 13 subunits of complex IV (COX) are encoded by common finding, but has been reported. 465 Single-fiber elec-
mtDNA. Mutations in mitochondrial DNA lead to a proliferation tromyography may reveal mild elevations in jitter and fiber
of mitochondria, perhaps in a compensatory response. Because density or be completely normal.165-309535 When abnormalities
SDH is encoded by nuclear DNA, its transcription is generally are detected, this suggests that there is some degree of motor
increased in disorders characterized by mtDNA mutations. The unit remodeling occurring even if abnormal spontaneous ac-
tivity is not appreciated, thus indicating a slowly progressive
Table 27-11. Mitochrondrial Myopathies: Clinical Features process.
Where electrodiagnostic findings are detailed in the specific
Features KSS MERRF MELAS mitochondrial myopathies, they are discussed in the relevant
Ophthalmoplegia + sections.
Retinal degeneration - -
-
-
SPECIFIC MITOCHONDRIAL MYOPATHIES (TABLE 27-9)
Heart block + _
CSF protein > 100 mg/dl + - - Myoclonic Epilepsy and Ragged Red Fibers (MERRF)
Myoclonus - + - Clinical Features. The complete spectrum of MERRF in-
Ataxia + + - cludes myoclonus, generalized seizures (myoclonic and tonic-
Weakness + + + clonic), ataxia, dementia, sensorineural hearing loss, optic
atrophy, as well as muscular weakness and atrophy (Table 27-
Seizures - + + Weakness and atrophy can be gen-
n),3oo.349.35i.352.589.759.869.948.io5i
Dementia + + eralized, but is usually more prominent in limb-girdle muscles.

Short stature + + + Some patients also have evidence of a generalized sensorimotor
polyneuropathy and pes cavus. Not all patients manifest the full
Episodic vomiting - - + expression of the disease, which probably is a reflection of the
Cortical blindness - - + percentage of abnormal mitochondria that segregated into the
Hemiparesis, hemianopia - - + respective tissues. Onset can be in childhood to adult life, and
Sensorineural hearing loss + + + can vary even within families. The course and severity are often
progressive but likewise can be variable. The myoclonus is
Lactic acidosis + + + stimulus-sensitive but can be present at rest. The seizures may
Positive family history - + + be photosensitive. Patients are often misdiagnosed as having ju-
Ragged-red fibers + + + venile myoclonic epilepsy until other signs or symptoms (e.g.,
weakness, ataxia) become apparent. Ptosis, ophthalmoparesis,
Spongy degeneration + + + and retinitis pigmentosa are not usually present. Cardiomy-
KSS = Kerns-Sayre syndrome; MERRF = myoclonus epilepsy with ragged-red opathy manifested by conduction block and heart failure can
fibers; MELAS = mitochondrial encephalopathy, myopathy, lactic acidosis, and also develop, especially patients with early disease onset. 759
stroke-like episodes; CSF = cerebrospinal fluid; large boldface plus and minus
signs highlight positive and negative differential features. Multiple symmetric lipomatosis has been described in a few pa-
From DiMauro S.Tonin P, Servidei S: Metabolic myopathies. In Rowland LP, tients.558-702 Patients with MERRF can develop life-threatening
DiMauro S (eds): Handbook of Clinical Neurology, Vol 18(62): Myopathies. hypoventilation in relation to surgery, sedation, or intercurrent
Amsterdam, Elsevier Science Publishers BV, 1992, pp 479-526, with permission. infection.314
Laboratory Features. Serum CK can be normal or mildly There is overlap with MERRF, in that myoclonus, seizures, or
elevated. Serum lactate also is often elevated. Electro- ataxia are evident in most patients. In contrast, features of
encephalography (EEG) may demonstrate generalized slowing Kearns-Sayre syndrome (e.g., ptosis, ophthalmoparesis, pig-
of the background activity as well as bursts of spikes and slow mentary retinopathy, cardiomyopathy) occur in less than 10%
waves. MRI or CT scan of the brain reveals cerebral and cere- of patients. Rare patients manifest with only diabetes mellitus
bellar atrophy. and/or deafness.
Histopathology. Muscle histopathology is as described Laboratory Features. Serum CK may be normal or ele-
above. Autopsies demonstrate neuronal loss and gliosis of den- vated. Lactate levels are elevated in the serum and CSF in the
tate nuclei, globus pallidus, red nuclei, substancia nigra, inferior majority of patients. Cortical atrophy and focal low-signal ab-
olivary nuclei, optic nerves, and the cerebellar cortex. 352 De- normalities are evident on CT and MRI scans of the brain.
myelination and gliosis are apparent in the spinothalamic tracts, Abnormal calcium deposition may be seen in the basal ganglia.
posterior columns, and cortical spinal tracts. Spike and slow wave activity may be appreciated on the EEG.
Molecular Genetics and Pathogenesis. There is non- Histopathology. Muscle biopsies are indistinguishable from
mendelian maternal inheritance of MERRF. Approximately other mitochondrial myopathies as described above. These
80% of affected patients have a point mutation at nucleotide po- ragged red fibers have variable COX staining, ranging from in-
sition 8344 of the mitochondrial genome resulting in an A to G creased reactivity to absent staining. This variability in COX
transition in the tRNA Lys gene. 413 941948 Other mutations in this staining is more prominent than that seen in MERRF. Arterioles
gene (positions 8356 and 8366), in the tRNA Leu gene (the gene are strongly SDH-reactive, and an increased number of mito-
most commonly mutated in MELAS; see below), and in the chondria are evident in muscular walls of small blood vessels.
gene for tRNA Ser also have been reported in patients with Defects in complex I, III, IV, and V activities have been demon-
MERRF.927 MERRF may also arise secondary to multiple mito- strated in muscle specimens.
chondrial DNA deletions.92 Of note, there is clinical heterogene- Molecular Genetics and Pathogenesis. MELAS is inher-
ity in patients with the common tRNALys mutations, as they can ited maternally in a non-mendelian pattern. Over 70% of cases
also manifest with PEO, Leigh's syndrome, or multiple sym- are caused by a mtDNA mutation, an A to G substitution, in the
metric lipomatosis.352-702 As described above, the mitochondrial gene encoding for tRNA Leu at nucleotide position 3243. 380
tRNA gene mutations impair the translation of mitochondrial Mutations have also been identified at positions 3252, 3260,
DNA-encoded respiratory chain proteins. Decreased activity of 3271, 3291 of the gene for tRNALeu as well as in the genes for
complex I and IV have been demonstrated. Expression of the tRNAVal, tRNA Cys , ND5 of complex 1, and in cytochrome B of
abnormal phenotype is believed to require that at least 90% of complex III.927 Besides the genetic heterogeneity of MELAS,
the mitochondria harbor mutations. 1135 Mutations can be there is phenotypic heterogeneity even in patients and within
demonstrated by polymerase chain reaction of mtDNA in leuko- families who carry the common 3243 mutation. Mutant mtDNA
cytes or muscle specimens, but the frequency of abnormal in cerebral blood vessels may be responsible for the stroke-like
mtDNA is greater in muscle. episodes secondary to impaired energy production in metaboli-
Electrophysiologic Findings. Decreased amplitudes of sen- cally active regions of the brain.
sory nerve action potentials consistent with a superimposed ax- Electrophysiologic Findings. Nerve conduction studies are
onopathy can be seen in some patients.300-672-796 Electromyography usually normal. 193 Electromyography may be normal or show
is typically normal, although small MUAPs with early recruit- myopathic MUAPs in patients with severe myopathic weakness.
ment can be present in advanced cases. Treatment. There is no specific therapy except for treatment
Treatment. There is no specific therapy for MERRF other of seizures and myoclonus. Treatment with coenzyme Q does
than treating the myoclonus (e.g., clonazepam) and the seizures not result in significant improvement. A small study reported
with antiepileptic medications (e.g., Depakote). A few patients some benefit with dichloroacetate, 886 but this has not been re-
with MERRF with short courses of creatine monohydrate (5-10 produced in a large, blinded, controlled study. Modest improve-
gm/day) apparently had slight benefit.1005 1006 Physicians need to ment in strength has been reported in a small number of patients
be aware that patients with mitochondrial myopathies can be with MELAS treated with short courses of creatine monohy-
very sensitive to sedating medications and anesthetic agents and drate (5-10 gm/day).1005-,0°6
can develop alveolar hypoventilation.314
Kearns-Sayre Syndrome (KSS)
Mitochondrial Myopathy Lactic Acidosis Clinical Features. KSS is characterized by the clinical
and Strokes (MELAS) triad of PEO, retinitis pigmentosa, and heart block with
Clinical Features. As the acronym implies, MELAS is char- onset usually before the age of 20 years (Table 27-
acterized by biochemical or morphologic evidence of mitochon- j 77.45i.547.68o.ii47 iviild proximal limb weakness can be seen.
drial abnormalities, high lactate levels in the serum or CSF, and Other abnormalities that may also be present include short
stroke-like episodes (Table 27-1 1 ).174-193-380-383-689-781 Onset occurs stature, sensorineural hearing loss, dementia, ataxia, de-
in the first year in less than 10% and before the age of 15 years pressed ventilatory drive, and multiple endocrinopathies
in 60-80% of patients.174-383 However, rare cases with onset as (e.g., diabetes mellitus, hypothyroidism, hypoparathy-
late as in the eighth decade have been reported.193 Most patients roidism, delayed secondary sexual characteristics). Affected
present with recurrent stroke-like episodes manifesting as mi- patients can develop hypoventilation in response to seda-
graine-type headaches with nausea and vomiting, hemiparesis, tives and anesthetic agents. 58158 Severe dysphagia due to
hemianopsia, or cortical blindness. These attacks may be pro- cricopharyngeal achalasia appears common. 5343
voked by exercise or intercurrent infection. Some patients de- Laboratory Features. Serum CK level is typically nor-
velop progressive dementia after repeated attacks. Proximal mal; however, lactate and pyruvate levels may be elevated.
muscle weakness is present in the majority of patients along CSF protein is usually increased. The EKG reveals conduc-
with exercise intolerance. Many patients are short-statured. tion defects.
Histopathology. Muscle biopsies demonstrate ragged red Histopathology. Muscle pathology is indistinguishable
fibers on Gomori trichrome stain. In contrast to MERRF and from KSS.
MELAS, there is little variability of COX staining, with most of Molecular Genetics and Pathogenesis. Some sporadic pa-
the ragged red fibers lacking COX reactivity.382 The number of tients with PEO have single large mtDNA deletions indistin-
ragged red fibers and COX-negative fibers correlated with the guishable from those seen in KSS.382-451-547-680-1147 Thus, as noted
percentage of mitochondria with large deletions. Autopsy may above, these patients could represent partial expressions of
reveal spongy degeneration of the cerebral white matter. KSS. Importantly, these deletions are believed to be sporadic in
Molecular Genetics and Pathogenesis. Single large mtDNA occurrence and not inheritable. Also, point mutations have been
deletions of varying sizes (ranging from 1.3 kB to 8.8 kB) can be demonstrated within various mitochondrial tRNAs (Leu, He,
demonstrated in most patients with KSS.382-451-680-1147 Twenty-three Asn, Tip) genes in several kinships with maternal inheritance of
to 43% of patients have a characteristic 4.9-kB deletion, suggesting PEO. 926 In addition, multiple mtDNA deletions have been de-
there may be "hot spots" in the mitochondrial genome for these scribed in a few kinships with autosomal dominant inheri-
large deletions. The percentage of affected mitochondrial genomes tance.547-926 The molecular defects are suspected to lie in nuclear
in muscle biopsies ranges from 20% to 90%.680 Mitochondrial dis- genes involved in regulating the mitochondrial genome.
orders with single large deletions need to be differentiated from dis- Autosomal dominant PEO appears to be genetically heteroge-
orders with multiple deletions (see below). Mitochondrial DNA neous, because the disorder has been localized to chromosome
deletions may be present in leukocytes and other tissues, but the 10q23.3-q24.3 in some kinships and in other families to chro-
sensitivity is much lower than that demonstrated in muscle. The mosome 3ql4.1-21.4. 508
large deletions usually involve several tRNA genes, thus impairing Electrophysiologic Findings. Nerve conductions are usu-
the adequate translation of mtDNA-encoded proteins. The single- ally normal but may reveal low-amplitude SNAPs.547-796 Electro-
deletion mutations are usually sporadic in nature, although rare myography can demonstrate a mixture of small and large
cases with familial occurrences have been reported.451-760 polyphasic MUAPs.
There is clinical heterogeneity in patients who exhibit these Treatment. No specific medical therapy is available.
single large mtDNA mutations. Besides KSS, these single large Surgery to correct ptosis may help as in KSS. Similar to KSS,
deletions have been demonstrated in some patients with mi- patients and their physicians need to be made aware of the po-
grainous strokes without PEO and otherwise typical KSS with tential for respiratory insufficiency and decreased ventilatory
strokes (possible MELAS overlap), PEO (with or without limb drive in relation to CNS depressants, surgery, and intercurrent
weakness, retinopathy, or deafness), encephalopathy without infections.58158
PEO, Leigh's syndrome, maternally inherited diabetes mellitus
and deafness, and Pearson's syndrome. 689 Autosomal Recessive Cardiomyopathy and
Electrophysiologic Findings. Nerve conduction studies are Ophthalmoplegia (ARCO)
usually normal, although findings suggestive of an axonal sen- Clinical Features. Six patients from two unrelated families
sory or sensorimotor polyneuropathy have been described.547-796 have been reported with this novel syndrome characterized by
Electromyography can be normal or demonstrate a mixture of childhood-onset PEO, facial and proximal limb weakness, and a
small and large polyphasic MUAPs. Usually insertional and fatal cardiomyopathy. 96162 The cardiomyopathy and autosomal
spontaneous activity is normal. recessive inheritance distinguish this myopathy from the above-
Treatment. There is no proven benefit of any medical ther- described autosomal dominant and maternally inherited PEO.
apy, other than hormone replacement for specific en- The reported patients had no evidence of pigmentary retinopa-
docrinopathies. Pacemaker insertion may be required because thy, hearing loss, ataxia, or peripheral neuropathy, although
of the associated cardiac conduction defects. Eyelid surgery to deep tendon reflexes were reduced. Patients frequently com-
correct ptosis can be performed provided there is sufficient plained of chest pain and palpitations secondary to severe di-
facial strength to allow full eye closure. Patients and their physi- lated cardiomyopathy.
cians need to be made aware of the extreme sensitivity to CNS Laboratory Features. Serum CK levels are mildly elevated.
depressants and potential for decreased respiratory drive.58158 Serum lactate can be normal at rest but increases excessively
during exercise. The EKG can reveal cardiac conduction de-
Progressive External Ophthalmoplegia (PEO) fects. Echocardiogram usually reveals a severe dilated car-
Clinical Features. Patients with PEO have ptosis and oph- diomyopathy with reduced ejection fractions.
thalmoparesis with or without limb weakness, but they lack pig- Histopathology. Muscle biopsies reveal ragged red fibers
mentary retinopathy, cardiac conduction defects, or other that are strongly reactive to SDH and are COX-negative. 96162
systemic manifestations (e.g., endocrinopathies).382-451-547-680-795 However, there are also many COX-negative fibers that do not
Some presentations probably represent a forme fruste of KSS, co-localize to ragged red and SDH-positive fibers. Biochemical
because they are sporadic and can be associated with single large assay demonstrates decreased activity of respiratory chain en-
deletions of mtDNA. However, this is a very heterogeneous dis- zymes containing mtDNA-encoded subunits, sparing the en-
order. There are autosomal dominant and maternally inherited tirely nuclear-encoded SDH and citrate synthetase.
forms of PEO that are genetically distinguished from the spo- Molecular Genetics. Multiple mtDNA deletions have been
radic subtype (see below). Patients with PEO can develop hy- demonstrated. The defect is suspected to lie in nuclear genes in-
poventilation in response to sedatives and anesthetic agents.58158 volved in regulating the mitochondrial genome.
Patients with PEO due to mtDNA deletions often complain of Electrophysiologic Findings. Motor and sensory nerve con-
dysphagia as a result of cricopharyngeal achalasia.534" duction studies are normal. Electromyography reveals "myo-
Laboratory Features. Serum CK, serum lactate, and CSF pathic" MUAPs. 96
lactate can be normal or elevated. CSF protein may be in- Treatment. Many patients will die of the severe cardiomy-
creased. In contrast to classic KSS, the EKG does not demon- opathy within the first two decades of life, unless they receive
strate cardiac conduction defects. cardiac transplantation.
Mitochondrial DNA Depletion Syndromes Treatment. No specific medical therapy has been demon-
Clinical Features. The severity of muscle weakness in this strated to be effective.
syndrome can vary. There is a severe early-onset form, termed
fatal infantile myopathy by some authors, that begins at birth Focal Mitochondrial Depletion
or shortly afterwards and is characterized by generalized hypo- Clinical Features. This disorder is distinguished from the
tonia and weakness. 2426591046104710681147 Skeletal muscle weak- above-described mtDNA depletion syndrome by the normal
ness may be associated with a cardiomyopathy or De quantity of mitochondrial DNA. There is significant clinical
Toni-Fanconi-Debre syndrome, a renal tubular defect. A few in- heterogeneity of the disorder. Genge et al reported three patients
fants have seizures or liver failure. Progressive generalized (two of them siblings) with exertional muscle pain and fatigue
proximal greater than distal muscle weakness is apparent on ex- beginning in the second decade of life.367 One patient gave a his-
amination. Some patients develop ptosis and ophthalmoplegia. tory of pigmenturia. Mild proximal weakness was evident in the
A peripheral neuropathy is evident on examination in some af- two related patients. Nishino and colleagues reported four pa-
fected individuals, but this is usually subclinical. Deep tendon tients from three unrelated families with congenital onset of
reflexes are diminished or absent. Weakness is progressive, generalized weakness and hypotonia as well as mental retarda-
leading to feeding difficulties, respiratory failure, and death tion.732 Motor milestones were delayed, but patients eventually
usually within the first year of life. Most of these infants die were able to ambulate.
within the first year of life. Laboratory Features. Serum CK levels are mild to moder-
There is also a benign infantile myopathy that early on can ately elevated. Serum lactate levels are normal. Decreased sele-
resemble the fatal form of myopathy.150-244104710891146 Patients nium levels were described in one patient.732
can develop symptoms shortly after birth or later in childhood. Histopathology. The most striking histologic feature is
Infants can have severe hypotonia, weakness, and respiratory focal depletion of mitochondria in the center of the sar-
and feeding difficulties. Although weakness may be so severe as coplasm in type 2 muscle fibers. At the periphery of muscle
to require ventilatory assistance, these infants demonstrate im- fibers, the mitochondria are enlarged. Scattered degenerating
provement in their strength during the first year of life. Motor and regenerating fibers can be appreciated. Immunostaining for
milestones may be delayed but are usually attained, and occa- dystrophin, adhalin, merosin, and (3-dystroglycan are normal.
sionally children can appear normal by age 2 or 3 years. Molecular Genetics and Pathogenesis. Presumably the dis-
Affected individuals can have a normal life expectancy, but order can be inherited in an autosomal recessive fashion. No
some die in the first two decades of life. In contrast to the fatal molecular or quantitative defects of mtDNA have been reported
infantile form, patients with the benign infantile myopathy usu- in patients with this syndrome. Similar histologic findings have
ally do not have a renal tubular defect. been demonstrated in patients with myopathy believed to be re-
Laboratory Features. Serum CK can be normal or elevated lated to selenium deficiency.757
(up to 30 times normal).643-1089'1090 Serum lactate levels may also Electrophysiologic Findings. Routine nerve conduction
be elevated. The associated renal tubular defect results in studies are normal. Electromyography has demonstrated small
glyosuria, proteinuria, and aminoaciduria. MRI of the brain polyphasic MUAPs in some but not in all patients.367
may reveal cerebral atrophy and patchy areas of hypomyelina- Treatment. There is no specific medical therapy. A trial of
tion of subcortical white matter.1089 selenium replacement should be considered in patients who are
Histopathology. Muscle biopsies demonstrate ragged red deficient in selenium.
fibers, foci of intense NADH and SDH staining, and many
COX-negative fibers.6431501046-1047-1089 An increased number of Mitochondrial Neurogastointestinal
lipid droplets are also evident. EM shows enlarged mitochon- Encephalomyopathy (MNGIE)
dria, some with concentric or whorled cristae, dense bodies, or Clinical Features. MNGIE, also referred to as POLIP syn-
paracrystalline inclusions. Biochemical assay of COX activity drome (polyneuropathy, ophthalmoplegia, leukoencephalopathy,
in skeletal muscle tissue of affected patients is greatly dimin- and intestinal pseudo-obstruction), is an autosomal recessive mito-
ished or absent. chondrial disorder.56-442*734-949 As the acronyms imply, the disorder is
Molecular Genetics and Pathogenesis. Inheritance of this associated with a sensorimotor polyneuropathy, leukoencephalopa-
disorder is autosomal recessive. A quantitative defect in mtDNA thy on MRI of the brain, ragged red fibers on muscle biopsy, and
was first described by Moraes et al in 1991. 681 Subsequently, chronic intestinal pseudo-obstructions. Patients exhibit generalized
there have been several other reports confirming mtDNA de- muscle weakness and atrophy that are more prominent distally.
pletion.,50-333-62710191°47-1089 One or more mutations of nuclear Sensory loss is also apparent in a stocking-glove distribution, and
genes important in regulating the mitochondrial genome are be- deep tendon reflexes are reduced throughout. Despite the leukoen-
lieved to be responsible for mitochondrial DNA depletion. The cephalopathy apparent on MRI and on autopsies, most affected pa-
severity of the depletion correlates with the clinical severity of tients have no obvious intellectual impairment or other CNS
the disorder. As much as a 99% reduction in mtDNA is present symptoms, However, rare patients with mental retardation and
in the fatal infantile myopathy form of the disease, while the ataxia have been reported. Ophthalmoparesis and ptosis are evident
more benign myopathy has been demonstrated to have a smaller in most cases. Some have retinal pigmentary degeneration, sen-
depletion (36-88%) of mtDNA. sorineural hearing loss, facial weakness, hoarseness, or dysarthria.
Electrophysiologic Findings. Electromyography may The earliest and most consistent symptoms are referable to gas-
demonstrate numerous fibrillation potentials and positive sharp trointestinal dysmotility and include dyspepsia, bloating, eructa-
waves at rest.1047 Motor units can have a mixed myopathic and tions, cramps, intolerance of large meals, and episodic nausea,
neuropathic appearance.1047-1089 In some patients, electromyog- vomiting, and diarrhea. Onset of symptoms begins before the age
raphy has been reported as normal. Nerve conduction studies of 20 years in the majority of patients (mean 13.9 years, range
can be normal or reveal features of a axonal or sometimes de- 2.5-32 years).442 The course is progressive with severe disability or
myelinating sensorimotor neuropathy.1089 death by the third or fourth decade of life.
Laboratory Features. Serum CK can be normal or mildly of the pyruvate dehydrogenase (PDH), pyruvate decarboxylase
elevated. Lactate, pyruvate, and CSF protein levels are typically (PDC), COX, and complex I have been described in some pa-
elevated. MRI of the brain demonstrates leukoencephalopathy tients with Leigh's syndrome. MRI demonstrates symmetric le-
of the cerebral and cerebellar white matter. Radiologic studies sions in the thalamus, brain stem, cerebellum, and spinal cord,
also demonstrate dilatation and dysmotility of the esophagus, reflecting the underlying pathology.
stomach, and small intestine. EKG has shown right bundle Histopathology. COX stain demonstrates decreased or
branch block in a few patients, although cardiac symptoms have absent staining of muscle fibers, while ragged red fibers are
not been described. usually not seen. A decrease in mitochondrial and nuclear-en-
Histopathology. Muscle biopsies demonstrate ragged red coded COX subunits, without a specific defect in any one of
fibers, fibers with increased NADH and SDH staining, and them, has been demonstrated. 590 Unlike fatal infantile myopa-
muscle fibers with deficient COX staining. 442 Evidence of neu- thy, COX staining is also deficient in muscle spindles and in the
rogenic atrophy has been noted on biopsies of distal muscles. smooth muscle of intramuscular blood vessels. Autopsy studies
Nerve biopsies have shown loss of myelinated nerve fibers, de- of the brain demonstrate symmetric cystic necrosis, s p o n g i -
myelination/remyelination, and rare onion bulb formation, in form changes, demyelination, and vascular proliferation in the
addition to features of axonal degeneration. Abnormal mito- thalamus, basal ganglia, brain stem, cerebellar white matter,
chondria with paracrystalline inclusions have been demon- dentate nuclei, and posterior columns of spinal cord.
strated in muscle fibers and Schwann cells. Diminished COX Molecular Genetics and Pathogenesis. Leigh's syndrome
and other respiratory complex activities have been described in is a genetically heterogeneic disorder. Various mutations in the
enzymatic assays of muscle tissue. 442 Autopsies have revealed mitochondrial ATPase 6 gene has been demonstrated in ma-
widespread endoneurial fibrosis and demyelination in the pe- ternally inherited cases of Leigh's syndrome.927-942 Of note, mu-
ripheral nervous system, possibly secondary to axonal atrophy, tations in this gene are also responsible for the mitochondrial
and poorly defined white matter changes in the cerebral and disorder termed NARP (neuropathy, ataxia, and retinitis pig-
cerebellar white matter.949 Cranial nerves and spinal roots are mentosa). When the proportion of mutated mitochondrial DNA
less severely involved. Neurons of the brain stem and spinal is high (> 90%), Leigh's syndrome occurs; but NARP develops
cord are relatively intact. In addition, there is loss of neurons when the burden of mitochondrial DNA mutations is lower.
and fibrotic changes of the autonomic ganglia and of the celiac, Less commonly, point mutations have been reported in tRNA Lys
myenteric, and Auerbach plexuses.949 and tRNA^ 1 . 168 997 Single large deletions of mtDNA have also
Molecular Genetics and Pathogenesis. Multiple mtDNA been demonstrated.1129 Mutations in the gene encoding for El a
deletions similar to those found in some cases of autosomal subunit of the pyruvate dehydrogenase complex that is located
dominant PEO have been demonstrated in some patients with on the X-chromosome have been found in several cases of X-
autosomal recessive MNGIE.442-733-734 MNGIE has been local- linked Leigh's syndrome.231-586-624 Some cases of Leigh's are in-
ized to chromosome 22ql3.32-qter, where mutations in the herited in an autosomal recessive fashion, but specific mutations
thymidine phosphorylase gene have been identified.443-733-734 have not yet been identified.
Electrophysiologic Findings. Motor and sensory nerve con- Electrophysiologic Findings. The central nervous system
duction velocities are typically slowed to be within the demyeli- abnormalities overshadow the neuromuscular abnormalities in
nating range.442-949 Likewise, F-waves are markedly prolonged. Leigh's syndrome, and details of electrodiagnostic studies are
CMAP amplitudes are normal or only mildly decreased, while too scant to comment.
SNAP amplitudes are decreased. Electromyography may show Treatment. There is no specific medical therapy available.
a miid increase in spontaneous activity with fibrillation poten-
tials and positive sharp waves.442 Recruitment has been noted to Mitochondrial Myopathies Associated
be decreased, suggestive of denervation. However, quantitative with Recurrent Myoglobinuria
electromyography of proximal muscles reveals small-duration Clinical Features. Recurrent myoglobinuria beginning in
MUAPs suggesting a superimposed myopathic process. infancy or early adulthood can be the only clinical manifesta-
Treatment. No specific medical therapy has been demon- tion of a mitochondrial myopathy. Episodes of myoglobinuria
strated to be beneficial. Patients with severe gastrointestinal can be provoked by exercise and alcohol intake, although
dysmotility may require PEG tube placement or parenteral feed- provocative factors need not be present.
ings for nutritional support. Ankle-foot orthoses may be benefi- Laboratory Features. Serum lactate and pyruvate are
cial in patients with distal lower limb weakness. normal at rest but become significantly elevated with aerobic
activity. Serum CK can be normal or mildly elevated between
Leigh's Syndrome episodes of myoglobinuria.
Clinical Features. Most patients with Leigh's syndrome or Histopathology. Muscle biopsies demonstrate ragged red
subacute necrotizing encephalomyopathy usually present in fibers, increased SDH and NADH stains in scattered fibers, as
infancy or early childhood, but the disorder can rarely develop well as COX-negative fibers. Decreased COX activity has been
in adult life.168-590-689 Affected patients manifest with a variety of found on enzyme analysis of muscle tissue in some902 but not all
abnormalities, including recurrent vomiting, psychomotor retar- cases.753 Abnormal mitochondria with paracrystalline inclusions
dation, hypotonia, generalized weakness and atrophy, ptosis, can be detected on EM.
ophthalmoplegia, poor suck, respiratory failure, nystagmus, Molecular Genetics and Pathogenesis. This is a geneti-
optic atrophy, hearing loss, involuntary movements, seizures, cally heterogeneous group of disorders. Multiple mtDNA dele-
spasticity, ataxia, and peripheral neuropathy. The rate of pro- tions were demonstrated in two brothers with presumed
gression varies but is generally fatal. autosomal recessive inheritance.753 In addition, point mutations
Laboratory Features. Serum and CSF lactate levels are ele- in tRNA Phe have been found in kinships with maternal inheri-
vated, as can be the lactate:pyruvate ratio in some patients. The tance of recurrent myoglobinuria, 170 and microdeletions within
syndrome is biochemically heterogeneous. Defects in activity the gene encoding for COX III have been reported in sporadic
cases. Other cases of exercise intolerance and recurrent myo- Laboratory Evaluation. Serum CK was elevated at 1326
globinuria have been ascribed to mutations in the mtDNA genes IU/L (normal < 220 IU/L). EKG revealed sinus tachycardia and
encoding for subunit 4 of NADH dehydrogenase (ND4) 19 and a primary A-V block. An echocardiogram demonstrated global
cytochrome b. 1718 hypokinesis, a dilated left ventricle, focal wall abnormalities,
Electrophysiologic Findings. There is no description of the and an ejection fraction of 25-30%.
electrodiagnostic findings in these rare patients. Nerve Conduction Studies. Nerve conduction studies are
Treatment. There is no specific medical therapy other than performed in the right upper and lower limbs. The mid-palm
treatment of myoglobinuria and avoidance of strenuous activity temperature is noted to be 32.5°C on the right, while the tem-
and alcohol. perature posterior to the right lateral malleolus is 31.1°C .
Nerve DSL S Amp DML M Amp NCV
Succinate Dehydrogenase (SDH) Deficiency (ms) (pV) (ms) (mV) (m/s)
Clinical Features. Patients with SDH deficiency present R median 3.2 40 3.6 6.0 54.0
with exercise intolerance, myalgias, and myoglobinuria.407 They R ulnar 3.0 25 3.1 6.5 52.0
can develop palpitations and dyspnea with only modest degrees R peroneal 4.4 5.0 46.0
of exercise. During an attack of myoglobinuria, muscles are R sural 3.5 16
swollen, tender, and weak. However, between episodes the neu- Temperature at all recording sites maintained above 33.0°C.
rologic examination is normal. DSL, distal sensory latency; S Amp, sensory amplitude; DML,
Laboratory Features. Serum CK levels are elevated, partic- distal motor latency; M Amp, motor amplitude; NCV, nerve
ularly after exercise. conduction velocity; ms, milliseconds; pV, microvolts; mV, mil-
Histopathology. Muscle biopsies demonstrate ragged red livolts; m/s, meters/second. Motor and sensory amplitudes are
fibers with reduced SDH staining. Biochemical analysis reveals measured baseline to peak. Sensory latencies are measured to
diminished SDH activity. peak, while motor latencies are measured to initial negative
] Molecular Genetics and Pathogenesis. SDH functions to onset.
oxidize succinate in the citric acid cycle and is a component of Needle Electromyography. A needle electromyographic in-
complex II of the respiratory chain. Recall that the all subunits vestigation was performed on the right upper and lower limb
of complex II, including SDH, are nuclear encoded. Mutations using a disposable monopolar needle.
in the gene encoding for SDH have been identified in SDH-defi- Muscle Rest Activity Recruitment
cient patients.105 Deltoidt 3+Fibs/PSW Early
Electrophysiologic Findings. Electromyography may Bicepst 3+Fibs/PSW Early
demonstrate myopathic appearing MUAPs following multiple Extensor digitorum com 3+Fibs/PSW Early
attacks of rhabdomyolysis. First dorsal interosseous 3+Fibs/PSW Early
Treatment. No specific medical therapy is available. Gluteus mediusf 3+Fibs/PSW Early
Patients should be cautioned in regards to exercise. Vastus lateralis! 3+Fibs/PSW Early
Tibialis anteriorf 3+Fibs/PSW Early
Gastrocnemius 3+Fibs/PSW Early
ILLUSTRATIVE CASE Thoracic paraspinals (T 8) 3+Fibs/PSW
t: Quantitative analysis using a trigger-and-delay line revealed
ELECTRODIAGNOSTIC MEDICINE CONSULTATION MUAPs with durations significantly reduced below 20% of that
anticipated for these muscles. The amplitudes were small, and
Reason for Referral. A 24-year-old man was referred by the MUAPs were markedly polyphasic. In addition, there were
the cardiology service for evaluation of persistently elevated a few scattered long-duration polyphasic potentials.
serum creatine kinase (CK) levels (1200-1900 IU/L). The pa-
tient denied weakness, ocular symptoms, myalgias, or history of Summary of Findings
myoglobinuria. His past medical and family history were re- 1. Sensory and motor nerve conduction studies are all within
markable for familial cardiomyopathy (hypertrophic-obstruc- normal limits.
tive). At least 10 family members over four generations were 2. Of significance is the detection of abundant amounts of
affected with a cardiomyopathy leading to death in their teens membrane instability throughout with marked insertional PSWs
or twenties. The patient was diagnosed with a cardiomyopathy (pseudomyotonic discharges).
at the age of 14 years. He complained of increasing dyspnea on 3. MUAP morphology suggested a myopathic process with
exertion and occasional chest pain over the past 5 years. In addi- the frequent short-duration, small-amplitude, polyphasic
tion, he noticed hoarseness for several months. MUAPs that recruited early. The scattered long-duration units
Physical Examination. Neurologic examination was re- also recruited early and most likely reflect the chronicity of the
markable for Medical Research Council (MRC) grade 4 to 4+ disease rather than a superimposed neurogenic process.
strength in proximal and distal limb muscles. His voice was
hoarse. Extraocular, face, jaw, palate, and tongue muscles were Electrodiagnostic Medicine Impression
normal. There was no evidence of percussion or action myoto- This electrodiagnostic study suggests a chronic myopathic
nia in proximal or distal muscles or paramyotonia. Sensation process associated with significant muscle membrane instability.
and coordination were intact. Muscle stretch reflexes were un-
obtainable in the arms and normal in the legs. He had difficulty Clinical Impression
arising form a chair without using his arms to push up. He had a The family history is most suggestive of an autosomal domi-
positive Gower's sign upon trying to arise form the floor. His nant-inherited myopathy associated with cardiopathy. He has
gait was wide-based and waddling, and he had slight foot-drop generalized proximal and distal weakness with possible vocal
bilaterally. cord involvement. This pattern of weakness is not typical of
autosomal dominant Emery-Dreifuss muscular dystrophy or lesion (i.e., anterior horn cell, peripheral nerve, neuromuscular
LGMD IB associated with lamin A/C mutations, cardiopathy, junction) is in doubt despite a detailed examination and labora-
and skeletal muscle weakness. The autosomal dominant history tory work-up. Although the electrodiagnostic abnormalities
rules a dystrophinopathy, sarcoglycanopathy, glycogen, or lipid (e.g., myotonic discharges) may also help narrow down the dif-
storage disease. Occasionally mitochondrial myopathies can ferential diagnosis, many of these abnormalities are non-spe-
manifest in an autosomal dominant fashion and affect the car- cific. Making the specific diagnosis usually requires DNA
diac and skeletal muscle. Despite the "pseudomyotonic" dis- testing or a muscle biopsy with immunohistochemistry, im-
charges on EMG, he does not have clinical myotonia, but this munoblot (Western blot), and metabolic analysis. With the ad-
does not exclude the diagnosis of myotonic dystrophy. vances in molecular genetics, diagnosis will no doubt rely more
Myofibrillar myopathy may manifest with cardiomyopathy, and more on DNA testing than on muscle histopathology and
proximal and/or distal weakness, hoarseness, increased CK, and electrodiagnostic testing. Thus, the electrodiagnostic specialist
is often associated with myotonic or pseudomyotonic dis- as the neuromuscular expert must be able direct the appropriate
charges on EMG. work-up (e.g., ordering the appropriate DNA test) rather than
applying a costly and ineffective shotgun approach. Finally,
Recommendations specialists in electrodiagnostic medicine should have a good un-
1. Left biceps brachii muscle biopsy with tissue sent for rou- derstanding of the pathogenic and genetic basis of these heredi-
tine histochemistry and special immunohistochemistry (to in- tary myopathies.
clude desmin, emerin, lamin A/C, dystrophin, sarcoglycan), a
piece for electronmicroscopy, and specimens for possible ge-
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Chapter 28
Acquired Myopathies
CHAPTER OUTLINE
Idiopathic Inflammatory Myopathies Myopathies Associated with Malignancy
Polymyositis • Dermatomyositis • Overlap Syndromes
• Scleroderma * Sjogren's Syndrome • Systemic Lupus Paraneoplastic Necrotizing Myopathy • Focal Metastatic Lesion
Erythematosus • Rheumatoid Arthritis • Mixed Connective Other Myopathies Secondary to Systemic Disease
Tissue Disease * Inclusion Body Myositis • Infantile Amyloid Myopathy • Critical Illness Myopathy/Acute
Myositis/Congenital Inflammatory Myopathy • Focal Myositis Quadriplegic Myopathy
• Dropped Head Syndrome • Eosinophilic Polymyositis
• Diffuse Fasciitis with Eosinophilia • Granulomatous and Toxic Myopathies
Giant Cell Myositis * Sarcoid Myopathy • Behcet's Disease Necrotizing Myopathies • Drug-Induced Myopathies
• Treatment of Idiopathic Inflammatory Myopathies • Alcoholic Myopathy • Myopathies Secondary to Illicit
Drugs
Myositis Associated with Infections
Viral Infections • Bacterial Infections • Fungal Myositis Focal Muscle Disorders
• Parasitic Infections Injection Injuries • Needle Muscle Injury
• Rhabdomyolysis/Myoglobinuria
Endocrine Myopathies
Thyroid Disorders • Adrenal Disorders • Pituitary Disorders Ill-Defined Disorders
• Diabetes Mellitus Polymyalgia Rheumatica * Fibromyalgia/Myofascial Pain
Syndrome
Myopathies Associated with Electrolyte Imbalance
Disorders of Potassium • Disorders of Calcium • Disorders Illustrative Cases
of Phosphate • Disorders of Magnesium
Progressive Proximal Weakness
In the previous two chapters we reviewed our approach to pa- INFLAMMATORY MYOPATHIES
tients suspected of having a myopathy and the specific hereditary
myopathies. Now we turn our focus to the acquired forms of my- Inflammatory myopathies are a heterogeneous group of disor-
opathy (Table 28-1). In many ways these disorders are more im- ders characterized by muscle weakness, elevated serum creatine
portant to diagnose early because most are treatable. As with kinase (CK) levels, inflammation on muscle biopsy, and electro-
other neuromuscular disorders, the key to early diagnosis and physiologic evidence of muscle membrane instability and fiber
treatment lies in obtaining and performing a good medical history loss. The inflammatory myopathies can be divided into the more
and physical examination followed by ordering the appropriate common idiopathic group with unknown etiology, myositis asso-
laboratory work-up. The electrodiagnostic medicine examination ciated with underlying connective tissue disorders and other in-
is invaluable in localizing the lesion to the muscle, particularly flammatory diseases, and myositis secondary to various
when trying to exclude other neuromuscular disorders (e.g., infections (Table 28-2). The electromyographic abnormalities
myasthenia gravis, Lambert-Eaton syndrome, spinal muscular at- associated with the different forms of inflammatory myopathies
rophy, chronic inflammatory demyelinating polyneuropathy) that are not disease-specific (i.e., electromyography does not differ-
can manifest with symmetric proximal and distal weakness of the entiate polymyositis from dermatomyositis), nor are they spe-
limbs (the most common pattern of weakness seen in the acquired cific for inflammatory myopathies (i.e., electromyography does
myopathies). Needle electromyography is also helpful, in combi- not differentiate inflammatory myopathy from necrotizing toxic
nation with the physical examination, in assessing which muscle myopathies). We begin by focusing on the three major categories
to biopsy, particularly in patients with only mild weakness. of idiopathic inflammatory myopathies: (1) polymyositis (PM),
1371
Table 28-1. Acquired Myopathies and IBM occurring in families, suggesting a possible genetic
Inflammatory Myopathies Endocrine Myopathies predisposition, perhaps through inherited human leukocyte anti-
Dermatomyositis Thyroid gens (HLA).19-58-160313-448-703
Polymyositis Parathyroid
Overlap syndromes Adrenal IDIOPATHIC INFLAMMATORY MYOPATHIES
Inclusion body myositis Pancreas
Myositis secondary to infection Pituitary Polymyositis
Other Clinical Features. Polymyositis typically presents in pa-
Myopathies Associated with Other Systemic Disorders tients over the age of 20 years with progressive, symmetric,
Electrolyte imbalance proximal weakness (Table 28-3). ,5 - ,6 - 2, l8°-229-295-398-75^ It is more
Malignancy prevalent in women than in men. The rate of progression is
Critical illness myopathy/Acute quadriplegic myopathy highly individualized, but the disease usually develops over sev-
eral weeks or months. Patients complain of increasing difficulty
Drug-Induced/Toxic Myopathies climbing stairs or arising from a chair or the commode. The
Necrotizing myopathy arms are increasingly required for assistance, such as using a
Amphiphilic myopathy handrail for stair climbing and pushing off the knees to arise
Antimicrotubular myopathy from a seated position. Further progression begins to limit the
Mitochondrial myopathy patients' ability to wash and comb their hair or brush teeth, i.e.
Inflammatory myopathy tasks necessitating muscular stabilization of the shoulder region
Myopathy secondary to impaired protein synthesis or increased (proximal upper limb muscles). Problems of lifting the head
catabolism when supine or maintaining an erect head position when sitting
Drug-induced hypokalemic myopathy suggest neck flexor and extensor muscle weakness. Usually the
Myopathy due to alcohol or illicit drugs fine motor abilities of the hand are unaffected because the distal
musculature is less involved. Nevertheless, distal limb weak-
ness is typically evident on examination, especially in patients
(2) dermatomyositis (DM), and (3) inclusion body myositis with significant proximal weakness. If there is severe proximal
(IBM) (Table 28-3). Importantly, these disorders are clinically, weakness with normal strength of the distal muscles, a different
histologically, and pathogenically distinct. The annual incidence disorder, such as a limb-girdle muscular dystrophy, needs to be
of the idiopathic inflammatory myopathies is approximately one considered.
in 100,000.' 80497 Unfortunately, it is difficult to estimate the inci- As many as one-third of patients complain of muscle pain or
dence of each specific type of inflammatory myopathy because tenderness. However, muscle pain is rarely the chief complaint. A •
many of the large epidemiologic studies in the past grouped primary complaint of myalgia without weakness should lead to '
these various types together. There are a few reports of PM, DM, the consideration of other disorders, such as polymyalgia
Table 28-2. Inflammatory Myopathies

Idiopathic Inflammatory Myopathies Bacterial
Polymyositis Staphylococcus aureus
Idiopathic Streptococci
Associated with connective tissue disorders (overlap syndromes) £ coli
Dermatomyositis Yersinia
Idiopathic Legionella
Associated with connective tissue disorders (overlap syndromes) Fungal
Inclusion body myositis Candidiasis
Other Idiopathic Inflammatory Myopathies Cryptococcosis
Focal myositis Sporotrichosis
Eosinophilic polymyositis Actinomycosis
Diffuse fasciitis with eosinophilia Histoplasmosis
Granulomatous and giant-cell myositis Parasites
Sarcoid myopathy Protozoans
Behcet's disease Toxoplasmosis
Inflammatory Myopathies Associated with Infections Sarcocystis
Viral Trypanosomiasis
Human immunodeficiency virus (HIV) Cestodes (tapeworms)
Human T-cell leukemia virus I (HTLV-I) Cysticercosis
Influenza virus type A, B, C (rare) Hydatidosis
Hepatitis B and C Coenurosis
Less common: adenovirus, coxsackievirus, echovirus, Sparganosis
parainfluenza virus, Epstein-Barr virus, arbovirus, Nematodes (unsegmented roundworms)
respiratory syncytial virus, cytomegalovirus, Trichinosis
herpes simplex virus Visceral/cutaneous larva migrans
Dracunculiasis
Chapter 28 ACQUIRED MYOPATHIES — 1373
Table 28-3. Idiopathic Inflammatory Myopathies: Clinical and Laboratory Features
Typical Age Pattern of Cellular Response to Common Associated
Disorder Sex at Onset Rash Weakness CK Muscle Biopsy Infiltrate IS Therapy Conditions
DM F>M Childhood Yes Proximal > Increased Perimysial and CD4+ Yes Myocarditis, inter-
and adult distal (up to 50x perivascular T-cells; stitial lung disease,
normal) inflammation; B-cells malignancy, vascu-
MAC, Ig, litis, other con-
C deposition nective tissue
on vessels diseases
PM F>M Adult No Proximal > Increased Endomysial CD8+ Yes Myocarditis, inter-
distal (up to 50x inflammation T-cells; stitial lung disease,
normal) macro- other connective
phages tissue diseases
IBM M>F Elderly No Proximal = Normal or Endomysial CD8+ None or Neuropathy,
(> 50 yrs) distal; mildly inflammation; T-cells; minimal autoimmune
predilection increased rimmed vacu- macro- disorders—
for finger/ (< lOx oles; amyloid phages uncommon
wrist flexors, normal) deposits;
knee EM: 15-18 nm
tubulofilaments
DM, dermatomyositis; PM, polymyositis; IBM, inclusion body myositis; F, female; M, male; IS, immunosuppressive; Ig, immunoglobulin; MAC, membrane attack complex;
C, complement; CK, creatine kinase; EM, electronmicroscopy.
From Amato AA, Barohn RJ: Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615-648, with permission.
rheumatica or fibromyalgia, rather than polymyositis. Myalgias details regarding the appropriate therapy and response are dis-
and muscle tenderness are more likely to occur in patients with cussed in the section on treatment.
an acute presentation and can be associated with slight muscle Some investigators have tried to define a distinct subgroup of
swelling or inflammation of the overlying fascia, i.e., fasciitis. PM on the basis of the presence of cytochrome oxidase (COX)-
Not surprisingly, muscle pain can be exacerbated by exercise in negative fibers on muscle biopsy and a modest response to
these conditions. methotrexate in a small number of patients.87-451 The clinical
Mild facial weakness may also be apparent in patients with features of this subgroup are male predominance, age over 60
polymyositis. 15 ,6 About one-third of patients have difficulty years, prominent quadriceps weakness, mildly elevated serum
swallowing secondary to pharyngeal and esophageal muscle CK levels, and poor response to corticosteroid treatment. As il-
weakness and dysmotility.I516-20-2' Occasionally, dysphagia can lustrated below, these are the characteristic features of inclusion
be quite severe and compromise nutritional intake. Also, im- body myositis (IBM), which is the most likely diagnosis of this
paired swallowing can lead to aspiration and necessitate a feed- "subgroup" of patients.15,294 The modest response to methotrex-
ing tube. Extraocular movements are spared, as is sensation. ate reported in some of these patients451 does not exclude IBM
Muscle stretch reflexes are also preserved. as the possible diagnosis. Other small retrospective studies of
There are numerous systemic manifestations of polymyosi- IBM have reported similar modest benefit in a few patients with
tis. Although overt cardiac symptoms are uncommon, electro- IBM. 363 445 Ragged red fibers and COX-negative fibers are
cardiographic abnormalities, including conduction defects and common in IBM muscle biopsies because of the higher fre-
arrhythmias, may be seen.47-198-287-327-383-725-735-749 However, peri- quency of mitochondrial mutations than that seen in age-
carditis, myocarditis, and congestive heart failure may occur matched patients with PM. Because of sampling errors, each of
secondary to inflammation of cardiac muscle. At least 10% of the characteristic histologic features of IBM are not always seen
patients with polymyositis develop interstitial lung disease on every muscle biopsy; more than one biopsy is often required
(ILD).207-260-340"458-674-734-749 ILD manifests with dyspnea and non- to confirm the clinical impression of IBM. 15
productive cough and may begin abruptly or insidiously. Laboratory Features. Although multiple muscle enzymes
Additionally, ILD may precede muscle weakness or begin after can be assessed, creatine kinase (CK) is considered the most
the myopathy has presented. Polyarthritis is seen in as many as sensitive in determining the presence of active muscle disease.
45% of patients at the time of diagnosis. 749 The risk of malig- Serum CK is elevated 5-50-fold in most patients with
nancy is slightly higher in polymyositis than in the general polymyositis.1516-93-341-749 However, serum CK may rarely be
population, but it is significantly lower than that seen in der- normal in polymyositis patients with objective weakness and
matomyositis.93-129-694-749 Work-up for an underlying malignancy can be elevated in some patients with no discernible weakness.
should be symptom-directed. 1617 Because the serum CK level does not correlate with disease ac-
Most patients with polymyositis respond to treatment with tivity or severity, it should be used only in conjunction with ob-
immunosuppressive agents. 1516 Some retrospective studies sug- jective manual muscle testing. Besides elevated CK levels,
gest the response to treatment is not as favorable as that seen in elevations in SGOT, SGPT, and LDH are also detected in pa-
dermatomyositis. 15 - 363 Poor prognostic features include older tients with active disease. It is important to remember that ele-
age, concomitant ILD or cardiac disease, and delayed or inade- vations of these "liver function tests" are not specific for liver
quate treatment.16 Mortality rate in patients with polymyositis is disease, because these enzymes are present in muscle tissue.
four times that of an age-matched control population. 203 More Prior to embarking upon an extensive liver work-up, serum CK,
changes can be indistinguishable from a muscular dystrophy. In
as many as 25% of polymyositis patients, the muscle biopsies are
normal or demonstrate only nonspecific abnormalities. This most
likely reflects a sampling error due to the multifocal nature of the
disease, even within involved muscle, or perhaps the inappropri-
ate biopsy of a relatively unaffected muscle. In patients with only
subtle weakness on examination, electromyography can be very
helpful in determining which muscle group to biopsy.
Pathogenesis. The histologic and immunologic features
seen on the muscle biopsies suggest that polymyositis is the
result of an HLA-restricted, antigen-specific, cell-mediated
autoimmune response directed against muscle fibers. l620J86a
The trigger of this autoimmune response is not known. Some
have speculated on a viral etiology, although viral antigens and
genomes have not been identified in muscle tissue.180-229-444-795
Viral infection could perhaps indirectly trigger an autoimmune
Figure 28-1. Polymyositis. Muscle biopsies demonstrate en-
response secondary to cross-reactivity with muscle-specific
domysial mononuclear inflammatory cells invading nonnecrotic muscle
antigens, altering the expression of self-antigens on muscle
fibers. Modified Gomori-trichrome. (From Amato AA, Barohn RJ:
fibers, or by the physiologic loss of self-tolerance.229
Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615-648, The cytotoxic T cells appear to induce cell death via the per-
with permission.) forin pathway. The autoinvasive T-cells in PM contain perforin
granules, which are oriented to the surface of the muscle
fibers.282 When released by exocytosis, these granules induce
which is specific for muscle disease, and GGT, which is specific pore formations on the sarcolemma and result in osmolysis of
for liver disease, should be determined. We have seen a number muscle fibers. 282 Although regenerating and degenerating
of patients with primary muscle diseases who underwent unnec- muscle fibers express Fas and Fas ligand (a proapoptotic com-
essary liver imaging tests and biopsies prior to their primary plex), 71266 there is no evidence that apoptosis plays a role in
care physician considering the possibility of a myopathy. muscle fiber destruction. 670 It is possible that the increased ex-
Erythrocyte sedimentation rate is normal in the majority of pa- pression of Bcl-2, an antiapoptotic protein, protects against the
tients.16 Antinuclear antibodies are present in 16-40% of patients potential apoptotic effect of Fas/Fas ligand.71
with polymyositis. 16-93 341,458J49 Myositis-specific antibodies (e.g., Matrix metalloproteinases (MMP-1, MMP-2, MMP-9) are ex-
anti-Jo-1 and anti-signal recognition protein) are more common pressed on T-cells, endothelial cells, and muscle fibers which
in polymyositis than dermatomyositis.16'512,586587 Jo-1 antibodies may facilitate migration of inflammatory cells through the vessel
are detected in about 20% of patients with polymyositis and are walls and extracellular matrix to the musclefibers.145a-186a*389aThe
associated with ILD.340-458-734 Antibodies directed against signal invading cytotoxic T-cells express interleukin-2 (IL-2), IL-4, IL-
recognition protein are present in 4% of polymyositis patients, 5, and interferon-y (IF-y) while macrophages release IL-1, IL-6,
and are associated with an acute onset of severe weakness, myal- and tumor necrosis factor-a (TNF-a). 186a These cytokines may
gias, myocarditis, a poorer response to treatment, and a 5-year exert direct or indirect toxic effects on muscle fibers.
mortality rate of 25%.339-363'458-734 MRI of skeletal muscle can
demonstrate signal abnormalities but these changes are not spe- Dermatomyositis
cific for inflammatory myopathies.16-379-584 Clinical Features. The clinical presentation and laboratory
Histopathology. The alterations noted in the muscle biopsy features for polymyositis apply to patients with dermatomyositis
are dependent upon the severity of the disease and the timing of (Table 28-3). 15.i6.20.21.i80.229.295 However, there are distinct clinical,
the biopsy with respect to the patient's presentation. The char- histologic, and pathogenic differences between polymyositis and
acteristic histologic feature in polymyositis is endomysial in- dermatomyositis. As with polymyositis, females are affected
flammation with invasion of non-necrotic muscle fibers (Fig. more commonly than males. Unlike polymyositis, dermato-
28-1). Scattered necrotic and regenerating fibers are also noted. myositis also develops in children. 21112 It appears to have a bi-
Major histocompatibility complex class 1 antigen, which is not modal age distribution, with peaks at 5-24 years and 45-64
normally present on the surface of muscle tissue, is expressed years of age.180 Although childhood and adult dermatomyositis
on all of the invaded and some of the noninvaded muscle are similar in pathogenesis, there are important differences of
fibers.222 The invading inflammatory cells consist primarily of various clinical features and associated systemic disorders in the
activated CD8+ (cytotoxic), alpha/beta T-cells, and macro- childhood and adult form of the disease.21
phages.28 The oligoclonal pattern of gene rearrangement and the Weakness is usually subacute, developing over a few weeks, but
restricted motif of the CDR3 within the T-cell receptor suggest it can begin abruptly, over a few days, or more insidiously, over a
that the immune response is antigen-specific.474 Unlike dermato- period of months. Proximal muscles are the earliest and most se-
myositis, there is no evidence of a humorally mediated vascu- verely affected, but distal weakness also occurs. Children are more
lopathy, and perifascicular atrophy is not seen on biopsy. In likely to present with an insidious onset of weakness, myalgias, fa-
chronic polymyositis, there can be significant muscle fiber size tigue, and low-grade fever.21 Some patients have masseter muscle
variation with increased amounts of fatty and fibrous connective weakness resulting in difficulty chewing. Dysphagia develops in
tissue throughout the endomysial regions. Small groups of approximately 30% of patients. Involvement of pharyngeal and
muscle fibers with the same histochemical type secondary to tongue muscles can also lead to dysarthria. In young children, this
splitting are also commonly noted. In the absence of inflamma- can lead to speech delay.561 As with polymyositis, the extraocular
tory cells invading non-necrotic muscle fibers, these histologic muscles, sensation, and muscle stretch reflexes are preserved.
Figure 28-2. Dermatomyositis. A, Muscle biopsy reveals charac-

teristic perifascicular atrophy and microvacuolated muscle fibers, modi-
fied Gomon-trichrome. B, Prominent perivascular inflammation is
evident in a perimysial blood vessel, modified Gomori-trichrome. C,
The earliest histologic abnormality on light microscopy is the deposi-
tion of membrane attack complex (C5b-9) on small blood vessels.
(From Amato AA, Barohn RJ: Idiopathic inflammatory myopathies.
Neurol Clin 1997; 15:615-648, with permission.)
The most obvious distinguishing feature between dermato- Unfortunately, treatment of calcinosis is quite difficult. Various
myositis and polymyositis are the characteristic skin manifes- medications (e.g., colchicine, probenecid, warfarin, phosphate
tations of dermatomyositis. A sun-sensitive erythematous flat buffers) and surgery have been used with limited success.16
rash appears on the face, upper trunk, and limbs accompanying Systemic complications of dermatomyositis are common. As
or preceding the onset of weakness.16-244 Typically, there is a vi- described with polymyositis, inflammation of the pericardium
olaceous coloration of the upper eyelids (heliotrope), often as- and cardiac muscle can occur resulting in arrhythmias, conduc-
sociated with periorbital edema. A rash appears over the neck tion defects, and congestive heart failure.47•,98•287•3,8339•725•749 ILD
and anterior chest (V-sign), on the posterior neck and back of develops in approximately 10% of adult dermatomyositis patients
the shoulders (shawl sign), and on the malleoli, knees, and and may also occur in children.260-340-561-567-674 Inflammation of
elbows. Papular erythema of the metacarpophalangeal and in- smooth muscles of the gastrointestinal tract leads to delayed
terphalangeal joints with scaling of this skin (Gottron's sign) motility and gastroparesis. Vasculitis/vasculopathy of the gas-
is also classic. Careful inspection of the nailbeds may reveal di- trointestinal tract is a serious problem and is much more common
lated capillary loops, occasionally with thrombi or hemor- in childhood dermatomyositis compared to adult cases. There is
rhage. Rarely, patients may primarily manifest with the an increased incidence of underlying malignancy in adult der-
above-noted skin lesions but have normal strength (amyo- matomyositis, ranging from 6 to 45%.68-92-94128-,29-34,-62,-694J49 This
pathic dermatomyositis). 233 This suggests that dermatomyosi- risk is greater than that seen in polymyositis. The association with
tis is really a disease with a spectrum of skin and muscle tissue cancer is not apparent in children. The search for an underlying
involvement in which both skin and muscle may be affected, or malignancy should begin with a comprehensive history and phys-
primarily the skin with little in the way of concomitant muscle ical examination, including breast and pelvic examinations in
pathology. Hydroxychloroquine, chloroquine, topical steroids, women and testicular and rectal examinations in men. We order
and sunscreen can be used to treat the rash when weakness is chest radiographs, pelvic ultrasound, and mammograms as well
not apparent.16-785 as a complete blood count, routine chemistries, prostate-specific
A distinctive feature of dermatomyositis is the appearance of antigen urinalysis, and stool specimens for occult blood.
subcutaneous calcification, which occur in 30-70% of children, However, more extensive laboratory and radiologic work-up for
but is an uncommon finding in adults.16-21-155 These calcifications malignancy should be sign- and symptom-related.
tend to develop over pressure points (e.g., buttocks, knees, In the absence of malignancy, prognosis is favorable. Poor
elbows) and present as painful hard nodules. They are more likely prognostic features are increased age, associated ILD, cardiac
to develop in children who have been inadequately treated. These disease, and late or previous inadequate treatment.152 34'-363-533-749
subcutaneous calcifications can become quite large and even ul- Five-year survival rates of adult DM range from 70 to
cerate through the skin, with ensuing superficial infections. 93%.341-363-802 The mortality rate in children is very low.561
Laboratory Features. Muscle enzyme abnormalities decreased expression of adhesion molecules and integrins on
scribed for polymyositis apply equally to dermatomyositis. leukocytes and their respective ligands on endothelial cells.1863
Serum CK is elevated in 90% of dermatomyositis patients and This process facilitates the migration of inflammatory cells
can be as high as 50 times the upper limit of normal.15_l7-20-21 (mainly B cells and CD + 4 cells) into the perimysium. Questions
However, serum CK levels can be normal, particularly early in that remain unanswered include: (1) whether these B cells pro-
the course of the disease. Erythrocyte sedimentation rate is duce antibodies directed against endothelial cells; (2) what trig-
normal or only mildly elevated and, like serum CK level, is not gers complement deposition on blood vessels; and (3) what role,
a marker of disease severity. Antinuclear antibodies are present if any, F cell mediated cytotoxicity plays in the pathogenesis of
in 24-60% of patients but are much more common in patients dermatomyositis.1863
with overlap syndromes (see below).341-458-734 Jo-1 antibodies are
more common in polymyositis than dermatomyositis and are as- Overlap Syndromes
sociated with ILD. Anti-Mi-2 antibodies are seen almost exclu- Approximately 20% of patients with dermatomyositis and
sively in dermatomyositis, occurring in 15-25% of patients.16-512 polymyositis display clinical and laboratory features suggestive
Other myositis-specific antibodies are uncommon. of a concomitant connective tissue disorder.16-20-21-180-229-295-398-416
Histopathology. Because the pathologic process is multifo- These disorders include scleroderma (systemic sclerosis or
cal, the frequency and severity of histologic abnormalities can CREST syndrome), mixed connective tissue disease, Sjogren's
vary within the muscle biopsy specimens. The characteristic syndrome, systemic lupus erythematosus, and rheumatoid arthri-
histologic feature is perifascicular atrophy, which occurs in tis. The clinical, laboratory, electrophysiologic, and histopatho-
up to 90% of children but in less than 50% of adults with DM logic features and the pathogenesis of the myositides associated
(Fig. 28-2). 1617 - 21180 The perifascicular area contains small de- with these syndromes are similar to isolated forms of polymyosi-
generating and regenerating fibers as well as fibers with mi- tis and dermatomyositis. Some have suggested that the myositis
crovacuolation and myofibrillar disruption. Occasionally, is more amenable to treatment in the overlap syndromes than in
wedge-shaped microinfarcts of muscle fascicles are apparent. patients with isolated polymyositis and dermatomyositis.
Scattered necrotic fibers may be present; however, in contrast to
polymyositis and inclusion body myositis, invasion of non- Scleroderma
necrotic fibers is not prominent. In fact, inflammation can be Clinical Features. Proximal muscle weakness is common in
quite sparse. When present, inflammation is predominantly scleroderma; however, many of the patients have normal serum
perivascular and located in the perimysium rather than the en- CK values and electromyography.16-229-295 Some investigators
domysium (Fig. 28-2). In contrast to polymyositis and inclusion have documented electrophysiologic findings similar to
body myositis, the inflammatory infiltrate is composed primar- polymyositis. 33a l52a-2I5a-3,7a-558a Usually muscle biopsies demon-
ily of B-cells, CD4+ (T-helper) cells, and macrophages.28 strate only mild variability in fiber size with atrophy of type 2
The muscle biopsy can look completely normal by routine muscle fibers and perimysial fibrosis.228 However, polymyositis
light microscopy, especially early in the course of the disease. or dermatomyositis has been reported in 5-17% of patients with
The earliest demonstrable histologic abnormality in DM is de- scleroderma and can occur in either of its two major forms—
position of the C5b-9 complement membrane attack complex progressive systemic sclerosis or CREST syndrome.252-477-629-746
(MAC) on small blood vessels (Fig. 28-2).223-395-396 MAC depo- Laboratory Features. Anticentromere antibodies are seen
sition precedes the appearance of perivascular inflammation and in the majority of patients with CREST syndrome, while anti-
other structural abnormalities (e.g. perifascicular atrophy) in the Scl-70 antibodies are common in patients with progressive sys-
muscle on light microscopy and is specific for dermatomyositis. temic sclerosis. In addition, approximately 25% of North
Other complement components (C3 and C9), IgM, and less American patients with scleroderma-myositis have anti-PM-Scl
often IgG are also deposited within the walls of intramuscular (also called anti-PM-1) antibodies. 734 Anti-PM-Scl is not spe-
blood vessels and can be demonstrated on special immunohisto- cific for this disorder, because only 50% of patients with this
chemistry stains.772 There is necrosis of the small blood vessels antibody have the scleroderma-myositis overlap syndrome.
resulting in a reduction in the capillary density (number of cap- Histopathology and Pathogenesis. Muscle biopsies can
illaries per area of muscle). 223 Transforming growth factor (3 demonstrate features of either polymyositis or dermatomyositis.
(TGF-J3) and its messenger RNA are upregulated in regions of The pathogenesis of the myositis can therefore be a cell-medi-
severe ischemia, which probably accounts for the increased fi- ated attack against the muscle fibers (polymyositis) or a hu-
brosis in these areas.159 Electron microscopy reveals small intra- morally mediated microangiopathy (dermatomyositis).
muscular blood vessels (arterioles and capillaries) with
endothelial hyperplasia, microvacuoles, and cytoplasmic inclu- Sjogren's Syndrome
sions; these ultrastructural abnormalities precede other features Clinical Features. Sjogren's syndrome is characterized by
that may be absent on routine light microscopy.58-204 dryness of the eyes, mouth, and other mucosal membranes
Pathogenesis. The etiology of dermatomyositis is unknown (sicca syndrome). Myalgias and weakness are common in
but is presumed to be autoimmune in nature. The immunologic Sjogren's syndrome, but actual myositis is rare.229-295 Weakness
studies and other histologic features on muscle biopsies suggest is more often related to disuse atrophy secondary to arthritis and
that dermatomyositis is a Immorally mediated microangiopa- pain. Nonetheless, there are reports of both dermatomyositis
thy. 16J86a This is in contrast to polymyositis, in which immuno- and polymyositis associated with Sjogren's syndrome.200-590-629
histologic studies point to cell-mediated immune response Laboratory Features. About 90% of patients have ANAs
directed against the muscle fibers. The microangiopathy leads directed against ribonucleoproteins, specifically SS-A (Ro) and
to ischemic damage and occasionally infarction of muscle less commonly SS-B (La) antibodies.228
fibers. The perifascicular atrophy is felt to be a reflection of hy- Histopathology and Pathogenesis. Biopsies can be typical
poperfusion in the watershed region of muscle fascicles. of either polymyositis or dermatomyositis with the respective
Cytokines induced by complement activation lead to the in- pathogenesis discussed previously.
Systemic Lupus Erythematosus and fibrillation potentials. In patients with acute disease, needle
Clinical Features. Systemic lupus erythematosus (SLE) is insertion feels comparable to that of normal muscle. During the
an autoimmune disorder affecting multiple organ systems. chronic stages of the disorder, especially in patients treated in-
Weakness is not unusual in SLE but is most often the result of adequately or with very prolonged disease, there may be a
disuse atrophy.222-295 Inflammatory myositis is uncommon in "gritty" feel to needle insertion secondary to replacement of-
SLE. However, some series have reported that up to 8% of der- muscle tissue by significant amounts of connective tissue.
matomyositis and polymyositis patients have SLE.255-734 At rest, sustained membrane instability can also be observed.
Laboratory Features. The majority of patients with SLE There is a rough relationship between the degree of membrane
have positive ANA titers that are directed against native DNA instability and severity of the disease process.723-744 In the acute
(highly specific for SLE) and ribonuclear proteins (RNP). The untreated compared to chronic treated stages of the disease,
anti-RNP antibodies are present in less than half of SLE patients there can be significant degrees of positive sharp waves and fib-
and include anti-SS-A and anti-SS-B (also present in Sjogren's rillation potentials in various muscles. Because patients are re-
syndrome), anti-Ul RNP (also present in mixed connective ferred for electrodiagnostic medicine evaluations during various
tissue disease), and anti-Sm (specific for SLE). stages of the disease process, it is difficult to comment on the
Histopathology and Pathogenesis. Both polymyositis and myriad of studies discussing spontaneous activity. Generally,
dermatomyositis can occur with SLE. either or both positive sharp waves and fibrillation potentials are
detected in 80-100% of patients with acute myositis provided
Rheumatoid Arthritis an appropriate search is performed.425,517,723,744 In a carefully
The most common etiology of weakness in patients with performed investigation, 35% of patients demonstrate mem-
rheumatoid arthritis is type 2 muscle fiber atrophy secondary to brane instability in all muscles examined, an additional 35% re-
chronic steroids or disuse because of severe arthralgias. vealed fibrillation potentials and positive sharp waves in more
Rheumatoid arthritis (RA) has been reported in up to 13% of pa- than half of the muscles, 20% of patients had these potentials in
tients with dermatomyositis and polymyositis, although the inci- less than half of muscles, while in the final 10% of patients only
dence of inflammatory myopathy in patients with RA is much one or two muscles showed membrane instability.723
lower.56- The laboratory findings, histopathology, and pathogene- Both proximal and distal muscles must be examined, includ-
sis are similar to either dermatomyositis or polymyositis. ing the deltoid and gluteus maximus/medius muscles. It is para-
mount to examine the paraspinal muscles, because a few patients
Mixed Connective Tissue Disease may manifest only with findings in this location.517-722 One side
Mixed connective tissue disease (MCTD) has clinical fea- should be explored at multiple levels along the cervical, thoracic,
tures of scleroderma, SLE, rheumatoid arthritis, and myositis.687 and lumbosacral regions. The other side can be used for a muscle
Dermatomyositis is more common than polymyositis, although biopsy. Unlike a radiculopathy examination, it is not necessary
both have been described in association with MCTD.16180 29Ia-463-687-734 to attempt insertion into the multifidi layer and the more superfi-
High titers of anti-Ul RNP antibodies are common in MCTD; cial layers suffice. Between 93 and 100% of patients can have
however, these antibodies can also be detected in SLE. Clinical abnormalities in the paraspinal region, which is not surprising
and histologic features are similar to those described above. given that the paraspinals are the most proximally located mus-
Acute necrotizing myopathy is much less common but can cles and polymyositis and dermatomyositis have a propensity for
also complicate MCTD224a-29la as well as malignancies.2243-450 affecting proximal muscles.517-723,744 If a patient is strongly sus-
Patients can present with subacute or insidiously progressive pected of having an inflammatory myopathy, the needle exami-
generalized symmetric proximal and distal muscle weakness and nation should not be terminated after exploring only a few
elevated CK levels. Muscle biopsies demonstrate scattered muscles. If a limited examination must be performed for various
necrotic fibers, pipe-stem capillaries, perivascular inflammation, reasons, it is a good idea to at least perform a needle investiga-
and membrane attack complex suggesting a humorally mediated tion of the paraspinal muscles, particularly in the thoracic area.
microangiopathy as the underlying process, similar to dermato- The thoracic paraspinal muscles are less likely to demonstrate
myositis. However, perifascicular atrophy is not evident on biop- muscle membrane instability related to degenerative spine dis-
sies and patients do not exhibit the rash of dermatomyositis. ease than the cervical or lumbosacral paraspinal muscles.
In patients with chronic forms of the disorder who may not
Electrophysiologic Findings in Polymyositis, have received treatment, the positive sharp waves and fibrilla-
Dermatomyositis, and Overlap Syndrome tion potentials may be decreased compared to acute disease.
Nerve Conduction Studies. Assuming the patient does not Additionally, the size of the spontaneous potentials is reduced
have concomitant peripheral neuropathy, the sensory and motor compared to the acute stage, i.e., approximating 100 p.V or less
nerve conduction studies are normal.10M43-634 Rarely, there is a versus greater than 100-200 |iV. The decreased number of
reduction in the CMAP amplitude secondary to the loss of spontaneous potentials is likely a result of significant degrees of
muscle fibers. muscle tissue loss with replacement of the muscle volume by
Needle Electromyography. An important characteristic of connective tissue. The small size of the potentials results from
inflammatory myopathies is the rather patchy nature of electri- long-standing failure of reinnervation with a reduction in
cal findings. If abnormalities are not found in a particular region muscle fiber size secondary to atrophy.
of a muscle, the needle electrode should be withdrawn and a Following treatment, most commonly with corticosteroids, the
second insertion site examined. Also, investigation of multiple degree of membrane instability decreases.662 This decrease can be
muscles may be necessary to document sufficient abnormalities dramatic, with essentially complete resolution of positive sharp
to properly diagnose the disease. Adequate time should be allot- waves and fibrillation potentials over the course of several weeks
ted to perform a complete examination. to months. There are occasional patients who continue to demon-
In patients with active disease, insertion of the needle elec- strate relatively easily elicitable membrane instability despite ad-
trode typically results in the production of positive sharp waves equate treatment and symptom resolution. This may be a result of
focal regions of muscle where the segmented regions were not proven myositis is too inconsistent to make or break a diagnosis
reinnervated and hence continue to fibrillate. There is a sugges- of polymyositis or dermatomyositis.
tion that the earliest finding following treatment is the reduction Most practitioners begin an evaluation of voluntary MUAPs
in the amount of fibrillation potentials and positive sharp waves.92 with a free-running instrument screen and qualitatively evaluate
Some investigators report the detection of myotonic poten- the MUAPs at low levels of force production. Unfortunately,
tials in patients with polymyositis and dermatomyositis. Other many practitioners then request the patient to produce a maximal
investigators have not adequately documented this finding, and contraction, and then investigate another muscle. This practice is
we have not observed true myotonic potentials in inflammatory fraught with potential for missing mild disease, because many
myopathies. Decrescendo trains of positive sharp waves that patients have a mixture of normal and abnormal MUAPs, partic-
appear as positive sharp wave myotonic potentials are common. ularly early in the course of the disease. If there is any suspicion
However, we consider these trains pseudomyotonic potentials of a myopathy, a trigger and delay line as well as an averager
as opposed to true myotonic potentials, because they do not wax should be used in order to appreciate any subtle abnormalities
and wane in frequency and amplitude. Further investigation is regarding the various MUAP parameters, particularly duration.
required prior to fully accepting true myotonic discharges as a Perhaps the easiest MUAP parameter to evaluate is the major
finding in these disorders. spike component's peak-to-peak amplitude. This aspect of the
The explanation for fibrillation potentials and positive sharp MUAP is classically considered to be reduced in polymyositis or
waves occurring in a myopathic disorder such as polymyositis in dermatomyositis.92-203-425-557-619-762 Careful studies of simple and
which there is supposedly an absence of axonal loss is still de- polyphasic MUAPs in patients with inflammatory myopathies
bated. Histochemistry reveals unquestionable evidence of seg- reveal significant amplitude variation in both patient and control
mental degeneration and occasionally small groupings of similar populations.115-744 The difference in mean amplitude of the first
fiber types.329 Detailed electrophysiologic testing of the same pa- recruited MUAPs in inflammatory myopathy patients from
tients shows an increase in fiber density, and elevations in jitter normal controls is not statistically significant (265 p.V vs. 260
and blocking as measured on single-fiber electromyography. The JLIV).744 In patients with long-standing disease, large-amplitude
combination of both anatomic and electrophysiologic data sug- (> 3 mV) and long-duration (> 13 ms) MUAPs can be de-
gests that the segmental necrosis is the primary generator of pos- tected.496-536-571-752 Concomitant muscle biopsy studies in these pa-
itive sharp waves and fibrillation potentials, because these tients demonstrate small fiber type grouping. As previously
segments of muscle are effectively denervated by way of physi- described, it is likely that segmental necrosis followed by collat-
cal separation from the endplate region. Following the creation eral regeneration occurs in inflammatory myopathies. In chronic
of segments of muscle tissue, it is possible for collateral sprouts disease, this process may be repeated multiple times with focal
from the same or different nearby axons to reinnervate the seg- regions of fiber type grouping. Also, fiber hypertrophy and split-
mented muscle tissue. If this process happens frequently enough, ting may also occur. If a needle recording electrode is located in |
it can lead to small fiber type grouping as well as an increase in a region of muscle with the above characteristics, then large am-
fiber density. The newly created neuromuscular junctions will at plitude potentials can be anticipated as there are more fibers
first display unstable transmission characteristics through in- (electrical generators) belonging to the same motor unit in close
creased jitter and blocking. An alternative hypothesis is that the proximity to the electrode. If they all fire at or about the same
disease process results in damage to the terminal intramuscular time, the summated electrical activity can generate unexpectedly
axons with secondary muscle denervation in the classic sense of large MUAPs. Also, as noted previously, amplitude is highly de-
neural deprivation.485496-774 The ensuing collateral sprouting from pendent upon the needle electrode's recording surface with re-
nearby intact axons can also result in both the histologic and spect to the electrical generator. Slight alterations in distance can
neurophysiologic findings noted above. There is documentation result in profound amplitude changes. Although of interest,
of intramuscular axonal damage; however, the primary etiology MUAP amplitude most likely should be considered less impor-
is questionable, i.e., intrinsic muscle disease or the actual separa- tant than duration when attempting to formulate a diagnosis. j
tion process. At the present time, the segmental fiber necrosis There is characteristically an increase in the number of polypha-
with segmental innervation is favored over an axonal loss patho- sic potentials recorded in both the acute and chronic forms of the
genesis. The controversy may be eventually resolved to include disease compared to controls, i.e., approximately four times as
some small degree of axonal insult as a result of the inflamma- many in patients.92-I15-426-496-571,744 The explanation for these findings
tory or connective tissue proliferation process. in inflammatory myopathies is believed to be a combination of
Complex repetitive discharges are commonly seen in patients fiber size variation and random loss of muscle fibers in the acute
with polymyositis or dermatomyositis in the subacute or more stages of the disease with continued fiber size variation and collat-
chronic stages of the disease. Several investigators have popu- eral sprouting in the intermediate and chronic stages. It is the au-
larized this particular potential as being a major electrodiagnos- thors' opinion that an increase in polyphasia can be best
tic medicine finding in patients with these disorders. 92571 The appreciated with a trigger and delay line, especially in myogenic
absence of complex repetitive discharges, however, should not disorders, because the early recruitment phenomena generating
question the diagnosis of an inflammatory myopathy when both multiple MUAPs at low levels of force with a potential for signifi-
the clinical, histologic, and additional electrodiagnostic data cant overlap make individual MUAP parameter identification diffi-
suggest such a disease. It is the authors' opinion that this partic- cult. Aside from contributing to the diagnosis of a myopathy,
ular potential, while suggestive of a chronic process in which polyphasic potentials must be quantified from the standpoint of du-
muscle fibers are ephaptically driven by a fibrillating single ration when attempting to diagnose a possible myopathic disease.
muscle fiber, should not be included in the electrodiagnostic Duration is the most sensitive electrophysiologic MUAP pa-
medicine criteria for polymyositis or dermatomyositis. The ra- rameter not requiring specialized instrumentation for diagnos-
tionale for this suggestion is that the detection of these poten- ing myopathic conditions.116118-743 There is considerable overlap
tials in the acute phase of the disorders is unlikely, and the in MUAPs between control populations and patients with
documentation of complex repetitive discharges in patients with polymyositis or dermatomyositis. In other words, normal persons
can have "short" duration MUAPs but the percentage of all L DPP,
MUAPs with durations less than 6 ms and 8 ms is 5% and 21%,
respectively. 744 This is balanced by MUAPs with durations
longer than 16 ms (14%). The net result is a mean duration that
reflects the combination of the various durations. In patients
with an inflammatory myopathy, the percentage of short-dura-
tion MUAPs (< 8 ms) is considerably increased (46%), with a
reduction in long-duration MUAPs (6%). This shifts the mean
duration of MUAPs in patients to less than that in controls;
however, the scatter of durations is similar for both groups (pa-
tients 3.3 ± 0.8 ms vs. controls 3.6 ± 0.7 ms). This is important
because both patients and normal individuals have similar varia-
tions in MUAP duration, except that there are significantly more
short-duration potentials in inflammatory myopathies.
Practically, this also means that when examining normal indi-
viduals quantitatively, a number of short-duration MUAPs can
be expected, thus the importance of recording and quantitatively
measuring at least 20 MUAPs. Multiple sites within a muscle
must be explored to ensure a wide sampling distribution.
Of importance in patients with possible myopathic conditions |o.1 ntV
is the relationship of MUAP duration and phases. There is an in- 5 msec
crease in the percentage of long-duration polyphasic MUAPs Figure 28-3. Several examples of long-duration polyphasic
compared to normal persons. 744 The combination of simple and MUAPs in patients with inflammatory myopathies.The upper
polyphasic MUAPs of all durations in patients generates a mean trace in each group represents the real-time potential, while the lower
duration shorter than in normal individuals. This difference is ac- trace is an averaged potential. In the upper group of potentials are
centuated if only simple as opposed to complex or polyphasic recorded MUAPs with a highly complex shape and long duration.The
potential is measured. Considering all potentials in a disease middle group of potentials represent MUAPs that are not only com-
may decrease the diagnostic sensitivity of this parameter. It is plex but contain late components. In the lower trace are MUAPs with
recommended that when patients with inflammatory myopathies clearly observed satellite potentials. (From Uncini A, Lange DJ,
are evaluated, a sufficient number of MUAPs be obtained so that Lovelace RE: Long duration polyphasic motor unit potentials in my-
at least 20 MUAPs of simple shape are recorded.744 This may ne- opathies. Muscle Nerve 1990; 13:263-267, with permisson.)
cessitate the quantitative evaluation of 30 or 40 total MUAPs. In
patients with early myopathic or subtle disease, considering only
simple MUAPs might permit a correct diagnosis, whereas the in- Treatment with corticosteroids not only results in a reduc-
clusion of polyphasic potentials may delay the diagnosis until a tion in the number of fibrillation potentials and positive sharp
stage of greater disease progression is reached. waves, but a reduction in both the number of polyphasic poten-
Interestingly, very long and complex potentials can also be ob- tials and the number of short-duration MUAPs, i.e., an increase
served in inflammatory myopathies (Fig. 28-3).,6-62432-4%-536-571-752 toward normal in the muscle's mean MUAP duration. 496 The
These long-duration potentials may take three major forms. final MUAP duration in a patient who is adequately treated
First, highly complex potentials with abnormally long durations may not only return to normal, but in some patients may actu-
comprised of clearly defined phases can be readily observed in ally become longer than normal 2-6 years later. Despite ade-
patients. 752 A second type of potential consists of a major quate treatment, some patients may continue to demonstrate
MUAP spike followed by several very low-amplitude com- focal regions of abnormal spontaneous activity as well as alter-
plexes that are continuous with the major spike. It may be easy ations in MUAP parameters.
to miss these potentials unless a high amplifier gain is used to Quantitative Electromyography. Various methods of quan-
resolved the small trailing components. Finally, true satellite titative electromyography can be used during the electrophysio-
potentials, at least 5 ms of quiet baseline between the major logic evaluation of a patient suspected of having an inflammatory
spike and time-locked potentials, can be observed. These poten- myopathy. We used the technique described by Buchtal of
tial are usually missed unless a trigger and delay line are used triggering and measuring the durations of 20 individual MUAPs
because the duration of the total potential including the satellite and found that it is particularly helpful in patients with only
can approach 40 ms. Overlap of other motor units secondary to subtle weakness. II5J16 In most patients, however, the qualitative
a patient's inability to recruit only one or two MUAPs in myo- assessment of experienced electromyographers using conven-
pathic states precludes separating individual MUAPs with long tional needle examination suffices. We have not found programs
components without the assistance of a trigger/delay line. All of that measure "clouds" (e.g., turns/amplitude or interference pat-
these potentials are found with increasing frequency as the dis- tern analysis) to be particularly useful. Some computerized de-
ease progresses from the acute to the more chronic stages. composition programs are available that automatically select and
These potentials are likely to result from significant conduction analyze recruited MUAPs for duration, amplitude, and turns. We
velocity variation within a motor unit secondary to muscle fiber and others have not found this program to be particularly
size variation and slowing along focal regenerating muscle seg- useful.369 Only the measured decrease in MUAP duration in pa-
ments. Long and/or immature collateral terminal nerves rein- tients with inflammatory myopathies is significantly abnormal
nervating segmented muscle fibers may also play a role. As compared to normal controls.369
noted above, all of these satellite potentials should be excluded Single-Fiber Electromyography. As noted above, single-
when calculating mean MUAP duration. fiber electromyographic analysis of patients with polymyositis
Figure 28-4. Inclusion body myositisThe earliest clin-

ical features are severe atrophy and weakness of the quadri-
ceps and volar forearms muscles. A, Severe weakness of the
quadriceps muscles is usually present at the time of presen-
tation. Many patients are not able to extend the knees fully
at the time of diagnosis. B, Severe atrophy of the volar fore-
arm muscles is also evident early in the course of the ill-
ness. C, Involvement of these muscle manifests as weakness
in wrist and finger flexion. Note the inability of the patient
to flex the fingers and make a tight grip. (From Amato AA,
Barohn RJ: Idiopathic inflammatory myopathies. Neurol Clin
1997; 15:615-648, with permission.)
reveal a number of nonspecific findings.254 Single muscle fiber wrist and finger flexors) (Figs. 28-4B and 28-4C), and the ankle
jitter values are mildly to moderately increased in most patients dorsiflexors.I5-20-294-457 We have invariably found that the manual
with polymyositis/dermatomyositis. Blocking can also be ob- muscle scores of the finger and wrist flexors are lower than
served, although it is not always prominent. Fiber density is those of the shoulder abductors and the muscle scores of the
usually moderately increased in all patients. These findings all knee extensors are lower than those of the hip flexors in patients
suggest that there is remodeling of the motor unit through col- with IBM. 15 The opposite relationship between muscle scores
lateral sprouting of nerves most likely reinnervating segmented are present in dermatomyositis and polymyositis. In addition,
portions of muscle fibers. Histologic assessment of muscle tis- muscle involvement in IBM is often asymmetric, in contrast to
sues confirms various degrees of fiber type grouping as sug- the symmetric involvement in dermatomyositis and polymyosi-
gested by single-fiber electromyographic studies. tis. The presence of slowly progressive, asymmetric quadriceps
and wrist/finger flexor weakness in a patient over 50 years of
Inclusion Body Myositis age strongly suggests the diagnosis of IBM, regardless of what
Clinical Features. Inclusion body myositis (IBM) is the the muscle biopsy might show.
third major type of idiopathic inflammatory myopathy. IBM is Dysphagia is common, occurring in up to 40% of patients, and
characterized clinically by the insidious onset of slowly pro- can be debilitating, requiring cricopharyngeal myotomy or even
gressive proximal and distal weakness developing in patients a feeding tube.18919,-457-759-78° Mild facial weakness is apparent on
usually over the age of 50 years (Table 28-3).,5-,6-20 i35-180-294-457- examination in at least 33% of IBM patients; however, this
575a.632,797.679 Although frequently misdiagnosed, IBM is in fact weakness is clinically insignificant.1516 Extraocular muscles are
the most common inflammatory myopathy in patients over the spared. Although most patients have no sensory symptoms, evi-
age of 50 years. There is typically a delay in diagnosis, averag- dence of a generalized peripheral neuropathy can be detected in
ing approximately 6 years from the onset of symptoms, most up to 30% of patients on clinical examination and electrophysio-
likely related to the slow evolution of the disease.15-457 Males are logical testing.15 Muscle stretch reflexes are normal or slightly
much more commonly effected than females, in contrast to the decreased. In particular, the patellar reflexes are lost early.457
female predominance seen in dermatomyositis and polymyosi- Unlike polymyositis and dermatomyositis, IBM is not associ-
tis. The clinical hallmark of IBM is early weakness and atrophy ated with myocarditis or ILD, nor is there an increased risk of
of the quadriceps (Fig. 28-4A), volar forearm muscles (i.e., malignancy. 129 Autoimmune disorders such as SLE, Sjogren's
Figure 25-5. Inclusion body myositis. A, Muscle biopsy reveals muscle fibers with rimmed vacuoles and endomysial inflammatory cells invad-
ing non-necrotic fibers, H&E. B, Congo red staining demonstrates amyloid deposition using polarized light. (From Amato AA, Barohn RJ: Idiopathic
inflammatory myopathies. Neurol Clin 1997; 15:615-648, with permission.)
syndrome, scleroderma, thrombocytopenia, and sarcoidosis have fibers.453-294 Expression of aB-crystallin, a member of the heat
been reported in up to 15% of IBM patients.188-401-509 Diabetes shock protein family, was demonstrated to be increased not only
mellitus was reported in 20% of patients in one large series,457 in abnormal muscle fibers, but even more so in normal-appear-
but others have not noticed a similar increased incidence.679 ing muscle fibers (so-called "X-fibers") in IBM patients.61
Most of the IBM patients are older and life expectancy does A small study found that the number of vacuolated and amy-
not appear to be significantly altered. IBM is slowly progressive loid-positive fibers increased with time in most patients. 64
and does not respond well to immunosuppressive medications. Interestingly, there is an increased number of ragged red fibers in
In our experience, most patients remain ambulatory, although IBM compared to dermatomyositis and polymyositis patients and
they frequently require or at least benefit from a cane or a age-matched controls. 626 Electron microscopy demonstrates
wheelchair for long distances. However, some patients become 15-21 nm cytoplasmic and intranuclear tubulofilaments.294-457
severely incapacitated and require a wheelchair or become bed- Vacuolated fibers also contain cytoplasmic clusters of 6-10 nm
ridden within 10-15 years. amyloid-like fibrils.294 Because of sampling error, repeat muscle
Many patients with so-called steroid-resistant or "refractory" biopsies may be required to identify the rimmed vacuoles, en-
polymyositis eventually are diagnosed with IBM. Importantly, domysial inflammation, and either the abnormal tubulofilament
there are patients who clinically resemble IBM, but in whom a or amyloid accumulation necessary to histologically confirm the
definitive diagnosis cannot be confirmed on muscle biopsy. 15 diagnosis of IBM. 15 This sampling error probably accounts for
We diagnose these patients with "possible" or "probable" IBM being misdiagnosed as PM or "inflammatory myopathy
IBM.15-294 Although we offer a 6-month trial of high-dose pred- with COX-negative muscle fibers."87-450 Immunostaining for a B -
nisone in patients with histologically confirmed or clinically crystallin may increase the diagnostic yield, particularly when it
probable IBM, we do not advocate more aggressive immuno- is overexpressed in normal-appearing muscle fibers.61
suppressive agents because they are unlikely to respond. As with polymyositis, the inflammation in IBM is en-
Laboratory Features. Serum CK is normal or only mildly domysial and composed of macrophages and CD8+ cyto-
elevated (less than 10-fold above normal).15-294-457 Autoanti- toxic/suppressor T-lymphoeytes, which invade non-necrotic
bodies are usually absent except for the occasional patients with fibers.509 MHC class 1 antigens are expressed on necrotic and
concurrent CTD, although some series have reported positive non-necrotic muscle fibers.222 Investigations of the T-cell recep-
ANAs in approximately 20% of patients.401-458 There is a signifi- tor repertoire demonstrate an oligoclonal pattern of gene re-
cant incidence of the HLA DR3 phenotype in IBM.271 MRI may arrangement and heterogeneity in the CDR3 domain.474-555
show early selective atrophy of the volar forearm and quadri- These immunologic findings suggest that the T-cell response is
ceps muscles. not directed against a muscle-specific antigen, although the re-
Histopathology. The light microscopic findings are en- sponse could be triggered by a superantigen.
domysial inflammation, small groups of atrophic fibers, Pathogenesis. The pathogenesis of IBM is unknown.
eosinophilic cytoplasmic inclusions, and muscle fibers with one Currently, there is ongoing research revolving around whether
or more rimmed vacuoles lined with granular material (Fig. 28- IBM is a primary inflammatory myopathy, or a myopathy in
5^ i5.294.457 Abnormal deposition of amyloid can be demonstrated which the inflammatory response plays a secondary role, such
in vacuolated muscle fibers on Congo red staining using polar- as a dystrophy. The histologic and immunologic studies de-
ized light or fluorescence techniques.40-45a-502 In addition, (3-amy- scribed above provide evidence that IBM may be an autoim-
loid, C- and N-terminal epitopes of p-amyloid precursor protein mune disorder mediated by cytotoxic T-cells. Matrix
(p-APP), prion protein (PrP c ), apolipoprotein E, al-antichy- metalloproteinases (MMP-4, MMP-2, MMP-9) are expressed
motrypsin, ubiquitin, hyperphosphorylated tau protein, and neu- on invading cytotoxic cells, endothelial cells, necrotic and non-
rofilament heavy chain similar to that observed in the brains of necrotic muscle fibers, which may facilitate the migration of the
Alzheimer's patients accumulate within IBM vacuolated inflammatory cells from the vasculature of the muscle
fibers.I45a-,86a-389a Cytokines released by cytotoxic T-cells (IL-2, fibers and mitochondrial DNA mutations are more frequent in
IL-4, IL-5, and IF-y) and by macrophages (IL-1, IL-6, and TNF- IBM patients than in age-matched patients and those with other
a) may exert direct or indirect toxic effects on muscle fibers.1863 types of inflammatory myopathy.294-556-626 However, these mito-
As with PM, the autoinvasive T-cells in IBM contain perforin chondrial abnormalities are thought to be secondary changes
granules. Upon release of these granules, pores form on the and not the primary cause of the myopathy. Increased im-
muscle membrane, resulting in osmolysis and the death of munoreactivity for nitrotyrosine and both the inducible and nu-
muscle fibers.282 Pruitt et al. reported that the frequency of in- clear forms of nitric oxide synthetase have been demonstrated
vaded fibers was greater than either necrotic or amyloidogenic in vacuolated muscle fibers suggesting that nitric oxide-induced
fibers, suggesting that the inflammatory response plays a more oxidative stress may play a role in the pathogenesis of IBM.791
important role in the pathogenesis of IBM than the-accumula- The recent observation of aB-crystallin expression, a member
tion of vacuoles or amyloidogenic filaments.593 of the small heat shock protein family, is increased in IBM muscle
However, the lack of a significant clinical response with vari- tissue, particularly normal-appearing fibers, suggests that there is
ous immunosuppressive therapies alone or in combination a pathologic stressor acting upstream to the development of struc-
argues against IBM being a primary autoimmune disorder. In a tural abnormalities.61 Of note, increased aB-crystallin expression
small study, eight patients with IBM were treated for 6-24 occurred in muscle fibers that did not show increased expression
months with immunosuppressive medications and their re- of nitric oxide synthetase, implying that nitric oxide-induced ox-
sponse to treatment as well as their pre- and post-treatment idative stress is not likely to be the primary pathogenic process.
muscle biopsies analyzed.66 Despite lower serum CK levels and A viral etiology has also been speculated in the pathogenesis
reduced inflammation on the post-treatment muscle biopsies, of IBM. An early hypothesis was that IBM was caused by chronic
none of the patients improved in strength or function. persistent mumps based on immunostaining of inclusions by anti-
Interestingly, the amount of vacuolated muscle fibers and fibers mumps antibodies.146147 However, this was subsequently rejected
with amyloid deposition were increased in the follow-up biop- after in-situ hybridization and polymerase chain reaction studies
sies. These findings suggest that the accumulation of vacuoles failed to confirm mumps infection.373-444- 541-604 Interestingly, histo-
and amyloid could have a significant role in the pathogenesis of logic abnormalities on muscle biopsy similar to IBM have been
IBM, while inflammation may play a secondary role. reported in patients with retroviral infections and post-polio syn-
Another line of evidence suggesting that IBM could be a drome.171679-683 It is possible that an unknown viral infection could
degenerative disorder of muscle rather than autoimmune in- be the trigger for the pathogenic process and that the increased
flammatory myopathy is the accumulation of "Alzheimer-char- aB-crystallin expression is a response to this biologic stressor.61
acteristic proteins" in vacuolated muscle fibers. 35~44-45a-294 Electrophysiologic Findings. Electrodiagnostic medicine
Abnormal accumulation of p-amyloid, C- and N-terminal epi- findings in IBM are similar to those in patients with chronic
topes of P-amyloid precursor protein (p-APP), prion protein polymyositis and dermatomyositis with a few subtle differences, i
(PrP c ), apolipoprotein E, al-antichymotrypsin, ubiquitin, hy- These differences, although notable in retrospect once the muscle I
perphosphorylated tau protein and neurofilament heavy chain biopsy is performed, can be easily missed in many patients.
similar to that observed in the brains of Alzheimer's patients is Sensory Nerve Conduction Studies, In most but not all pa-
evident within IBM vacuolated fibers.35-45 Interestingly, a study tients with IBM, sensory conduction studies are normal.
of 14 IBM patients reported a significant increase in the Although patients are usually asymptomatic, a mild sensory
apolipoprotein E E4 frequency, a finding observed in Alzheimer neuropathy may be evident on clinical examination or nerve
patients.272 However, other studies of IBM patients reported no conduction studies in approximately 30% of IBM patients.15-216-
significant increase in apolipoprotein E e4 allele frequency.45-316 2i8.3i7.37o.42i.457 ^ few G f the patients have clearly had diabetes
Increased acetylcholine receptor, PrP c and p-APP mRNAs have mellitus, but a number of patients had no identifiable cause of
been found in IBM vacuolated fibers. 663 This suggests the in- the abnormality. The SNAPs may be diminished in amplitude in
creased prion and p-amyloid deposition in these muscle fibers a pattern suggestive of a distal symmetric preferentially mild
probably result, in part, from increased transcription of the PrP c sensory peripheral neuropathy. Sural nerve biopsies have re- j
and P-APP genes. Supporting this hypothesis, investigators vealed mild and nonspecific decreases in myelinated fibers.15-421 1
transfected muscle fibers in vitro with p-APP cDNA using a re- Both the neuropathologic and electrophysiologic findings may
combinant-deficient adenovirus vector and demonstrated Congo be age-related, because IBM generally develops in patients over
red-positive, vacuolated fibers with tubulofilaments, and abnor- 50 years of age.
mal mitochondria typical of those observed in IBM.43-44 Motor Nerve Conduction Studies. As with sensory studies,
Interestingly, p-amyloid and prion proteins can induce apop- mild abnormalities of motor nerve conduction, particularly in the
tosis of neurons in vitro.348 In this regard, regenerating and de- lower limbs, can be observed in some patients with IBM.218-370-457
generating muscle fibers express Fas and Fas ligand, a F-waves have been reported to be normal, suggesting that the pe-
proapoptotic complex.71-266 However, there is no evidence that ripheral nerve slowing is preferentially located distally as op-
apoptosis plays a role in muscle fiber destruction in IBM.348-670 posed to proximally or diffusely. Focal prolongation of the
Perhaps, as in PM, the demonstrated increased co-expression of median distal motor latency across the wrist has also been re-
the anti-apoptotic protein, Bcl-2, in muscle fibers protects ported, supporting the likelihood of finding a median neuropathy
against the potential apoptotic effect of Fas/Fas ligand. 71 at the wrist in some patients.216-457 A detailed analysis of multiple
Although intriguing, the pathogenic relationship of the patients with IBM is needed to properly assess the potential of
Alzheimer-characteristic proteins in IBM and the pathogenesis these persons to develop multiple entrapment neuropathies. In
of the myopathy is not clear. The accumulation of these proteins our experience, entrapment neuropathies are uncommon.
in IBM vacuolated muscle fibers may be an epiphenomenon Needle Electromyography. The most commonly reported
rather than the primary pathogenic defect of IBM.16 electrophysiologic evaluation is needle electromyography.
Besides the accumulation of rimmed vacuoles and tubulofila- Unfortunately, very few reports detail the findings other than
ments. mitochondrial abnormalities as indicated by ragged red to state the needle electromyographic examination is either
"neuropathic," "myopathic," or "mixed neuropathic and myo- fiV) MUAPs in about 56% of patients. The second most
pathic." Few reports have described the MUAPs using quantita- common pattern of MUAP findings consisted of membrane in-
tive needle electromyography but those that do report MUAPs stability combined with both short-duration, small-amplitude
consistent with a myopathy.623-103 IBM usually displays prominent MUAPs as well as long-duration (> 18 ms), large-amplitude (> 5
positive sharp waves and fibrillation potentials.216-457 Complex mV) MUAPs noted in approximately 37% of patients. This com-
repetitive discharges are also prominent in some patients.216-457 bination of abnormalities may be seen a in single patient, even in
Quantitative needle electromyography can reveal several ab- the same muscle. The least frequently observed pattern of abnor-
normal patterns. The majority of patients demonstrate polypha- malities was membrane instability and long-duration, large-am-
sic MUAPs that are short in duration.125-134-187-216-218.370.421.457.460
A plitude MUAPs (7%). Another study compared 13 quantitative
striking feature is the concomitant documentation of long-dura- electromyography studies to eight studies using conventional
tion, large-amplitude, polyphasic MUAPs. A few patients have qualitative electromyography in patients with biopsy-proven
been reported with primarily the latter type of MUAPs mixed IBM. 103 The interpretation of the examinations using conven-
with normal-appearing ones and few, if any, short-duration tional electromyography was frequently that of a neurogenic
MUAPs. Unfortunately, the details of duration measurement are process (four of eight) or nondiagnostic (three of eight). Only
frequently lacking. This becomes important in quantitative elec- one patient was correctly identified as having a myopathy. In
tromyography because it is recommended that polyphasic poten- contrast, the diagnosis of a myopathic process was correctly as-
tials of any duration be ignored when calculating mean MUAP sessed in all 13 patients undergoing quantitative electromyogra-
duration. If this procedure is not followed, erroneous results can phy. All of these findings are compatible with a primary muscle
be obtained when attempting to diagnose a myopathic disorder disease and point out that one cannot have a mind set about spe-
based on duration criteria. It is the detection of long duration and cific patterns of abnormality dictating a unique disease process.
relatively large amplitude for first recruited MUAPs that has Single-Fiber Electromyography. A few studies have per-
caused confusion in the past as to whether IBM is primarily a formed single fiber analysis in patients with IBM. There is a
"neurogenic" or "myogenic" disorder. characteristic increase in jitter, but this elevation is usually mild.
As noted above, careful analysis of patients with unquestion- A few single fiber pairs demonstrate blocking. It is also
able polymyositis and dermatomyositis occasionally reveal common for fiber density to be mildly and rarely moderately in-
rather large numbers of long-duration, large-amplitude MUAPs, creased in the majority of patients examined. Although not
especially in more chronic forms of the disease. Segmental specifically investigated, it appears that patients with more
necrosis with regeneration and collateral sprouting, fiber split- chronic disease and preferential distal involvement, the fiber
ting, and fiber hypertrophy lead to the high amplitude potentials density is more significantly elevated and correlates with a
when the needle electrode is located in proximity to the remod- higher number of long-duration, large-amplitude MUAPs.218-370
eled regions of the motor unit. Fiber size variation and motor Macro-Electromyography. In contrast to conventional elec-
unit remodeling with expansion of the endplate zone lead to tromyography, macro-electromyography records the electrical
long-duration MUAPs. These findings are all compatible with activity from an entire motor unit. Therefore, the areas and am-
what is noted in both polymyositis, dermatomyositis, and IBM plitudes obtained on macro-electromyography provide informa-
histologically as well as electrophysiologically. Similarly, tion regarding the size of the motor unit and can help
MUAPs with satellite potentials can be generated by this mecha- differentiate between a myopathic and a neurogenic process. A
nism and may be observed in IBM when a trigger and delay line study of 11 patients with IBM using concentric needle and
are used. Increased jitter and fiber density noted on single-fiber macro-electromyography demonstrated findings that did not
electromyographic evaluation of patients with IBM218-370 are also suggest a coexisting neurogenic component. 460 Although con-
noted in polymyositis.329 None of these findings are incompati- ventional needle electromyography revealed a mixture of large-
ble with a primary myopathic etiology of IBM and there is no and small-duration polyphasic MUAPs, macro-electromyogra-
need to invoke a potential neurogenic basis for the MUAP alter- phy demonstrated normal or small amplitudes and areas consis-
ations. There may be a mild peripheral neuropathy associated tent with a myopathic disorder.
with some patients who have IBM, but these peripheral nerve
changes are insufficient to account for the abnormalities noted OTHER IDIOPATHIC INFLAMMATORY MYOPATHIES
on needle electromyography, particularly in proximal muscles.
Few studies have analyzed the recruitment frequencies in pa- These other idiopathic inflammatory myopathies are much
tients with IBM.216-218 These investigations demonstrate both a less common than polymyositis, dermatomyositis, inclusion
reduced ("neurogenic") and early ("myogenic") recruitment in- body myositis, and the overlap syndromes (Table 28-2). The
terval in different patients. These apparently disparate findings electrophysiologic features are similar to those described above
may simply reflect the chronicity of the disease state with more for polymyositis and dermatomyositis.
profound muscle loss appearing more like a motor unit loss (neu-
rogenic) pattern versus less long-standing disease maintaining Infantile Myositis/Congenital Inflammatory Myopathy
the random dropout of muscle fibers (myopathic pattern). Myositis with perinatal onset was first described in Japan.392
Because of the frequent mixed myopathic-neurogenic appear- Subsequently, there have been several reports in the western
ance of IBM with conventional qualitative electromyography, hemisphere of so-called infantile myositis or congenital inflam-
quantitative electromyography has been demonstrated to be matory myopathy.393-534-637-689-737 The disorder is characterized by
quite useful.103-370 One carefully performed quantitative monopo- the antenatal or perinatal presentation of hypotonia and general-
lar needle electromyographic study on 30 patients with IBM ized weakness associated with the presence of inflammation on
demonstrated three major patterns of MUAP findings, with some muscle biopsy. Serum CK is usually elevated and the electro-
type of abnormality noted in all patients. 370 The first pattern myogram is myopathic. However, careful review of the clinical
demonstrated a combination of significant membrane instability features of most of the patients are suggestive of a congenital
combined with short-duration (< 6 ms), small-amplitude (< 500 muscular dystrophy (i.e., Fukuyama-type, Walker-Warburg
syndrome, or the classic/occidental type). 20 Only one case, which Eosinophilic Polymyositis
had perifascicular atrophy and immunoglobulin and complement Clinical Features. Eosinophilic polymyositis usually occurs as
deposition on muscle biopsy characteristic of DM and improved a part of the hypereosinophilic syndrome (HES).60-440-520 The diag-
with steroids, was strongly suggestive of a primary myositis.637 nostic criteria of HES are: (1) persistent eosinophilia of 1500
Most of the reported children did not significantly improve with eosinophils/mm3 for at least 6 months, (2) no evidence of parasitic
corticosteroids. In addition, the biopsies had dystrophic features or other recognized causes of eosinophilia, and (3) signs and symp-
in addition to the inflammatory infiltrates. Importantly, the pres- toms of organ system involvement related to infiltration of
ence of inflammation is not specific for a primary inflammatory eosinophils. Eosinophilic PM is characterized by an insidious onset
myopathy and can be demonstrated in Duchenne, facioscapulo- of muscle pain and proximal weakness. The myopathy is often ac-
humeral, congenital and other forms of muscular dystrophies.558 companied by other systemic manifestations of HES, including en-
There have been several reports of patients with the occidental cephalopathy, peripheral neuropathy, myocarditis/pericarditis (i.e.,
type of congenital muscular dystrophy with hypomyelination fibrosis, CHF, arrhythmia, conduction block), pulmonary (i.e., fi-
who had prominent inflammation and merosin (a2 laminin) de- brosis, pleuritis, and asthma), renal and gastrointestinal involve-
ficiency on muscle biopsy.503-529-575 Of note, mutations within the ment, and skin changes (e.g., petechial rash, splinter hemorrhages
merosin gene were demonstrated. It is likely that the majority of of the nail beds, livedo reticularis, and Raynaud's phenomenon).
infants with inflammation findings on biopsy have a form of con- Early reports suggested a poor prognosis for long-term sur-
genital muscular dystrophy rather than a primary myositis. vival with 3-year survival of less than 20% . However, these
series may have been biased by the inclusion of autopsied cases.
Focal Myositis Response to corticosteroids has been inconsistent, but has been
Clinical Features. Focal myositis is a rare disorder that can effective in some patients in reducing the eosinophilia and end-
develop in infancy, to late adult life.I26-156-323-325*523-530 It presents as a organ damage. Second-line cytotoxic agents should be tried if
solitary, painful, and rapidly expanding skeletal muscle mass that patients fail to improve with steroids (see Treatment).
often mimics a malignant soft tissue tumor. The leg is the most Laboratory Features. Hypereosinophilia, hypergamma-
common site of involvement but it can also affect the upper limbs, globulinemia, anemia, elevated serum CK, and rheumatoid
abdomen, and head and neck. There are rare cases of focal myosi- factor are evident. ESR is elevated in less than 50% of cases,
tis generalizing to more typical polymyositis. 324 The disorder and ANA is usually negative. The EKG may demonstrate car-
needs to be distinguished from sarcoidosis, Behcet's disease, and diac arrhythmias or conduction block. Pulmonary infiltrates
vasculitis, which can begin focally and involve skeletal muscle as may be apparent on chest x-ray.
well as soft tissue tumors, e.g. sarcoma. The lesions may resolve Histopathology. Muscle biopsies demonstrate perivascular
spontaneously, following surgical excision or biopsy, or with corti- and endomysial inflammation composed predominantly of
costeroid treatment. Rarely, focal myositis can recur.693 eosinophils. Necrotic, invaded, and regenerating muscles fibers
Laboratory Features. Serum CK and ESR are usually are evident. Nodular granulomas may also be evident.
normal. MR and CT imaging demonstrate edema within the af- Pathogenesis. The etiology of eosinophilic polymyositis
fected muscle groups.126-523-530 and HES is unknown. Tissue destruction may be related to infil-
Histopathology. Mononuclear inflammatory cells com- tration by eosinophils and the release of toxins contained within
posed of CD4+ and CD8+ T-lymphocytes and macrophages are the eosinophilic granules.
present in the endomysium. 126 Necrosis and phagocytosis of
necrotic fibers are apparent. Nonspecific myopathic features Diffuse Fasciitis with Eosinophilia
such as fiber size variability, split fibers, increased central Clinical Features. Diffuse fasciitis with eosinophilia, also
nuclei, and endomysial fibrosis are also described. One report known as Shulman's syndrome, is characterized by scleroderma-
noted that MHC class 1 antigens were not expressed on muscle like skin changes and peripheral eosinophilia.60-424-692 Men are af-
fibers, in contrast to polymyositis, in which these antigens are fected more commonly than women, with a ratio of 2:1. The
typically expressed on the fibers.126 majority of patients are between 30 and 60 years of age, but the dis-
Pathogenesis. The etiology is unknown. Immunologic stud- order has been reported in children. Early symptoms include myal-
ies suggest the disorder is distinct from polymyositis and not gias, muscle tenderness, arthralgias, and low-grade fever.
the result of a cell-mediated attack directed against a muscle- Thickening of the skin with edema and dimpling ("peau d'orange")
specific antigen.126 develops in the limbs and occasionally the trunk. Joint contractures
may develop in the hands, elbows, knees, and less commonly at the
Dropped-Head Syndrome shoulders and hips secondary to immobilization due to severe pain.
Some cases of so-called dropped-head syndrome may repre- Proximal muscles may be weak, although quantification is difficult
sent focal myositis restricted to the paraspinal muscles, particu- secondary to decreased effort because of the pain. Unlike HES with
larly the cervical muscles.82-378-641 This myopathy is discussed in eosinophilic PM, the heart, lungs, kidneys, and other visceral
greater detail in the chapter on hereditary myopathies. Most of organs are usually not involved. However, there does appear to be a
the patients reported in the literature have not had inflammation disproportionate number of hematologic complications, including
demonstrated on biopsies of cervical paraspinal muscles. aplastic anemia, idiopathic thrombocytopenia, leukemia, lym-
Nevertheless, inflammatory infiltrate can occasionally be seen phoma, and other lymphoproliferative disorders.
and some patients appear to improve with immunosuppressive Prognosis is favorable with treatment. Patients usually re-
agents.82 Therefore, a focal myositis as the pathogenic basis for spond rapidly to corticosteroid treatment. In addition, sponta-
this disorder is possible. However, one must remember that in- neous remission may also occur. Relapses have been reported in
flammatory infiltrates can be seen in various forms of muscular a minority of patients. The prognosis is not as favorable in cases
dystrophy and in myasthenia gravis (i.e., lymphorrhages). The with hematologic complications.
presence of inflammation alone does not prove that this disorder Laboratory Features. Peripheral eosinophilia (> 7%) occurs
is an autoimmune myositis. in over two-thirds of patients.60-424-692 Hypergammaglobulinemia
and elevated ESR occur in at least one-third of patients. Serum
CK is usually normal, while ANA testing is positive in up to
26% of patients. Electromyography may demonstrate myo-
pathic MUAPs and muscle membrane instability in the superfi-
cial subfascial layers.
Histopathology. Full-thickness biopsy extending from the
skin to muscle is required for diagnosis." Histologic sections
demonstrate thickened fascia infiltrated by lymphocytes,
macrophages, plasma cells, and eosinophils.60-424-692 Inflammatory
infiltrates may invade the adjacent subcutaneous tissue, perimy-
sium, and endomysium. Scattered necrotic fibers and perifascicu-
lar atrophy have been described. Immunoglobulin and C3
deposition in the fascia have also been reported in some patients.
Pathogenesis. The etiology of diffuse fasciitis with eosino-
philia is not known. Laboratory and histologic features suggest
an autoimmune basis. The disorder shares many clinical and
histologic features with the eosinophilic myalgia334 and toxic oil Figure 28-6. Giant-cell myositis. Muscle biopsy demonstrates en-
syndrome 390 that are caused by the ingestion of tryptophan and domysial inflammatory cells, including multinucleated giant cells
denatured rapeseed, respectively. The similarity of these condi- (arrow) in a patient with malignant thymoma, myasthenia gravis, and
tions suggests the possibility of a toxin-induced fasciitis; how- myositis (H&E stain).
ever, the majority of patients with eosinophilic fasciitis report
no known toxic exposures.
can be focal, multifocal, or generalized. Patients may develop
Granulomatous and Giant-Cell Myositis focal muscle pain, tenderness, atrophy, and weakness, or the
Clinical Features. An interesting variant of polymyositis process can be generalized, affecting proximal greater than
is granulomatous or giant-cell polymyositis.332-537-574-590a Many distal weakness. Asymptomatic granulomas may be palpated
patients also have myasthenia gravis and/or a thymoma, which within the muscle. Occasionally, a superimposed neuropathy is
can be benign or malignant. The myositis can develop before also evident. There have been a few reports of patients with sar-
or after the clinical presentation of myasthenia gravis or thy- coid myopathy who concomitantly have clinical and histologic
moma diagnosis. Besides proximal weakness, patients with features of dermatomyositis or IBM. A single case has been re-
concurrent myasthenia gravis also had diplopia, ptosis, and ported with a patient demonstrating widespread electrical my-
bulbar dysfunction. A granulomatous myocarditis can also de- otonia suggesting adult-onset acid maltase deficiency.205
velop manifesting as congestive heart failure and arrhythmia. Treatment of sarcoidosis is usually focused on other systemic
Some patients improve with corticosteroids, although the re- manifestations as the myositis is typically asymptomatic.
sponse does not seem to be as favorable as evident in the more Corticosteroids are effective in treating the myositis.
common idiopathic polymyositis. The poorer response is probably Laboratory Features. Serum angiotension-converting
related to the frequent myocardial involvement and the superim- enzyme levels are often elevated. The patients are frequently an-
posed myasthenia gravis and thymoma. More aggressive immuno- ergic to antigen skin testing. Chest films usually demonstrate
suppressive therapy with high-dose corticosteroids and second-line hilar lymphadenopathy and parenchymal involvement of the
agents such as azathioprine and methotrexate may be warranted. lungs. Serum CK is usually normal or only mildly elevated. A
Laboratory Features. Serum CK is usually elevated. single person with sarcoid myopathy is reported to have had
Acetylcholine receptor antibodies and a decrement on repetitive abundant myotonic potentials in multiple muscles.205
nerve stimulation may be evident in patients with superimposed
myasthenia gravis.
Histopathology. Features typical of polymyositis are pre-
sent on muscle biopsy. In addition, granulomas and multinucle-
ated giant cells are evident in skeletal and often cardiac muscle
as well (Fig. 28-6).332-537-574-590a
Pathogenesis. This myositis is an autoimmune disorder of
unknown etiology. The granuluomatous inflammation and giant
cell formation suggest an abnormality in cell-mediated immu-
nity, whereas the frequent occurrence of myasthenia gravis sup-
ports aberrant humorally mediated immunity.
Sarcoid Myopathy
Clinical Features. Sarcoidosis is more prevalent in black
than white patients and in women more than men. Although un-
common, it has been reported in children. The majority of pa-
tients present with pulmonary symptoms and lymphadenopathy.
Erythema nodosum and arthralgias are also early features.
Many patients with sarcoidosis have granulomas in the muscle, Figure 28-7. Sarcoid myopathy. Muscle biopsy reveals a granulo-
although signs and symptoms of muscle involvement are present matous infiltrate within the endomysium in a patient with sarcoidosis
in the minority of patients.605903-695-720-7304-7333 Muscle involvement (H&E stain).
Histopathology. The lesions predominate perivascularly in myopathy. Serum CK, aldolase, AST, ALT, and LDH may be ele-
the connective tissue and take the form of noncaseating granu- vated, but they can be normal in patients with an inflammatory
lomas consisting of clusters of epithelioid cells, lymphocytes, myopathy, particularly with IBM and early in DM. Besides a
and giant cells (Fig. 28-7).590a Because of the multifocal in- serum CK, we routinely order CBC, serum electrolytes, renal and
volvement, several pieces of muscle and serial sections may be liver profiles, urinalysis, thyroid function tests, ANA, ESR,
required to demonstrate the granulomas. rheumatoid factor, and chest x-rays in patients suspected of
Pathogenesis. The exact pathogenic mechanism is unknown having an inflammatory myopathy. The performance of a detailed
but involves abnormal cell-mediated immunity as reflected by and quantitative electrodiagnostic medicine consultation is also
the granulomas and T-cell anergy in vitro and in vivo. important in determining the presence of a myopathic disorder.
Electromyography is useful in assessing which muscle to biopsy,
Behcet's Disease particularly in patients with only subtle weakness on examina-
Clinical Features. Behcet's disease is a multisystemic disor- tion. Muscle biopsy analysis of an affected muscle is the forth and
der with recurrent mucocutaneous and ocular manifestations (e.g., most critical aspect of diagnosing an inflammatory myopathy. A
oral and genital ulcers, hypopyon, iritis). Other manifestations in- nonspecific myopathic muscle biopsy or even a normal biopsy in
clude erythema nodosum, thrombophlebitis, colitis, meningoen- a patient with highly suspicious clinical findings does not imme-
cephalitis, and peripheral neuropathy. In addition, there are reports diately rule out an inflammatory myopathy, but may suggest a
of myositis and myocarditis in Behcet's disease.7-208 245-433-454-787-793 sampling error due to multifocal involvement of muscle tissue.
Onset can be in childhood or late adult life. Patients frequently Repeat muscle biopsies are sometimes required to confirm the
complain of focal myalgias with or without weakness, although clinical suspicion of an inflammatory myopathy.
symptoms can be generalized. There is a predilection for involve-
ment of the lower limbs, particularly the calves. TREATMENT OF IDIOPATHIC
Laboratory Features. Usually there is leukocytosis, ele- INFLAMMATORY MYOPATHIES
vated ESR and C-reactive protein levels, and normal or mildly
elevated serum CK levels. Approximately 50% of patients are The response of the inflammatory myopathies to im-
HLA-B5-positive. 787 munomodulating therapies has been the subject of a large
Histopathology. Light microscopy demonstrates granulo- number of studies.16-17-398 Unfortunately, many of these studies
cytic-monocytic inflammation with invasion of non-necrotic grouped adult and childhood dermatomyositis together with
muscle fibers. Immunocytochemistry reveals predominantly polymyositis and IBM patients. Another obstacle to interpreting
macrophages along with CD4+ and CD8+ lymphocytes. 787 the literature is that most of the treatment trials were retrospec-
MHC class 1 antigens are expressed on most muscle fibers. tive, unblinded, and lacked placebo controls. Further, results of
Deposits of complement factor C3 and immunoglobulins may treatment for the less common idiopathic inflammatory my-
be found in blood vessel walls.787 opathies are derived mostly from small anecdotal reports. There
Pathogenesis. The etiology of Behcet's disease is unknown. have only been four published prospective, double-blinded,
The immunohistologic findings suggest a cell-mediated attack placebo-controlled trials in the treatment of inflammatory my-
directed against muscle fibers. However, recent studies demon- opathy: one involved azathioprine in the treatment of polymyosi-
strating enhanced neutrophil migration and immune complex tis122 and the other three studied intravenous immunoglobulin
deposition on blood vessels support a leukocytoclastic vasculi- (IVIG) in the treatment of dermatomyositis 181 and IBM. 185186b
tis or vasculopathy in the pathogenesis of the disease.787 Another impediment in interpreting results of treatment is that in
Prognosis. The myositis is responsive to immunosuppres- several reports, patients with subjective improvement or lower
sive therapy. serum CK levels were defined as positive responses rather than
the more important objective improvement in muscle strength
DIAGNOSTIC EVALUATION OF PATIENTS WITH and function.363-445 Nevertheless, it is clear to experienced clini-
SUSPECTED INFLAMMATORY MYOPATHY cians that various modes of immunotherapy are helpful in der-
matomyositis and polymyositis in improving muscle strength
The differential diagnosis of an inflammatory myopathy is and function.1617 In contrast, IBM is generally refractory to im-
based on the clinical and histologic findings more than on the elec- munosuppressive therapy. Various treatment modalities used in
trophysiologic aspects noted above. The electrophysiologic fea- idiopathic inflammatory myopathies are listed in Table 28-4.
tures of the inflammatory disorders are unfortunately not unique Corticosteroids. Most authorities recommend prednisone as
to these diseases. Short-duration polyphasic MUAPs accompanied the first-line treatment of dermatomyositis and polymyositis. 1617
by early recruitment and membrane instability can be observed in Retrospective studies have demonstrated that high-dose pred-
a number of myopathic conditions, including but not limited to the nisone reduces morbidity and improves muscle strength and
muscular dystrophies, congenital myopathies, metabolic my- function.16-330-363-533-749-801 Short courses of intravenous (IV) sol-
opathies, and toxic myopathies. Thus, a muscle biopsy is usually umedrol have also been used with some success.3-438 In retro-
necessary for the definitive diagnosis of a myopathic condition. spective series, 58-100% of dermatomyositis patients improved
The diagnostic certainty of any disease is based on clinical and at least partially, whereas 30-66% responded completely to
laboratory data. With respect to inflammatory myopathies, four prednisone therapy.15 363 Over 80% of polymyositis patients im-
major aspects of patient evaluation are considered to define defi- proved at least partially, and 10-33% responded completely to
nite and probable disease certainty. The first aspect of any diag- prednisone.15-363 Most dermatomyositis and polymyositis pa-
nosis to consider are the patient's historical presentation and tients demonstrate objective clinical improvement within 3-6
clinical findings on physical examination. The pattern of muscle months of starting prednisone therapy. If no response is noted
weakness and the rate of progression are extremely important in after an adequate trial of high-dose prednisone, other alternative
differentiating inflammatory myopathies from other myopathic diagnoses (i.e., IBM or an inflammatory muscular dystrophy)
disorders and in distinguishing the different types of inflammatory should be considered.
Table 28-4. Immunosuppressive Therapy for Inflammatory Myopathies
Therapy Route Dose Side Effects Monitor
Prednisone PO 100 mg/day for 2-4 weeks, Hypertension, fluid and weight gain, hyper- Weight, blood pressure,
then 100 mg every other glycemia, hypokalemia, cataracts, gastric serum glucose/potassium,
day; single a.m. dose irritation, osteoporosis, infection, aseptic cataract formation
femoral necrosis
Methylprednisone IV I g in 100 ml/normal saline Arrhythmia, flushing, dysgeusia, anxiety, Heart rate, blood pressure,
over 1-2 hours, daily or every insomnia, fluid and weight gain, hyper- serum glucose/potassium
other day for 3-6 doses glycemia, hypokalemia, infection
Azathioprine PO 2-3 mg/kg/day; single a.m. dose Flu-like illness, hepatotoxicity, pancreatitis, Monthly blood count,
leukopenia, macrocytosis, neoplasia, liver enzymes
infection, teratogenicity
Methotrexate PO 7.5-20 mg weekly, single or Hepatotoxicity, pulmonary fibrosis, infection, Monthly liver enzymes, blood
divided doses; one day a week neoplasia, infertility, leukopenia, alopecia, count; consider liver biopsy
dosing gastric irritation, stomatitis, teratogenicity at 2 gm accumulative dose
IV/IM 20-50 mg weekly; one day a
week dosing
Cyclophosphamide PO 1.5-2 mg/kg/day; single a.m. dose Bone marrow suppression, infertility, Monthly blood count,
hemorrhagic cystitis, alopecia, infections, urinalysis
neoplasia, teratogenicity
! IV I g/m 2 /month Same as PO (although more severe), Daily to weekly blood
as well as nausea/vomiting, alopecia count, urinalysis
Chlorambucil PO 4—6 mg/day, single a.m. dose Bone marrow suppression, hepatotoxicity, Monthly blood count,
neoplasia, infertility, teratogenicity, infection liver enzymes
Cyclosporine PO 4-6 mg/kg/day, split into two Nephrotoxicity, hypertension, infection, Blood pressure, monthly
daily doses hepatotoxicity, hirsutism, tremor, gum cyclosporine level, creati-
hyperplasia, teratogenicity nine/BUN, liver enzymes
Intravenous IV 2 gm/kg over 2-5 days; then Hypotension, arrhythmia, diaphoresis, Heart rate, blood pressure,
immunoglobulin every 4-8 weeks as needed flushing, nephrotoxicity, headache, aseptic creatinine/BUN
meningitis, anaphylaxis, stroke
From Amato AA, Barohn RJ: Idiopathic inflammatory myopathies. Neurol Clin 1997;15:615-648, with permission.
Regarding IBM, most authorities report minimal, if any, clini- every morning. After 2-4 weeks of daily prednisone, we switch
cally significant improvement in strength or function with pred- to alternate-day dosing (i.e., 100 mg qod). 16 Patients with more
nisone or other second-line agents.14 l5-66-67-294-457-509 There are a few severe disease may need to be slowly tapered to alternate-day
retrospective, unblinded studies reporting mild or transient im- dosing over 2-3 months. 180184 We follow patients initially at
provement in IBM treated with prednisone. One group of re- least every 2-4 weeks and maintain the high-dose prednisone
searchers has reported that 40-58% of patients partially responded until the patients are back to normal strength or until improve-
to prednisone, although none had complete remission.363-445 ment in strength has reached a plateau (usually 4-6 months).
However, in these studies, a positive response could be defined as Subsequently, we slowly taper the prednisone by 5 mg every
subjective improvement or lower serum CK levels following treat- 2-3 weeks. Once the dose is reduced to 20 mg qod, prednisone
ment. The same researchers also conducted a small (11 patients), is tapered no faster than 2.5 mg every 2 weeks. If a patient does
unblinded, prospective, cross-over study comparing prednisone not significantly improve after 4-6 months of prednisone, or if
plus azathioprine and oral methotrexate to prednisone plus IV there is an exacerbation during this period, we add a second-line
methotrexate.445 Although, no clinically significant improvement agent (azathioprine or methotrexate). At the same time, the
in strength was noted, the serum CK levels decreased in 66-70% prednisone dose is doubled and given daily (no more than 100
of the patients, and there was no decline in strength over the 6- mg per day) for at least 2 weeks before switching back to alter-
month treatment period in most of the patients in both study arms. nate-day dosing. Once a patient has regained his or her strength,
The authors concluded that the combination of immunosuppres- we resume the prednisone taper at a slower rate. Although
sive medications stabilized the disease process. Unfortunately, be- serum CK levels are monitored, adjustments of prednisone and
cause IBM is a slowly progressive disorder, the trial lasted only 6 other immunosuppressive agents should be based on the objec-
months, and the study was neither blinded nor placebo-controlled, tive clinical examination and not the CK levels or the patient's
the authors' assertion that immunosuppressive medications stabi- subjective response. As we discussed previously, serum CK
lize the course of IBM may have been premature. levels can be elevated in patients with no objective weakness or
Most authorities agree that prednisone should be started at a normal or only mildly elevated in patients with active disease.
high dose (1.0-2.0 mg/kg/day) in the treatment of dermato- An increasing serum CK can herald a relapse, but without ob-
myositis and polymyositis.16-20-21-180-229-295-551 We initiate treatment jective clinical deterioration we do not recommend increasing
with a single dose of prednisone (1.5 mg/kg up to 100 mg) the dose of the immunosuppressive agent. However, the dose
may be held or the taper slowed. A maintenance dose of pred- physical therapy and encouraged to slowly begin an aerobic ex-
nisone may be required to sustain the clinical response. ercise program. Blood pressure is measured with each visit
Some advocate maintaining treatment with daily prednisone along with periodic eye examinations for cataracts and glau-
rather than switching to alternate-day therapy.551 In addition, coma. Fasting blood glucose and serum potassium levels are
some authorities split the daily dose of prednisone (e.g., three periodically checked. Potassium supplementation may be re-
times a day) instead of consolidating the prednisone into a quired if the patient becomes hypokalemic.
single morning dose.551 We have found no advantage in splitting v Second-Line Therapies. These agents have been used pri-
the dose of prednisone or maintaining daily dosing. Further, it marily in patients who respond poorly to prednisone or who re-
has been shown that alternate-day treatment with prednisone lapse during prednisone taper as well as for their potential
given as a single dose in the morning is as effective and associ- steroid-sparing effect.
ated with less side effects than daily, split-dose steroids.165-750 Azathioprine. Several retrospective studies have suggested
High-dose, long-term steroids and lack of physical activity can that azathioprine could be effective therapy in dermatomyositis
cause type 2 muscle fiber atrophy with proximal muscle weak- and polymyositis.143-330-363-749 One study reported that azathio-
ness. This needs to be distinguished from weakness due to relapse prine improved strength in 64% of dermatomyositis and
of the myositis. Serum CK is normal and electromyography usu- polymyositis patients, although a complete response occurred in
ally does not demonstrate abnormalities in patients with type 2 only 11%. 363 Patients who had a previously good response to
muscle fiber atrophy. Some have found that neck flexor strength prednisone were more likely than prednisone-refractory patients
usually remains relatively stable with type 2 muscle fiber atrophy to improve with the addition of azathioprine. In a prospective,
but worsens with relapse of the myositis.180 Patients who become double-blind study comparing azathioprine (2 mg/kg) in combi-
weaker during prednisone taper, have increasing serum CK nation with prednisone to placebo plus prednisone, there was no
levels, and abnormal spontaneous activity on electromyography significant difference in objective improvement at 3 months. 120
are more likely to be experiencing a flare of the myositis. In con- In the open-label follow-up study, patients on the combination
trast, patients with normal serum CK and electromyography and of azathioprine and prednisone did better than those on pred-
other evidence of steroid toxicity (i.e., Cushingoid appearance) nisone alone. 121 In addition, patients on azathioprine also re-
may have type 2 muscle fiber atrophy and could benefit from quired lower doses of prednisone. Azathioprine has been used
physical therapy and reducing the dose of steroids. effectively in childhood dermatomyositis, but is generally
Concurrent Management. We obtain a chest x-ray and a pu- avoided given its oncogenic potential with long-term use.21
rified protein derivative (PPD) skin test with controls on all pa- We start azathioprine at a dose of 50 mg per day in adults and
tients prior to initiating immunosuppressive medications. 16 gradually increase over 2 months to a total dose of 2-3
Patients with prior history of tuberculosis or those with a posi- mg/kg/day in hope of reducing possible side effects.1617 A sys-
tive PPD may need to be treated prophylactically with isoniazid. temic reaction characterized by fever, abdominal pain, nausea,
In addition, we measure bone density with dual-energy x-ray ab- vomiting, and anorexia occurs in 12% of patients requiring dis-
sorptiometry (DEXA) at baseline and every 6 months while pa- continuation of the drug.394 This systemic reaction generally
tients are receiving corticosteroids. A bone density less than 2.5 occurs within the first few weeks of therapy and resolves within
standard deviations below normal is considered positive for os- a few days of discontinuing the azathioprine. Rechallenge with
teoporosis. Calcium supplementation (1 g/day) and vitamin D azathioprine usually results in the recurrence of the systemic re-
(400 IU/day) are started for prophylaxis against steroid-induced action. Other major complications of azathioprine are bone
osteoporosis. Postmenopausal women should be treated with es- marrow suppression, hepatic toxicity, pancreatitis, teratogenic-
trogen unless contraindicated (e.g., breast cancer), because es- ity, oncogenicity, and risk of infection. Allopurinol should be
trogen is effective in preventing and treating osteoporosis. avoided, because combination with azathioprine increases the
Postmenopausal women who cannot or do not wish to take estro- risk of bone marrow and liver toxicity. A major drawback of aza-
gen should be treated with a bisphosphonates (e.g., alendronate) thioprine is that it often takes 6 months or longer to be effective.
which have been demonstrated to be effective in the prevention We monitor CBC and liver function tests (LFTs), including AST,
and treatment of osteoporosis.2-655 Efficacy in preventing osteo- ALT, bilirubins, and y-glutamyl transpeptidase (GGT), every 2
porosis has been reported in postmenopausal women with and weeks until the patient is on a stable dose of azathioprine, then once
without concurrent estrogen therapy, premenopausal women, a month. It is important to check the GGT as the most reliable indi-
and in men who were receiving corticosteroids. 655 Thus, some cator of hepatic dysfunction, because the AST and ALT are often
authorities advocate alendronate (5-10 mg orally per day) as elevated from muscle involvement. If the white blood cell (WBC)
prophylaxis for osteoporosis on any patient placed on corticos- count falls below 4,000 per mm 3 , we decrease the dose.
teroids.655 However, the long-term side effects of biphosphonates Azathioprine is held if the WBC declines to 2,500 per mm 3 or the
are not known, especially in men and young premenopausal absolute neutrophil count falls to 1000 per mm3. Leukopenia can
women. We reserve prophylactic alendronate (5 mg per day) for develop as early as 1 week or as late as 2 years after initiating aza-
postmenopausal women. If DEXA scans demonstrate osteoporo- thioprine.394 It usually reverses within a month, and it is possible to"
sis at baseline or during follow-up studies, we initiate alen- then rechallenge the patient with azathioprine without recurrence
dronate at 10 mg per day. Alendronate can cause severe of the severe leukopenia. In addition, we discontinue azathioprine
esophagitis and absorption is impaired if taken with meals. if the LFTs increase more than twice the baseline values. Liver tox-
Therefore, patients must be instructed to remain upright and not icity generally develops within the first several months of treatment
eat for at least 30 minutes after taking a dose of alendronate. and can take several months to resolve. Patients can occasionally
We do not prophylactically treat with H 2 -receptor blockers be successfully rechallenged with azathioprine after LFTs return to
unless the patient develops gastrointestinal discomfort or has a baseline without recurrence of hepatic dysfunction.394
history of peptic ulcer disease. Patients are instructed to start a Methotrexate. Methotrexate has long been used to treat pa-
low-sodium, low-carbohydrate, high-protein diet to prevent ex- tients refractory to prednisone, although there are no prospective,
cessive weight gain. In addition, patients are also prescribed blinded, controlled studies to support its benefit. In retrospective
series, as many as 71-88% of dermatomyositis and polymyositis of dermatomyositis and polymyositis patients improving with chlo-
patients, including those refractory to prednisone, improved at rambucil either alone or in combination with other immunosup-
least partially with the addition of methotrexate.124-280-363-505-712 pressive agents.124 551-701767 The risks of secondary malignancies as
Methotrexate has been used effectively for reducing morbidity in well as liver and bone marrow toxicity are presumably increased
refractory childhood dermatomyositis,355-513 although the poten- using combination chemotherapy. Obviously, CBCs and LFTs
tial side effects have limited its use in children. need to be monitored closely in patients treated with chlorambucil.
Methotrexate is administered only one day a week. We begin Cyclosporine and Tacrolimus. Several small series reported
methotrexate orally at 7.5 mg/week given in 3 divided doses 12 that cyclosporine (2.5-10 mg/kg/day) was efficacious in treat-
hours apart.16-17 The dose is gradually increased by 2.5 mg each ment of dermatomyositis and polymyositis, including childhood
week up to 20 mg/week. If there is no improvement after 1 DM. - ' - - - .366.368.382.462.498.583,596,612,614,755.799 Improvement
month of 20 mg/week of oral methotrexate, we switch to
100 16428! 283 299 321
weekly parenteral (intramuscular or intravenous) methotrexate in strength is noticeable within 2-6 weeks, and prednisone can
and increase the dose by 5 mg every week up to 60 mg/week. In be decreased or discontinued in the majority of patients. The cost
patients with severe muscle weakness and/or myocarditis, we and potential side effects have limited its use in most myositis
initiate methotrexate parenterally in doses of 20-25 mg per patients. A pilot study of tacrolimus (FK506) reported improve-
week in combination with corticosteroids. The major side ef- ment in a small number of refractory PM patients.551 Side effects
fects of methotrexate are alopecia, stomatitis, ILD, teratogenic- of cyclosporine and tacrolimus are renal toxicity, hypertension,
ity, oncogenicity, risk of infection, and bone marrow, renal, and electrolyte imbalance, gastrointestinal upset, hypertrichosis, gin-
liver toxicity. Patients receiving methotrexate are also started on gival hyperplasia, oncogenicity, tremor, and risk of infection.
folate supplementation. Doses over 50 mg/week require We start cyclosporine at a dose of 3.0-4.0 mg/kg/day in two
leukovorin rescue, although we rarely use such high doses. divided doses and gradually increase to 6.0 mg/kg/day as neces-
Because methotrexate can cause ILD, we do not recommend sary. 1617 The cyclosporine dose should initially be titrated to
its use in patients who already have the associated ILD. We maintain trough serum cyclosporine levels of 50-200 ng/ml.
always check for an anti-Jo-1 antibody titer in the serum be- Blood pressure, electrolytes and renal function, and trough cy-
cause of the risk of ILD with these antibodies. Baseline and pe- closporine levels need to be monitored periodically. We have
riodic pulmonary function tests need to be checked on patients not yet used tacrolimus in patients with myositis.
treated with methotrexate. As with azathioprine, CBCs and Intravenous Immunoglobulin (IVIG). IVIG has been used in
LFTs need to be followed closely. Liver toxicity is cumulative the treatment of many different autoimmune diseases and has
and patients receiving greater than 2 g total dose may need a become increasingly popular in the treatment of refractory myosi-
liver biopsy if the medication is to be continued. tis.274-739 Small, uncontrolled studies have reported beneficial re-"
Cyclophosphamide. The efficacy of cyclophosphamide is sponse in dermatomyositis and polymyositis with IVIG.638914, 3n -
358.434.639.72i ^ mild improvement in muscle strength was reported
controversial, and it has usually been reserved for patients rein three of four IBM patients treated with IVIG.713 However, we
fractory to prednisone, azathioprine, and methotrexate. Some were unable to document any significant clinical improvement in
studies have reported improvement in individual patients with nine IBM patients treated with IVIG.14 Likewise, we have been
oral and intravenous cyclophosphamide.99-304-404-447 749 However, unimpressed with IVIG in refractory polymyositis. A prospec-
other series have not reproduced a beneficial response but actu- tive, double-blind, placebo-controlled study of IVIG in IBM re-
ally found increased morbidity with intravenous cyclophos- vealed no significant improvement. 186 A subsequent controlled
phamide.167-184261 Cyclophosphamide has also been advocated in trial of IVIG and prednisone to prednisone plus placebo failed to
patients with ILD and has been used in children with dermato- demonstrate clinical efficacy of IVIG and prednisone.18615
myositis and vasculitis with some success.12-731 A prospective, double-blind, placebo-controlled study of 15 pa-
We have had only limited success using cyclophosphamide in tients with dermatomyositis demonstrated significant clinical im-
patients with refractory myositis. Cyclophosphamide can be provement with IVIG.181 Repeat biopsies in five of the responsive
given orally at a dose of 1.0-2.0 mg/kg/day.16 We reserve pulsed patients supported the clinical efficacy, revealing an increase in
IV cyclophosphamide at 1 g/m 2 /month for patients with severe muscle fiber diameter, increase in the number and decrease in the
refractory myositis and ILD. The major side effects are gastroin- diameter of capillaries, resolution of complement components on
testinal upset, bone marrow toxicity, alopecia, hemorrhagic cysti- capillaries, and a reduction in the expression of intercellular adhe-
tis, teratogenicity, sterilization, and increased risk of infections sion molecule-1 and major histocompatibility class 1 antigens.
and secondary malignancies. It is important to maintain a high We initiate IVIG (2 g/kg) slowly over 2-5 days and repeat in-
fluid intake to avoid hemorrhagic cystitis. Urinalysis and CBCs fusions at monthly intervals for at least 3 months. 16 All patients
need to be obtained frequently (every 1-2 weeks at the onset of should have an IgA level checked prior to treatment. Patients
therapy and then at least monthly). Cyclophosphamide should be with low IgA levels may be at risk for anaphylaxis. Patients, es-
decreased if the WBC decreases below 4000/mm 3 . Cyclo- pecially those with diabetes mellitus, should also have renal
phosphamide is held if the WBC declines below 3000/mm 3 , the functions checked because of a risk of IVIG-induced renal fail-
absolute neutrophil count falls below 1000/mm3, or if there is ev- ure. Flu-like symptoms—headaches, myalgias, fever, chills,
idence of hematuria. Cyclophosphamide can be restarted at a nausea, and vomiting are common and occur in as many as half
lower dose once the leukopenia has resolved; we do restart the the patients. Rash, aseptic meningitis, and stroke can also occur.
medication in patients with hematuria. Plasmapheresis and Leukopheresis. Uncontrolled series
Chlorambucil. Chlorambucil is not commonly used in the treat- have reported improvement in dermatomyositis, polymyositis,
ment of myositis because of its oncogenic potential and less pre- and IBM with plasmapheresis or leukopheresis. 23 - ,05 - ,92 !93-333
dictable effect on the bone marrow. Other significant side effects However, a controlled trial of 36 patients with DM and PM
include a hypersensitivity reaction with severe rash (Stevens- comparing plasmapheresis and leukopheresis to sham apheresis
Johnson syndrome), gastrointestinal disturbance, infection, terato- demonstrated no improvement with either plasmapheresis or
genicity, and liver toxicity. There are a few reports in the literature leukopheresis over the sham apheresis.511
Total Body Irradiation. There are a few case reports of re- sharp waves) as well as complex repetitive discharges in a few
fractory dermatomyositis and polymyositis cases improving fol- muscles. MUAPs are usually consistent with the above histo-
lowing total body irradiation (TBI).231-346-386-525 Others have not logic descriptions of random muscle fiber dropout and size vari-
found TBI to be effective in PM. 142 TBI is ineffective in IBM ation, i.e., short-duration, small-amplitude, and polyphasic
and may actually aggravate the disease. 385 MUAPs. Recruitment is consistent with the above-noted myo-
Thymectomy. Thymectomy has been performed on a small genic processes.
number of patients with dermatomyositis and polymyositis re- Treatment. There are no large controlled studies assessing
sulting in demonstrable improvement.169431 the efficacy of various treatment options in HIV-related myosi-
tis. A trial of antiretroviral medications may be of benefit if they
are not already prescribed. Steroids can be effective but there is
MYOSITIS ASSOCIATED W I T H INFECTIONS the risk of further immunosuppression. Treatment with IVIG is
potentially safer and may be useful. Nonsteroidal anti-inflam-
VIRAL INFECTIONS matory drugs (NSAIDs) have been advocated by some. 180
Human Immunodeficiency Virus (HIV) Human T-Cell Leukemia Virus Type I (HTLV-1)
Clinical Features. An inflammatory myopathy can occur in Clinical Features. HTLV-1 infection is associated with the
the setting of HIV infection.53174-177183'435-543-710-718 The disorder has development of adult-T-cell leukemia and tropical spastic para-
been reported almost exclusively in adults; however, as more chil- paresis (TSP).127-171-234-257-336-446-524 HTLV-1-related myositis can
dren become infected, myositis may become more frequently di- develop in patients with or without leukemia or TSP. The my-
agnosed. The myositis usually develops in patients with AIDS but opathy manifests as progressive proximal weakness similar to
can occur in the early stages of HIV infection. The clinical pre- HIV-related myositis. In a patient with TSP, concurrent myositis
sentation is similar to idiopathic PM with subacute or chronic, should be suspected clinically if the patient has proximal upper
progressive, symmetrical proximal weakness. Patients may com- limb and neck weakness.
plain of myalgias as well as sensory loss if there is a concurrent Laboratory Features. Serum CK is usually elevated.
HIV-related neuropathy. HIV-related myositis needs to be distin- Histopathology. Muscle biopsy is similar to that observed
guished from zidovudine (AZT) myotoxicity, HIV wasting syn- in idiopathic polymyositis and HIV-myositis. Cupler et al. re-
drome, and other neuromuscular disorders that can complicate ported a patient with HTLV-1-associated TSP who also had an
HIV infection. Rhabdomyolysis has also been reported as a com- inflammatory myopathy with histologic features of IBM.171
plication of HIV infection.470 Cupler et al. reported two HIV-in- Pathogenesis. Similar to HIV-related myositis, HTLV-1 can
fected patients who clinically and histologically resembled be demonstrated within some inflammatory cells but not in the
IBM.171 Features unusual for IBM in these patients were the early muscle fibers themselves. A T-cell-mediated and MHC-1-re-
age of onset (mid-30s) and the markedly increased CK (almost 30 stricted cytotoxic process identical to that described for HIV is
times the upper limit of normal) in one patient. suspected.
Laboratory Features. Serum CK is elevated in most patients. Electrophysiologic Findings. Electrophysiologic features
Histopathology. Perimysial and endomysial inflammation are similar to those described for HIV myositis. In addition, an
consisting mainly of CD8+ cytotoxic T-cells and macrophages upper motor neuron pattern of impaired modulation of recruit-
are evident on muscle biopsy.350 Invasion of non-necrotic ment can be seen in patients who also have TSP.
muscle fibers as well as necrotic and regenerating fibers are pre- Treatment. Small anecdotal reports of small series of pa-
sent. Perivascular inflammation is common, but actual necrotiz- tients suggest that the myositis may improve with corticosteroid
ing vasculitis is not seen. Occasionally, nemaline rods and treatment. In contrast, the myelopathy does not appear to be
cytoplasmic bodies can be found in a few scattered fibers.176 In very responsive to immunosuppressive agents.
addition, Cupler et al. reported HIV patients who had inflam-
matory myopathy with histologic features of IBM.171 HIV-re- fnfluenzavirus
lated myositis must be distinguished from AZT myotoxicity, Clinical Features. Influenza A, B, and rarely C are well-
which is a mitochondrial myopathy, and the HIV wasting syn- known causes of upper respiratory tract infection (URI). Acute
drome that results in severe type 2 muscle fiber atrophy. infection is commonly associated with myalgias when fever and
Pathogenesis. HIV can be detected by the polymerase chain other constitutional symptoms are present. In the majority of
reaction in muscle biopsy specimens. However, the virus is evi- cases, the myalgias are an indirect effect of influenza infection
dent by ultrastructural studies only in inflammatory cells and not and are presumably caused by the systemic release of cytokines.
in the actual muscle fibers.579 Thus, the myositis is probably not Nevertheless, active myositis can develop and the associated
caused by the direct infection of muscle fibers by HIV; rather, clinical syndromes appear different in children and adults.21-320
HIV infection likely triggers a T-cell-mediated and MHC-1-re- In children, as the URI symptoms begin to reside, the myositis
stricted cytotoxic autoimmune response against muscle fibers. presents as severe pain, swelling, and tenderness of the
Electrophysiologic Findings. Motor and sensory nerve con- calves. 2o,389.5oo.507,648 T n e se vere pain limits adequate assessment
3
duction studies in patients presenting with symptoms and signs of muscle strength. Patients may prefer to walk on the toes or
suggestive of polymyositis can be normal or abnormal depend- crawl. Prolonged immobilization can lead to contractures.
ing on whether or not there is a concomitant peripheral neuropa- However, in the majority of children the myositis is self-limited
t n y 53.4J5.696.794 Peripheral neuropathy is a common complication with symptoms lasting less than 1 week. There are rare reports
of HIV infection, particularly in patients with AIDS, and is of myoglobinuria; 150 one such patient had carnitine palmitoyl
much more frequent than inflammatory myopathy. Electro- deficiency that certainly could have predisposed the patient to
myographic features are indistinguishable from idiopathic rhabdomyolysis. 387 In adults, influenzavirus myositis appears
polymyositis. The needle electromyographic examination re- to be more severe.-320-514-526 Myalgias are more generalized but
veals membrane instability (fibrillation potentials and positive less prominent than seen in children. Generalized or proximal
weakness is evident in half the adult patients. Myoglobinuria is with coxsackievirus, parainfluenza, mumps, measles, aden-
more common in adults and can be complicated by renal failure. ovirus, herpes simplex, cytomegalovirus, hepatitis B and C,
Laboratory Features. CK is usually elevated in patients Epstein-Barr virus, respiratory syncytial virus, echovirus, and
with acute myositis, while it is typically normal in uncompli- possibly arboviruses.320 The clinical and electrophysiologic fea-
cated influenza infection.262 As noted above, myoglobinuria and tures of these viruses are indistinguishable from one another.
associated renal failure can be seen and is much more common For diagnosis, acute and convalescent titers (3 or 4 weeks after
in adults. infection) should be obtained from the serum. The blood, stool,
Histopathology. In the childhood type of influenza myosi- urine, and throat can be cultured in attempt to isolate the virus.
tis, scattered necrotic and regenerating muscle fibers are pre- Like influenza, the myositis associated with other viruses is
sent. Interstitial mononuclear and polymorphonuclear usually self-limited and requires only supportive therapy and
inflammatory cells are occasionally found. EM has not demon- treatment of myoglobinuria to prevent renal failure. There is a
strated any viral-like particles in the muscle biopsies, and viral paucity of information regarding the electrodiagnostic findings
culture performed on 10 muscle biopsies yielded only one with of these disorders. One can only speculate as to the electrodiag-
influenza B. In adults, the muscle biopsies also usually reveal nostic medicine findings in these disorders based on the biopsy
scattered necrotic and regenerating fibers. Scant mononuclear findings of muscle necrosis, regeneration, fiber size variation,
inflammatory infiltrates have been reported in a few patients. and atrophic fibers. It is anticipated that in persons with a severe
On EM, rare muscle fibers containing viral particles within myositis the needle electromyographic findings are compatible
membrane-bound vacuoles near the sarcolemma have been with those seen in polymyositis. Further work is required to
demonstrated. 269 In addition, intranuclear inclusions consisting more fully explore the electrophysiologic consequences of viral
of 7-9-nm parallel filaments were present in fibers that did not myositis.
contain viral particles. Influenzaviruses have also been isolated
following culture of adult muscle biopsy specimens. 320 BACTERIAL INFECTIONS
Pathogenesis. It is not known why only rare patients with
influenza infection develop myositis. Some patients may have Clinical Features. The term "pyomyositis" has been used
an underlying metabolic myopathy predisposing them to rhab- to describe the focal or multifocal abscesses associated with
domyolysis. Muscle destruction can be a direct effect of the bacterial infection of the muscle. Bacterial infections involving
viral infection or an indirect effect secondary to altering the muscle are more common in the tropical climates but have been
immune system. increasing in frequency in developed countries secondary to
Electrophysiologic Findings. Motor and sensory nerve con- HIV infection.27-638 Pyomyositis is also a complication of intra-
duction studies are anticipated to be normal in persons with in- venous drug abuse.344 Muscle pain, tenderness, and fever are the
fluenzavirus-induced myositis. Needle electromyographic initial symptoms. The most common sites of involvement are
examination may be normal if examined within several days of the the quadriceps, glutei, and deltoids. 145 If not treated early, pa-
weakness onset. In persons with various degrees of the disorder tients can become septic.
examined several weeks into the illness, typical short-duration, Laboratory Features. Most patients have a neutrophilic
small-amplitude, polyphasic MUAPs can be observed.170-206-648 The pleocytosis and elevated ESRs. Serum CK may be normal or el-
concomitant documentation of membrane instability is difficult to evated. Blood cultures are usually negative early in the course
comment on because no mention is made of this finding regarding of the infection until the patient becomes septic. 10 Ultrasound,
the electrodiagnostic medicine results in the reported cases. CT, and MRI of skeletal muscle can be useful in localizing pyo-
Observing necrotic muscle fibers on muscle biopsy is certainly genic abscesses for fine needle aspiration and diagnosis.10-559
consistent with the possible documentation of fibrillation poten- Histopathology. Intramuscular abscesses appear histologi-
tials and positive sharp waves. Of interest is the apparent predilec- cally as an area of necrotic tissue containing neutrophils,
tion for the lower limbs, particularly the more distally located macrophages, lymphocytes, and occasionally eosinophils. It is
muscles. This pattern is quite different than that found in the idio- often difficult to identify bacteria on light microscopy, but the
pathic or simple polymyositis. In patients suspected of a viral organisms can be cultured from the drained abscesses.
myositis, the gastrocnemius may be a good muscle to examine Pathogenesis. The most common organisms involved in py-
carefully, as well as the hip and shoulder girdle muscles. Single- omyositis are Staphylococcus aureus, streptococci, E. coli,
fiber electromyographic evaluation of patients with viral myositis Yersinia, and Legionella.mM5A51 Pyomyositis usually arises as an
demonstrates an increase in jitter similar to that found in idiopathic extension of the infection from adjacent tissues or via hemato-
polymyositis.263 More detailed electrodiagnostic medicine reports logic spread of the organisms. Infection of the muscle does not
are required to fully appreciate the true electrodiagnostic medicine usually develop in the absence of primary infection elsewhere.
features of influenza myositis with regard to any distinguishing Electrophysiologic Findings. There are limited electro-
characteristics compared to idiopathic inflammatory myopathy. physiologic data because electromyography is not recom-
Treatment. The disorder is usually self-limiting, although mended in the area of the abscesses.
rare patients have been reported with recurrences associated Treatment. Early in the course of the illness, microab-
with infection with different influenza types. 648 Treatment is scesses may respond to appropriate antibiotics. More severe in-
supportive with bed rest and hydration to avoid renal failure fections require incision and drainage of the abscesses as well
from myoglobinuria. Acetaminophen and NSAIDs (aspirin as antibiotic treatment. Despite treatment, mortality rates range
should be avoided in children) can be used to treat myalgias and from 1 to 10%.145
fever.
FUNGAL MYOSITIS
Other Viral Infection-Related Myositis
Acute viral myositis is not specific for influenza infection. Sim- Fungal infection of the muscles is uncommon and usually
ilar syndromes in children and adults can complicate infections occurs in an immunosuppressed patient. Candidiasis is the most
common fungal myositis and almost always associated with dif- instability may be observed in a few muscles and the MUAPs
fuse dissemination.30-360 Diffuse muscle pain, tenderness, weak- may be normal or only slightly reduced in duration. On the other
ness, fever, and a papular erythematous rash are evident but may hand, significant muscle parasitization can produce profuse de-
be obscured by other systemic symptoms. Muscle biopsy grees of positive sharp waves and fibrillation potentials obliterat-
demonstrates infiltration by hyphal and yeast forms of the or- ing the instrument's baseline, accompanied by early recruitment
ganism, inflammation, and hemorrhagic necrosis. Myositis has and short-duration small-amplitude MUAPs. Over the ensuing
also been reported complicating cryptococcal infection, 788 several weeks to months, the membrane instability decreases and
sporotrichosis,309 actinomycosis, and histoplasmosis.325 the MUAPs return to normal as does the recruitment.
Treatment. Thiabendazole is the drug of choice in treatment
PARASITIC INFECTIONS of the larvae and adult nematode, but efficacy has not been es-
tablished against the encysted larvae.59 Mebendazole may be ef-
There are three major groups of parasites with the potential fective against both circulating and encysted larvae. Because a
for infecting human skeletal muscle: (1) nematodes, (2) ces- Herxheimer-like reaction can develop following degeneration
todes, and (3) protozoans.59 There is a distinct lack of electrodi- of the larvae, concurrent corticosteroid administration is benefi-
agnostic medicine findings in the literature regarding these cial. In immunocompetent patients, there is usually complete
disorders. The majority of reports only note that the "EMG is recovery within several months.
consistent with a myopathy." This is hardly enough documenta-
tion to provide substantial information about the electrophysio- Cestodes
logic presentations of specific disorders. Clinical Features. Segmented hermaphroditic tapeworms
parasitizing vertebrate intestinal tracts are known as cestodes.59-666
Nematodes A number of cestode disorders can result in muscle colonization:
Clinical Features. Nematodes are unsegmented parasitic cysticercosis {Taenia solium), hydatidosis (Echinococcus), co-
roundworms. 59 There are four nematodes with the potential for enurosis (Multiceps) and sparganosis {Spirometra mansonoides).
invading muscle tissue: trichinae (Trichinella spiralis), visceral The most common and best described disorder is cysticercosis.
larva migrans (Toxocara canis, T. cati), cutaneous larva mi- Infection of skeletal muscles is manifested by myalgias, tender-
grans {Ancylostoma canimtm), and dracunculus {Dracunculus ness, and mild weakness. Often, there is pseudohypertrophy of
medinensis). infected muscles, especially the tongue and calves.59-354-666 The
Trichinosis is the most common parasitic disease of skeletal central nervous system is commonly affected and can result in
muscle and is best characterized electrophysiologically. The other focal neurologic deficits, encephalopathy, and seizures.
nematodes are very rare in the United States and have not been Laboratory Features. Elevated serum CK and peripheral
the subject of detailed electrophysiologic reports. Two to twelve eosinophilia are usually evident.
days following ingestion of inadequately cooked meat (usually Histopathology. Fibrotic changes and a mixed inflamma-
pork), the larval form of the nematode disseminates through the tory infiltrate consisting of eosinophils, plasma cells,
bloodstream and invades the musculature.137-195-428-490-491 The most macrophages, lymphocytes, and occasionally giant cells sur-
frequent muscles invaded, in order of frequency, are the di- round the larvae. The encysted larvae eventually calcify.
aphragm, extraocular, tongue, laryngeal, jaw, intercostal, trunk, Pathogenesis. Infection results from ingestion of under-
and limbs.59195 Patients develop fever, abdominal pain, diarrhea, cooked meat, mainly pork, which contain the larval form of T.
generalized myalgias, and weakness. Periorbital edema, ptosis, solium. The tapeworms mature in the small intestine and release
subconjunctival hemorrhage, and an erythematous urticaria or pe- ova. Ingestion of food or water contaminated by ova results in
techial rash are often present. Myalgias and weakness peak in the hematogenous spread and infection of the muscle.
third week of the infection but can last for several months. Severe Electrophysiologic Findings. There are incomplete data in
disease can be complicated by myocarditis and central nervous the literature regarding the specific types of abnormality likely ,
system infection. to be found in cestode infestations. One can only speculate that !
Laboratory Features. Most patients have eosinophilic membrane instability can be anticipated when there is direct de-
leukocytosis and elevated serum CK. Serum antibodies against struction of muscle tissue. Loss of muscle tissue should result in
T. spiralis can be demonstrated 3-4 weeks after infection.297 short-duration potentials. As with most of the parasitic disor-
Histopathology. In the early stage of infection, infiltration of ders, a complete electrophysiologic characterization of the spe-
the muscle by eosinophils and polymorphonuclear leukocytosis cific disease awaits further reports.
is prominent. In chronic stages of infection, mononuclear in- Treatment. Praziquantel is effective in reducing the size and
flammatory cells are more common. Larvae, cysts, focal calcifi- number of cysts in the CNS but efficacy in treating myositis has
cation of the cysts, fibrosis, and granulomas may be observed. not been established. 59 Niclosamide and paromomycin are the
Pathogenesis. Following ingestion of meat infected with en- drugs of choice for removing the adult tapeworm. 59 Con-
cysted larvae, gastric juices liberate the larvae that infect the comitant administration of corticosteroids is used to suppress
gut.59 Maturation of the parasite occurs in the gut. Next, second- the inflammatory reaction against degenerating parasites.
generation larvae migrate into the bloodstream and lymphatics
to invade the muscle and provoke the inflammatory response. Protozoans
The organism matures and remains within single muscle fibers Clinical Features. The protozoans are unicellular organisms
until consumed by another organism, thereby completing the that usually infect the muscle of animals such as cattle, sheep,
life cycle. Myocarditis can also manifest with a potential for and hogs. If the meat from these animals is inadequately cooked
cardiac failure. and ingested, the protozoan gains entry to the human body
Electrophysiologic Findings. The electrodiagnostic medicine through the digestive tract to subsequently reside in muscle.
findings vary depending upon the degree to which the muscle tis- There are four protozoan infections described in humans:
sue is affected.297-476-770 In mild infestations only subtle membrane toxoplasmosis, sarcocystis, African trypanosomiasis (sleeping
sickness), and American trypanosomiasis (Chagas' disease). Of Thyrotoxic Myopathy
these, the most commonly encountered is toxoplasmosis Clinical Features. Only 5% of patients with thyrotoxicosis
{Toxoplasma gondii). Toxoplasmosis can present clinically as present with muscle weakness, although 61-82% of patients
fever, lymphadenopathy, meningoencephalitis, hepatospleno- with this dysthyroid state have some degree of weakness on ex-
megaly, uveitis, pneumonia, myocarditis, or rash. Skeletal amination. 375.597.606-608,664 Although thyrotoxicosis is more
muscle involvement is uncommon but can occur in isolation or common in females, myopathy secondary to this endocrinopa-
associated with systemic symptoms.59-70-278 328-3719'589-645-742 The thy occurs equally in men and women. The mean age of onset is
myositis presents as fever, myalgias, and weakness. in the fifth decade. The incidence of weakness correlates with
Laboratory Features. Serum CK is often elevated. The di- the duration of hyperthyroidism; however, the severity of the
agnosis of toxoplasmosis can be established with serologic myopathy does not necessarily relate to the severity of the thy-
studies (i.e., Sabin-Feldman dye, complement fixation, indirect rotoxicosis. Muscle symptoms usually appear several months
hemagglutination, indirect fluorescent antibody). after the onset of other clinical symptoms associated with mild
Histopathology. Inflammatory cells consisting of lympho- hyperthyroidism ,608
cytes, macrophages, and occasionally giant cells are evident in Thyrotoxic myopathy is characterized by proximal muscle
the endomysium and perimysium. Cysts containing the brady- weakness and atrophy.227-397-597-608-650 Patients usually note an in-
zoite stage of T. gondii are more commonly identified in muscle creased difficulty arising from low chairs, commodes, and in par-
than the free tachyzoite form. ticular limited function with respect to activities of daily living
Pathogenesis. In the United States, just under half of the requiring overhead activities. The proximal arms can be more
cats are believed to be infected with the organism that is trans- prominently affected in some individuals, resulting in severe
ferred to humans through contact with the cat's fecal material. shoulder girdle atrophy and scapular winging.397 Approximately
Another common mode of infection is by ingestion of food con- 20% of patients complain of predominantly distal limb weak-
taminated by oocysts or ingestion of cysts containing brady- ness.597 Muscle pain and fatigue are common. Dysphagia, dyspho-
zoites in undercooked food. The organism usually matures to nia, and respiratory distress can arise secondary to involvement of
the tachyzoite form and invades the bloodstream and lymphatics bulbar, esophageal-pharyngeal muscles and respiratory mus-
and disseminates to other tissues. Systemic disease is most cles.494-508 Weakness of extraocular muscles and proptosis occur in
common in patients with immunodeficiency.69-278-407 The organ- the setting of Graves' disease. Rarely, rhabdomyolysis with myo-
ism can readily cross the placenta and cause a congenital form globinuria can develop in severe thyrotoxicosis.75
of the disease. Deep tendon reflexes can be brisk due to shortened relaxation
Electrophysiologic Findings. The electrophysiologic pre- times. In addition, fasciculations and myokymia are occasionally
sentation of toxoplasmosis-induced polymyositis is essentially seen, which probably reflects thyrotoxicosis-induced irritability
the same as that previously described for the idiopathic or of the anterior horn cells or peripheral nerves.243-314,319 493 An as-
simple form of the disease. A few patients have been reported sociation of hyperthyroidism with peripheral neuropathy is quite
with a distinct absence of membrane instability, while others rare, but a demyelinating polyneuropathy has been reported.243
had profuse degrees of fibrillation potentials; however, detailed Other systemic symptoms of hyperthyroidism include ner-
studies are lacking.70139-645-660 A single electrodiagnostic medi- vousness, anxiety, psychosis, tremor, increased perspiration,
cine evaluation reported evidence suggestive of a chronic neu- heat intolerance, palpitations, insomnia, diarrhea, increased ap-
rogenic process coexistent with clinical and muscle biopsy data petite, and weight loss. Common signs include goiter, tachycar-
highly suggestive of an inflammatory myopathy.292 The electro- dia, atrial fibrillation, widened pulse pressure, as well as warm,
diagnostic medicine findings in the remaining protozoan infec- thin, and moist skin.
tions are inadequately characterized. When there is significant The autoimmune basis of both Graves' disease and myasthe-
muscle tissue destruction, one can expect to find membrane in- nia gravis results in a relatively common association between
stability combined with the above-described MUAP changes. these two disorders. It can be difficult in distinguishing which
Treatment. The treatment of choice is a combination of neuromuscular symptoms are related to Graves' disease and
pyrimethamine and sulfadiazine or trisulfapyrimidines.59 Com- which are related to myasthenia gravis. Muscle weakness asso-
bination therapy is effective against the trophozoites but not ciated with hyperthyroidism does not fluctuate or significantly
against encysted protozoa. improve with anticholinesterase inhibitors.
Thyrotoxicosis is also associated with an unusual form of hy-
pokalemic periodic paralysis. Thyrotoxic periodic paralysis
ENDOCRINE MYOPATHIES occurs sporadically, and although more commonly reported in
Asians, it is not restricted to this population.397-664 There may be
Various endocrinopathies are associated with my- an autosomal dominant inherited susceptibility to thyrotoxic pe-
opathies.375-398 In this section, we review myopathies that result riodic paralysis. The attacks of weakness are similar in onset,
from thyroid, parathyroid, adrenal, pituitary, and pancreatic frequency, duration, and pattern of muscle involvement to those
dysfunction. It is important to properly diagnose these disorders described in familial hypokalemic periodic paralysis. While
because adequate therapeutic intervention can minimize the most cases of hypokalemic periodic paralysis occur within the
impact of the disease on patients' lives.391 first three decades of life, onset of thyrotoxic periodic paralysis
can occur later in adult life. Serum potassium levels tend to be
THYROID DISORDERS low during the attacks of weakness, but also can be normal.
Complete resolution of symptoms are achieved with the attain-
Myopathy can develop in patients who are hyperthyroid or ment of an euthyroid state. Beta-adrenergic blockers also im-
hypothyroid. In addition, peripheral neuropathy and neuromus- prove the myopathy.
cular junction abnormalities can be associated with dysthyroid Laboratory Features. Primary hyperthyroidism is diagnosed
states. on the basis of elevated thyroxine (T4) levels and occasionally
only the triiodothyronin (T3) level, while thyroid-stimulating hor- patients with 20 Hz stimulation). There was no improvement
mone (TSH) level is low. In thyrotoxic periodic paralysis serum with Tensilon.
potassium levels are also decreased. The serum CK levels are The nonspecific myopathic features of mild muscle fiber at-
usually normal. rophy and fiber size variation predict the needle electromyo-
Histopathology. Routine muscle biopsies usually do not graphic changes.319-461-597-607 Insertional activity is normal and
reveal any striking abnormalities in patients- with clinical fea- fibrillation potentials and positive sharp waves are unusual but
tures of thyrotoxic myopathy.226-319-347-766 Nonspecific findings may be found in distal muscles.597-608 When significant degrees
of mild fatty infiltrates, muscle fiber atrophy of all types, vari- of positive sharp waves and fibrillation potentials are found,
ability in muscle fiber size, scattered isolated necrotic fibers, other causes of myopathy need to be sought.608 Complex repeti-
decreased glycogen, and increased internal nuelei may be tive discharges also are rare. However, fasciculation potentials
noted. There are also nonspecific ultrastructural findings on may be evident reflecting thyrotoxicosis-induced membrane in-
EM, including Z-band streaming, focal swelling of the T- stability of the motor nerves. Very rarely, a patient may present
tubules, elongated mitochondria, decreased mitochondria, and with focal or generalized myokymia.314
subsarcolemmal glycogen deposition. 225 Quantitative assessment of MUAPs reveals a reduction in the
In patients with thyrotoxic periodic paralysis, muscle biop- duration as well as an increase in the number of polyphasic po-
sies reveal changes similar to those seen in familial hy- tentials. A mixture of normal and abnormal MUAPs is com-
pokalemic periodic paralysis. Light microscopy demonstrates monly detected. Quantitative assessment with the calculation of
vacuolar changes. On EM, sarcolemmal blebs filled with glyco- a mean MUAP duration from 20 MUAPs may be necessary to
gen and dilated terminal cisternae of the sarcoplasmic reticulum definitively determine if a particular muscle displays a MUAP
are apparent. pattern consistent with a myopathic process. An early recruit-
Pathogenesis. The thyroid gland excretes T 4 that is con- ment pattern is not a particularly prominent finding unless the
verted to the more active T 3 in the periphery. These thyroid patient has severe muscle weakness. The electrodiagnostic ab-
hormones are largely bound to plasma proteins. Free thyroid normalities correlate with the degree of muscle atrophy and
hormones bind to cytoplasmic receptors on target cells and weakness but not with the severity of the thyrotoxicosis. 319
are internalized into the nucleus, where they regulate the tran- Appropriate reconstitution of a euthyroid state can be expected
scription of specific genes. Type 1 muscle fibers have a to resolve the abnormalities. This suggests that the alteration in
greater density of thyroid receptors than type 2 fibers.359 The the MUAP parameters may not be entirely due to actual loss of
exact pathogenesis of thyrotoxic myopathy is unknown but is muscle fibers, but possibly some form of dysfunction whereby
felt to be due to enhanced muscle catabolism. Glucose uptake the "altered" muscle fibers temporarily do not contribute to the
and glycolysis are stimulated in muscle independent of in- MUAP. Further work is required to fully elucidate the relation-
sulin.136 The basal metabolic rate is increased and there is in- ship between MUAP normalization and treatment of the under-
creased mitochondrial consumption of oxygen, pyruvate, and lying hyperthyroidism.
malate. 359 An insulin-resistant state with fasting hyper- Treatment. The myopathy improves with successful treat-
glycemia and glucose intolerance develops that leads to ment of the hyperthyroid state. Improvement in muscle strength
glycogen depletion and decreased ATP production. Insulin re- occurs gradually over several months and precedes the return of
sistance also may interfere with insulin's anabolic effect on normal muscle bulk.397 As noted above, treatment of thyrotoxi-
amino acid and protein metabolism. 212 There is an inadequate cosis also results in resolution of episodes of periodic paralysis.
level of protein synthesis to meet the demands of accelerated Propranolol can also prevent and lessen the attacks of periodic
breakdown, which in turn may be driven by increased lysoso- paralysis. Unlike the familial form of hypokalemic periodic
mal protease activity.110-528 paralysis, acetazolamide is ineffective in preventing attacks of
Thyroid hormones increase potassium efflux from muscle. 236 weakness associated with thyrotoxicosis.
This is followed by an increased number and activity of Extraocular muscle weakness can persist for months or years
sodium-potassium ATPase pumps. The increased activity of after treatment of Graves' disease. Artificial tears and oph-
these pumps leads to a depolarization of the muscle membrane. thalmic ointments are used to prevent drying of the cornea and
Diminished muscle membrane excitability may also be sec- exposure keratitis that can result from severe lid retraction.
ondary to depolarization-induced sodium channel inactiva- Immunosuppression with corticosteroids or cyclosporine can be
tion649 and impaired propagation of the action potential across beneficial in some patients but is associated with significant
altered T-tubules. 215 The resulting muscle membrane inex- side effects.594
citability is probably responsible for episodes of thyrotoxic pe-
riodic paralysis. Hypothyroid Myopathy
Electrophysiologic Findings. Routine motor and sensory Clinical Features. Approximately one-third of patients with
nerve conduction studies are normal. 117 There is one well doc- hypothyroidism develop proximal upper and lower limb muscle
umented case of severe paraparesis in a patient with thyrotox- weakness.227-397 Fatigue, myalgias, cramps, and muscle "stiff-
icosis associated with demyelinating nerve conduction ness" are also common complaints. Muscle atrophy is rarely ob-
studies (velocities of the peroneal and posterior tibial nerves served. In contrast, some patients develop enlarged muscles.
were 25 m/s and 31 m/s, respectively). 243 The patient im- The combination of muscle hypertrophy, weakness, slow move-
proved with treatment of the thyrotoxicosis. However, ments, and cramps in adults has been termed Hoffmann's syn-
whether or not this represented an incidental case of Guillian- drome. Similar features without muscle pain in children have
Barre syndrome is not clear. A decrementing response to been referred to as Kocher-Debre-Semelaigne syndrome.
repetitive stimulation (2 to 20 Hz) has been noted in a few pa- Hypothyroidism can present with rhabdomyolysis. 628 Rarely,
tients.546-598 In a study of 48 patients with thyrotoxicosis, five respiratory muscles can be involved.479
exhibited a decrementing response to repetitive stimulation A superimposed peripheral neuropathy may be evident. The
(one patient decremented with 2 Hz stimulation and four ankle reflex may demonstrate delayed relaxation, a finding best
appreciated by having the patient kneel on a chair or bench absorption occurs under the influence of vitamin D. There are
while striking the Achilles' tendon. Myoedema refers to pain- several forms of vitamin D: (1) vitamin D 3 or cholecalciferol,
less and electrically silent mounding of muscle tissue when which is derived from the skin; (2) vitamin D 2 or ergocalcif-
firmly percussed and is observed in approximately one-third of erol, which is dietary and absorbed through the intestines; and
patients with hypothyroidism.518-658 Myasthenia gravis has been (3) 25-hydroxy-vitamin D, which is made in the liver and con-
reported in patients with hypothyroidism.730 verted to the more potent metabolite, 1,25-dihydroxy-vitamin
Laboratory Features. The serum CK levels are usually ele- D, in the kidneys. Parathyroid hormone regulates blood calcium
v; ed as much as 10 to 100 times normal. In primary hypothy- concentration by promoting bone resorption, increasing renal
roidism, serum T 4 and T 3 levels are low, while TSH levels are calcium absorption and phosphorus excretion, and enhancing
elevated. 1,25-vitamin D conversion. Diet, intestinal absorption, and
Histopathology. Histological abnormalities are nonspecific renal excretion determine serum phosphorus levels. Increased
and generally correlate with the duration and severity of muscle. parathyroid hormone leads to an increased synthesis of 1,25-di-
Variability in muscle fiber size with atrophy of type 2 and occa- hydroxy-vitamin D, hypercalcemia, and hypophosphatemia.
sionally type 1 fibers as well as scattered hypertrophic muscle Persistently elevated parathyroid hormone results in resorption
fibers can be appreciated.235-347-439 An occasional necrotic fiber of minerals within bone and replacement by fibrous tissue, a
with regenerating fiber may be observed. Increased internal condition termed osteitis fibrosa, or osteitis fibrosa cystica in
nuclei, ring fibers, glycogen accumulation, vacuoles, and in- severe forms.397
creased connective tissue can be seen. Nonspecific ultrastruc-
tural features noted on EM include mitochondrial swellings and Hyperparathyroidism and Osteomalacia
inclusions, myofibrillar disarray with central core-like changes, Clinical Features. Muscle weakness is very common in os-
autophagic vacuoles, glycogen accumulation, excess lipid, di- teomalacia, occurring in as many as 72% of patients in some
lated sarcoplasmic reticulum, and T-tubule proliferation.235 series.709 Weakness develops in only 2-10% of patients with iso-
Pathogenesis. Muscle weakness is the result of severe meta- lated hyperparathyroidism.76-422-709 Because better techniques are
bolic derangement. Reduced anaerobic and mitochondrial aero- currently available for the early diagnosis and treatment of hy-
bic metabolism of carbohydrates and fatty acids leads to perparathyroidism and osteomalacia, neuromuscular complica-
diminished production of ATP.338-673 Hypothyroidism also impairs tions nowadays are milder 747 than those reported in earlier
adrenergic function and produces a concomitant insulin-resistant j 84.471.573.708.709.760
state. Protein synthesis is reduced, as is protein catabolism.
s e r e s
The myopathy associated with primary hyperparathyroidism

Electrophysiologic Findings. The motor and sensory or osteomalacia is characterized by symmetric proximal weak-
nerve conduction studies are usually normal. 117 Some patients ness and atrophy, which are worse in the lower limbs.
have slow motor or sensory nerve conduction studies, suggest- Significant lower limb weakness leads to a waddling gait in
ing a concomitant peripheral neuropathy.521-668-690 There may some patients. Patten and colleagues reported several patients
be a propensity for patients with hypothyroidism to develop with bulbar involvement resulting in hoarseness and dyspha-
entrapment neuropathies such as carpal tunnel or tarsal tunnel gia.573 Rare cases with severe neck extensor weakness, the so-
syndrome.611-677 called dropped-head syndrome, and severe respiratory muscle
Needle insertional activity is usually normal, although rarely involvement have been described.76-276 Cramps and paresthesia
a few positive sharp waves and fibrillation potentials consistent are reported in approximately 50% of patients.747
with the minimal degree of fiber necrosis can be demon- Besides proximal weakness and atrophy, examination of pa-
strated.48-668 Complex repetitive discharges are also an uncom- tients with hyperparathyroidism may reveal brisk muscle stretch
mon finding. Myotonic potentials have been reported in a reflexes with flexor plantar responses. There are rare reports of
patient with hypothyroidism and no family history of myoto- spasticity and extensor plantar responses in patients with hyper-
nia.757 Short-duration, low-amplitude, polyphasic MUAPs may parathyroidism,132-275 although these patients most likely had co-
be appreciated in severely affected muscles.48-221-399-547 However, incidental motor neuron disease. 353 In addition, in 29-57% of
quantitative analysis of MUAPs can be completely normal. 777 patients, there is a stocking-glove loss of pain or vibratory sen-
Likewise, recruitment is usually normal, unless the patient has a sation and decreased muscle stretch reflexes suggestive of an
particularly profound myopathy. underlying peripheral neuropathy.573-747 Patten and colleagues
Insertion of a needle electrode into a region of muscle experi- also described abnormal tongue movements reminiscent of fas-
encing myoedema demonstrates electrical silence. In patients ciculations, 573 but this feature has not been noted by others. 353
experiencing cramps, the electrical activity simply consists of Finally, neurobehavioral abnormalities (memory loss, poor con-
normal or abnormal (if the patient has short duration/polyphasic centration, personality changes, inappropriate behavior, anxiety,
MUAPs) voluntary MUAPs firing rapidly generating a full in- and hallucinations) can also occur.
terference pattern. Secondary hyperparathyroidism can occur in patients with
Treatment. The myopathy and electrophysiologic abnor- chronic renal failure, in whom weakness similar to that observed
malities improve with treatment of the hypothyroidism. in primary hyperparathyroidism and osteomalacia can de-
However, some degree of weakness can persist even 1 year after velop.250-442-5903 Rare cases of arterial calcification with secondary
return to a euthyroid state. muscle necrosis and myoglobinuria have been reported in this
condition, termed calciphylaxis.620 Calciphylaxis can also occur
PARATHYROID DISORDERS in patients with renal failure without overt hyperparathyrodism.609
Laboratory Features. Serum CK levels are usually normal
Muscle weakness is common in disorders of calcium and in primary and secondary hyperparathyroidism and osteomala-
phosphorus homeostasis. Calcium and phosphorus homeostasis cia. In primary hyperparathyroidism, serum calcium levels are
requires a complex interaction of intestinal, renal, hepatic, usually elevated and serum phosphate levels are low, while uri-
endocrine, skin, and skeletal functions. 397 Intestinal calcium nary excretion of calcium is low and excretion of phosphate is
high. In patients with concurrent hypoalbuminemia, serum cal- SNAP and CMAP amplitudes. Also, persons with nutritional
cium levels may be normal, and in these cases ionized calcium deficits may have a resultant peripheral neuropathy.704
should be measured and is typically elevated. Increased urinary As can be seen by the above histopathologic findings, there
excretion of cyclic adenosine monophosphate in the presence of is little in the way of structural abnormalities in the muscle
hypercalcemia is indicative of hyperparathyroidism. In primary tissue suggesting that any electrophysiologic abnormalities
hyperparathyroidism, serum parathyroid hormone levels and present can be anticipated to be mild. Needle insertional activ-
1,25-dihydroxy-vitamin D levels are elevated. In secondary hy- ity is normal and there is typically an absence of positive sharp
perparathyroidism due to renal failure, serum calcium levels are waves and fibrillation potentials. However, an occasional pa-
low while 1,25-dihydroxy-vitamin D levels are decreased. Non- tient may be observed to have a few fibrillation potentials and
invasive imaging techniques, such as ultrasound, thallium/tech- positive sharp waves, especially in the tibialis anterior muscle,
netium scintigraphy, computed tomography, and magnetic but this is a rare finding.471 There is a mixture of normal and
resonance imaging, may be useful in localizing abnormal abnormally short-duration polyphasic MUAPs.84-256-351-471-478-573-
parathyroid glands.548 59i.67i.708 7 n e m o r e severe the disease, the more prominent the
In osteomalacia, serum calcium levels are low or normal and short-duration potentials. It may be necessary to quantitate the
serum phosphate is variably low depending on the degree of various MUAP parameters in order to document the presence
secondary hyperparathyroidism. Serum vitamin D levels are of a myopathy. Occasionally, in long-standing disease, long-
also usually decreased. Urinary excretion of calcium is low duration high-amplitude MUAPs may be observed. Finally, in-
(except in cases secondary to renal tubular acidosis), while ex- creased jitter on single-fiber EMG without significant blocking
cretion of phosphate is high. In addition, elevated serum alka- has been described.465
line phosphatase levels are present in 80-90% of cases and are a Treatment. Because rather extensive blood chemistries are
useful screening tool for osteomalacia. 653 Skeletal survey usu- now performed routinely, hyperparathyroidism is diagnosed
ally demonstrates a reduction in bone density associated with earlier than in the past and patients are frequently asymptomatic
loss of trabeculae, blurring of trabecular margins, and variably or only mildly affected. In symptomatic patients, medical or
thinned cortices.285 surgical treatment is very effective and improvement of muscle
Histopathology. Muscle biopsies usually demonstrate non- strength is usually noticeable within a few months.397-548-549-573
specific myopathic features with atrophy predominantly of type Parathyroidectomy is the treatment of choice in symptomatic
2 fibers, but occasionally also of type 1 fibers. patients with primary hyperparathyroidism. 549 In patients with
Pathogenesis. Primary hyperparathyroidism can be caused adenoma, the affected gland is removed, while additional glands
by parathyroid adenomas or hyperplasia as well as pituitary may be biopsied. Patients with hyperplasia of all four glands
adenomas. Secondary hyperparathyroidism is frequently caused generally have subtotal (three and a half glands) parathyroidec-
by chronic renal failure, which results in the reduction of 1,25- tomies. Medical management of primary hyperparathyroidism
dihydroxy-vitamin D conversion. This in turn causes decreased is reserved for asymptomatic patients or those with significant
intestinal absorption of calcium and decreased renal phosphorus perioperative risk.549 Patients with secondary hyperparathy-
clearance, which leads to secondary hyperparathyroidism and roidism usually improve with vitamin D and calcium replace-
osteomalacia. In addition to acquired forms, there are hereditary ment, or renal transplantation if they are in end-stage renal
forms of primary hyperparathyroidism 303 and vitamin D defi- failure.471-590a-708 Occasionally, subtotal parathyroidectomy is
ciency and osteomalacia.285 performed in patients with secondary hyperparathyroidism.
The accumulation of unmineralized bone matrix leads to Likewise, the myopathy associated with osteomalacia responds
rickets in children and osteomalacia in adults. As noted above, well to vitamin D and calcium replacement and to treatment of
osteomalacia can complicate hyperparathyroidism and rarely the underlying responsible condition.285-351-471-653-671-708
hypoparathyroidism. Other etiologies of osteomalacia include
vitamin D deficiency, inadequate nutrition, phosphate depletion, Comment on Possible Relationship
acidosis, and renal tubular disorders.285 to Motor Neuron Disease
The mechanism of weakness in hyperparathyroidism and os- There are a few reported cases of hyperparathyroidism that
teomalacia is not known. Some authors have suggested a neuro- the authors felt mimicked amyotrophic lateral sclerosis.132-275-573
genic basis,50-471-573 although most authorities suspect a Some of these patients improved following resection of parathy-
myopathic process.397441 Parathyroid hormone enhances muscle roid adenomas. However, close review of these patient reports
proteolysis and impairs energy production, transfer, and utiliza- suggests that they did not have amyotrophic lateral sclerosis,
tion.52-397-486 In addition, parathyroid hormone may diminish the but rather parathyroid myopathy.353 In our experience, the pres-
sensitivity of contractile myofibrillar proteins to calcium and ence of hyperparathyroidism in patients who meet clinical and
activate a cytoplasmic protease, thus impairing the bioenerget- electrophysiologic criteria for amyotrophic lateral sclerosis ap-
ics of muscle.375 Interestingly, calcium and phosphorus levels do pears to be coincidental, and patients do not improve with
not correlate well with the clinical severity of muscle weak- parathyroidectomy.353
ness. 256.573.709 vitamin D has a direct effect on muscle: it in-
creases muscle adenosine triphosphatase concentration, Hypoparathyroidism
accelerates amino acid incorporation into muscle proteins,83-397 Clinical Features. Myopathy secondary to hypoparathy-
and increases the uptake of calcium by the sarcoplasmic reticu- roidism is unusual, although paresthesia and tetany secondary
lum and mitochondria.173-588 to hypocalcemia do occur. Chvostek's sign (ipsilateral facial
Electrophysiologic Findings. If a person has primary contraction upon tapping the facial nerve at the external audi-
parathyroid disease, the motor and sensory nerve conduction tory meatus) and Trousseau's sign (thumb adduction, metacar-
studies can be expected to be normal. However, when renal fail- pophalangeal joint flexion, and interphalangeal joint extension)
ure is present, a concomitant peripheral neuropathy may result may be demonstrated in hypocalcemic patients. There are
in slowing of motor and sensory nerves with reduction in the only a few reports of mild proximal weakness in patients with
hypoparathyroidism. 408 - 71 !-784-790 Akmal described a case with The first region secretes glucocorticoids that are the most rele-
painless myoglobinuria but without objective weakness or vant with respect to the development of a myopathy. Aldo-
tetany.9 sterone is produced by the second region and when produced in
Laboratory Features. Serum CK can be normal or mildly excess by a tumor of the adrenal gland can result in muscle
elevated in patients.343-686 Hypoparathyroidism is associated weakness due to hypokalemia. Adrenal androgens arise from
with low serum parathyroid hormone and calcium levels and the third region of the adrenal gland but do not result in a my-
high serum phosphate levels. However, serum parathyroid hor- opathy. We are concerned primarily with muscle weakness due
mone levels are low in pseudohypoparathyroidism. to hyper- or hypocortisolism.
Histopathology. Muscle biopsies may reveal nonspecific
myopathic features that may reflect muscle damage secondary Cushing's Syndrome/Iatrogenic Steroid Myopathy
to episodes of tetany.347-397 Decreased glycogen phosphorylase An excess of corticosteroid within one's system either from
activity of muscle biopsy specimens has also been described.374 endogenous (Cushing's syndrome) or exogenous (steroid adminis-
Pathogenesis. Hypoparathyroidism is seen in a number of tration) sources results in the same neuromuscular manifestations.
conditions, including complications of surgery, Hypomagne- Corticosteroid myopathy is the most common endocrine-related
semia or hypermagnesemia, irradiation, drugs, sepsis, infiltra- myopathy. However, muscle weakness is rarely the presenting
tive diseases of the parathyroid, and autoimmune, hereditary, or manifestation of endogenous hypercortisolism.
developmental disorders.246 Decreased parathyroid hormone re- Clinical Features. Although estimates are crude, approxi-
sults in diminished synthesis of 1,25-dihydroxyvitamin D, mately 50-80% of patients with Cushing's disease manifest
hypocalcemia, and hyperphosphatemia. Osteomalacia can also some degree of weakness prior to receiving appropriate treat-
develop in association with hypoparathyroidism. ment. ioi.227.397p a tients with hypercortisolism develop predomi-
The etiology of the rare myopathy associated with hy- nantly proximal muscle weakness and atrophy of the lower and
poparathyroidism is even less well understood. Elevated serum upper limbs. Distal limb, oculobulbar, and facial muscles are
CK and mild histologic abnormalities on muscle biopsy are spared. Sensation and deep tendon reflexes are normal. An in-
generally considered secondary to muscle damage from tetany. crease in truncal adipose tissue and pigmentation of the skin
Decreased serum calcium concentration causes a shift in the become prominent features of the disease with time, i.e., the so-
cellular activation potential toward the resting potential.9-106- called cushingoid appearance.
258.259Therefore, less current is required to elicit an action poten- The incidence of exogenous corticosteroid myopathy is un-
tial and tetany can result. known and individuals may have a different propensity for de-
Electrophysiologic Findings. The altered extracellular ionic veloping weakness. Women appear to be more prone to
milieu does not substantially affect the velocity of conduction developing exogenous steroid-induced weakness than men, ap-
for either motor or sensory nerves. Hence, even though the pa- proximately 2:1, for a given steroid dose, but the reason is un-
tient may have significant symptoms, the motor and sensory clear. Prednisone doses of 30 mg/day or more (or equivalent
nerve conduction studies are normal. doses of other corticosteroids) are associated with an increased
Needle electromyographic examination reveals normal inser- risk of myopathy.397 Any synthetic glucocorticoid can cause the
tional activity. There are no positive sharp waves or fibrillation po- myopathy, but those that are fluorinated (triamcinolone > be-
tentials. The most striking abnormality noted is the spontaneous tamethasone > dexamethasone) have a greater propensity for
occurrence (lack of volitional control) of MUAPs that fire rapidly producing muscle weakness than the nonflourinated com-
in succession creating so called doublets or triplets (multi- pounds. 237 Alternate-day dosing appears to reduce the risk of
plets).201-409-411-412-569-728 These doublets or triplets can be either corticosteroid-induced weakness. Muscle weakness may begin
single muscle fibers or whole/partial MUAPs firing repetitively within several weeks following the administration of steroids
with interdischarge intervals between 2 and 20 ms. The second po- but more typically develops after chronic administration of
tential of the doublet appears the same as the first potentials aside high-dose oral steroids. An acute onset of severe generalized
from a slight reduction in amplitude. Hyperventilation exacerbates weakness can occur in patients receiving high dosages of intra-
the problem, whereas calcium administration reduces their fre- venous corticosteroids with or without concomitant administra-
quency. The tetanic potentials may be occasionally observed in tion of neuromuscular blocking agents (see section on acute
normal persons who are extremely anxious and hyperventilating quadriplegic myopathy). 418
during the needle examination, or in persons with systemic alkalo- Laboratory Features. Serum CK is normal. Serum potas-
sis subjected to limb ischemia. In addition to the doublets and sium can be low as a result of glucocorticoid excess.
triplets, fasciculation potentials can be observed in some persons. Histopathology. One of the major changes noted on muscle
In order to detect these potentials, it may be necessary to leave the biopsy is a preferential atrophy of type 2 fibers, especially the
needle in the muscle for approximately one minute without fast-twitch glycolytic type 2B fibers (Fig. 28-8).347-585 There may
moving it. Asking a patient to mildly hyperventilate may increase also be a lesser degree of atrophy of type 1 muscle fibers. A dis-
the ease of observing the multiplets or fasciculation potentials. tinct lack of necrosis or regeneration is observed. Lipid droplets
Otherwise, MUAP morphology and recruitment are normal. are commonly noted in type 1 fibers. Mild mitochondrial
Treatment. The rare myopathy associated with hy- changes are found on EM.
poparathyroidism improves following correction of the hypo- Pathogenesis. Corticosteroids bind to receptors on target
calcemia and hyperphosphatemia with vitamin D and calcium cells and are subsequently internalized into the nuclei where
administration.784-790 they regulate the transcription of specific genes. The exact
mechanism of corticosteroid myopathy is unknown but has been
ADRENAL DISORDERS speculated to be related to decreased protein synthesis, in-
creased protein degradation, alterations in carbohydrate metab-
The adrenal gland cortex consists of three major regions: (1) olism, mitochondrial alterations, and reduced sarcolemmal
zona fasciculata, (2) zona glomerulosa, and (3) zona reticularis.397 excitability.375-397 Which, if any of these, events is the primary
and encouraging exercise to prevent concomitant disuse atro-
phy.397 Experimental studies suggest that insulin-like growth
factor-1 (IGF-1) may have a prophylactic effect on preventing
steroid myopathy.376
Of particular clinical relevance is the patient who is prescribed
steroids for treatment of an immune-mediated neuromuscular
disorder with weakness (e.g., inflammatory myopathy).5-467-775
Following an initial improvement, some patients experience a
subsequent decline in muscle function. The question that arises
is the cause of the relapse, i.e., disease exacerbation or steroid-
induced weakness. If the weakness developed while the patient
was tapering the steroids, relapse of the underlying disease
process should be considered. In contrast, if weakness occurred
while the patient was on a chronic high dose of steroids, a
steroid-induced myopathy is more likely. In the case of an in-
flammatory myopathy, an increasing serum CK would point to
Figure 28-8. Steroid myopathy. Selective atrophy of type 2B an exacerbation of the myositis. 46 An electromyogram can be
fibers is evident (ATPase pH 4.5). useful in that it is usually normal in steroid-induced myopathy in
contrast to the prominent increase in spontaneous activity, myo-
pathic MUAPs, and early recruitment typically seen in inflam-
cause of muscle weakness and atrophy remains to be elucidated. matory myopathies. In some cases, it is impossible to state with
In addition, electrolyte disturbances (reduced serum potassium certainty whether the new weakness is related a relapse of the
levels) can cause weakness. underlying disease or secondary to the steroid treatment. In such
Electrophysiologic Findings. Excess glucocorticoids, nat- cases, the best approach is to taper the steroid medication and
ural or synthetic, do not appreciably alter the peripheral nerves, closely observe the patient. If improvement occurs, then the pre-
thus the motor and sensory nerve conductions can be expected sumed cause of the worsened clinical condition is a result of the
to be normal. 1,7 There may be slight abnormalities noted in el- medication. If the patient deteriorates, the weakness may be re-
derly persons with Cushing's disease; however, these are likely lated to the underlying autoimmune disease and the patient may
a result of the effects of aging on nerve conduction and not the require increased doses of corticosteroids or other immunosup-
steroid excess. Repetitive stimulation studies do not demon- pressive medication.
strate a significant decrement or increment.
During the needle examination insertional activity is normal. Adrenal Insufficiency j
There is little in the way of spontaneous activity particularly re- Adrenal insufficiency can result from a number of causes in-
garding positive sharp waves and fibrillation potentials. The ab- cluding intrinsic gland disease as well as extrinsic or pituitary dys-
sence of muscle fiber necrosis is the most likely explanation for function.227397-592 Subjective weakness and fatigue commonly
the lack of abnormal insertional or spontaneous activity. occur with adrenal insufficiency. Objective weakness is usually as-
Morphologic analysis of the MUAPs is usually normal, al- sociated with electrolyte disturbances or concurrent en-
though there may be a mild reduction in the maximum peak-to- docrinopathies. 397 The histopathologic and electrodiagnostic
peak MUAP amplitude during maximal recruitment.162-532-792 medicine examinations are essentially normal in these persons.
The reduction in amplitude is a very subtle finding because of Symptoms improve with proper replacement of adrenal hormones.
inadequate control values for the population as a whole, or for
the individual in particular. The paucity of findings is under- PITUITARY DISORDERS
standable given the above noted histopathologic finding of pref-
erentially type 2 muscle fiber dysfunction. The first recruited Acromegaly I
motor units are comprised of type 1 muscle fibers. Because they Clinical Features. Individuals with acromegaly usually
are not affected as severely as type 2 fibers, there is little in the have normal strength until late in the disease course.227-397-453-580
way of electrophysiologic pathology to observe. Only when the As the disease progresses, some individuals develop insidious
disorder is profound enough to cause atrophy of sufficient num- muscle weakness primarily affecting the proximal shoulder and
bers of type 1 fibers are there any detectable abnormalities hip girdle muscles. Little in the way of muscle atrophy or wast-
(short-duration, small-amplitude MUAPs). By the time the type ing is noted. In fact, muscle groups can appear enlarged despite
2 fibers are recruited, far too many type 1 fibers are simultane- being weak. There are multiple other neurologic problems en-
ously firing, creating substantial electrical noise and MUAP countered in patients with acromegaly secondary to bony over-
overlap. This precludes quantitatively assessing the type 2 fiber growth with potentially devastating consequences about the
MUAPs parameters in detail, thus limiting the sensitivity of the spinal canal. Nerve root and spinal cord compression can result
needle examination in disorders preferentially affecting type 2 in significant neurologic compromise. These patients also suffer!
muscle fibers. In moderate to profound disease, careful analysis from multiple entrapment neuropathies such as carpal tunnel
may reveal recruitment abnormalities, however, this is not an and cubital tunnel syndromes.459-464-719 Degenerative joint
early finding. changes can produce profound disability and pain.
Treatment. Removal of the glucocorticoid excreting tumor Laboratory Features. Serum CK levels can be normal or
in cases of endogenous hypercortisolism is the treatment of mildly elevated.
choice and results in gradual strength return. Treatment of Histopathology. Variability in muscle fiber size with hyper-
muscle atrophy and weakness from exogenous steroids requires trophy and atrophy involving either or both type 1 and type 2
reduction in the dose, switching to an alternate day regimen, fibers can be seen.480-716 Mild degrees of segmental necrosis can
be observed in some patients while others simply demonstrate lack of sexual and muscular development. Deficiency of growth
nonspecific changes of moderate atrophy. Satellite cell hyper- hormone appears to have a greater role in the myopathy associ-
trophy is a common finding in acromegaly. Myofibrillar loss ated with prepubertal panhypopituitarism. Administration of
and glycogen deposition are noted on electron microscopy. only thyroid and adrenal hormones does not result in improved
Pathogenesis. The development and severity of muscle strength unless, growth hormone is also replaced.600
weakness correlates with the duration of acromegaly rather than
the levels of serum growth hormone.535-580 Growth hormone leads DIABETES MELLITUS
to an increase in protein synthesis and muscle hypertrophy.81595
It is not clear why muscle weakness develops despite increased Neuromuscular complications of diabetes are usually refer-
muscle bulk in acromegaly. The respiratory quotient of resting able to peripheral neuropathies. The only myopathic disorder
forearms muscles of patients with acromegaly is lower than clearly associated with diabetes is thigh infarction.
normal (0.68 vs. 0.76).601 Fatty acid oxidation is increased and
glucose utilization is reduced with growth hormone administra- Diabetic Thigh infarction
tion.778 These findings suggest that, under the influence of Clinical Features. Ischemic infarction of thigh muscles usu-
growth hormone, muscle preferentially utilizes lipid rather than ally occurs in poorly controlled diabetic patients who have other
carbohydrates, which may have an effect on dynamic muscle ac- evidence of end-organ damage (retinopathy, nephropathy, neu-
tivity and fatigue. In addition, there may be reduced myofibrillar ropathy).25-57-64-85-90144751 Patients usually develop an acute onset of
ATPase activity, despite increased concentrations of actin and pain and swelling in one thigh. A palpable tender mass is felt most
myosin.249 Further, muscle membranes may be slightly depolar- often in the vastus lateralis, biceps femoris, or thigh adductors.
ized rendering them less excitable.375 Laboratory Features. Serum CK levels are usually normal.
Electrophysiologic Findings. The nerve conduction studies MRI or CT of the thigh demonstrates signal abnormalities in the
depend primarily upon the length of disease process, patient region of the "mass."
presentation, and extent of bony exostosis at various critical Histopathology. Muscle biopsies demonstrate muscle in-
portions of the nervous system. Sensory nerve abnormalities of farction with large areas of necrosis, edema, and inflammatory
the ulnar and median nerve may be detected secondary to focal infiltrate (Fig. 28-9). Eventually, there is connective tissue and
entrapment of the median and ulnar nerves at the carpal and cu- fat infiltration. Small and medium-sized blood vessels demon-
bital tunnels respectively, or due to a peripheral neuropa- strate hyperplasia of the media and lumens occluded by fibrin,
m y 459.464.7i9 Slowing of median nerve distal motor latencies and calcium, and lipid.57 Hemorrhagic necrosis of the muscle fibers
motor conduction across the elbow may be noted for the ulnar with extravasation of blood between muscle fibers may be seen.
nerve in peripheral entrapment neuropathies. Abnormal H-re- Pathogenesis. Muscle histology suggests the disorder is sec-
flexes can be expected when the S1 nerve root is compromised ondary to ischemic damage and secondary hemorrhagic infarc-
with an associated radicular process. Abnormal somatosensory tion resulting from long-standing, diabetic vasculopathy.
evoked potentials are also possible in patients with cauda equina Electrophysiological Findings. Electromyography demon-
or spinal cord compromise at some level. strates fibrillation potentials and positive sharp waves as well as
Needle electromyographic findings can be consistent with a small, polyphasic MUAPs with early recruitment in the in-
myopathic process in persons without a superimposed entrap- volved muscles.64
ment of a peripheral nerve structure.480 Short-duration low-am- Treatment. The infarct resolves spontaneously over several
plitude MUAPs may be detected in the proximal muscles about weeks, although it may recur in the contralateral thigh. Treat-
the shoulder and hip regions.453-580 In this type of myopathic ment consists of immobilization and pain control. Biopsy
process, there is an absence of positive sharp waves and fibrilla- should be avoided when the diagnosis is suspected because of
tion potentials. When a superimposed entrapment of a peripheral the risk of subsequent hemorrhage into the tissue.57
nerve or radicular process is operational, membrane instability
and MUAPs consistent with a chronic neurogenic processes (de-
creased recruitment, large-amplitude long-duration MUAPs ac-
companied by positive sharp waves and fibrillation potentials)
can be found. If a patient has a combined myopathy and periph-
eral entrapment neuropathy for example, there may be low-am-
plitude short-duration MUAPs in the deltoid and biceps muscles,
but long-duration large-amplitude potentials in the abductor pol-
licis brevis or first dorsal interosseous muscles. In short, one
must anticipate a mixed type of needle electromyographic pic-
ture in some patients who have two different consequences oper-
ational as a result of the acromegalic process.
Treatment. Lowering of growth hormone levels can result
in improved muscle strength.580
Panhypopituitarism
Pituitary failure in adults commonly leads to muscle weakness
and fatigue.104 The myopathy can be attributed to secondary defi-
ciencies of thyroid and glucocorticoid hormones and improves Figure 28-9. Diabetic thigh infarction. Widespread muscle fiber
with replacement of these hormones. Growth hormone defi- necrosis and phagocytosis of necrotic debris by inflamatory infiltrate is
ciency may perhaps also contribute to the myopathy in adults. evident on the quadriceps muscle biopsy of diabetic patient who pre-
Prepubertal panhypopituitarism is associated with dwarfism and sented with severe pain and swelling of the thigh (H&E).
MYOPATHIES ASSOCIATED W I T H potentials and positive sharp waves as well as early recruitment of
ELECTROLYTE IMBALANCE short-duration, low-amplitude MUAPs in severely weak muscles.
Treatment. Muscle strength returns with correction of the
DISORDERS OF POTASSIUM hypokalemia. The patients need a medical work-up to elucidate
the underlying cause of the hypokalemia.
Hypokalemia
Hyperkalemia
Clinical Features. Hypokalemia is the most common elec- Clinical Features. As with hypokalemia, there are a number
trolyte abnormality that results in muscle weakness.158 Clinical, of medical causes of hyperkalemia that require investigation
laboratory, and electrophysiologic features are similar to those (Table 28-5). Generalized muscle weakness may develop sec-
seen in familial hypokalemic periodic paralysis. The causes of ondary to hyperkalemia. Some patients have evidence of in-
hypokalemia are numerous (Table 28-5) and patients must be creased neuronal or muscle membrane excitability as manifested
evaluated for other etiologies of hypokalemia before a diagnosis by the presence of Chvostek's sign or myotonic lid lag.602
of familial hypokalemic periodic paralysis is made. Patients can Laboratory Features. Serum potassium levels are usually
present with proximal or generalized weakness. Usually muscle greater than 7 mEq/L in patients with severe generalized weak-
involvement is symmetric, although we have seen patients with ness. Renal insufficiency and acidosis are present in some cases
asymmetric muscle weakness. Some patients complain of of hyperkalemia. Serum CK levels are usually normal. EKG
muscle pain and cramps. Severe rhabdomyolysis accompanied may demonstrate tall, peaked T-waves.
by myoglobinuria can also complicate hypokalemia. Histopathology. Muscle biopsies are typically normal.
Laboratory Features. Potassium levels are usually less than Pathogenesis. Hyperkalemia can result in prolonged depo-
3 mEq/L. Serum CK is usually elevated proportional to the larization of the muscle membrane, which leads to sodium
severity of muscle weakness. The EKG may demonstrate brady- channel inactivation and subsequent loss of muscle membrane
cardia, flattened T waves, prolonged PR and QT intervals, and excitability.
notable U waves. Electrophysiologic Findings. Routine nerve conduction
Histopathology. Biopsies of very weak muscles may studies are usually normal. Small "myopathic" MUAPs may be
demonstrate vacuoles and scattered necrotic fibers. evident of electromyography, but fibrillation potentials and posi-
Pathogenesis. The mechanism by which muscle weakness tive sharp waves are not observed. Unlike the familial or primary
develops secondary to hypokalemia is not known. As discussed forms during needle potassium-sensitive periodic paralysis, my-
with primary hypokalemic periodic paralysis, reduced extracel- otonic discharges are never seen.
lular potassium concentration may result in an abnormal ratio of Treatment. Muscle strength returns with correction of hy-
gated sodium channels in the active compared to inactive state. perkalemia. The underlying cause of the hyperkalemia must be
In a partially depolarized state, the number of sodium channels elucidated and treated.
available to activate is reduced, making the muscle membrane
less excitable. Hypokalemia may also diminish blood flow and DISORDERS OF CALCIUM
suppress the synthesis and storage of glycogen in muscles.
Electrophysiologic Findings. Nerve conduction studies are Muscle weakness secondary to hypercalcemia and hypocal-
usually normal. Electromyography can demonstrate fibrillation cemia was discussed in the section regarding parathyroid
myopathies.
Table 28-5. Etiologies of Secondary Hypokalemic and
Hyperkalemic Paralyses DISORDERS OF PHOSPHATE
Hypokalemic Paralysis Hypophosphatemia
Thyrotoxic periodic paralysis Hypophosphatemia may be seen in the setting of diabetic ke-
Renal tubular acidosis toacidosis, acute alcohol intoxication, hyperalimentation with
Villous adenoma phosphate-poor preparations, severe diarrhea, and in patients
Bartter's syndrome taking phosphate-binding antacids.296 Severe hypophosphatemia,
Hyperaldosteronism levels less than 0.4 mmol/L, can be associated with generalized
Chronic or excessive use of diuretics, corticosteroids, licorice muscle weakness, rhabdomyolysis, and myoglobinuria.400 Some
Amphotericin B toxicity patients complain of paresthesiae and develop reduced deep
Alcoholism tendon reflexes, suggesting a superimposed neuropathic process.
Toluene toxicity Detailed electrophysiologic studies and histopathology are lack-
Barium poisoning ing in hypophosphatemia-induced muscle weakness. Muscle
Hyperkalemic Paralysis strength returns with correction of the hypophosphatemia.
Addison's disease
Hypoaldosteronism (hyporenemic) DISORDERS OF MAGNESIUM
Isolated aldosterone deficiency
Excessive potassium supplementation Hypermagnesemia can result secondary to abuse or acciden-
Potassium-sparing diuretics (e.g., spironolactone, triamterene) tal overdose of magnesium-containing laxatives, particularly in
Chronic renal failure the setting of renal insufficiency.522 Hypermagnesemia can also
Rhabdomyolysis develop during treatment of eclampsia with magnesium sulfate.
Modified from Griggs RC, Mendell JR, Miller RG: Muscle pain and fatigue. In Severe generalized weakness and respiratory failure can com-
Evaluation and Treatment of Myopathies. Philadelphia, FA Davis, 1995, pp plicate hypermagnesemia, but are reversible with magnesium
389-407, with permission. correction.
Hypomagnesemia can result in muscle and nerve hyperex- Treatment. Survival is limited secondary to the underlying
itability as characterized by Chovstek's and Trousseau's signs cancer. Some patients reportedly benefited from corticosteroids 450
and tetany.247 However, hypocalcemia and other electrolyte dis- This does not prove an autoimmune basis for the myopathy in such
turbances typically accompany hypomagnesemia; therefore, it cases because steroids have many other direct effects on muscle.
is difficult to attribute the neuromuscular abnormality solely to
the low serum magnesium levels. FOCAL METASTATIC LESION
Rarely, patients with malignancy can have spread of the tumor

MYOPATHIES ASSOCIATED into a region of muscle.211-322 Any muscle group can be invaded
W I T H MALIGNANCY resulting in pain, swelling, and weakness. Needle electromyo-
graphic examination of the affected muscle can reveal membrane
Patients with malignancies frequently develop generalized instability and MUAPs with short duration and low amplitudes.
weakness. The majority of patients do not have a true paraneo- Muscle biopsy can demonstrate evidence of tumor emboli.
plastic syndrome. There are a few well defined paraneoplastic
syndromes, including sensory neuronopathies or sensorimotor
neuropathies (e.g., anti-Hu syndrome) and Lambert-Eaton syn- OTHER MYOPATHIES SECONDARY
drome, resulting in generalized weakness. Myopathies can occur T O SYSTEMIC DISEASE
in the setting of cancer, most notably dermatomyositis as previ-
ously discussed. Muscle weakness is much more likely related to AMYLOID MYOPATHY
impaired nutrition, increased catabolic state induced by the
tumor, disuse atrophy, and perhaps toxic effects of chemothera- Clinical Features. Amyloid myopathy secondary to sys-
peutic agents. Cytokines released by tumor cells may accelerate temic amyloidosis is most commonly associated with light-
muscle catabolism. Nevertheless, there are scattered reports of chain immunoglobulin amyloidosis (AL).210277 342538631640647 7,4
"paraneoplastic" necrotizing myopathy and, rarely, focal my- Myopathy secondary to familial amyloidosis (FA) is less
opathies related to local tumor invasion or metastasis. common,113-714 789 while myopathy has not been described with
secondary amyloidosis (AA). Cardiac muscle, peripheral nerves,
PARANEOPLASTIC NECROTIZING MYOPATHY skin, kidneys, and other organs are also involved besides skeletal
muscle. In fact, most patients present with non-muscle related
Clinical Features. A generalized necrotizing myopathy can symptoms. Amyloid myopathy usually manifests with an insidi-
develop as a paraneoplastic syndrome or occur in the setting of ous onset of progressive proximal weakness. Distal muscles can
an underlying connective tissue disease, particularly an also be affected, particularly in the gelsolin form of FA.714
MCTD. 11 1-224a.45o.706.753.765j n j s myopathy is characterized by a Muscles can appear hypertrophic, in particular the tongue, pro-
gradual onset over 1-3 months of symmetrical proximal weak- ducing macroglossia. Some patients have normal or atrophic
ness. Some patients complain of myalgias. The myopathic muscles. Diaphragm involvement can lead to respiratory failure.
symptoms usually develop simultaneously with other symptoms Muscle induration, stiffness, and pain are also variably present.
of cancer. The most common associated malignancies are ade- Approximately 20% of patients have a coexistent generalized pe-
nocarcinomas of the gastrointestinal tract and small- and non- ripheral neuropathy; mononeuropathies such as carpal tunnel
small-cell carcinomas of the lung. syndrome and ulnar neuropathy also occur.714
Laboratory Features. Serum CK may be elevated 8 to 100 Laboratory Features. Serum CK is usually elevated two to
times normal. five fold but has been as high as 70-fold in a patient with gel-
Histopathology. Muscle biopsies reveal scattered necrotic solin FA.714 AL is associated with monoclonal light chain im-
muscle fibers, so-called "pipestem" capillaries and small arteri- munoglobulins (X greater than K) in the serum or urine.
oles with thickened endothelium, perivascular inflammation, Histopathology. Muscle biopsies demonstrate variability in
and membrane attack complex deposition on the small blood fiber size with hypertrophic fibers intermixed with atrophic
vessels.224a-29la-450 In this regard, the disorder is similar to der- fibers.714 Scattered necrotic and regenerating fibers may be seen.
matomyositis, which is also commonly associated with an un- Signs of mild denervation may be present as well. Amyloid de-
derlying malignancy. However, perifascicular atrophy is not position is best visualized using rhodamine optics of Congo-red
evident on biopsies and patients do not exhibit the characteristic stained section.714 After employing this technique in the routine
rash of dermatomyositis. evaluation of all muscle specimens, the Mayo Clinic demon-
Pathogenesis. The pathogenesis is unknown; however, the strated a 10-fold increase in the diagnosis of amyloid myopathy,
deposition of membrane attack complex on small arterioles and suggesting it is probably an underdiagnosed entity.714
capillaries with thickened endothelial walls suggests a hu- The amyloid deposits infilrate and surround small arterioles
morally mediated microangiopathy.224"-2913-430 There may be and venules. Muscle fibers are also partially or completely en-
some antigenic similarity between proteins expressed in the cased by amyloid deposits. Immunohistochemical studies reveal
tumors and those on vessel walls. Perhaps the imune attack is A, and/or K light chain deposits and amyloid P in AL.714 Gelsolin
the body's way of choking off the blood supply to the tumor. deposition colocalizing with membrane attack complex was
Necrotic fibers may also be the result of the release of tumor- identified immunuhistochemically in a case of FA. ApoE was
related cytokines (e.g., tumor necrosis factor, interleukins) deposited in all patients regardless of the type of systemic amy-
demaging the muscle tissue. loidosis in one large series of patients.714 EM confirms the depo-
Electrodiagnostic Findings. Electromyography may reveal sition of short, nonbranching 10-nm amyloid filaments around
a significant number of fibrillation potentials and positive sharp small blood vessels and muscle fibers.
waves. Short-amplitude, small polyphasic MUAPs with early Pathogenesis. The exact mechanism by which amyloid depo-
recruitment should be apparent in very weak muscle groups. sition causes muscle fiber damage is not known. The myopathy
may be a result of ischemic damage secondary to deposition of The incidence for developing CIM in the ICU is not known, as
amyloid in blood vessel walls. Encasement of muscle fibers by there are only a few published prospective series.130 Douglass et al.
the amyloid may interfere with the transport of nutrients and evaluated 25 consecutive patients requiring mechanical ventilation
wastes into and out of muscle fibers. There may also be mechan- for severe asthma.21 la They were each treated with dexamethasone
ical interference of muscle contraction secondary to amyloid in- 10 mg every 8 hours or hydrocortisone 250 mg every 6 hours; 22 of
filtration. Alternatively, the amyloid may interfere with electrical the 25 patients also received vecuronium. Elevated serum CK was
conduction along the sarcolemma. Of note, there is no evidence detected in 19/22 (76%) of the patients, while clinical myopathy
of apoptosis by EM or TUNEL (terminal deoxynucleotidyl was evident in 9/25 (36%). Mechanical ventilation lasted an aver-
transferase-mediated X-dUTP nicked-end labeling) assay.714 age of 3.1 ±3.1 days in patients without myopathy and 12.9 ± 6.6
Electrodiagnostic Features. Nerve conduction-studies are days in those with myopathy. In a prospective study of 100 consec-
abnormal in patients with coexistent peripheral neuropathy. In utive adult patients undergoing liver transplantation, Campellone
such cases, the amplitudes of the CMAPs and SNAPs are often and colleagues reported the development of CIM in seven pa-
reduced. Mild slowing of conduction velocities may also be pre- tients.130 Each patient was treated in the perioperative period with
sent.630-647-714-773 Electrophysiologic evidence of carpal tunnel non-depolarizing neuromuscular blocking agents and high-dose
syndrome is not uncommon. steroids. Three of six patients tested had elevated serum CK levels,
Electromyography reveals evidence of muscle membrane ir- as high as 10 times the upper limit of normal, 25 days postopera-
ritability with frequent fibrillation potentials and positive sharp tively. Four patients had muscle biopsies demonstrating necrosis
waves, particularly in the paraspinal and proximal limb mus- and selected loss of myosin (see below). Three patients later died
cles. 34.210.362.538.630.640.647.714.773 Complex repetitive discharges and, from sepsis and multiorgan failure. The remaining patients slowly
less commonly, myotonic discharges have also been described. regained strength and the ability to ambulate over 1-3 months.
Short-duration, low-amplitude, polyphasic MUAPs with early Patients with CIM exhibit severe generalized muscle weakness
recruitment are present in the majority of weak proximal mus- that develops over a period of several days. Rare patients have oph-
cles. In addition, long-duration, large-amplitude MUAPs may thalmoplegia.702 Occasionally the weakness can be quite asymmet-
also be noted, especially in distal muscles. ric and mimic a stroke.727 The myopathy may be first recognized by
Treatment. There is no known treatment of the myopathy the inability to wean the patient from the ventilator. Reflexes are di-
secondary to systemic amyloidosis. minished. Sensory examination is usually normal, albeit sometimes
difficult to interpret in an intubated patient with concurrent altered
CRITICAL ILLNESS MYOPATHY/ACUTE mental status. Deep tendon reflexes are decreased or absent. The
QUADRIPLEGIC MYOPATHY mortality is high, approximately 30% in one large series, secondary
to multiple organ failure and sepsis rather than the myopathy.420
Weakness developing in a patient in the intensive care unit The morbidity and mortality in CIM appears to be similar to that of
(ICU) may be secondary to critical illness polyneuropathy,98-803 critical illness neuropathy.420 In patients who survive, muscle
prolonged neuromuscular blockage,65-286 or secondary to a myo- strength recovers slowly over several months.
pathic process. This myopathic disorder has been termed critical Laboratory Features. Serum CK levels can be normal but
illness myopathy (CIM), acute quadriplegic myopathy (AQM), is moderately elevated in about 50% of patients.418-420"
acute illness myopathy, and myopathy associated with thick fila- Histopathology. Muscle biopsies demonstrate a varied spec-
ments (myOSin) - - < I8^t20.420a.436a,495,605.617.691.702 Jj- c a n J^g
l 3 J 9 0 > 197 30! 337 4
trum of histologic abnormalities. Often, there is type 2 muscle

very difficult to distinguish the myopathy from the neuropathy or fiber atrophy with or without type 1 fiber atrophy.13-301-337-419-420-
from prolonged neuromuscular blockade. Patients can potentially 420a.436a.69i.702,804 ^ few re ports described muscle fiber necrosis
have a combination of critical illness myopathy and neuropathy. (Fig. 28-10A).130-420-436a-605-691-804 Focal or diffuse loss of reactivity
Some series of patients with ICU weakness have reported critical for myosin ATPase activity in type 1 fibers more than type 2
illness neuropathy to be more frequent than CIM,560-781 while fibers can be seen. This corresponds to the loss of thick fila-
others found the myopathy to be more common.420-437-617 In the ments (myosin) apparent on immunohistochemistry and EM
largest series involving 88 patients who developed weakness (Fig. 28-10B). 130 l90197-337-419-420-436;'-691 Other structural proteins
while in an ICU, CIM was three times as common as critical ill- (actin, titin, nebulin) are spared or affected only at an advances
ness neuropathy (42% vs. 13%); prolonged neuromuscular block- stage of the disease. 436 " 691 However, not all cases of CIM
ade occurred in only one patient who also had CIM 420 demonstrate loss of myosin. Interestingly, calpain expression is
Clinical Features. The first reported case of CIM involved a markedly enhanced in myosin-deficient CIM muscle biop-
24-year-old woman who developed severe weakness after being sies.691 Immunohistochemistry and ultrastructural analysis
treated for status asthmaticus with neuromuscular blockade and demonstrate abnormalities suggesting apoptosis.208"
high doses of intravenous corticosteroids. Subsequently, there Pathogenesis. The variable laboratory, histologic, and elec-
have been numerous reports of CIM usually developing in patients trophysiologic features suggest that the pathogenesis is multi-
who received high-dose intravenous corticosteroids and/or non- factorial. Some biopsies demonstrate widespread necrosis,
depolarizing neuromuscular blockers.13.130.190.337,4i8-420.420a.436a.605. which certainly can account for the muscle weakness observed
6i7.69i.702 Tj lc disorder has also been reported in critically ill patients in patients. The mechanism of muscle fiber necrosis is not
with sepsis or multiorgan failure who have not received other cor- known, and importantly, not all patients have significant necro-
ticosteroids or non-depolarizing neuromuscular blocking sis on biopsy. Myosin is selectively lost in some patients, as
agents. 197-30l -434n-691 There may be a predilection for development of noted above. However, myosin loss alone would not explain the
CIM in transplant patients, who receive high doses of intravenous muscle membrane inexcitability that occurs with this myopathy.
corticosteroids for prevention of rejection and neuromuscular The observation that muscle fibers exhibit reduced evoked re-
blocking agents in the perioperative period. These patients are also sponses to direct motor stimulation suggests diminished muscle
prone to infection and sepsis secondary to their underlying ill- membrane excitability (see below).616-617 Three factors may be
nesses and immunosuppressed state. important in reducing muscle membrane excitability: (1) partial
Figure 28-/0. Critical illness/acute quadriplegic myopathy. A, Widespread necrosis of muscle fibers is evident on this biopsy of an
ICU patient who became weak after treatment with high doses of corticosteroids and depolarizing neuromuscular agents during liver
transplantation. B, EM demonstrates a muscle fiber with a preserved sarcomere adjacent to a fiber with selected myosin filament loss.
depolarization of the resting membrane potential, (2) reduced mildly reduced (greater than 80% of the lower limit of normal).
muscle membrane resistance, and (3) decreased sodium cur- Some series have reported decrement of CMAP amplitude on
rents.618-631 Rich and colleagues created an animal model for CIM repetitive stimulation (fast and slow rates), although usually
by denervating rats (removing a segment of sciatic nerve) and treat- repetitive stimulation is normal.286-633-804 A decrementing re-
ing the rats with high doses of intraperitoneal steroids.618 Nerve sponse may be demonstrated within 7 days of discontinuation
section reproduces the physiologic effects in the muscle expected on non-depolarizing neuromuscular agents and is usually asso-
from neuromuscular blockade. Specifically, denervation and neu- ciated with renal insufficiency and persistently elevated levels
romuscular blockade normally results in a decrease in the resting of the metabolites of the neuromuscular blocking agent.
membrane muscle potential, and increase in membrane resistance Rich and colleagues utilized the technique of direct muscle
secondary to decreased chloride conductance, and an increase in stimulation to help in distinguishing CIM from critical illness neu-
sodium channels. In denervated rats treated with steroids, the rest- ropathy.616-617 Direct muscle stimulation bypasses the distal motor
ing membrane potential decreased, but was not significantly differ- nerve and neuromuscular junction. In critical illness neuropathy or
ent from denervated, non-steroid-treated controls. However, prolonged neuromuscular blockade, the muscle membranes
muscle membrane resistance was reduced as a result of increased should retain its excitability and the direct muscle stimulation
chloride conductance. This lower membrane resistance decreased CMAP (dmCMAP) should be near-normal despite a low or absent
the depolarization caused by the opening of sodium channels. nerve stimulation evoked CMAP (neCMAP). In contrast, if the
Further, there was a reduction in the sodium currents either sec- muscle membrane excitability is reduced, both the neCMAP and
ondary to a reduction in the actual number of sodium channels or dmCMAP should be very low. Theoretically, the ratio of neCMAP
an alteration in sodium channel conductance or voltage-dependent to dmCMAP should be close to 1:1 in a disorder of muscle mem-
gating. How muscle membrane inexcitability ties in with the ob- brane inexcitability (as well as normal controls) and approach zero
served loss of myosin thick filaments is unclear. There is evidence in a neuropathy or neuromuscular junction disorder. In fact, absent
that electrical activity driven by transmembrane ion fluxes affect or reduced amplitudes of the dmCMAP with neCMAP/ dmCMAP
gene expression via intracellular messengers and signal cascades ratios greater than 0.9 were demonstrated in 11 patients with CIM,
involving kinases.669" The increased intracellular calcium via influx while neCMAP/dmCMAP ratios were 0.5 or less in patients with
through L-channels and release by the sarcoplasmic reticulum in severe neuropathy.6166,7
the course of excitation-contraction coupling may trigger the depo- Electromyography frequently demonstrates prominent fibrilla-
larization-transcription cascade.420" Decreased myosin messenger tion potentials and positive sharp waves; however, abnormal spon-
RNA has been observed in muscle biopsies, supporting the possi- taneous activity is not always present. 13 - 130 - 190 - 1 ^
bility that transcription of myofilaments might be altered.420" 436*691.702.804 Myotonic discharges were reported in one patient with
Muscle biopsies demonstrate increased calcium-activated proteases CIM, but this patient apparently was also receiving either
(calpains) that may increase degradation of myosin filament.691 tacrolimus or cyclosporine, which are known to cause electrophys-
Perhaps, abnormal membrane excitation-transcription coupling re- iologic myotonia.130 Short-duration, small-amplitude, polyphasic
sults in the enhanced expression of calpains. Cytokines released MUAPs that recruit early are evident. In severe cases, it may be dif-
during sepsis can also induce a catabolic state in muscle with ficult to recruit any MUAPs. Sequential electromyographic studies
breakdown of proteins, glycogen, and lipid. The activation of prote- have reported profuse spontaneous activity and inability to actively
olytic proteases may induce muscle fiber degeneration via apopto- recruit MUAPs early followed by the appearance of small polypha-
sis reported on some muscle biopsies.280" Further work is necessary sic MUAPs with early recruitment during the recovery period.633
to unravel the pathogenic basis of CIM. Treatment. There is no medical therapy other than support-
Electrophysiologic Findings. Nerve conduction studies ive care and treating underlying systemic abnormalities (e.g.,
demonstrate significantly diminished amplitudes of CMAPs antibiotics in sepsis, dialysis in renal failure). If patients are still
with normal distal latencies and conduction velocities.13130-190197- receiving high doses of corticosteroids or non-depolarizing
3oi.337.4i9.420.69i.702.8O4 I n c o n trast, SNAP amplitudes are normal or neuromuscular blockers, the medications should be stopped.
Patients require extensive therapy to prevent contractures and induction of a generalized necrotizing myopathy. Focal prob-
help regain muscle strength and functional abilities. lems may be diagnosed by their highly localized nature within
select muscle groups predisposed to muscular injection sites. In
these disorders there is an absence of more widespread com-
T O X I C MYOPATHIES plaints or abnormalities. More generalized problems are sus-
pected by diffuse complaints of pain and/or weakness, which
Multiple drugs and toxins have been implicated in causing may be accompanied by myoglobinuria. As would be antici-
muscle damage. For the most part, the vast majority of medica- pated with any substance causing muscle necrosis, the serum
tions are safe when administered according to recommended CK is elevated and depends upon the amount of muscle tissue
therapeutic regimens. Patients at risk for developingâdverse re- disrupted.
actions are typically those with reduced abilities to metabolize
or excrete the drug and its metabolites as is the case in liver and Cholesterol-Lowering Drugs
renal failure, infants/children, and the elderly. Also, myopathy The hypocholesterolemic drugs, including fibric acid deriv-
can develop in patients who knowingly or are inadvertently atives, 436469 475 3-hydroxy-3-methyl-glutaryl-coenzyme A re-
given inappropriately large doses. Some patients, for unknown ductase (3-HMG-CoA) inhibitors, 78163 202475 613669740741 and
reasons, are particularly sensitive to certain medications. niacin,455-613 can result in the development of either insidious or
Muscle tissue is highly sensitive to both drugs and toxins be- rapidly developing primarily proximal lower limb myopathy oc-
cause of its high metabolic activity and multiple potential sites for casionally associated with myoglobinuria. Patients complain of
foreign substances to disrupt the energy-producing pathways. The muscle tenderness, occasional cramps, and difficulty negotiat-
exact manner in which drugs and toxins result in muscle dysfunc- ing stairs or arising from low chairs over the course of several
tion is highly diverse and directly dependent on the substance in days to years. Upon stopping the medication, symptoms tend to
question. Exogenous substances can have either a primary or sec- completely resolve in several days to months.
ondary adverse affect on muscle tissue. The primary effect can be
focal, as might occur secondary to a drug being injected into Fibric Acid Derivatives
tissue, or generalized. Secondary toxic effects may result from the Clinical Features. Clofibrate and gemfibrozil are branched-
substance creating an electrolyte imbalance, inducing an immuno- chain fatty acid ester used for the treatment of hyperlipidemia.
logic response, precipitating ischemia from a vascular reaction, or The myopathy most often presents within 2-3 months after start-
secondary to compression by causing the patient to become un- ing the drug but can be delayed up to 2 years.688 The myopathy is
conscious. Muscle fibers may undergo necrosis as a result of the characterized by generalized weakness, myalgias, cramps, and
drug/toxin directly disrupting the sarcolemma. One mechanism of occasionally myoglobinuria. 149 213-267-436-456-469-475-581-582-652 Patients
insult includes an increased ionic permeability of the sarcolemma with renal insufficiency and those concurrently taking both clofi-
to calcium ions, which eventually leads to death of the muscle cell. brate and gemfibrozil or an HMG-CoA inhibitor are predisposed
Some drugs cause autophagic degeneration of the muscle tissue. to developing a severe myopathy.
Some toxic substances may adversely affect glycogen or lipid me- Laboratory Features. Elevated serum CK levels are usually
tabolism, thus compromising energy production. Another pathway noted.
that can be disrupted is that of protein synthesis. Histopathology. In animal models, clofibrate is known to
Drugs or toxins can produce relatively mild symptoms of result in a noninflammatory necrosis of muscle tissue with fiber
muscle pain and cramps or cause a severe weakness in which size variation and groups of small atrophic muscle fibers.8
the patient may expire as a result of widespread rhabdomyolysis Pathogenesis. The pathogenic mechanism of the myopathy as-
and renal failure. Any patient suspected of being a drug addict sociated with fibric acid derivatives is not known. It has been pos-
or who was therapeutically started on a new medication and ex- tulated that these medications somehow destabilize the lipophilic
periences progressive muscle weakness should be considered to muscle membrane leading to muscle fiber degeneration.581
have an adverse reaction to the drug or toxin. An accurate his- Electrodiagnostic Findings. Motor and sensory nerve con-
tory and diagnosis are obviously crucial because most patients duction studies are completely normal.267-436-382 Needle elec-
recover when the offending agent is withdrawn provided signif- tromyographic examination demonstrates normal MUAPs in
icant or irreversible muscle damage has not occurred. mildly affected persons or clear reductions in MUAP duration
We classify the toxic myopathies according to their pre- and amplitude when significant weakness is present.1J99-406-652
sumed pathogenic mechanisms (Table 28-6). A detailed de- Abnormal spontaneous activity is usually not prominent, al-
scription of all of the possible drugs/toxins and the manner in though fibrillation potentials, positive sharp waves, complex
which they adversely affect muscle tissue is beyond the scope repetitive discharges, and myotonic discharges have been re-
of this text. The interested reader is encouraged to consult sev- ported.456 Myotonic discharges have been demonstrated in ani-
eral well-done and detailed compendiums of toxin/drug in- mals that received clofibrate.417
duced myopathies.31-54-414-429-482'483-761 In this section we focus on
a number of drugs/toxins representative of major pathogenic HMG-CoA Reductase Inhibitors
processes affecting skeletal muscle with the understanding that Clinical Features. 3-HMG-CoA reductase is a rate-control-
related substances have similar effects. Unfortunately, detailed ling enzyme in cholesterol synthesis. A myopathy characterized
electrophysiologic analyses have not been performed in all cat- by myalgias, proximal weakness, and less commonly, myoglobin-
egories of muscle dysfunction due to drugs or toxins. uria, has been reported with all of the major HMG-CoA reductase
inhibitors: lovastatin,163-367-475-613-740 simvastatin,78-194-202-268-504
NECROTIZING MYOPATHIES provastatin,367 504 atorvastatin,55 213 367 fluvastatin,367 and ceriva-
statin.764 The incidence of elevated serum CK and/or sympto-
Several drugs can result in muscle fiber necrosis, either fo- matic myopathy varies from series to series but is generally
cally about the region of injection or systemically with the considered to be low. In a large study of over 6500 patients
Table 28-6 Drug- and Toxin-Induced Myopathies
Disorder Drug/Toxin Clinical Features Serum CK EDM Findings
Necrotizing Cholesterol-lowering agents Acute or insidious onset Elevated PSWs & Fibs proportional to
myopathy Cyclosporine Progressive proximal ± myalgias degree of weakness; BSAPP
Labetalol
Propofol
EACA
Alcohol
Amphiphillic Chloroquine Proximal weakness; ± myalgias Elevated Axonal sensorimotor neuropathy;
myopathy Hydroxychloroquine Sensorimotor neuropathy PSW & Fibs; BSAPPs
Amiodarone Cardiomyopathy
Acute or insidious onset
Antimicrotubular Colchicine Acute or insidious onset Elevated Axonal sensorimotor neuropathy;
myopathy Vincristine Sensorimotor neuropathy PSW & Fibs; BSAPP
Proximal weakness
Mitochondrial Zidovudine (AZT) Proximal weakness Normal or Fibs & PSWs rare; may have
myopathy Myalgias mild increase BSAPP
Insidious onset
Inflammatory L-tryptophan Proximal weakness ± myalgias Mildly increased Fibs & PSWs; BSAPP
myopathy D-penicillamine Acute onset
Cimetidine
Procainamide
L-Dopa
Phenytoin
Lamotrigine
Myofibrillar Emetine (Ipecac) Proximal weakness Mildly increased Fibs & PSWs; BSAPP
myopathy Cardiomyopathy
Elinafide
Acute onset
Hypokalemic Diuretics Episodic weakness Increased Fibs & PSWs; BSAPP
myopathy Laxatives Acute onset
Amphotericin
Toluene abuse
Licorice
Corticosteroids
Alcohol abuse
Alcohol Acute weakness secondary Acute myopathy: Acute myopathy:Fibs, PSWs,
myopathy hypokalemia or necrosis increased CK; BSAPPs; normal in chronic
Chronic proximal weakness Chronic myopathy: myopathy
May have sensorimotor normal CK May have axonal sensorimotor
peripheral neuropathy neuropathy
Malignant General anesthesia Hyperthermia Increased CK
hyperthermia Non-depolarizing Muscular rigidity
neuromuscular Autonomic instability
blocking agents Acute onset
Myopathies in Heroin Muscle abscess Normal or Fibs, PSWs, and BSAPPs in
drug addicts Cocaine Induration and contracture of increased necrotic muscle
Pentazocine muscle from fibrosis
Amphetamines Muscle ischemia from vaso-
constriction
Rhabdomyolysis from prolonged
seizures or LOC
EDM, electrodiagnostic medicine; BSAPP, brief small abundant polyphasic motor unit action potentials; EACA, epsilon aminocaproic acid; LOC, loss of consciousness;
PSW, Positive sharp wave; Fibs, Fibrillation potentials.
Modified from Argov and Mastaglia;31 Lane and Mastaglia;429 Mastaglia;4*2-483 and Victor.76'
treated with lovastatin, up to 35% had elevated serum CK levels lovastatin. Other studies have reported asymptomatic serum CK
sometime during the study; however, 29% of patients receiving elevations in approximately 1% of patients taking lovastatin
placebo had similar CK elevations. 214 Approximately 7-9% of with myalgias, mild proximal weakness, and myoglobinuria de-
patients in both the treatment and placebo groups complained of veloping in less than half of these patients.738-741 Overall, it is es-
muscle discomfort during the study; however, clinical evidence timated that approximately 5% of patients taking lovastatin
of myopathy was detected in only 0.08% of patients receiving develop signs or symptoms of a myopathy.688
The incidence of myopathies in patients receiving other statin Electrophysiologic Findings. Routine motor and sensory
agents has been less well studied. Myopathy has also been re- nerve conduction studies should be normal. Fibrillation poten-
ported with the newer statin medications but the incidence ap- tials, positive sharp waves, and occasionally myotonic dis-
pears to be less frequent than that seen with lovastatin. Myopathy charges may be seen. 504 Early recruitment of small-duration
has been described in only 0.08% of patients treated with simvas- MUAPs is apparent in patients with significant weakness. Elec-
tatin.88 Similarly, only 0.01% of patients receiving pravastatin de- tromyography of patients with asymptomatic serum CK eleva-
veloped significantly elevated (> 10 times normal) serum CK tiojis is usually normal.
levels.688 There are also rare cases of myopathy associated with
atorvastatin.55-213-367 In a review of 337 patients taking atorvastatin, Niacin
only two had CK elevations greater than five times normal and There are only a few descriptions of patients treated with niacin
both were asymptomatic. 55 Three patients complaining of myal- who have developed a necrotizing myopathy.453-613 Myalgias and
gias had normal serum CK levels. In an 8-week study comparing cramps of the lower limbs were described in three patients receiv-
the efficacy and safety of lovastatin, simvastatin, pravastatin, ing medication. Serum CK levels were elevated as much as 10-
atorvastatin, and fluovastatin in 518 patients, myalgias were pre- fold. The symptoms improved and CK levels normalized after
sent in approximately 1.5% of patients in each treatment group discontinuation of niacin. Electrodiagnostic studies and muscle
and no one had a CK level greater than three times normal.367 biopsies were not performed. Of note, niacin can inhibit HMG-
The concomitant use of fibric acid derivatives,2,3'456-58,-6,3-74a741 CoA reductase; therefore, the pathogenic mechanism of the my-
niacin,455-613 erythromycin, 51 and cyclosporine 740 markedly in- opathy is likely similar to that of the statins.
creases the risk of toxic myopathy, as does renal insufficiency and
hepatobiliary dysfunction. For example, approximately 5% of pa- Immunophilins: Cyclosporine and Tacrolimus
tients taking both- lovastatin and gemfibrozil developed a severe Clinical Features. The immunophilins, cyclosporine and
myopathy,581 while a severe myopathy complicated as many as tacrolimus, are commonly used immunosuppressive agents, espe-
30% of patients receiving both lovastatin and cyclosporine.163-740 cially in transplantation patients. A few patients taking cy-
Laboratory Features. As noted above, asymptomatic eleva- closporine develop generalized myalgias and proximal muscle
tion of serum CK has been reported in 1-35% of patients on lo- weakness within months after starting therapy.29-I04a l66-289-293-542 Rare
vastatin. Serum CK can be elevated as much as 1000 times cases of rhabdomyolysis with myoglobinuria have also been re-
normal in patients with severe toxic myopathy.504 ported, usually in patients receiving cyclosporine concurrent with
Histopathology. Muscle fiber necrosis with phagocytosis cholesterol-lowering agents or colchicine.544-625-740-763 Tacrolimus
and small regenerating fibers are evident on biopsies of severely has also been associated with severe rhabdomyolysis335 as well as
affected patients. However, necrotic fibers can be scant or not hypertrophic cardiomyopathy with congestive heart failure.49
evident.504 EM demonstrates the subsarcolemmal accumulation Myalgias, muscle strength, and cardiac function improve with re-
of autophagic lysosomes. One study reported mild inflammatory duction or discontinuation of the offending immunophilin.
infiltrates and membrane attack complex deposition on small Laboratory Features. Serum CK is elevated.
blood vessels reminiscent of dermatomyositis in a patient who Histopathology. Muscle biopsies demonstrate necrosis, vac-
developed severe proximal weakness, elevated serum CK levels, uoles, and type 2 muscle fiber atrophy.
and an erythematous rash while being treated with pravastatin.669 Pathogenesis. The pathogenic basis of immunophilin-in-
Pathogenesis. The pathogenesis of the myopathy secondary duced myopathy and cardiomyopathy is not known.104a Perhaps,
to HMG-CoA reductase inhibitors is unknown. Mevalonate is the the agents destabilize the lipophilic muscle membrane leading
immediate product of HMG-CoA reductase metabolism. to muscle fiber degeneration, similar to the cholesterol-lowering
Subsequently, mevalonate is metabolized to farnesol and then to agents. In this regard, cyclosporine has a cholesterol-lowering
either squalene or geranylgeroniol. 248 Squalene is the first effect. This may explain the increased risk of myopathy in pa-
metabolite committed to the synthesis of cholesterol. On the other tients receiving cyclosporine and other lipid lowering agents
hand, geranylgeroniol is a metabolite in the biosynthesis of coen- (e.g., fibric acid derivatives, statins).
zyme C 10 (important in mitochondrial ATP production), dolichol Electrophysiologic Findings. Nerve conduction studies are
(important in glycoprotein synthesis), isopentyladine (a compo- normal. Electromyography is remarkable for evidence of in-
nent of tRNA), and is also important in the activation of certain creased muscle membrane instability. Fibrillation potentials,
regulatory proteins (G-proteins).248-268 It has been postulated that positive sharp waves, and myotonic potentials can be demon-
the lipid-Iowering effect of HMG-CoA reductase inhibitors may strated.166 In patients with severe weakness, small-amplitude,
disrupt the cholesterol content in muscle membranes predispos- short-duration MUAPs with early recruitment may be evident.
ing the muscle fibers to rhabdomyolysis. 456 However, one study
suggested that the depletion of metabolites of geranylgeroniol, Labetalol
and not inhibition of cholesterol synthesis, are responsible for Clinical Features. Labetalol is an antihypertensive drug that
myotoxicity.248 In this regard, HMG-CoA reductase inhibitors has been associated with rare reports of necrotizing myopa-
have been demonstrated to decrease the levels of coenzyme Q, thy.736-776 The myopathy can present acutely of insidiously with
which may impair energy production.251 HMG-CoA reductase in- proximal weakness and/or myalgias. Symptoms improve fol-
hibitors may increase the release of calcium or reduce the uptake lowing discontinuation of the medication.
of calcium by the sarcoplasmic reticulum, leading to disruption Laboratory Features. Serum CK can be markedly elevated,
of normal excitation contraction coupling.504 Increased intracyto- up to 27,000 IU/L.
plasmic calcium levels may activate a calcium-dependent phos- Histopathology. Routine light microscopy can be normal736
phokinase that in turn regulates chloride conductance. The or reveal necrotic and regenerating fibers.776 EM revealed sub-
subsequent decreased chloride conductance across the sarcolem- sarcolemmal vacuoles in one case.736
mal membrane may be responsible for the myotonic discharges Pathogenesis. The pathogenic etiology for the muscle necro-
observed on needle electromyography.504 sis seen is not known.
Figure 28-11. Toxic myopathy. A, Chloroquine can cause a vacuolar myopathy (modified Gomori-trichrome). B, Electron microscopy reveals
a bundle of dilated tubules. (From Wasay M, Wolfe Gl, Herrold JM, et al: Chloroquine myopathy and neuropathy with elevated CSF protein.
Neurology 1998;51:1226-1227, with permission.)
Electrophysiologic Findings. Electromyography demon- Histopathology. Muscle biopsies reveal significant degrees of
strates increases of insertional and spontaneous activity with fibril- segmental myonecrosis and scattered regenerating muscle fibers.
lation potentials and positive sharp waves. Short-duration, Pathogenesis. The pathogenic mechanism is not known. The
small-amplitude, polyphasic MUAPs that recruit early are evident. myopathy may be related to ischemia secondary to thrombosis
of small capillaries.388
Propofol Electrophysiologic Findings. Motor and sensory nerve con-
Clinical Features. Propofol is a new anesthetic agent that has duction studies are normal with the exception of a reduced
been increasingly used for sedating mechanically ventilated patients CMAP when obtained from profoundly involved muscles.
and for treatment of status epilepticus. There have been several re- Needle electromyographic examination usually reveals a reduc-
ported cases of rhabdomyolysis with myoglobinuria, metabolic aci- tion in the amplitude and duration of voluntary MUAPs.466-527-756
dosis, hypoxia, and myocardial arrest associated with the use of The recruitment pattern is early in that there are multiple MUAPs
propofol in children. 3iam724 No similar cases have been reported in during minimal levels of force production. Profuse fibrillation po-
adults. The syndrome differs from malignant hyperthermia because tentials and positive sharp waves can be detected in clinically af-
of the lack of persistent hyperthermia and muscular rigidity. fected muscles, although a few patients with mild disease failed
Laboratory Features. Serum CK levels are markedly ele- to reveal any abnormal spontaneous potentials.107-109-430-466-527-756
vated and myoglobinuria with renal failure can be seen. Complex repetitive discharges can occasionally be seen. There is
Hyperkalemia develops secondary to massive muscle destruc- a single report of true myotonic discharges being recorded on
tion. Serum chemistries and blood gases demonstrate severe needle examination in a patients with significant weakness.430
metabolic acidosis and hypoxemia. Treatment. Following drug discontinuation, both the my-
Histopathology. Muscle biopsies have revealed necrosis of opathy and electrical abnormalities resolve over the course of
skeletal and cardiac muscle. several months.
Pathogenesis. The mechanism for muscle destruction is
unknown. Amphiphilic Drug Myopathy (Drug-Induced
Electrophysiologic Findings. Electrophysiologic studies Autophagic Lysosomal Myopathy)
have not been performed or were not reported. Amphiphilic drugs contain a hydrophobic region and a hy-
Treatment. Propofol should be discontinued and supportive drophilic region containing a primary or substituted positively
therapy for myoglobinuria, metabolic acidosis, hyperkalemia, charged amine group. These properties account for the ability of
and renal failure instituted. the drugs to interact with the anionic phospholipids of cell
membranes and organelles. These medications also cause a neu-
Epsilon-Aminocaproic Acid ropathy that may impair function more than the myopathy.
Clinical Features. Epsilon-aminocaproic acid, a mono-
aminocarboxylic acid, is a drug with efficacy in reducing the in- Chloroquine
cidence of recurrent hemorrhage after the recent rupture of an Clinical Features. Chloroquine is a quinoline derivative
intracranial aneurysm prior to operative intervention. Its mode of used for treating malaria, sarcoidosis, systemic lupus erythe-
action as an antifibrinolytic is believed to be the inhibition of matosis, scleroderma, and rheumatoid arthritis. One of the more
plasminogen activation conversion to plasmin. Some patients re- serious side effects of this drug is irreversible macular damage to
ceiving the drug for a period of 4-7 weeks complain of signifi- the eye. Patients with a chloroquine myopathy develop slowly
cant muscle pain either in the calves or about the shoulder and progressive, painless, proximal weakness and atrophy, which is
pelvic girdle regions. ,07J09 - 377 - 388 ^ Proximal muscle worse in the legs than the arms.217-232-481-483-768 A cardiomyopathy
weakness and myoglobinuria can occur. can also occur. Sensation is diminished in some patients sec-
Laboratory Features. Serum CK levels are usually markedly el- ondary to a superimposed neuropathy. Deep tendon reflexes may
evated in cases of severe necrotizing myopathy and myoglobinuria. be diminished, particularly at the ankle. The "neuromyopathy"
usually appears in patients taking 500 mg for a year or more but compatible with a demyelinating polyneuropathy. 356 Electro-
has been reported with doses as low as 200 mg per day. The myography demonstrates fibrillation potentials and positive
neuromyopathy is reversible following discontinuation of the sharp waves in proximal and distal muscles. In proximal mus-
medication. cles, MUAPs are typically polyphasic, short in duration, small
Laboratory Features. Serum CK levels are usually elevated. in amplitude, and recruit early. Distal muscles are more likely to
Histopathology. The most prominent abnormality is the have large amplitude, long duration polyphasic MUAPs with
presence of positive vacuoles in as many as 50% of skeletal and decreased recruitment.
cardiac muscle fibers (Fig. 28-11). These vacuoles stain intensely
for acid phosphatase. Type 1 fibers appear to be preferentially ANTIMICROTUBULAR MYOPATHIES
affected. On EM, the vacuoles are noted to contain'concentric
lamellar myeloid debris and curvilinear structures. 768 Colchicine
Autophagic vacuoles are also evident in nerve biopsies. Clinical Features. Colchicine is commonly prescribed for
Pathogenesis. As noted above, the drug is thought to inter- individuals with gout. The medication is weakly amphiphilic,
act with the lipid membranes. The drug-lipid complexes arc re- but its therapeutic and toxic effects are thought to be secondary
sistant to digestion by lysosomal enzymes, thus resulting in the to its binding with tubulin and prevention of tubulin polymer-
formation of the autophagic vacuoles filled with myeloid debris. ization into microtubular structures.483-761 Colchicine can cause
Electrophysiologic Findings. Patients with a superimposed both a generalized peripheral neuropathy and myopathy. The
neuropathy demonstrate mild slowing of both motor and sen- neuromyopathy usually develops in patients over the age of 50
sory nerve conduction velocities associated with a mild to mod- years, but it can also develop secondary to acute intoxica-
erate reduction in the amplitudes and slightly prolonged tion.413415627 Chronic renal failure appears to be a risk factor for
F-waves. 232481768 Patients with only the myopathy usually have development of the neuromyopathy. Patients present with pro-
normal motor and sensory studies. 217 On electromyography, gressive proximal muscle weakness over several months. One
there is an increase in insertional activity with significant patient has been described with clinical myotonia. 654 There is
amounts of positive sharp waves and fibrillation potentials pri- distal sensory loss as well as diminished reflexes. A loss of fine
marily, but not exclusively, in the proximal limb mus- motor coordination may be noted in the hands. The neuromy-
cles 217.232,4s i,768 Voluntary MUAPs are significantly decreased in opathy weakness resolves within four to six months after dis-
amplitude and duration with a predominance of polyphasic continuing the colchicine.
MUAPs. Of interest, several investigators have noted prominent Laboratory Features. Serum CK level is elevated, up to 50-
myotonic potentials despite a lack of clinical myotonia.232-481 fold, in symptomatic patients. Serum CK may also be mildly el-
evated in asymptomatic patients taking colchicine.
Hydroxychloroquine Histopathology. Muscle biopsy demonstrate acid phos-
Hydroxychloroquine is structurally similar to chloroquine phatase-positive autophagic vacuoles containing membranous
and produces a neuromyopathy. 232 The muscle weakness and debris. Necrotic fibers are rare. Nerve biopsies reveal evidence
histologic abnormalities are usually not as severe as seen in suggestive of a mild axonal neuropathy.
chloroquine myopathy. Vacuoles are typically absent on biopsy Pathogenesis. Disruption of the microtubules is felt to lead
but EM still usually demonstrates the abnormal accumulation of to defective intracellular movement or localization of lyso-
myeloid and curvilinear bodies. somes, resulting in the accumulation of autophagic vacuoles.415
Electrodiagnostic Findings. Nerve conduction studies com-
Amiodarone monly show a prolongation of the distal motor and sensory la-
Clinical Features. Amiodarone is an antiarrhythmic med- tencies in both the upper and lower limbs.405-413-415-627 A reduction
ication that also causes a neuromyopathy similar to chloro- in the CMAP and SNAP amplitudes may also be noted. F-waves
quine. 1 i-i65.35M99.643 Severe proximal and distal weakness can can be expected to be significantly prolonged and H-reflexes
develop in the legs worse than the arms combined with distal may be prolonged or absent. Needle electromyography demon- j
sensory loss. Other abnormalities include tremor and ataxia. strates two distinct patterns of abnormality. In the distal muscles
Deep tendon reflexes are diminished. Amiodarone can also of the upper and lower limbs, a reduced number of long dura-
cause hypothyroidism that as discussed previously can cause tion and high amplitude MUAPs firing at high rates can be
proximal weakness. Patients with renal insufficiency may be found. This is compatible with the drop-out of entire motor
more at risk for developing the neuromyopathy. Muscle strength units, i.e. the above noted peripheral neuropathy. On the other
gradually improves following discontinuation of the drug. hand, quantitative analysis of MUAPs from proximal limb and
Laboratory Features. Serum CK levels are elevated. paraspinal muscles reveals early recruitment of MUAPs with
Histopathology. Muscle biopsies demonstrate autophagic short durations and low amplitudes. This finding is certainly
vacuoles with myeloid inclusions. In addition, neurogenic atro- consistent with the myopathic process noted on muscle biopsy.
phy can also be appreciated, particularly in distal muscles. These so-called myopathic MUAP abnormalities can be masked
Besides myeloid debris, EM reveals myofibrillar disorganiza- in the distal limb muscles secondary to the superimposed pe-
tion. Myeloid inclusions are also evident on nerve biopsies. ripheral neuropathy. Positive sharp waves, fibrillation poten-
These lipid membrane inclusions noted on muscle and nerve tials, and complex repetitive discharges are detected with ease
biopsies have persisted as long as 2 years following discontinu- in all muscle regions. These potentials probably arise proxi-
ation of the medication. mally from the myopathic muscle degeneration and distally
Pathogenesis. The pathogenesis is presumably similar to from the combination of intrinsic muscle disease and the super-
other amphiphilic medications (e.g., chloroquine). imposed peripheral neuropathy induced muscle denervation. In
Electrophysiologic Features. Decreased amplitudes of addition, myotonic discharges have been described in four pa-
CMAPs and SNAPs, particularly in the lower limbs are evi- tients with colchicine neuromyopathy, one of whom also had
dent.499 Some studies have noted slowing of conduction velocities clinical myotonia.654
Vincristine response to treatment (e.g., prednisone) or withdrawal of AZT are
Clinical Features. The chemotherapeutic agent, vincristine, required to determine the relative frequencies of these neuromus-
primarily acts by disrupting RNA and protein synthesis as well cular disorders in HIV infected individuals manifesting general-
as the polymerization of tubulin into microtubules. 483 A severe ized weakness. Although there are limitations of the reported
axonal sensorimotor polyneuropathy with associated distal studies to date, a review of a few important published series of
muscle weakness and sensory loss is the most frequent adverse patients illustrates the controversial nature of the subject.
effect limiting its use. Much less common is the development of In the first large double-blind, placebo-controlled study of AZT
a proximal muscle weakness and myalgias.102 involving 289 patients with AIDS, myalgia was reported in 8% of
Laboratory Features. Unfortunately, serum CK levels have patients receiving the drug compared to 2% of the patients in the
not been reported in patients suspected of having a superim- placebo group.622 However, detailed neuromuscular examination,
posed myopathy. laboratory evaluation, or muscle histology was not described.
Histopathology. Biopsies of distal muscles demonstrate evi- Simpson and colleagues retrospectively analyzed the clinical
dence of neurogenic atrophy and occasionally the accumulation and laboratory data from a double-blind, placebo-controlled
of lipofuscin granules. Proximal muscle biopsies reveal foci of study of AZT in individuals with early, mild HIV infection (1987
segmental necrosis.102 On EM, prominent myofibrillar degener- to 1989) in order to assess the prevalence of AZT myopathy.6993
ation is evident. There is subsarcolemmal accumulation of os- In their study, 351 patients were assigned to placebo and 360 to
miophilic material. In addition, some myonuclei contain AZT (200 mg q 4 hrs) with a mean duration of follow-up of 39.4
membrane bound inclusions. Autophagic vacuoles with spher- weeks. There was no significant difference in the frequency of
omembranous debris seen in animals treated with vincristine myalgias or between the AZT-treated group and the placebo
have not been demonstrate in humans.24102-288-705 group. Over 50% of patients in both groups complained of some
Pathogenesis. The pathogenic basis of the neuromyopathy degree of myalgia, but objective weakness was found in less than
is presumably similar to that of colchicine. 5% of patients. The prevalence of myalgia in the AZT and
Electrophysiologic Findings. Nerve conduction studies placebo groups in this study was much higher than the other
demonstrate electrophysiologic data compatible with an axonal large double-blind, placebo-controlled study of AZT described
peripheral neuropathy. The amplitudes of SNAPs and CMAPs above.622 Elevated serum CK levels were evident in 29% of AZT-
are significantly reduced, the distal latencies are slightly pro- treated group and 22.2 % of the placebo-treated group (not sta-
longed, and conduction velocities are mildly slow.102 Needle tistically significant), but were elevated to greater than six times
electromyography demonstrates positive sharp waves, fibrilla- normal in only 2-3% in both groups (also not statistically signif-
tion potentials, and neurogenic appearing MUAPs in the distally icant). The only five patients with objective weakness and serum
located muscles of the upper and lower limb. Electromyography CK elevations belonged to the AZT group. Reduction of AZT
of proximal muscles, even in patients with myalgias, are report- dose led to an improvement in muscle strength in only one pa-
edly normal. 102 However, quantitative MUAP analysis has not tient. The authors concluded that myalgias and minor serum CK
been commented on in detail. elevations are not uncommon in individuals with early HIV in-
fection, regardless of AZT status, and does not necessarily imply
DRUG-INDUCED MITOCHONDRIAL MYOPATHY a myopathic process is responsible for their symptoms or that re-
duction of AZT dose is indicated. However, the prevalence of
Zidovudine (Azidothymidine) myopathy in this study may have been underestimated given the
Background. Myopathies related to HIV infection are hetero- retrospective nature of the analysis and lack of electromyo-
geneous and include an inflammatory myopathy (polymyositis), graphic and muscle biopsy data. Further, the study addressed the
microvasculitis, noninflammatory necrotizing myopathy, type 2 frequency of myopathy in patients with early HIV infection, not
muscle fiber atrophy secondary to disuse and wasting do to their those with AIDS, who may be at an increased risk for the various
chronic debilitated state, and a toxic myopathy secondary to zi- myopathies associated with HIV infection.
dovudine (azidothymidine, AZT).53-80138179-290-473-578-615-696-700 Fur- In a very controversial paper, Simpson et al. reported 50 pa-
ther, weakness in an HIV-infected patient can also be secondary tients with HIV infection and myopathy.698 This series apparently
to peripheral neuropathy (e.g., chronic inflammatory demyelinat- included patients from their earlier reports.696-697 Thirty one pa-
ing polyneuropathy) or myasthenia gravis. tients were treated with AZT (23 had AIDS or ARC), while 19 had
Clinically, AZT myopathy and the other myopathic disorders not received AZT (only 10 had AIDS or ARC). Myalgias were
associated with HIV infection are indistinguishable, compound- more common in the group that received AZT (61 % of patients)
ing the diagnostic difficulty. Regardless of etiology of the my- compared to those who had not received AZT (26%). There was
opathy, patients can present with progressive proximal muscle no difference in serum CK levels, which were mildly elevated, or
weakness and myalgias. In addition, muscle weakness may be needle electromyography, which was myopathic. AZT was dis-
multifactorial: an individual patient can have an HIV-associated continued in 15 patients. Four patients had improved strength,
myositis, nemaline rod myopathy, AZT-induced mitochondrial three had reduction in myalgias, and eight experienced no change.
myopathy, and type 2 muscle fiber atrophy (not to mention an Twelve of 13 patients treated with prednisone demonstrated im-
HIV-related or toxic peripheral neuropathy). proved strength. Interestingly, the authors felt that ragged-red
Retrospective series have reported variable frequencies of HIV- fibers were absent in the majority of their patients and rare when
associated myopathies and AZT myopathy, due in part to differ- present. They felt it was impossible to distinguish a myopathy sec-
ent definitions of myopathy. Some series define the presence of ondary to AZT from other myopathies related to HIV infection on
myalgias or elevated serum CK as indicative of a myopathy, the basis of clinical, laboratory, or histological features and that in
while more stringent studies have required objective weakness, the majority of patients the myopathy is not related to AZT. This
electrophysiologic abnormalities, and abnormal muscle histol- study was criticized because of the lack of mitochondrial abnor-
ogy. Prospective studies assessing objective weakness, CK eleva- malities associated with AZT use that had been reported by other
tion, electromyographic abnormalities, histopathology, and the authorities (see below).179-182-279-290-291-506-699
Dalakas et al. reviewed the clinical and histologic features of 20 Peters et al. evaluated 118 patients with AIDS every 4 weeks
patients with HIV infection (all with AIDS or ARC) and myopa- for 1 year to determine the incidence of myopathy (defined as
thy.179 Ragged-red fibers were evident only in the fifteen patients weakness and elevated serum CK levels).578 Eighty eight patients
who had been treated with AZT (frequency ranged from 2 to 48% were treated with AZT. Only seven patients, all of whom received
of muscle fibers). Of note, all 20 patients had inflammation on AZT, developed myopathy, giving an incidence of 8% (7/88). The
biopsy, which by immunocytochemistry was indistinguishable incidence of myopathy in patients taking AZT for longer than 270
from typical polymyositis. Nemaline rods and cytoplasmic bodies days was 17% (7/41). Myalgias were present in six of the seven
were also evident in the majority of patients. Among the 15 AZT- patients, but the incidence of myalgias in other patients was not
treated patients, eight improved following discontinuation of AZT, described. Electromyography was performed in only six patients
four responded to prednisone (one of whom had initially worsened and was normal in three. Three patients had small MUAPs with
after AZT was stopped), and two improved with NSAIDs. Two pa- early recruitment. There was no mention of fibrillation potentials,
tients had exacerbation of their symptoms and elevation of serum positive sharp waves, or muscle membrane instability. Muscle
CK levels when rechallenged with AZT. Of the five patients who biopsy was done in only four patients and revealed nonspecific
had previously not received AZT, two improved with steroids, one myopathic features. None had inflammation or ragged-red fibers
failed steroids but improved when AZT was added, one failed on biopsy; however, electron microscopy revealed mitochondrial
steroid treatment and died, and one responded to NSAIDs. The abnormalities. All seven patients showed improved strength and
study illustrates that AZT-induced mitochondrial myopathy and lower CK levels after AZT was discontinued. This study may
immune-mediated myositis can coexist in individual patients, but have underestimated the incidence of myopathy in this group be-
in any given patient, it is unclear which pathogenic process is pri- cause patients with weakness but normal CK levels and those pa-
marily responsible for the clinical features. tients with elevated CK levels but normal strength were not
Mhiri et al. reported the clinical, laboratory, and histologic fea- further evaluated or the details were not reported.
tures of 48 patients infected with HIV (all with AIDS or ARC) It is clear from numerous studies that there is an association
who presented with neuromuscular symptoms.506 Thirteen patients between AZT use and the presence of ragged-red fibers on
had ragged-red fibers on biopsy, ranging from 4 to 30% of the muscle biopsy. However, it remains very controversial as to what
muscle fibers. Assay of mitochondrial enzymes revealed a decline role this AZT-induced mitochondrial myopathy plays in patients
in respiratory chain capacity. There was a dose relationship be- with myalgias, weakness, and elevated serum CK levels.
tween AZT and mitochondrial dysfunction. All 13 patients with Clinical Features. With the above caveats in mind, several
ragged red fibers were treated with AZT (cumulative dose was 498 comments regarding the clinical features of patients with AZT
± 145 grams). However, eight of these 13 patients concomitantly myopathy may be made. Patients taking AZT develop an insidi-
had inflammation on biopsy and five patients also had nemaline ous onset of progressive proximal muscle weakness and atro-
rods. Eight of nine patients in whom AZT was discontinued im- phy. Myalgias also appear to be common. However, these
proved over a period of several weeks or months, but one of these clinical features do not help distinguish AZT myopathy from
patients was also treated with prednisone. One patient deteriorated other HIV-related myopathies.
after AZT was stopped. Subsequently, two patients were rechal- Laboratory Features. Serum CK levels are normal or only
lenged with AZT without reproduction of symptoms. mildly elevated in AZT myopathy. However, similar elevations
Fifty consecutive HIV-infected patients were evaluated for the are evident in other forms of HIV-related myopathy. A markedly
prevalence of myopathy.290 Strength of the deltoid muscles were elevated serum CK (e.g., greater than 5 or 10 times the upper
measured with a myometer and muscle biopsies were performed limit of normal would make the diagnosis of AZT-induced mi-
on all patients. Thirty nine patients received treatment with AZT. tochondrial myopathy less likely.
The series was divided into two subgroups: group 1 with cumu- Histopathology. Muscle biopsies are remarkable for the
lative AZT dose under 200 g and group 2 with a cumulative AZT presence of ragged-red fibers, suggesting mitochondrial abnor-
dose over 200 g. All the patients in group 2 had AIDS, while over malities in AZT myopathy. The number of ragged-red fibers on
one-third of patients in group 1 had early disease. Myalgia was muscle biopsies appears to directly correlate with the cumula-
uncommon but slightly more frequent in group 2 (4/26 patients) tive dose of AZT received by the patients.290-506 In addition,
compared to 2/24 patients in group 1. The majority of patients necrotic fibers, cytoplasmic bodies, nemaline rods, and fibers
were weak on examination (38/50), but there was no difference with microvacuolation may be found on biopsy and coexist with
in muscle strength between the two groups. Serum CK levels the ragged-red fibers.171-181 183-290-506 EM confirms abnormalities
were slightly elevated in both groups (no significant difference). of the mitochondria, myofilaments, and tubules. In contrast to
Muscle biopsies demonstrated ragged red fibers (range 1-15% HIV-associated inflammatory myopathy, significant endomysial
of total muscle fibers) in 16 of 24 patients in group 2, six of inflammation and invasion of non-necrotic fibers may be lack-
whom were asymptomatic for myopathy. Ragged-red fibers ing in pure AZT-myopathy.
were evident in only one of 26 patients in group 1. A definite re- Pathogenesis. AZT acts as a false substitute for the viral re-
lationship between the total lifetime dose of AZT and the per- verse transcriptase, thereby inhibiting its enzymatic activity and
centage of ragged fibers was demonstrated. However, other replication of the HIV virus. However, AZT also inhibits the ac-
histopathologic features (e.g. rod bodies, inflammation, necro- tivity of mitochondrial DNA polymerase that probably accounts
sis) were also evident in muscle biopsies. The authors concluded for the mitochondrial abnormalities present on muscle biopsy.
that the prevalence of myopathy in HIV infected individuals was There is a decrease in quantity of mitochondrial DNA and de-
high and that mitochondrial myopathy was related to cumulative cline in respiratory chain enzymatic activity in HIV patients
AZT dose. However, they noted that a significant proportion of treated with AZT compared to untreated infected patients.32-506 It
patients with ragged-red fibers on biopsy were asymptomatic is clear that AZT is responsible for the mitochondrial abnormal-
and question the clinical significance of this morphologic abnor- ities evident on muscle biopsy. However, as discussed above,
mality. They speculated that most patients with ragged-red fibers the contribution of these mitochondrial abnormalities to the
were weak from some other factors in the muscle. muscle weakness remains controversial.
Electrophysiological Findings. Motor and sensory nerve contaminant in the manufacturing of L-tryptophan.72-209-334-483-656-657-707
conduction studies are normal, unless there is a concomitant pe- The clinical, laboratory, electrophysiologic, and histopathologic
ripheral neuropathy from the disease. Needle electromyo- features are similar to that seen in diffuse fasciitis with eosino-
graphic examination has been reported to demonstrate an philia (Shulman's syndrome). 692 Patients developed a subacute
increase in needle insertional activity with at times florid sus- onset of generalized muscle pain and tenderness with variable de-
tained runs of positive sharp waves and fibrillation potentials in grees of weakness. Interestingly, the onset of symptoms can begin
some patients with HIV-related myopathies and AZT myop- within a few weeks or there can be a latency of several years from
athies. 1 38.565.696-698 Occasional complex repetitive discharges are the start of tryptophan ingestion. Associated symptoms included
also noted in multiple muscles. Early recruitment of short dura- numbness, paresthesias, arthralgias, lymphadenopathy, dyspnea,
tion, small amplitude, polyphasic MUAPs can be demonstrated abdominal pain, mucocutaneous ulcers, and an erythematous rash.
particularly in proximal muscles. However, it is difficult to in- Some patients developed a severe peripheral neuropathy simulat-
terpret the electromyographic features because most studies do ing Guillain-Barre syndrome (GBS)326-707 or mononeuropathy
not correlate these findings with muscle histopathology. multiplex.682
Remember, many patients with ragged-red fibers indicative of Laboratory Features. The serum CK level can be normal
AZT-induced mitochondrial myopathy also have evidence of or elevated. Autoantibodies are absent and ESR is usually
necrosis, an inflammatory myopathy, cytoplasmic or rod bodies normal. The absolute eosinophil count is elevated(> 1 x 10 9
on muscle biopsy. It is difficult to determine from the literature cells/L).
whether or not patients with only ragged-red fibers on muscle Histopathology. Muscle biopsies reveal prominent inflam-
biopsy (a pure AZT myopathy) have muscle membrane instabil- matory infiltration of the surrounding fascia, perimysium, and
ity and myopathic appearing MUAPs on electromyography. In to a lesser extent the endomysium. 224 The inflammation can be
this regard, Chalmers et al. reported that fibrillation potentials diffuse or perivascular. The majority of inflammatory cells are
were common in HIV infected patients with an inflammatory CD8+ T-cells and macrophages. Eosinophils and B-cells ac-
myopathy on biopsy but were rare in patients without inflam- count for less than 3% of the inflammatory cells. There is no de-
mation. 26 In addition, small polyphasic MUAPs with early re- position of membrane attack complex on blood vessels, unlike
cruitment but no abnormal spontaneous activity was reported in dermatomyositis. Nerve biopsies have also revealed inflamma-
AIDS patients with ultrastructural mitochondrial abnormalities tory infiltrate, mainly mononuclear with occasional eosinophils
without inflammation or nemaline rods on biopsy.578 and often perivascular in the epineurium, endoneurium, and/or
Treatment. The percentage of patients with myopathies that perineurium accompanied by evidence of vasculopathy and an-
improve following AZT withdrawal has varied between 18 and gioneogenesis.326-682-707-748 Significant axonal degeneration has
100%.138179-290-47- -578-699 However, discontinuation of AZT may be also been appreciated.
associated with a deleterious increase in HIV replication. Pathogenesis. As noted above, the disorder was caused by a
Further, AZT may be beneficial in patients with HIV-associated contaminant(s) in the manufacture of tryptophan. Two trace
inflammatory myopathy. Therefore, it would be helpful to es- adulterants have been identified as the possible toxins: 3-pheny-
tablish a histologic diagnosis prior to making a decision discon- Iaminoalanine (PAA) and l,l'-ethylidene-bis-tryptophan
tinuing AZT. However, the diagnosis may still not be clear even (EBT).487 The mechanism by which this contaminant resulted in
after a muscle biopsy as some patient may exhibit signs of both the disorder is unknown but the eosinophilia and eosinophilic
an inflammatory myopathy and ragged-red fibers. The presence infiltrate in tissues suggest some form of allergic reaction.
of abundant abnormal spontaneous activity on electromyogra- Electrophysiologic Findings. Patients with peripheral neu-
phy or markedly elevated serum CK levels would lead us to ropathy demonstrate diminished amplitudes of compound
favor an inflammatory myopathy rather than a mitochondrial muscle and sensory nerve action potentials with normal or
myopathy as responsible for the patient's symptoms and signs. mildly reduced conduction velocities.682-707 Needle electromyo-
In such a case, we recommend a trial of IVIG and, if ineffective, graphy reveals muscle membrane instability in the form of fib-
treatment with NSAIDs or corticosteroids should be considered. rillation potentials, positive sharp waves, and complex repetitive
In patients with normal or only mildly elevated serum CK and discharges.326-656-707 There can be a mixture of small and large
normal or only slightly increased spontaneous activity on elec- polyphasic MUAPs with early recruitment as a result of the
tromyography it is impossible to distinguish AZT myopathy chronic myopathy.656-707 Large polyphasic MUAPs with de-
from other HIV-associated myopathies. A reasonable approach creased recruitment may be apparent in patients with weakness
would be trying an NSAID with or without decreasing the dose secondary to a concomitant severe neuropathy. 707 A mild in-
of AZT.178 If there is no significant improvement in strength, one crease in fiber density and jitter can be appreciated on single-
should consider discontinuation of AZT and trying one of the fiber electromyography. A few patients with a severe GBS had
other antiviral medications such as dideoxyonisine (ddl), di- electrophysiologic studies showing multifocal conduction block
doxycytidine (ddC), and protease inhibitors,361 If there is still no and slowing of conduction velocities indicating segmental de-
objective improvement, patients should undergo a muscle biopsy myelination. 326 The electrophysiologic abnormalities improve
and be considered for immunomodulating therapy (e.g., IVIG) with discontinuation of tryptophan.
or corticosteroid treatment if there is histologic evidence of an Treatment. Discontinuation of L-trytophan and treatment
inflammatory myopathy. Patients can be rechallenged with AZT, with high-dose corticosteroids was usually effective. Some pa-
particularly if there are no ragged-red fibers on biopsy. tients experienced relapses upon withdrawal of steroids.
DRUG-INDUCED INFLAMMATORY MYOPATHIES Toxic Oil Syndrome
The toxic oil syndrome is quite similar to the eosiniophia-
L-Tryptophan/Eosinophilia-Myalgia Syndrome myalgia syndrome associated with tryptophan.390 This condition
Clinical Features. Eosinophilia-myalgia syndrome was a was restricted to Spain and has not recurred since 1981. The dis-
disorder described in the late 1980s and early 1990s caused by a order was linked to the ingestion of illegally marked, denatured
rapeseed oil as a cooking substitute for olive oil. Interestingly, Lamotrigine
the toxic contaminant in the rapeseed oil, 3-phenyIamonium- We have seen a case of severe myoglobinuria and renal fail-
1,2-propanediol, is chemically similar to PAA, the adulterant in ure associated with a generalized rash, anemia, leukopenia, and
tryptophan causing the eosinophilia-myalgia syndrome.487 thrombocytopenia shortly after the patient was started on lamot-
rigine. The clinical and laboratory features resemble thrombo-
D-Penicillamine cytic thrombocytopenic purpura. The patient improved with
D-penicillamine is used for the treatment of Wilson's disease, plasmapheresis and discontinuation of lamotrigine.
rheumatoid arthritis, and other connective tissue disorders.
Patients treated with D-penicillamine have a 0.2-1.4% incidence MYOPATHIES SECONDARY TO IMPAIRED PROTEIN
of developing an inflammatory myopathy. 196-308-48-y29-732 Both SYNTHESIS OR INCREASED CATABOLISM
polymyositis and dermatomyositis have been reported and the
clinical, laboratory, histologic, and electrodiagnostic findings are Steroid Myopathy
essentially the same as those found in idiopathic forms of inflam-
matory myopathy. Fortunately, cessation of the drug results in Myopathies related to steroid use were previously discussed
resolution of the symptoms. The medication may be restarted at a in the sections on endocrine myopathies and critical illness
lower dosage without recurrence of the inflammatory myopathy. myopathy.
Cimetidine Finasteride
Rare cases of inflammatory myopathy have been reported with Clinical Features. Finasteride is a 4-azasteroid that inhibits
cimetidine, an H 2 receptor antagonist. 769 One patient developed 5oc-reductase, thus blocking dihydrotestosterone production and
generalized weakness and myalgias associated with renal failure androgen action in the prostate and skin. It has been used for
and was diagnosed with "polymyositis" and interstitial nephritis. treatment of prostatic hypertrophy. A generalized myopathy
Serum CK levels were markedly elevated (up to 40,000 IU/L) and characterized by severe proximal greater than distal weakness
electromyography was described as compatible with polymyosi- and atrophy was reported in one patient treated with finasteride
tis. The muscle biopsy revealed mainly perivascular inflammation, (5 mg/day).302 Sensation and deep tendon reflexes were normal.
predominantly consisting of CD8+ lymphocytes suggestive of a Laboratory Features. Serum CK levels are normal.
humorally mediated vasculopathy similar to dermatomyositis. No Histopathology. Muscle biopsy demonstrates only mild
deposition of immunoglobulin or complement on small blood ves- variability in fiber size, type 2 muscle fiber atrophy, and in-
sels was noted. This patient did not have a cutaneous rash, al- creased central nuclei.
though other cases of cutaneous vasculitis have been reported.516 Pathogenesis. The pathophysiologic mechanism for the my-
opathy is not known. Finasteride is a 4-azasteroid, and both its
Procainamide parent compound and its metabolites have structural similarity
Proximal muscle weakness and myalgias have been reported to corticosteroids. Thus, the pathogenic mechanism may be
following procainamide administration.253-452 Serum CK levels similar to that seen in steroid myopathy.
are elevated. Electromyography was reported as being consis- Electrophysiologic Findings. Nerve conduction studies are
tent with a "patchy" myopathy. Muscle biopsies demonstrated normal.302 Electromyography reveals small polyphasic MUAPs.
perivascular inflammation and rare necrotic muscle fibers. The Abnormal spontaneous activity has not been described.
pathogenesis may related to lupus-like vasculitis that can occur Treatment. Discontinuation of finasteride is associated with
in patients treated with procainamide. The myopathy resolves normalization of strength and improvement in electromyo-
following discontinuation of procainamide. graphic abnormalities.
Levodopa Emetine (Ipecac)
The authors are aware of a single case of proximal muscle weak- Clinical Features. Emetine hydrochloride is the major con-
ness and myalgias following treatment of Parkinson's disease with stituent of the emetic agent, ipecac, and is also used for the
levodopa.783 The patient developed the muscle symptoms after treatment of amebiasis as well as in aversive conditioning for
treatment with L-dopa for over four years. The serum CK was ele- the treatment of chronic alcoholism. The drug has been abused,
vated 10-fold. Nerve conduction velocities were reported as being particularly in patients with anorexia and bulimia. Overuse of
"slow," although no data were given. Electromyography demon- emetine (500-600 mg per day for over 10 days) can result in a
strated rare fasciculation potentials. Gastrocnemius and quadriceps profound, predominantly proximal myopathy and cardiopa-
muscle biopsies revealed perivascular inflammation and rare thy. 1-74.484.563 p a tients may complain of muscle pain, tenderness,
3
necrotic fibers. The authors suggested the patient developed a hy- and stiffness. Deep tendon reflexes are usually diminished, but
persensitivity vasculitis to the L-dopa; however, this has not been the sensory examination is completely normal. The myopathy is
substantiated by other reports. reversible following discontinuation of the medication.
Laboratory Features. The serum CK levels may be mildly
Phenytoin to moderately elevated.
Hypersensitivity reactions to phenytoin can also result in myal- Histopathology. Histologic examination in both humans
gias and muscle weakness. 315 Serum CK levels are elevated. and animals given the medication reveals generalized muscle
Muscle biopsies have demonstrated scattered necrotic and regen- fiber atrophy, necrotic fibers, and small regenerating fibers and
erating muscle fibers. Electromyography can reveal increased necrotic fibers. Notably, scattered fibers contain cytoplasmic
spontaneous activity with fibrillation potentials and positive sharp bodies. Oxidative enzyme stains demonstrate targetoid or moth-
waves. Small-amplitude, short-duration, polyphasic MUAPs that eaten structures. On EM, there is evidence of myofibrillar de-
recruit early may be seen. The myopathy improved with discon- generation in addition to compacted myofibrillar debris
tinuation of the phenytoin and a short course of corticosteroids. (cytoplasmic bodies). The histologic appearance of light and
electron microscopy is similar to that seen in myofibrillar my- with paresthesia and a stocking distribution of sensory loss.
opathy (desmin myopathy). Some patientt complain of myalgias. 241 Deep tendon reflexes
Pathogenesis. Emetine is thought to produce its myotoxic are diminished or absent.
effect by inhibiting muscle protein synthesis, but the exact path- Laboratory Features. Serum CK levels are normal or mildly
ogenic basis for the disorder is not known. elevated.
Electrophysiologic Findings. Sensory and motor nerve con- Histopathology. Muscle biopsies in two patients revealed
duction studies, including repetitive nerve stimulation, are only type 2 muscle fiber atrophy.241273 Superficial peroneal nerve
normal.74-484-563 Needle electromyographic examination can biopsy in one patient demonstrated axonal degeneration.241
demonstrate normal or increased insertional activity. Positive Pathogenesis. The pathogenic mechanism for the neuromy-
sharp waves and fibrillation potentials are usually evident. opathy is unknown.
Voluntary MUAPs are reduced in size and duration with in- Electrophysiologic Findings. Nerve conduction studies are
creased numbers present at low levels of force production (early consistent with an axonal sensorimotor polyneuropathy with re-
recruitment). duced amplitudes of sensory nerve and compound muscle
Treatment. The myopathy improves with discontinuation of action potentials in the lower limbs.241 Electromyography may
the emetine. reveal small polyphasic MUAPs.273
Treatment. Muscle strength improves, sensory symptoms
Elinafide disappear, and serum CK levels normalize following discontin-
Clinical Features. Two patients have been reported who de- uation of omeprazole. Symptoms may recur if omeprazole is
veloped proximal muscle weakness secondary to an experimen- restarted.
tal chemotherapy with elinafide, a DNA intercalator that also
inhibits the enzyme topoisomerase II.18-22 The myopathy im- MYOPATHIES ASSOCIATED WITH ANESTHETIC AGENTS
proved following discontinuation of elinafide AND CENTRALLY ACTING MEDICATIONS
Laboratory Features. Serum CK levels were mildly elevated.
Histopathology. The muscle biopsies demonstrated the ac- Malignant Hyperthermia
cumulation of cytoplasmic bodies and other features similar to Malignant hyperthermia can occur in genetically susceptible
emetine myopathy. Abnormal accumulation of desmin, dys- individuals secondary to various anesthetic agents and depolar-
trophin, gelsolin, neural cell adhesion molecule, p-amyloid pre- izing neuromuscular blockers (see chapter 27).
cursor protein, and various cell cycle regulatory proteins similar
to hereditary and sporadic cases of myofibrillar myopathy were Neuroleptic Malignant Syndrome
demonstrated. 1822 Clinical Features. Neuroleptic malignant syndrome resem-
Pathogenesis. The pathogenic mechanism of myofibrillar bles malignant hyperthermia but has a clearly different patho-
degeneration and the accumulation of cytoplasmic bodies is not genesis. The disorder is characterized by hyperthermia,
known. Topoisomerase inhibitors can cause apoptosis, How- diaphoresis, muscular rigidity, tremor, autonomic dysfunction
ever, Amato et al. found no evidence of apoptosis by TUNEL in with tachycardia and blood pressure fluctuations, as well as al-
the cases of myofibrillar myopathy, including the two enli- teration of consciousness. 4 79133-380 Rhabdomyolysis with myo-
nafide-induced myopathies. 1822 globinuria and subsequent renal failure can complicate this
Electrophysiologic Findings. Electromyography revealed central nervous system disorder. Neuroleptic malignant syn-
increased insertional activity, abundant fibrillation potentials drome usually develops within days of initiation of a neuroleptic
and positive sharp waves, and small polyphasic MUAPs that re- agent or an increase in the dosage. The incidence of this syn-
cruited early. These myopathic abnormalities were more promi- drome in patients taking neuroleptic medications is between 0.5
nent in the more proximal and weaker muscles. and 2.4%.4133-380 and the mortality ranges from 0.05 to 20%. 79133
Treatment. The myopathy improved within several weeks Patients with history of neuroleptic malignant syndrome do not
after discontinuation of elinafide treatment. appear to be at increased risk for malignant hyperthermia when
given anesthetic agents and, as expected, muscle contracture
DRUG-INDUCED HYPOKALEMIC MYOPATHY tests are normal in these individuals.331-380
Laboratory Features. Serum CK is usually elevated and is
Hypokalemia can be caused by a number of medications (e.g., accompanied by myoglobinuria in severe cases. Leukocytosis is
diuretics, laxatives, mineralocorticoids, amphotericin, lithium). also usually evident.
Excessive licorice intake can also result in hypokalemia due to Histopathology. Necrotic and regenerating muscle fibers
its aldosterone-like effect. As discussed below, hypokalemic my- would be expected on biopsy shortly after an attack.
opathy has also been associated with alcohol abuse and inhala- Pathogenesis. Unlike malignant hyperthermia, neuroleptic
tion of toluene. The clinical, laboratory, histopathologic, and malignant syndrome is not caused by a defect in release of cal-
electrophysiologic features of hypokalemic myopathy are dis- cium from the sarcoplasmic reticulum. Rather, the syndrome is
cussed on the sections regarding the periodic paralyses and elec- caused by central dopaminergic blockade that results in intense
trolyte imbalance. These features are similar regardless of the muscle rigidity, persistent muscle contraction, and hypermetab-
etiology of the hypokalemia. olism with hyperthermia which lead to rhadomyolysis and myo-
globinuria.381 Central dopaminergic blockade is also responsible
MYOPATHIES OF UNCLEAR PATHOGENESIS for the autonomic dysfunction apparent in affected patients.
Electrophysiologic Findings. There are no detailed descrip-
Omeprazole tions of the electrophysiologic findings in patients with neu-
Clinical Features. Several cases of a neuromyopathy have roleptic malignant syndrome. As this is not a primary disorder
been reported with omeprazole.24'-273-681 Patients develop proxi- of the peripheral nervous system or muscle, one would not
mal weakness, predominantly in the lower limbs, associated expect to find any significant interictal abnormalities. Obviously,
fibrillation potentials and positive sharp waves along with myo- Muscle weakness evolves over the time period of one or two
pathic MUAPs may be seen shortly after a severe case of rhab- days. Serum CK levels are markedly elevated. Serum potassium
domyolysis, as in any necrotizing myopathy. is very low, ranging between 1.4 and 2.1 mEq/L. Muscle biopsy
Treatment. Early recognition and discontinuation of the of- within the acute time frame demonstrates vacuolar changes.
fending neuroleptic agent is essential. Both sinemet and Both the clinical symptoms and histologic abnormalities resolve
dopamine agonists (e.g., bromocriptine) are effective therapies rather quickly once the hypokalemia is adequately treated.
and should be administered. Dantrolene can also help in reduc- Chronic alcoholic myopathy is characterized by an insidious
ing muscle rigidity by blocking the release of calcium form the onset of primarily proximal limb girdle weakness, especially the
sarcoplasmic reticulum. lower limbs. The degree of weakness may vary. Muscle biopsy
reportedly reveals a random pattern of muscle fiber atrophy,
Serotonin Syndrome necrosis, and regeneration. Whether the muscle weakness in this
The clinical and laboratory features of serotonin syndrome disorder is caused by a toxic influence of alcohol on muscle (a
are similar to neuroleptic malignant syndrome.79-91 Patients de- true "myopathy") or if the weakness arises from malnutrition or
velop alterations in mental status, myoclonus, hyperthermia, a toxic peripheral neuropathy is controversial.
and autonomic instability. Muscle rigidity occurs but is less An asymptomatic alcoholic myopathy has been suggested
prominent than that seen in neuroleptic malignant syndrome on the basis of elevated serum CK levels found coincidentally in
and malignant hyperthermia. However, rhabdomyolysis and alcoholics evaluated for unrelated conditions. There is no com-
myoglobinuria can be seen.510 The disorder usually develops plaint of weakness and the physical examination does not reveal
after the addition or increase in dosage of a serotonergic med- striking evidence of a myopathic disorder. Histologic findings
ication to a therapeutic regimen which already includes sero- are not available for this class of patients and the true nature of
tonin-enhancing medications.79-91 this presumed form of alcoholic myopathy is questionable. The
The pathogenesis of the disorder is related to serotonin over- elevated serum CK may be related to subclinical necrotizing
activity. Selective serotonin reuptake inhibitors (e.g., fluoxetine) myopathy, hypokalemia, or muscle trauma.
can cause an upregulation of serotonin receptors. The addition Pathogenesis. The pathogenic basis for the various forms of
of other serotonergic agents, medications that inhibit serotonin alcoholic myopathies is not known. The metabolism of alcohol
breakdown (e.g., monoamine oxidase inhibitors), or agents that may lead to the accumulation of toxic metabolites (e.g., acetalde-
increase serotonin release (e.g., amphetamines), can result in an hyde) or free radicals which may be toxic to lipid membranes.761
excess of serotonin and development of the syndrome. Alcohol may also have a direct toxic effect on various ion chan-
Treatment involves withdrawal of the offending agents, the use nels. Some authorities have speculated that chronic alcohol abuse
of benzodiazepines for sedation, p-blockers for arrhythmias, impairs glycolysis and glycogenolysis.97-745 However, defects in
and the lowering of the core body temperature. oxidative metabolism were not demonstrated in other detailed
biochemical studies.131 Further work is required to fully elucidate
MYOPATHIES SECONDARY TO DRUGS OF ABUSE the pathogenic role of alcohol in myopathies.
Electrophysiologic Findings. Some patients present with
Alcoholic Myopathy acute muscle weakness (acute necrotizing myopathy or hy-
Chronic alcohol abuse is more often associated with neuropa- pokalemic myopathy) without a superimposed significant pe-
thy than myopathy.761 Nevertheless, five types of muscle disor- ripheral neuropathy. Normal or only mildly abnormal sensory
ders are recognized with respect to the toxic effects of alcohol: and motor studies are recorded. Needle electromyographic ex-
(1) acute necrotizing myopathy, (2) acute hypokalemic myopa- amination of the proximal muscles reveals clear evidence of
thy, (3) chronic alcoholic myopathy, (4) asymptomatic alcoholic positive sharp waves, fibrillation potentials, and short-duration
myopathy, and (5) alcoholic cardiomyopathy. In this discussion low-amplitude MUAPs firing at high rates with minimal force
we are primarily concerned with the disorders affecting skeletal production.172-219-488-553-576-646 These findings suggest a primary
muscle secondary to alcohol.31-172-219-483-576-577-642-761-786 myopathic process with little evidence of a peripheral neuropa-
Acute necrotizing myopathy usually develops in patients thy. Upon medical support and correction of any electrolyte dis-
consuming alcohol in excessive amounts for some time. Patients turbances, the membrane instability resolves and there is little
present with acute muscle pain, tenderness to palpation, cramp- in the way of residual MUAP abnormalities.
ing, swelling, and weakness following or during a recent partic- Many patients with a history of chronic excess alcohol abuse
ularly intense binge. The number, location, and degree of develop symptoms and signs of a sensorimotor peripheral neu-
muscle involvement is highly variable. Some patients develop ropathy.238-239-552-577-786 Sensory nerve conduction studies demon-
myoglobinuria and acute renal failure. The muscle cramps re- strate either absent or markedly reduced SNAP amplitudes with
solve over the course of several days, while the remainder of normal or mildly prolonged distal latencies and some degree of
symptoms may last several weeks. Serum CK levels are obvi- conduction velocity slowing. Similarly, the distal motor latency
ously markedly elevated during these attacks. Histologic exami- may be moderately prolonged with some degree of nerve conduc-
nation of muscle reveals widespread muscle fiber necrosis. tion slowing and a normal or reduced CMAP amplitude. The
There is intracellular edema with separation of myofibrils. needle electromyographic examination in a patient with these
Tubular aggregates have been noted. EM demonstrates disorga- nerve conduction findings may reveal the presence of sustained
nizing of the sarcomere structure and degeneration of mitochon- positive sharp waves and fibrillation potentials, primarily the
dria. Patents require appropriate supportive medical care and distal muscles of the upper and lower limbs. MUAPs are either
nutritional supplementation, because many are malnourished. normal or of long duration and increased amplitude with more
Acute hypokalemic myopathy secondary to alcohol abuse than the normal number of phases. Careful analysis with a trigger
manifests as acute generalized weakness similar to other forms of and delay line can reveal satellite potentials and reduced numbers
hypokalemic myopathy. Unlike acute necrotizing myopathy, there of MUAPs firing at rapid rates with attempts at high-force outputs.
is an absence of muscle cramping, pain, swelling and tenderness. In patients with only a peripheral neuropathy, needle investigation
of proximal muscles usually does not reveal significant MUAP drug abuse, especially with pentazocine, to result in both clinical
abnormalities or recruitment alterations. It is the peripheral neu- and electrodiagnostic medicine abnormalities.I48-365-449-501-543-554 The
ropathy that can lead to diagnostic confusion with respect to the repeated injection of substances into the same muscle may lead to
presence or absence of a myopathic process. muscle necrosis and eventual fibrosis with significant portions of
When patients present with either of the acute forms or the the muscle replaced with fibrous connective tissue. In the deltoid
chronic type of alcoholic weakness, it is important to first deter- this can lead to not only a grossly wasted proximal arm, but a con-
mine the status of the peripheral nervous system. The presence of tracture with an inability to passively rest the arm against the
a peripheral neuropathy can result in abnormal spontaneous ac- thorax, the so-called levitation sign. The physical examination
tivity preferentially localized to the distal muscles with long dura- demonstrates only a focal abnormality in not only appearance but
tion high amplitude MUAPs firing in reduced numbers. muscular strength as well. The remainder of the sensory and motor
Examination of the proximal muscles can also demonstrate sus- examination are normal. Patients may inject foreign substances
tained positive sharp waves and fibrillation potentials at times in into multiple muscles, thereby inducing a multifocal myopathic
quite significant degrees. It is unlikely that an alcohol-related pe- process. It is important to remember that the serum CK level may
ripheral neuropathy would result in such profound abnormalities be elevated in patients without intrinsic muscle disease following
in the proximally located muscles. Of crucial importance is the the intramuscular injection of therapeutic medication.
quantification of MUAP parameters with special attention to du- The electrodiagnostic medicine examination can demonstrate a
ration. A number of investigations have documented the presence number of findings. Motor and sensory nerve conduction studies
of not only proximally located membrane instability, but MUAPs are normal throughout in patients with only a focal myopathic
with decreased duration and amplitude and increased numbers of process secondary to repeated injections. The needle electromyo-
polyphasic MUAPs. Recruitment is early in these cases. There is graphic examination can demonstrate normal MUAPs with elec-
a distinct difference in the MUAP parameters as recorded in prox- trical silence at rest provided the time period of injections is
imal compared to distal muscles. A combined "myopathic" and relatively brief. More commonly, with chronic abuse cases, there
"neuropathic" pattern is noted in these patients with the former is noted to be significant focal physical resistance to needle inser-
occurring in the proximal muscles and the latter present and over- tion in the affected muscle secondary to profound muscle fibro-
shadowing the myopathic features in the distal musculature. sis. A reduction in electrical insertional activity is common
secondary to the loss of muscle tissue.364 There may be an ab-
MYOPATHIES SECONDARY TO ILLICIT DRUGS sence of positive sharp waves and fibrillation potentials, if the
muscle has completely degenerated, or varying degrees of these
Illicit drugs and controlled narcotics (e.g., heroin, meperidine, potentials depending upon the amount of excitable tissue remain-
cocaine, pentazocine, piritramide, amphetamines, etc.) have ing. Voluntary MUAPs are reduced in duration and amplitude
been reported to result in muscle fiber necrosis.31-153-483-623-624-754 with prominent polyphasic potentials. Rarely, when there is pro-
Muscle injury can be related to direct muscle trauma (e.g., found muscle tissue loss, there can be a complete absence of vol-
needle injury), rhabdomyolysis secondary to pressure, ischemic untary MUAPs. Significant degrees of abnormal spontaneous
necrosis related to prolonged loss of consciousness, ischemia potentials can be found in or about a muscle that has been trau-
due to vasoconstriction, rhabdomyolysis caused by generalized matized by a muscle biopsy.570 Similarly, a patient who has sus-
status epilepticus, or the direct toxic effects of the drugs (or adul- tained significant muscle trauma following a motor vehicle
terants) on muscle tissue. As expected, serum CK levels are accident may also reveal positive sharp waves and possibly fibril-
markedly elevated. Muscle biopsies demonstrate widespread lation potentials, and this may take several days to resolve de-
necrosis. Nerve conduction studies are normal. Needle elec- pending upon the severity of muscle injury.
tromyographic examination reveals fibrillation potentials and
positive sharp waves. MUAPs with short durations and ampli- NEEDLE MUSCLE INJURY
tude recruited early with minimal contraction can be observed.
Inhalation of volatile agents (e.g., toluene) also causes general- A second type of focal muscle injury can result from the
ized muscle weakness and, occasionally, myoglobinuria. Toluene trauma induced by a penetrating needle itself.143-149-230-661 This
causes distal renal tubular acidosis with associated severe hy- may result from needling a region in a patient receiving myofas-
pokalemia, hypophosphatemia, and mild hypocalcemia. Muscle cial pain injections, intramuscular injections for therapeutic rea-
strength returns after correction of the electrolyte abnormalities sons, or even from the needle electromyographic examination
and abstaining from inhaling volatile agents. itself. There are usually no electrophysiologic abnormalities;
however, a problem may arise if the serum CK level is measured
within a short time of the examination or a muscle biopsy is
FOCAL MUSCLE DISORDERS taken from the region of muscle examined with the needle elec-
trode. The serum CK level may rise slightly in normal persons or
There are a number of focal muscle disorders that can result achieve relatively high levels in those individuals with intrinsic
in a localized disease process intrinsic to muscle tissue. The muscle disease. In either case, a falsely elevated level is gener-
mechanisms of injury may be related to sharp or blunt trauma in ated that is more reflective of the muscle trauma from the needle
the way of needle injections and the dissipation of energy than intrinsic muscle disease. It is important not to biopsy a
during the injection of the drug into muscle tissue. muscle recently traumatized by the needle electrode. The ensu-
ing muscle necrosis can lead to a false histologic impression.
INJECTION INJURIES
RHABDOMYOLYSIS/MYOGLOBINURIA
A well known complication of needle injections is injury to a
peripheral nerve.77 It is also possible for the chronic injection of As evident from the reading of this chapter, rhadbdomyolysis
therapeutic medications or intramuscular injection associated with and myoglobinuria can occur in a number of myopathic disorders,
(416 — PART IV CLINICAL APPLICATIONS
Table 28-7. Causes Of Myoglobinuria

Metabolic Defects Endocrine Toxins
Glycogen storage disease Hypothyroid myopathy Snake or spider bites
Phosphorylase b kinase deficiency Hypoparathyroid (e.g., following prolonged tetany) Wasp, hornet, or bee stings
Myophosphorylase deficiency Mitochondrial Myopathies Drugs
Phosphofructokinase deficiency Multiple mtDNA deletions Alcohol
Phosphoglycerate kinase deficiency mtDNA point mutations v Heroin, cocaine, amphetamine
Phosphoglycerate mutase deficiency COX III microdeletion Diuretics (secondary hypokalemia)
Lactate dehydrogenase deficiency Muscular Dystrophy Cholesterol-lowering agents
Carnitine Palmitoyltransferase
Acyl-CoA dehydrogenase deficiencies Dystrophinopathies Ischemic Damage
Myoadenylate deaminase Other forms of dystrophy Mechanical, Electrical, Burn,
Electrolyte Disturbances Excessive Heat/Exercise Crush Injuries
Hypocalcemia Heat stroke Inflammatory Myopathies
Hypokalemia Malignant hyperthermia Dermatomyositis
Hypophosphatemia Neuroleptic malignant syndrome Polymyositis
Serotonin syndrome Infectious (e.g., viral myositis)
including the muscular dystrophies, metabolic myopathies, mito- Treatment. Patients should be treated with bed rest to pre-
chondrial myopathies, inflammatory myopathies, endocrin- vent further muscle damage. Passive range of motion exercises
opathies, electrolyte imbalance, toxic myopathies, muscle are necessary to prevent contractures. Importantly, maintaining
ischemia, and trauma (Table 28-7). It is not uncommon for the urine output by hydrating the patient with intravenous saline
electromyographer to be asked to assist in the evaluation and (infusion rate of 150 ml/hr), giving intravenous diuretics (man-
treatment of myoglobinuria. In this regard, we make some gen- nitol: 0.3-0.5 g/kg, furosemide 40-80 mg), and the use of
eral comments regarding the care of patients with myoglobinuria. sodium bicarbonate to alkalinize the urine and increase myoglo-
Clinical Features. Regardless of the etiology, myoglobin- bin solubility is the standard for prevention and treatment of
uria results from necrosis of muscle tissue. Thus, myoglobinuria acute tubular necrosis.79
is usually, but not always, associated with muscle pain, tender-
ness, and swelling. ILL-DEFINED DISORDERS
Laboratory Features. Myoglobin is a major component of
skeletal and cardiac muscle, where it serves as an oxygen store Polymyalgia Rheumatica
and carrier. Normally, myoglobin is present in negligible Clinical Features. Polymyalgia rheumatica occurs in pa-
amounts in the serum (less than 80 ng/ml) and in the urine (less tients over the age of 55 years (peak incidence of 70-79 years)
than 12 fig/ml). In addition to CK and other muscle enzymes with a female predominance.60-151,372 Patients usually describe
(e.g., ALT, AST, LDH, aldolase), myoglobin is released from either an insidious, or sometimes acute, onset of diffuse nonar-
necrotic muscle tissues. When serum appears amber and myo- ticular pain beginning about the neck and shoulder region with
globinuria is apparent to the naked eye, at least 200 g of muscle progression to the rest of the body. Muscle pain, as opposed to
have been necrosed and serum myoglobin concentration ex- weakness, is the major limiting factor in this disorder. An accom-
ceeds 1 mg/ml. The major complication of myoglobinuria is panying low grade fever and a vague sense that there is a general
renal failure due to acute tubular necrosis. In addition, hyper- lack of well being can be associated with the pain complaints.
kalemia can develop with subsequent cardiac dysrhythmias. Approximately 16% of patients develop temporal arteritis.155
Histopathologic Features. Large numbers of necrotic muscle Laboratory Features. Patients with polymyalgia rheumat-
fibers are evident on biopsies shortly after an attack of myoglo- ica typically have an elevated ESR in excess of 40 mm/hr.
binuria. Subsequently, phagocytosis of the necrotic muscle fibers Serum CK should be normal.
and small regenerating muscle fibers are apparent. Later biopsies Histopathology. The muscle biopsy in patients with
may show little in the way of muscle damage, other than in- polymyalgia rheumatica is typically normal, but there can be
creased internal nuclei suggestive of muscle fiber degeneration mild nonspecific findings (e.g., type 2 fiber atrophy, fiber size
and regeneration. Obviously, histologic or biochemical analysis variation, and moth-eaten fibers).60-372 Importantly, there is no
may be abnormal in specific myopathic disorders (e.g., dys- evidence of significant inflammation in the muscle or overlying
trophinopathies, metabolic myopathies). fascia.
Electrophysiologic Findings. The electrodiagnostic features Pathogenesis. Polymyalgia rheumatica is thought to be a
are not specific to the underlying etiology of the myoglobin- form of connective tissue disease. The elevated ESR and excel-
uria. One would expect to see evidence of muscle membrane lent response to corticosteroids suggests an immunologic mech-
irritability (e.g., fibrillation potentials and positive sharp anism but the exact pathogenesis of the disorder and the
waves) and small-amplitude, short-duration, polyphasic MUAPs mechanism for muscle pain is not known. Some cases are
that recruit early in weak muscles shortly after an attack of clearly associated with arteritis/vasculitis.
myoglobinuria. Myopathic MUAPs may persist in patients Electrophysiologic Findings. Very few comments are avail-
with recurrent attacks of myoglobinuria or in certain myo- able regarding the electrodiagnostic medicine findings in pa-
pathic disorders (e.g., dystrophies, dermatomyositis). As exten- tients with polymyalgia rheumatica. The nerve conduction
sively discussed in the relevant sections, patients with chronic studies are believed to be normal aside from changes usually
myopathic disorders may also have a mixture of large polypha- found in persons of advanced age. Needle electromyography
sic MUAPs. may be normal or demonstrate MUAPs that are of short duration
and small amplitude mixed with normal appearing MUAPs. 728 of a variety of nonspecific symptoms, including muscle pain,
Early recruitment can also be detected, but insufficient studies weakness, numbness, paresthesia, fatigue, headache, memory
regarding this entity are available for critical review. loss, sleep disorder, athralgias, rashes, alopecia, dyspnea, and
Treatment. The administration of corticosteroids results in gastrointestinal problems. Some have suggested that these
considerable symptom relief within a few days. symptoms were the result of toxic exposures (e.g., chemical or
biological war agents, pyridostigmine, pesticides, multiple vac-
Fibromyalgia and Myofascial Pain Syndrome cinations, depleted uranium) related to service in the Persian
Fibromyalgia and myofascial pain syndrome are commonly Gulf War.305-357
diagnosed disorders of an extremely controversial nature be- Jamal et al. reported the neurologic evaluation of 14 selected
cause of the lack of objective evidence of organic disease.95-96-296 British Gulf War veterans with unexplained symptoms selected
Fibromyalgia is dominated by subjective complaints of general- from a group of 40 veterans. 357 There were numerous flaws in
ized muscle pain in addition to other somatic complains. In this their methodology and statistical analysis. 17 Their major find-
regard, it shares many features with the somatoform disorders ing was that these symptomatic veterans had more symptoms
and the equally dubious chronic fatigue syndrome.284-403 than asymptomatic veterans. Electromyography was normal.
There is no gold standard for diagnosing fibromyalgia. Out of 19 different nerve conduction and evoked potentials
Advocates of the fibromyalgia diagnose the disorder based on studies, they found values statistically significant compared to
the assessment of so-called tender points. Criteria for diagnos- a control group of 13 patients. A sural SNAP distal latency
ing fibromyalgia have been devised based on the number and (mean 3.42 ms) was considered prolonged and median SNAP
location of tender points elicited. Unfortunately, the study by amplitude (mean 18.3 p.V) was low. Quantitative sensory test-
which these criteria were based is scientifically flawed.95-96 The ing revealed only diminished cold perception; heat and vibra-
investigators predetermined that tender points were necessary tory threshold were normal. It is unlikely that the patients had a
for diagnosis. They all received training in how to identify such demyelinating neuropathy in the upper limbs (responsible for
tender points. Patients diagnosed with fibromyalgia based on prolonged median SNAP distal latency), but an axonal neu-
the presence of tender points were then evaluated by other in- ropathy of the legs (causing the low amplitude sural SNAP).
vestigators to confirm their presence. The fact that these tender Further, these rare nerve conduction "abnormalities" would
points were reproducible (good intraobserver reliability) served suggest involvement of the large diameter axons. However,
as a validation of the diagnosis for the investigators. Skeptics quantitative sensory testing of vibratory perception was
criticize the study confirming little more the prejudged features normal, while only one small fiber parameter (cold perception),
of the investigators.154 The many problems with this study, in- was abnormal.
cluding lack of adequate controls, errors in logic and statistical Haley et al. purport that there are at least three distinct Gulf
analysis are beyond the scope of this chapter but are reviewed in War syndromes.305-306-307 Besides the limitations of their
detail elsewhere.95-96 Importantly, detection of these tender methodology,l7a-427 there are numerous problems with the sta-
points is dependent on the patient's subjective input and is in no tistical analysis and interpretation of neurophysiologic
way a truly objective marker. The neurologic examination in- data. ,7a Importantly, the neurologic examinations of these vet-
cluding muscle strength testing and laboratory evaluation is oth- erans were no different than the healthy controls. In addition,
erwise normal in these patients. Likewise, nerve conduction independent neurologists reviewed the clinical and laboratory
studies and electromyography (even of in the areas of tender findings of each subject and were unable to diagnose specific
points) are normal. Finally, there is no difference in the fre- neurologic disorders.
quency of abnormal histologic findings compared to control We reported the extensive clinical, laboratory, neurophysio-
populations.798 logic (motor and sensory nerve conduction studies, repetitive
Myofascial pain syndrome (MPS) is similar to fibromyalgia nerve stimulation, quantitative and single-fiber electromyogra-
but the pain is described as being more focal or regional as op- phy) and histologic evaluation (muscle biopsies) of 20 patients
posed to generalized.95-96 Rather than tender points, advocates of with the most severe neuromuscular symptoms and concluded
the disorder suggest patients have "trigger points." These trig- there was no evidence to suggest a neuromuscular disorder
ger points have been associated with "taut bands," "nodules," unique to the Persian Gulf War or that the veterans' symptoms
and "local twitch responses." However, a blinded, controlled were related to toxic exposures.16-17
study demonstrated the low sensitivity and specificity of this
presumed diagnostic marker of MPS. 784 One study described
"spontaneous EMG" activity in the area of the trigger points.345 ILLUSTRATIVE CASES
However, review of the figures submitted by the authors suggest
this was just normal endplate spike activity. The majority of CASE 1: PROGRESSIVE PROXIMAL WEAKNESS
electromyographers have not been able to verify the presence of
any electrophysiologic abnormalities in MPS.95-96 As with fi- Reason For Referral. Progressive proximal weakness and
bromyalgia, there are no objective abnormalities apparent on fatigue.
clinical examination, electrophysiologic testing, or muscle his- History. A 37-year-old woman presents with a 6-week his-
tology (when interpreted blindly and compared to normal con- tory of progressive difficulty climbing stairs and arising from
trols). A more detailed review of the topic is beyond the scope the commode and low-set chairs. She states the weakness began
of this discussion but is reviewed elsewhere.96 in her lower limbs and for the past 2 weeks she has had increas-
ing difficulty placing objects on shelves above her head. The pa-
Is There a Toxic Myopathy or Neuromuscular Disorder tient notes that she has a habit of watching television in bed with
Associated with Persian Gulf War Syndrome? her head propped on a pillow. It used to be easy for her to lift
Following return from the Persian Gulf area in 1991, some per- her head up and glance at the clock on a nearby table but re-
sonnel deployed to the region during the war began to complain cently this task is all but impossible. Maintaining her grooming
with respect to hair care is becoming increasingly difficult sec- Gastrocnemius 1+Fibs/PSW Early
ondary to the prolonged time necessary to accomplish overhead Cervical paraspinals* 3+Fibs/PSW Early
activities. Over the past 2 weeks the patient has also noted diffi- Thoracic paraspinals* 3+Fibs/PSW Early
culty swallowing liquids. Riding a stationary bicycle, previ- Lumbosacral paraspinals* 3+Fibs/PSW Early
ously performed 3 times per week for 20 minutes, is no longer * The cervical paraspinal muscles were examined at C6-T2
possible because of fatigue. The patients denies traveling to any bony levels, thoracic paraspinal muscles at bony levels
exotic places or consuming any unusual substances over the T10-T12, and lumbosacral paraspinals at L4-S1 bony levels on
past several months. There is no family history of any neuro- the right.
muscular disorder. T Quantitative analysis using a trigger and delay line revealed
Physical Examination. The patient is alert and oriented and MUAPs with durations significantly reduced below 20% of an-
attempting to comply with the physical examination to the best ticipated for these muscles. There was an absence of long dura-
of her ability. On gross observation there is no overt evidence of tion or satellite potentials. It appeared as though there was an
muscle wasting. The skin is clear, without signs of rashes or lo- increase in the number of polyphasic potentials and small am-
calized regions of erythema. Skin turgor is good and her hair is plitude potentials, however, no attempt was made to quantify
not overly dry or brittle. Manual muscle testing reveals intact these MUAP parameters.
cranial nerves with the exception of shoulder shrugging 3/5.
Neck flexors and extensors are 2+/5 with shoulder abductors Summary of Findings
3/5. Elbow flexors and extensors are 3+/5 with wrist flexors and 1. Sensory and motor nerve conduction studies are all within
extensors approximating 4-/5. Hand intrinsic muscles are 4+/5. normal limits.
Hip flexors and extensors are 3+ to 4-/5 and knee extensors and 2. There is an absence of decrement during repetitive stimu-
flexors are 4-/5. Ankle dorsiflexors and plantar flexors are 4/5. lation of the trapezius muscle.
Deep tendon reflexes are 1+/2+ throughout but sensation to all 3. Of significance is the detection of abundant amounts of
modalities of testing is normal. membrane instability in the above noted distribution more so
Nerve Conduction Studies. Nerve conduction studies are proximally than distally.
performed in the right upper and lower limbs. The mid-palm 4. MUAP durations were significantly shortened compared
temperature is 32.5°C on the right while the temperature poste- to normal values. In addition, the potentials were very polypha-
rior to the right lateral malleolus is 31.1 °C. sic and recruited early.
Nerve DSL S Amp DML M Amp NCV
(ms) (pV) (ms) (mV) (m/s) Electrodiagnostic Medicine Impression
R median 3.2 49.0 3.3 6.5 56.0 1. The patient demonstrates both spontaneous and voluntary
R median 1.9 54.0 electrophysiologic evidence consistent with a myopathic disorder.
(7.0 cm) 2. There are no data to suggest a neurogenic process or neu-
R ulnar 3.1 30.0 2.9 4.5 62.0 romuscular junction defect cause for the patient's symptoms.
R peroneal 4.3 4.9 47.5
R musculo- 3.9 1.2 Clinical Impression
cutaneous The subacute onset of symmetric, proximal greater than
R sural 3.7 22.0 distal muscle weakness, in a middle-aged female is most sus-
Repetitive Stimulation: % Decrement picious for polymyositis. The electrodiagnostic study sup-
Nerve 3 Hz Stimulation Immediate PE 5 Minutes PE ports the clinical impression of a necrotizing myopathy. The
R spinal 0.2 0.0 0.0 lack of a family history and absence of toxic or infectious
accessory agents diminishes the likelihood of other types of myopathic
Note: Recording for the spinal accessory nerve is the trapezius processes.
muscle. Temperature at all recording sites was maintained
above 33.0°C. Recommendations
DSL, distal sensory latency; S Amp, sensory amplitude; DML, 1. Laboratory evaluation to include serum CK, ANA, ESR,
distal motor latency; M Amp, motor amplitude; NCV, nerve con- rheumatoid factor, serum protein electrophoresis, thyroid func-
duction velocity; ms, milliseconds; p.V, microvolts; mV, milli- tion tests, complete blood analysis, stool for occult blood and
volts; m/s, meters/second; PE, post-exercise. Motor and sensory serum chemistries, including renal and liver function tests.
amplitudes are measured baseline to peak. Sensory latencies are 2. A muscle biopsy of a proximal muscle (e.g., biceps
measured to peak, while motor latencies are measured to initial brachii) on the left side as the needle electromyographic exami-
negative onset. nation was performed on the right.
Needle Electromyography. A needle electromyographic in- 3. Upper GI with barium swallow secondary to the history of
vestigation was performed on the right upper and lower limb dysphagia
using a disposable monopolar needle. 4. EKG
Muscle Rest Activity Recruitment 5. Chest x-Ray and pulmonary function tests
Supraspinal 3+Fibs/PSW Early 6. Baseline bone densitometry (DEXA) prior to starting
Deltoidf 3+Fibs/PSW Early steroids
Biceps f 3+Fibs/PSW Early 7. Start high-dose prednisone 100 mg q AM for 2-4 weeks,
Pronator teres1" 2+Fibs/PSW Early then switch to alternate-day therapy. The patient should also be
Abductor digiti minimi 1 +Fibs/PSW Early started on calcium supplementation (turns one tablet TID), vita-
Gluteus medius 1 3+Fibs/PSW Early min D (400 IU qd), and consider alendronate for osteoporosis
Vastus medialis f 2+Fibs/PSW Early prophylaxis.
Tibialis anterior^ 1+Fibs/PSW Early 8. Occupational and physical therapy consultations
Table 28-8. Electrodiagnostic Medicine Findings in Myopathies

I. Normal Electrodiagnostic Medicine Evaluation III. Abnormalities of MUAPs and Fibs/PSWs (cont)
Endocrine myopathies Toxic Myopathy
Corticosteroid excess (endogenous/exogenous) Alcohol
Hypothyroid disease
Hypoparathyroid disease (doublets/triplets) IV. Abnormalities of MUAPs Only
Osteomalacia Mild endocrine disorders
Hyperthyroid disease Hyperthyroid disease (rare fasciculations/myokymia)
Hyperparathyroid disease Hyperparathyroid disease
Metabolic myopathies Acromegaly
Myophosphorylase deficiency (electrically silent Osteomalacia
contracture during attack) Profound corticosteroid myopathy
Phosphofructokinase deficiency (electrically silent Mild congenital myopathies
contracture during attack) Congenital muscular dystrophy
Brancher enzyme deficiency Central core disease (rare fibs/PSWs)
Systemic carnitine deficiency Nemaline rod disease (rare fibs/PSWs)
Muscle carnitine deficiency Multicore disease
Carnitine palmitoyltransferase deficiency Reducing body myopathy
Mitochondrial myopathy Mild infectious disorders
Myoadenylate deaminase deficiency Viral myopathies
Congenital myopathy Mild toxic myopathies
Fiber type disproportion Emetine
Infectious myopathy Colchicine
Various viral disorders Alcohol
Toxic myopathy Profound muscular dystrophies
Mild/early alcohol abuse Facioscapulohumeral dystrophy (rare fibs/PSWs)
Vincristine (rare Fibs/PSWs) Becker muscular dystrophy
Periodic paralysis (interictal examination) Scapuloperoneal syndrome (rare fibs/PSWs)
Hyperkalemic periodic paralysis Oculopharyngeal muscular dystrophy
Type without myotonia Normokalemic periodic paralysis
Hypokalemic periodic paralysis (MUAP abnormalities during attack)
Recurrent inflammatory myopathies
II. Fibrillation Potentials/PSWs
Early inflammatory myopathies V. Electrical Myotonic Discharges
Early toxic myopathy Acid maltase deficiency
Chloroquine reaction Hypothyroid disease
Profound alcoholic myopathy Myotonia congenita
III. Abnormalities of MUAPs and Fibs/PSWs VI. Abnormalities of MUAPs and Fibs/PSWs (Myotonia)
Muscular dystrophies Polymyositis (possibly)
Duchenne muscular dystrophy Myotubular myopathy
Limb-girdle dystrophy Chloroquine myopathy
Becker muscular dystrophy Hyperkalemic periodic paralysis
Distal muscular dystrophies
Inflammatory Myopathies VII. Abnormalities of MUAPs and Myotonia (Fibs/PSWs)
Poly/dermatomyositis Myotonic dystrophy
Inclusion body myositis Paramyotonia congenita
Sarcoid myopathy VIII. Minimal Voluntary/Spontaneous Activity plus Atrophy
Myositis with collagen vascular disease Focal disorders
Focal myositis Limb-girdle dystrophy
Infectious myopathies Profound ischemic myopathy
Parasitic myopathies (patchy distribution) Profound traumatic insult
Occasional viral myopathies Proximal/symmetric findings
Congenital myopathy Profound chronic inflammatory disease
Myotubular myopathy Chronic Duchenne muscular dystrophy
Metabolic myopathy
Debrancher enzyme deficiency IX. PSWs Only and Normal MUAPs
Brancher enzyme deficiency
Myophosphorylase deficiency Diffuse insertional activity syndrome
Systemic carnitine deficieny
Muscle carnitine deficiency
Fibs, fibrillation potentials; PSW, positive sharp waves; MUAPs, voluntary motor unit action potentials.
Modified from Burk123 and Jablecki.352
Comment are more often associated with various abnormalities in inser-
The above patient presented with a history and has a physical tional and spontaneous activity (i.e., fibrillation potentials,
examination suggestive of a myopathy. The complaints of PSWs, myotonic discharges) and may be useful in helping to
weakness localized to proximal muscles with associated fatigue narrow the differential diagnosis. Usually the combination of a
progressing over the past several weeks may be a result of a my- detailed history, clinical examination, laboratory testing (e.g.,
opathy, a neuromuscular junction disorder, or intrinsic muscle serum CK, TFTs, electrolytes, SPEP, ANA, ESR), and the elec-
disease. Motor and sensory nerve conduction studies demon- trodiagnostic examination lead to the correct diagnosis. Muscle
strate that there is a distinct absence of any significant patho- biopsies are useful to confirm the diagnostic impression or to
logic involvement of the peripheral nervous system. The only make the diagnosis when it is still unclear after the above exten-
possible abnormal finding is a reduced CMAP as recorded from sive evaluation. Early diagnosis of the acquired myopathies can
the biceps brachii muscle, i.e., a proximally located muscle. be quite rewarding to the clinician and the patient because many
Repetitive stimulation evaluation of the trapezius muscle failed of these disorders are treatable.
to reveal any hint of a neuromuscular junction disorder.
Although it is not unusual for patients with neuromuscular junc-
tion disorders to have "normal" repetitive stimulation studies, it
is rather suspicious that this study is normal despite the pres- REFERENCES
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Chapter 29
Electrodiagnostic Medicine
Evaluation of Children
Maureen R. Nelson, M.D.
CHAPTER OUTLINE
Technique • Neuromuscular Junction * Muscle Disease • Systemic
Nerve Conduction Studies • Needle Electromyography Disease • Benign Congenital Hypotonia
• Muscle Biopsy Other Diagnostic Considerations in Children
Disease Processes in Children Acute Inflammatory Demyelinating Polyradiculopathy
• Critical Illness Polyneuropathy • Human Immunodeficiency
Floppy Infant Virus * Myasthenia Gravis • Birth Brachial Plexus Palsy
Etiology of Hypotonia in Infants • Brain • Spinal Cord • Dermatomyositis
• Anterior Horn Cell Disease • Peripheral Nerve
The electrodiagnostic medicine evaluation of children is NEURAL PHYSIOLOGY

similar to that of adults, but has some differences. The same
studies performed in adults (needle electromyography, nerve Neural myelination begins between the 10th and 15th week
conduction studies and evoked potentials) can also be per- of gestation30 and is complete by about 5 years of age.35 At 8-10
formed in children. Physiologic differences due to maturity, years of age, axons reach the adult diameter.35 Nerve conduction
growth, and development are important to note in infants and velocity (NCV) depends on axon length and diameter, myelin
children compared to adults. The approach to examining in- sheath thickness, internodal distance, and node of Ranvier
fants and children must be tailored to a child's behavioral width.81 The diameter of larger ulnar motor axons approaches
characteristics. The physical size of the infant or child also 3.5-4 Jim in 1 month preterm infants, 4-6 |im in term infants,
requires some variation in technique. Lastly, diagnostic con- and 9-13 Jim in adults.77
siderations vary between adults and children. Most common As the nodes of Ranvier mature, the internodal distances peak
studies in adults include those for median mononeuropathy at 5 years of age.35 Nerve maturation is measured by age from
at the wrist (carpal tunnel syndrome) and radiculopathy for conception, not birth, because there is no change in the rate of
persons with back or neck pain. However, these two disor- acceleration of myelination at birth.77 This finding was con-
ders are rare in children. The more commonly performed firmed for the posterior tibial nerve; however, ulnar nerve matu-
electrodiagnostic medicine studies in children are for evalua- ration in premature babies slows after birth.74 At least 5 weeks
tion of floppy infants, and congenital muscle or nerve dis- prior to term, there is an increase in the NCV. Because NCV is
eases. The electrodiagnostic medicine study may present correlated with gestational age, it may be useful in the assess-
more of a challenge in a child compared to an adult due to ment of neurologic maturity and evaluation of gestational age.77
technical considerations, and may have potentially even Additionally, twin studies have revealed that there is no correla-
more value due to the frequent inability of a child or infant to tion between NCV and birth weight.25 A study in rats has shown
cooperate with the physical examination or provide histori- that axonal regeneration is faster in those who are younger, and
cal information. Due to the age-appropriate growth and mat- the lag time before the axons begin to regenerate after injury is
uration of the nervous system, reference values vary with also shorter in younger rats.48
age, and reference tables must be consulted. Motor NCV in term newborns is faster than in premature in-
This chapter discusses the general principles of pediatric fants and slower than in newborns of prolonged gestational age
electrodiagnosis and the most frequent diagnostic categories. (43-^14 weeks).16 Also, NCV in twins depends on gestational age,
The reader is referred to the chapters on neuropathies and my- not birth weight. Term infants who are small for gestational age
opathies in this volume for more extensive diagnostic consider- have a NCV in the same range as larger term infants. 21617 Con-
ations. In addition, textbooks on childhood neuromuscular duction velocity at 23-24 weeks of fetal life is approximately
diseases and electrodiagnosis can also be consulted.26-43 one-third of term newborn NCV with a velocity of approximately
1433
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Figure 29-1. Relation of age and motor nerve conduction velocity in the ulnar nerve from the elbow to the wrist.The age at the
time of testing is plotted in relation to the infant's due date, calculated from last menses of the mother. (From Juergen T, Lambert E: Ulnar nerve
conduction velocity. J Appl Physiol 1960;15:1-9, with permission.)
7 m/s for the tibial nerve and 8 m/s for the median nerve.18 Distal of age, only to become more disparate between 1 and 2 years of
motor latencies and H-reflex latencies are approximately 2 times age. Compound muscle action potential (CMAP) amplitude is
longer than term newborns. This is a dramatic demonstration of quite variable in infants and children. Median CMAP ampli-
the rapid maturation of peripheral nerves during the last tudes average 4 millivolts (mV) at 1 month of age and increase
trimester of pregnancy.' 8 to 14.1 mV (peak to peak) at 6-11 years of age.16 The amplitude
Several studies have been done to determine normal NCV of the CMAP increases approximately three-fold from birth to
values in children. Ulnar nerve conduction velocity averages 21 11 years.17
m/s for premature infants and 28 m/s for term newborns, which Nerve conduction velocity (NCV) increases as temperature
is approximately half of the average adult value of 60 m/s. increases. Conduction velocity increases approximately 2
Normal NCV values are achieved by 3-5 years of age (Fig. 29¬ m/s/degree from 26 to 36°C.9 This is particularly critical in in-
1). The NCVs show good correlation with nerve fiber diame- fants in whom maintaining temperature is a challenge due to
ter.77 Larger stimulation intensity is required to obtain maximal their small size.
electrical responses in premature and term infants than in older The H-reflex is easily obtained from most muscles in prema-
children or adults.77 ture and term infants. However, it becomes increasingly diffi-
Median and tibial NCVs are significantly different in cult to obtain throughout the first year, and after age 1 year the
neonates, but this difference decreases from 3 months to 1 year H-reflex is rarely obtained, except for the tibial nerve.
Table 29-1. H-Reflex Latencies in Newborns

Median Nerve Tibial Table 29-2. H-Reflex Latencies in Neonates/lnfants
Age (APB) Age Nerve(s) Median Nerve Ulnar Nerve Tibial Nerve
32-37 19.5 31-34 19.2 (APB) (ADM) (PM)
38-42 18.1 35-39 16.7 Neonates 17.9 17.3 23.7
43^4 17.4 40-45 15.9 Infants (6-12 months) 15.7 15.8 18.4
Gestational age provided in weeks and latencies measured in milliseconds.APB, H-reflex latencies measured in milliseconds.APB, abductor pollicis brevis;ADM,
abductor pollicis brevis; S, soleus muscle. Modified from Bryant PR, Eng GD: abductor digiti minimi; PM, plantar muscles.
Normal values for the soleus H-reflex in newborn infants 31-45 weeks post- Modified from Misra UK.Tiwari S, Shukla N, et al: F-response studies in neonates,
conceptional age. Arch Phys Med Rehabil 1991 ;72:28-30, and Cruz Martinez A, infants, and children. Electromyogr Clin Neurophysiol 1989;29:251-254, and
Ferre MT, Martin MJ: Motor velocity and H-reflex in prematures with very short Mayer RF, Mosser RS: Excitability of motoneurons in infants. Neurology 1969; 19:
gestational age. Electromyogr Clin Neurophysiol 1983;23: 13-19. 932-945.
Chapter 29 ELECTRODIAGNOSTIC MEDICINE EVALUATION OF CHILDREN — 1435
In assessing the H-reflex, the IA afferent fiber conduction ve- Table 29-3. Median Nerve (APB) F-Wave Latencies
locity is approximately 10% faster than motor fibers in the same in Children52-71
segment of the nerve.1617-77 Similar differences have been de- Age Latencies (ms)
scribed in adults.77 H-reflexes are routinely obtained after median
and ulnar nerve stimulation in neonates, and in most infants less < 3 months 16
than 6 months of age (Tables 29-1 and 29-2).57-77 The H-reflex is 3 months-2 years 14.4
best obtained in awake and alert infants. Deep sleep suppresses the 3-5 years 17.1
H-reflex and it disappears with REM sleep. There is no change in
amplitude of the H-reflex with drowsiness or light sleep, but there 6-10 years 19.4
is a decrease in excitability and recovery of the H-reflex. 1 1-16 years 25.3
H-reflexes to the soleus muscle in premature and term infants APB. abductor pollicis brevis.
are also easy to obtain (Table 29-1). In adjusting these values
for infant leg length, there is a strong relationship of H-reflex
with age.8 The H-reflex and F-waves disappear at the same time Newborns' sensory nerve action potentials (SNAPs) have
during REM sleep. Responses vary in amplitude with contrac- been described as biphasic. The amplitude of the first peak aver-
tion of muscles. H-reflex latency is shorter in children than in ages 10 JIV, with the second peak 20-30% of the amplitude of
adults, which is secondary to shorter limbs. The H-reflex ampli- the first and the NCV 20-30% slower than the first. This is in-
tude increases after infancy, secondary to increased muscle terpreted to indicate two groups of fibers that have different de-
mass. 33 There is a good correlation between H-reflex latency grees of maturation.81
and body length of the child.56 Investigations have been performed regarding substances that
F-waves are also depressed during deep sleep with an ampli- may have an impact on various aspects of fetal growth. A study of
tude decrease and less frequent F responses obtained. The mean 25 neonates born to mothers on methadone who also may have
median nerve F-wave value is 15.3 ms from infancy to 2.5 years abused other drugs showed that NCVs are unaffected by maternal
of age. The F-wave latency then gradually increases and reaches drug intake or the severity of neonatal withdrawal symptoms.24
its adult value by approximately 20 years of life. The mean
ulnar nerve F-wave is 14.6 ms from infancy to 2.5 years and
then increases up to 20 years of age. The period with no change 600-| —x— POST TIBIAL
in F-wave latency is described as the "lag time" for F-wave —A— PERONEAL
values. This is the period when a very rapid increase in conduc- 550¬
- ULNAR
tion velocity is coincident with an increase in arm length, which
occurs during the first 3 years of life. The balance of these two 500 —•— MEDIAN
factors is reported to be responsible for the lag time. After ap-
proximately age 3, the arm length continues to increase and the
F-wave latency commensurately increases (Table 29-3). 50 450¬
F-wave latencies have shown a biphasic distribution; they are
slightly higher in neonates and in children than in infants.57-72 400
This is thought to result from the opposite influences of height
and degree of myelination. 57 F-wave studies are particularly 350¬
useful in infants and small children because they evaluate prox-
imal and distal nerve segments. The range of normal is smaller, 300-
and there is less influence of measurement error than on distal
studies over shorter distances (which is especially problematic i
in infants and small children due to their small size), because of
the relatively long segment of nerve that is used.57-72 250¬
A large study evaluated median, ulnar, and posterior tibial
nerve conduction in children. This investigation revealed differ- 200¬
ent growth curves for each nerve with respective peaks at just
over 4 years of age (Fig. 29-2). The ulnar and peroneal nerves
show similar values, but the ulnar NCV is faster than the per- 150¬
oneal NCV in adulthood. The peroneal NCV is faster in 5-
week-to 1-year-olds and subsequently decreases until it is 100
slightly less than ulnar NCV. Similarly, the median NCV values
overtake the peroneal NCV at approximately age 3. The poste- 50 H
rior tibial NCV is slower than the peroneal at all ages. Term
newborns have NCVs approaching 50% of adult values, and 30 35 40 45 50 55 60
attain adult levels at approximately 4 years of age.2 METERS /SECOND
A later large study evaluated motor and sensory NCS of chil-
dren 7 days to 14 years of age. This study showed a rapid in- Figure 29-2. Motor conduction velocity maturation. The
crease in NCV and amplitudes in the first year of life, especially NCVs of the ulnar, median, peroneal, and posterior tibial nerves are
in the motor fibers. The amplitude of the motor and sensory presented, and all reach adult values at approximately 200 weeks, or 4
action potentials increase dramatically in the first 6 months of years, of age. (From Baer RD, Johnson EW: Motor nerve conduction
life, and continues to increase, albeit less remarkably, up to 6 velocities in normal children. Arch Phys Med Rehabil 1965;46:698-704,
years of life (Tables 29-4 and 29-5 and Fig. 29-3).65 with permission.)
Table 29-4. Sensory Conduction Studies in 155 Children

Median Nerve Sural Nerve
Age (N) CV,ms Amp, uV CV.ms AMP, U.V
7day-l mo (20) 22.31 (2.16)* 6.22 (1.30) 20.26(1.55) 9.12(3.02)
1-6 mo (23) 35.52 (6.59) 15.86 (5.18) 34.63 (5.43) 11.66 (3.57)
6-12 mo (25) 40.31 (5.23) 16.00 ($.18) 38.18 (5.00) 15.10(8.22)
1-2 yr (24) 46.93 (5.03) 24.00 (7.36) 49.73 (5.53) 15.41 (9.98)
2-4 yr (22) 49.51 (3.34) 24.28 (5.49) 52.63 (2.96) 23.27 (6.84)
4-6 yr (20) 51.71 (5.16) 25.12 (5.22) 53.83 (4.34) 22.66 (5.42)
6-14 yr (21) 53.84 (3.26) 26.72 (9.43) 53.85 (4.19) 26.75 (6.59)
* Mean (SD).
CV, conduction velocity;AMP, amplitude.
From Parano E, Uncini A, DeVivo DC, Lovelace RE: Electrophysiologic correlates of peripheral nervous system maturation in infancy and childhood. J Child Neurol
1993;8:336-338, with permission.
Fetal nutrition studies demonstrated variable results. One as- physiologic features, including more subcutaneous tissue and
sessment of 27 term infants found a significant correlation be- different hemodynamics in girls, and not axonal differences be-
tween decreased skin fold thickness and reduced NCV. The tween the genders. 51 Motor and sensory NCVs increase in the
majority of the infants with the thinnest skin folds also had upper limbs relative to the lower limbs. This is felt to be due to
mothers who smoked cigarettes during pregnancy. Skin fold the balance of nerve maturation (axonal diameter increase in
thickness was thought to be a good assessment of fetal nutrition, late childhood and adolescence) with the increase in limb length
particularly in the third trimester when NCV has a rapid in- that is more dramatic in the legs than arms.51
crease and, therefore, was thought to be a better measure of nu- F-waves persist after 1 year of age, but H-reflexes in most
trition than birth weight. 68 Low maternal serum albumin was muscles are unobtainable. H-reflexes have a shorter latency in
found in mothers whose preterm infants had slow motor NCV children 3-7 years of age compared to adults due to shorter limb
and prolonged H-reflexes. The motor NCV was normal at 22 lengths. The amplitudes of H-reflexes increase with age in the
m/s in preterm infants whose mothers had a serum albumin of first year, which is thought to be secondary to an increase in
3.0 g/dl or higher, and only 15 m/s in infants whose mothers had muscle mass.53
lower serum albumin levels.4 Additionally, preterm infants had Blink reflexes have been described in a study of 30 neonates.
significantly slower motor NCVs and prolonged H-reflexes This report demonstrates an Rl latency in 27 subjects of 12.1
when compared to term infants with growth retardation; severe ms, with an R2 latency in only 20 of the infants, primarily ipsi-
growth retardation (infants less than 1800 grams) led to similar lateral to the stimulus. The Rl is present at a longer latency than
NCV slowing as preterm infants.5 Sleep has been demonstrated in adults and is believed to indicate incomplete myelination of
to adversely impact the excitability of nerves and the presence the facial and trigeminal nerves, and possibly the brainstem.
of late responses. Because Rl is easily elicited, however, this central reflex arc is
Nerve conduction changes in childhood and adolescence established at birth. Because R2 is present in only two thirds of
show different NCV maturation rates in boys and girls, with neonates, it is thought that at least a partial central connection is
NCVs being faster in all nerves except the median in girls com- present at birth. The R2 is so variably present and inconsistent
pared to boys. Skin temperature has an effect on nerve conduc- in newborns, especially contralateral^, that it cannot be inter-
tion velocities in all children studied, with more impact on preted as significant if absent or asymmetric. 46 Brainstem
sensory than motor values, and more so in boys than girls. The myelination is complete in children by approximately 6 years of
latter finding is believed to be more likely due to secondary age,23 when Rl and R2 are also reliably obtained.46
Table 29-5. Motor Conduction Studies in 155 Children

Median Nerve Peroneal Nerve
Age (N) DML, ms CV.ms F, ms AMP, mV DML, ms CV.ms F, ms AMP, mV
7 day-l mo (20) 2.23 (0.29)* 25.43 (3.84) 16.12(1 5) 3.00 (0.31) 2.43 (0.48) 22.43 (1.22) 22.07(1.46) 3.06 (1.26)
1-6 mo (23) 2.21 (0.34) 34.35 (6.61) 16.89(1 65) 7.37 (3.24) 2.25 (0.48) 35.18 (3.96) 23.11 (1.89) 5.23 (2.37)
6-12 mo (25) 2.13 (0.19) 43.57 (4.78) 17.31 (1 77) 7.67 (4.45) 2.31 (0.62) 43.55 (3.77) 25.86 (1.35) 5.41 (2.01)
1-2 yr (24) 2.04 (0.18) 48.23 (4.58) 17.44(1 29) 8.90 (3.61) 2.29 (0.43) 51.42 (3.02) 25.98 (1.95) 5.80 (2.48)
2-4 yr (22) 2.18(0.43) 53.59 (5.29) 17.91 (1 II) 9.55 (4.34) 2.62 (0.75) 55.73 (4.45) 29.52 (2.15) 6.10(2.99)
4-6 yr (20) 2.27 (0.45) 56.26 (6.61) 19.44(1 51) 10.37 (3.66) 3.01 (0.43) 56.14(4.96) 29.98 (2.68) 7.10(4.76)
6-14 yr (21) 2.73 (0.44) 57.32 (3.35) 23.23 (2 57) 12.37 (4.79) 3.25 (0.51) 57.05 (4.54) 34.27 (2.29) 8.15 (4.19)
*Mean(SD)
From Parano E, Uncini A, DeVivo DC, Lovelace RE: Electrophysiologic correlates of peripheral nervous system maturation in infancy and childhood. J Child Neurol
1993:8:336-338, with permission.
35r-
m/sec
30 -
25
20
1 5
Figure 29-4. Positioning for electrodiagnostic medicine eval-
uation of a young child. A small child comfortably seated on a
parent's lap, in a calm, quiet environment paves the way for a smooth
10 study. (Photograph by Paul Vincent Kuntz,Texas Children's Hospital.)
(EMLA) cream (lidocaine 2.5% and prilocaine 2.5%) may be

used in older infants or in children for local anesthesia of the
32 34 36 38 40 42 44 skin. EMLA cream should not be used in infants 1 month of
WEEKS age or younger, and the skin area involved must be limited in
babies and small children due to the possibility of systemic
Figure 29-3. Sensory conduction velocity in the ulnar nerve absorption. 66 The EMLA cream is applied and covered by an
related to age.These values were gathered from 34 newborns and a occlusive dressing or an EMLA anesthetic disc is placed over
literature review in children with no known neuromuscular disease. the muscles to be studied 1 hour prior to the needle EMG.
The broken lines represent 2 standard deviations around the regres- Sedation is not generally considered necessary or helpful for
sion line. (From Wagner AL, Buchthal F: Motor and sensory conduction the routine electrodiagnostic evaluation, although it is occa-
in infancy and childhood: Reappraisal. Dev Med Child Neurol sionally used for repetitive nerve stimulation studies, so-
1972; 14:189-216, with permission.) matosensory evoked potentials, behavioral issues, or other
special circumstances. One potential problem is decreased
ability to recruit motor units with some forms of sedation.
TECHNIQUE Versed (midazolam) intranasally may be useful, and gives the
benefit of amnesia as well as relaxation.
The electrodiagnostic medicine study should be carefully Reports about discomfort during pediatric electrodiagnosis
described to the parent and child, if old enough to understand, have been variable. In a recent survey of pediatric electrodiag-
in as calm, matter-of-fact, and straight-forward manner as nosticians regarding comfort, 44 of 84 respondents regularly
possible. A useful method of putting the parents at ease is to performed electrodiagnosis. 37 They reported 35% of patients
demonstrate electrical stimulation on oneself, describing the under 17 years of age had severe distress during EMG/NCS.
sensory response and showing a clinical motor response, and Seventy-three percent of the physicians report distress in chil-
then allow the parents to feel a low-intensity, sensory level dren 2-6 years old, with 48% noting distress in children under
shock on their own wrist. The needle electrode is best referred 2, 25% in those 7-12, and 14% in 13-17-year-olds. Seventy-
to as a "wire electrode" or "pin" to minimize the negative seven percent of physicians believe that EMG is more painful
emotional impact. The child, parent, and examiner must be as than NCS and 18% believe that they are equally uncomfort-
physically comfortable as possible. With an infant or small able. Sixty-eight percent of the physicians always perform the
child this usually means sitting on a parent's lap (Fig. 29-4). NCS first, and 30% vary their approach. Sixty percent of re-
When performing the study, one method to consider is cup- sponding physicians demonstrate an NCS prior to performing
ping the needle electrode in one's hand to preclude the par- it, with 39% demonstrating on herself or himself, 7% on a
ents from seeing it, because it may appear more ominous than parent, and 14% on both. Seventy-one percent felt that the dis-
it is. Parents of infants are particularly concerned about the traction of watching the screen and listening to the speaker
examination; it may help to state that the baby will likely be helped the patients. On average, 68% of the procedures were
irritated at the needle EMG study, but because of inability to performed with a parent present, including 14% of adoles-
follow commands, the discomfort is actually useful for get- cents. Forty-six percent of the responding physicians never
ting motor activity, and they should be assured that there are use pain medication and 48% use it occasionally (68% of the
no after-effects. Having toys available for an immediate post- time using chloral hydrate). No physician routinely used gen-
study distractor is generally effective. A small concentric or eral anesthesia, and 75% never used it.37 In other areas of pedi-
monopolar needle may be used. When the monopolar needle atrics where procedures are performed, both parents and
is used, a needle reference electrode may also be considered children were reported to be more satisfied when parents are
to help minimize electrical interference. Lidocaine-prilocaine present during procedures. 3
for infants and small children, so the traditional anatomic loca-
tions for stimulation are used and the distances reported with
the results (Fig. 29-6).
The largest source of error in nerve conduction studies in in-
fants is measurement, which is more of a problem in infants than
adults due to shorter nerve lengths.25 Surface measurement errors
of 1 cm can change the value of the infant's NCV by 15%.
Additionally, the bony landmarks are often difficult to evaluate
due to adipose tissue.80 Stimulus artifact causes more difficulties
in infants and small children compared to adults because of the
smaller distances between the simulating and recording elec-
trode. 56 This can be minimized by keeping the skin dry and by
decreasing the skin impedance. Commercially available self-ad-
hesive electrodes may help to minimize stimulus artifact.
Additionally, the self-adhesive ring electrodes are an ideal fit
compared to standard ring electrodes. Either a standard or pedi-
atric stimulator may be used. Some practitioners use a needle
Figure 29-5. Antidromic median sensory nerve conduction electrode instead of surface electrodes for simulation and record-
study in a baby. Self-adhesive ring electrodes provide a good fit, and ing sensory responses in infants because less stimulation inten-
a ring electrode to the fourth digit may be used as a reference for both sity is required; reportedly 10% of the intensity required with a
the median nerve to the third digit and the ulnar nerve to the fifth surface stimulation suffices for needle electrodes.81 Localization
digit, allowing adequate distance between the active and reference of the stimulus is also more precise with a needle electrode and
electrodes on small fingers. Orthodromic SNCS may also be done there is less possibility of unintentionally stimulating other
with stimulation from the digits. (Photograph by Paul Vincent Kuntz, nerves. An advantage of a recording needle electrode is precision
Texas Children's Hospital.) of measurement, and increased sensitivity in recording small po-
tentials by having the needle electrode closer to the nerve itself.
NERVE CONDUCTION STUDIES However, a needle recording electrode is not helpful in the as-
sessment of CMAP amplitude, so information regarding the
Sensory nerve conduction studies are frequently described in number of muscle fibers cannot be obtained with a surface
the pediatric literature, particularly the orthodromic technique recording electrode. 56 Temperature control is challenging and
for the median nerve.39-42«80 They can be performed using ring vital in evaluating an infant. The use of an incubator or warmer
electrodes to stimulate from the second or third digit, with the is sometimes helpful.
recording electrode over the median nerve at the wrist. This Infants differ from adults in their normal response to repeti-
study can also be performed in the usual antidromic manner, but tive nerve stimulation. It has been reported that at stimulation of
the grasp reflex may cause movement artifact to obliterate the less than 5 Hz, the CMAP in infants is stable. At 5-10 Hz some
results. For both sensory and motor studies the reference elec- normal infants show 10% or greater facilitation of CMAP. At 20
trode is usually placed on a separate digit to maintain an appro- Hz, most infants show a decrement of approximately 24%, with
priate interelectrode distance (Fig. 29-5). 42 A ring electrode the decrement greatest in 34-36-week premature infants. After
around the wrist or ankle may be used as a ground electrode. 50-Hz stimulation, virtually all infants show a decrement. It is
Standard stimulating distances of 8 and 14 cm are not possible believed this demonstrates that infants have less normal neuro-
muscular junction reserve than adults. 47 Unfortunately, subse-
quent literature was based on this report of only 17 infants from
34-41 weeks' gestation, using techniques of stimulation for 15 j
seconds, which is rarely done today. Further studies are required I
to more fully explore this issue.
NEEDLE ELECTROMYOGRAPHY
Needle electromyography must be carefully planned and effi-
ciently performed in an infant. The needle examination should
include proximal and distal musculature in upper and lower
limbs. Frequently, the discomfort of needle insertion allows im-
mediate evaluation of recruitment. If not, positive (reaching for a
toy or candy) or negative (sharp) stimuli, as well as primitive re- j
flexes, may be used to recruit motor units. Positioning of the t
muscle is also helpful for evaluating both recruitment and spon-
taneous activity of muscle. Due to the natural flexed positioning
of infants, the biceps brachii, iliopsoas, flexor digitorum superfi-
Figure 29-6. Motor nerve conduction studies in an infantThe cialis, and anterior tibialis muscles are frequently active and may
ulnar nerve will be stimulated at the medial wrist, with a self-adhesive be helpful in evaluating motor unit recruitment. Conversely, ex-
active bar electrode over the abductor digiti minimi and a reference tensor muscles may be good choices for evaluating insertional
ring electrode on the fifth digit. (Photograph by Paul Vincent Kuntz, and spontaneous activity. These muscles include the vastus later-
Texas Children's Hospital.) alis, gastrocnemius, first dorsal interosseous, and triceps 42 It was
previously hypothesized that babies normally displayed fibrilla- Table 29-6. Floppy Infant—Possible Etiologies
tions, particularly in the hands and feet.27 This theory has subse- Brain
quently fallen out of favor and it is believed that insertional and Hypoxia
rest activity, as well as motor unit configuration and recruitment Ischemia
patterns, are the same in babies and older individuals. Hemorrhage
Spinal Cord
MUSCLE BIOPSY Trauma (including birth)
Vascular compromise
Muscle biopsies are frequently used in evaluation of hypo- Congenital anomaly
tonic infants and as the "final" word, although the most appro-
priate diagnosis is made using all available information. The Anterior Horn Cell
preparation of the muscle biopsy is critical and should be done Spinal muscular atrophy
by someone experienced in the procedure. 38 Muscle biopsies Poliomyelitis
may at times be delayed until the child is several years old be- Peripheral Nerve
cause neonatal muscle undergoes rapid changes that can mimic
pathologic states.' 5 Guiliain-Barre syndrome
Hereditary motor sensory neuropathy type III (rarely I)
Congenital hypomyelinating disease
DISEASE PROCESSES Neuromuscular Junction
Myasthenia gravis (4 types)
FLOPPY INFANT Botulism
Medications (magnesium sulfate in mother; aminoglycosides)
Floppy infants are frequently referred for an electrodiagnos-
tic medicine evaluation. The etiology of this problem can be at Muscle
the level of the brain, spinal cord, anterior horn cell, nerve, neu- Congenital muscular dystrophy
romuscular junction, muscle, or connective tissue (Table 29-6). Congenital myotonic dystrophy
The etiology of hypotonia in an infant is most commonly cen- Congenital myopathies
tral.44-79 Nerve conduction studies and needle EMG can help dis- Systemic Disease
tinguish between different levels of involvement and assist with Prader-Willi syndrome
the diagnosis (Tables 29-7 and 29-8). Down syndrome
Metachromatic leukodystrophy
Etiology of Hypotonia in Infants Krabbe's leukodystrophy
Brain Benign Congenital Hypotonia
Floppy infants have a central nervous system (CNS) etiology
for hypotonia 80% of the time. 42 Hypoxia, ischemia, and hem- weeks following the injury in the involved peripheral and
orrhage are frequent causes of brain injury leading to hypotonia. paraspinal muscles. Evaluation of the lower limbs and anal
Premature infants have a higher incidence of hemorrhage than sphincter may be useful for documenting any area of sparing.
full-term infants due to the vulnerability of the periventricular Somatosensory evoked potentials may also be of help in docu-
white matter and germinal matrix at 26-32 weeks' gestation. menting an abnormality.80
Intraventricular hemorrhage occurs most frequently in the first Anterior Horn Cell Disease
3 days of life, with variable signs and symptoms, including hy-
potonia. 38 Damage may involve the cerebrum, cerebellum, or Spinal muscular atrophy (SMA) is the most common pe-
brainstem. ripheral neuromuscular etiology for a floppy infant.19,42-79 The
On physical exam, the differentiating factors pointing to a
central etiology include intact strength and hyperreflexia. There Table 29-7. Electrodiagnostic Approach to Evaluation of
also may be associated seizures, microcephaly, and develop- the Floppy Infant
mental delay. 1. Sensory nerve conduction studies
Electrodiagnostic changes in infants with hypotonia of cen- 3 limbs: 2 upper limbs and I lower limb, or I upper limb and 2
tral origin are nonspecific and minor, or the study is normal.62-70 lower limbs. Expect abnormalities in HSMN and polyneuropathy.
Muscle biopsy may be normal, show nonspecific changes, or at- 2. Motor nerve conduction studies
rophy of type II fibers.6-70 3 limbs: 2 upper limbs and I lower limb, or I upper limb and 2
Spinal Cord lower limbs. Include F waves.
The spinal cord may be damaged by trauma, vascular com- 3. Repetitive stimulation
promise, disease, or congenital anomaly. Spinal cord injury is Perform if maternal history of myasthenia gravis; if baby has ptosis
suggested by a history of traumatic birth or other severe neck or if there are multiple motor responses to a single stimulus. Ex-
trauma in the neonatal period. In the case of a spinal cord etiol- pect abnormalities in myasthenia gravis, botulism, aminoglycosides.
ogy for hypotonia, extreme weakness or absence of active 4. Somatosensory evoked potentials
movement is noted below the lesion's level. Nerve conduction
studies are normal, although F-waves and H-reflexes may be ab- Consider with differential diagnosis of spinal cord injury.
normal or absent, documenting proximal loss of continuity. 5. Electromyography
Needle EMG shows loss of motor units innervated at the in- Selective, with flexors to check recruitment, and extensors to
volved level, and fibrillation potentials may be seen several check rest activity.
Table 29-8. Infant Hypotonia: Electrodiagnostic Findings
Diagnosis Motor Conduction Sensory Conduction Spontaneous Activity Motor Units
SMA Decreased amplitude; may Normal Fibrillations ±; spontaneous Decreased number; may
show decreased velocity rhythmic motor unit firing show mild increase in
amplitude, duration
HSMN III Markedly prolonged Prolonged or absent 0 Reported normal
Hypomyelinating Markedly prolonged; markedly Prolonged or absent 0 Reported normal or
neuropathy decreased amplitude increased amplitude, dura-
tion; poor activation
Inflammatory Decreased amplitude; possible + Fibrillations may be present Decreased number
polyneuropathy decreased velocity; conduction
block
Botulism Decreased amplitude; normal Normal Fibrillation Decreased amplitude
velocity; decremental response duration
to MNCV facilitation > 20 Hz
Spinal cord Normal velocity and amplitude Normal Fibrillations may be present in Decreased number at
injury if nerves tested are not muscles innervated at level involved muscles; poor
originating at area of injury; of injury motor control below
F-wave and H-reflex may be level of injury
prolonged or absent
Congenital Normal velocity; amplitude Normal Fibrillations may be present Normal to decreased
myopathy may be decreased amplitude, duration;
increased polyphasicity
Congenital Normal Normal Reported 0 or fibrillations, Poor activation; likely
myotonic frequency varying trains of normal
dystrophy positive waves
Gycogen storage Normal Normal Fibrillations (ll,V,VII) frequency Decreased amplitude,
disease varying trains of positive waves duration
Metachromatic Decreased velocity, decreased Slowed
leukodystrophy amplitude
From Turk MA: Pediatric electrodiagnostic medicine. In Dumitru D (ed): Electrodiagnostic Medicine. Philadelphia, Hanley & Belfus, 1995, with permission.
different types of SMA and some rare diseases also affecting Increased polyphasicity may also be seen.19-42 79 There is also a
the motor neuron are summarized in Table 29-9. Infants with classically reported spontaneous, rhythmic motor unit activity
SMA classically have an active, lively facial expression and with a rate of 5-15 Hz seen in muscles at rest or during
a very floppy body. A frog-leg position of the legs and jug- sleep. 10 Three limbs should be examined, including at least
handle position of the arms are frequently described (Fig. 29-7). two muscles innervated by different root levels and peripheral
Paradoxical breathing may also be present. Tongue fascicula- nerves in each. 42 The EMG findings correlate with muscle
tions are classically noted. The clinical course may include res- biopsy in 85-93% of infants with SMA I.19-62-70 Muscle biopsy
piratory and feeding difficulties. Classification of SMA types typically reveals neurogenic changes; however, occasional
is by age at onset, clinical course, and survival time. The biopsies, especially early in the disease course, may show
International SMA classification 62 describes SMA type IA findings suggestive of a mild myopathy.I9-70-78
(Werdnig-Hoffmann disease) as having hyporeflexia, atrophy, Research suggests that the electrodiagnostic medicine
and fasciculations, with onset at less than 1 year, death at less evaluation may differentiate SMA types and predict out-
than 4 years, and the child never being able to sit unsupported. come. An investigation of 106 patients demonstrated that pa-
Type IB is somewhat more benign, although the child will never tients with high fibrillation density before 3 years of age had
walk and the patient generally survives for at least 10 years. 36 a poorer prognosis than those with less fibrillations. 49 It has
Types II and III have onsets generally after age 2 years and also been noted that fasciculations are rare in SMA IA com-
therefore are not involved in consideration of the floppy infant. pared to the other SMA types. i0 - 36 One study of 223 children
Laboratory evaluation in the patient with SMA shows an ele- with SMA showed that the mean amplitude of single motor
vated CK. units in the quadriceps muscles differentiated patients with
Nerve conduction studies in SMA I classically show low- the group IA form of the diseases. 36 A smaller review of 20
amplitude CMAPs, normal or minimally slowed motor NCVs, patients with SMA demonstrated that those with slowed
and a normal distal latency. Sensory nerve action potentials NCVs had shorter survival times than others, but this group
are normal.19-42-79 Needle EMG may show positive sharp waves did include adult patients. 70
and fibrillations potentails, but fasciculations are rarely seen. A major SMA locus in chromosome region 5ql3 has been
There are decreased numbers of motor unit action potentials identified. Therefore, it is possible to perform prenatal DNA
(MUAPs) recruited with increased firing frequency, and in- studies to check for the presence of this abnormality. 70 This
creased numbers of large-amplitude, long-duration MUAPs. gene likely acts with others to form the varying types of SMA.
Peripheral Nerve Table 29-9. Classification of the Spinal Muscular Atrophies
Peripheral nerve involvement in an infant with hypotonia in Childhood
may be congenital or acquired. Guillain Barre syndrome Hereditary
(GBS), also known as acute inflammatory demyelinating Hereditary proximal motor neuronopathies
polyradiculopathy (AIDP), has been described in the first few Type I (AR) (acute infantile, Werdnig-Hoffmann disease)
months of life. There are also reports that it may be acquired in Type II (AR) (chronic childhood)
utero.'-42 In GBS, the infant may show hypotonia, ascending Type III (AR) (juvenile onset, Kugelberg-Welander disease)
weakness, respiratory and feeding difficulty, and areflexia. Type IV (AD) (juvenile onset)
Autonomic abnormalities may also be present. Laboratory stud- TypeV (AD) (adult onset)
ies show cerebrospinal fluid (CSF) protein elevation. Nerve Hereditary distal motor neuronopathies (distal SMA, spinal form
conduction studies and needle EMG show findings similar to an of CMT disease)
older patient with GBS, including slow NCV, decreased Type I (AD) (juvenile onset)
CMAPs, and prolonged or absent F-waves; F-wave abnormali- Type II (AD) (adult onset)
ties occur prior to other abnormalities. Needle EMG can Type III (AR) (mild juvenile)
demonstrate signs of dennervation.39-42 Type IV (AR) (severe juvenile)
Congenital peripheral neuropathies in infants include hered- TypeV (AD) (upper limb predominance)
itary motor sensory neuropathies (HMSNs) and the more recently Hereditary motor neuronopathies with complex distributions
described congenital hypomyelination abnormalities. Peripheral Scapuloperoneal
polyneuropathy is a very uncommon cause of a floppy infant. Type I (AD)
Hereditary motor sensory neuropathy III (HMSN III, Dejerine- Type II (AD)
Sottas disease) may be a cause of floppy infant.' 9 Laboratory Other forms
values are normal except elevation of CSF protein. Nerve con- Facioscapulohumeral (AD)
duction studies show absent SNAPs, which is critical to the diag- Oculopharyngeal (AD)
nosis. These studies also reveal dispersed CMAPs, which are Bulbar (AR)
small and quite prolonged, along with unobtainable or very pro- Spinobulbar—the Kennedy syndrome
longed NCVs. Needle EMG reveals normal motor units and no
abnormal spontaneous activity. Nerve biopsy demonstrates seg- Acquired
mental demyelination with onion bulb formation. Muscle biopsy Juvenile motor neuron disease—amyotrophic lateral sclerosis
in HMSN III is normal for age.19-58 Charcot-Marie-Tooth disease Monomelic amyotrophy
(HMSN I) is a rare etiology of floppy infant. Paraneoplastic (Hodgkin's disease)
Congenital hypomyelinating neuropathy has more recently AR, autosomal recessive; AD, autosomal dominant; SMA, spinal muscular atro-
been described. Clinically, one notes a hypotonic, weak baby phy; CMT, Charcot-Marie-Tooth. Modified after Jones HR, Bolton CF, Harper
CM: Pediatric Clinical Electromyography. Philadelphia, Lippincot-Raven, 1996.
with abnormal sensation. Mild infections may cause severe res-
piratory compromise. 45 - 82 Nerve conduction studies reveal ex-
tremely slow conduction velocities of approximately 2-5 m/s. organism from stool samples. Antibiotics should be avoided as
Sensory responses are absent. With congenital hypomyelina- they may worsen the neuromuscular blockade. 33
tion, needle EMG generally demonstrates normal insertional Repetitive nerve stimulation shows an incremental response
and rest activity with normal motor units, but occasional com- at 50 Hz stimulation, always greater than the 20% percent facil-
plex repetitive discharges and neurogenic recruitment may be itation reportedly found in normal infants. This finding is usu-
seen.1-45 Sural and intramuscular nerves demonstrate almost ally seen at 20 Hz as well (Fig. 29-8). Some infants show a
total absence of myelin with preservation of axons, and atypical decremental response at 2-3 Hz repetitive nerve stimula-
onion bulb formation.'-82 Muscle biopsy is normal except for in- tion.33-42-79 Needle EMG frequently demonstrates short-duration,
tramuscular nerve myelin abnormalities. The changes noted are low-amplitude polyphasic potentials, and less commonly, pos-
described as similar to those in HMSN III, but much more itive sharp waves and fibrillations. 12 The electrophysiologic
severe. Clinically, ataxia remains a long-term problem.1
Neuromuscular Junction
Neuromuscular junction (NMJ) abnormalities leading to a
floppy infant can arise from botulism or a form of myasthenia
gravis. Botulism is caused by the anaerobic bacterium Clostri-
dium botulinum, which colonizes the intestinal tract of an infant
and then releases botulinum toxin.33 79 This leads to a presynap-
tic abnormality.42-79 Clinically the infant presents with a brief
history of constipation, occasional honey ingestion, followed by
weakness, poor suck and feeding, weak cry, and lethargy, most
commonly between 1 and 6 months of age.33-41-64-79 There is de-
scending paralysis with frequent early involvement of cranial
nerves. Upper and lower limbs may become weaker over time
until the child has little or no active movement. All cranial Figure 29-7. Spinal muscular atrophy type I.This hypotonic
nerves may be involved. There is hyporeflexia or areflexia. young child demonstrates a frog-leg position of the legs, jug handle
Mechanical ventilation may be required. 33 Laboratory studies arms, and an alert, active face. (From Brooke MH (ed): A Clinician's
including CSF, complete blood count, and electrolytes are View of Neuromuscular Disease, 2nd ed. Baltimore, Williams &
normal. Diagnosis is confirmed by isolation of the C. botulinum Wilkins, 1986, with permission.)
in the absence of the recognized family history, myotonia at
times may be detected on examination of family members. On
physical examination, the infant may reveal delay of motor de-
velopment, strabismus, and skeletal deformities, most com-
monly of the hips or feet. Facial weakness is frequently noted.
Neuroradiologic studies in some infants with myotonic dys-
trophy demonstrate ventricular enlargement. Electrodiagnostic
evaluation reveals normal motor and sensory NCS and fre-
quently normal needle EMG, although decreased motor unit re-
cruitment may be seen. Myotonic discharges are infrequently
seen in infancy but are more frequently seen after age 5 years. 69
Additionally, myotonic discharges are more commonly found
on needle EMG of the mother, and rarely in the father.
Figure 29-8. Incremental response to repetitive stimulation. Congenital muscular dystrophies (CMDs) often present as a
Typical response in an infant with botulism.At the left, 2 Hz stimu- floppy infant with weakness, contractures, arthrogryposis, and
lation yields a low-amplitude evoked response, followed by an incremen- hip dislocation. Laboratory evaluation may reveal a somewhat
tal response to titanic stimulation, and finally, post-tetanic 2 Hz elevated CK level. Congenital muscular dystrophy may be seen
stimulation reveals facilitation followed by decrement. (From Turk MA: in combination with central nervous system and ocular abnor-
Pediatric electrodiagnostic medicine. In Dumitru D (ed): Electro- malities. These combined diagnoses include Fukuyama CMD,
diagnostic Medicine. Philadelphia, Hanley & Belfus, 1995, with permission.) which shows type II lissencephaly and ocular anomalies; the
Walker-Warburg syndrome with lissencephaly, hydro-
abnormalities occur secondary to the botulinum toxin irre- cephalus, and ventricular dilatation; and muscle-eye-brain dis-
versibly binding to the presynaptic membrane, inhibiting acetyl- ease (MEBD, Santavuori's syndrome), which shows cerebellar
choline (ACh) release.33 hypoplasia, ventricular dilatation, progressive hydrocephalus,
Congenital myasthenic syndromes are a heterogeneous and absent septum pellucidum. 64,83 In these disorders, cranial
group of genetic or transient disorders. The transient form is computed tomography (CT) or magnetic resonance imaging
secondary to a simple transfer of maternal ACh receptor anti- (MRI) along with an electroencephalogram (EEG) may provide
bodies with eventual resolution.42-64 There are four distinct ge- useful diagnostic information. Needle EMG demonstrates low-
netic, or congenital, myasthenic syndromes: (1) familial amplitude, short-duration MUAPs, or no abnormality. Diagnosis
(defects in ACh synthesis or mobilization), (2) decreased is made with muscle biopsy.42-64 Differential diagnosis for CMD
number of ACh receptors (endplate AChR deficiency), (3) includes polymyositis, which is rarely seen in an infant, or
defect in ACh breakdown by acetylcholinesterase (endplate myophosphorylase deficiency (glycogenosis type V, McArdle's
AChE deficiency), and (4) prolonged open time of the ACh re- disease), which both potentially demonstrate elevated serum CK
ceptor channel (slow channel syndrome). 33 - 42 Electrodiagnostic and show increased insertional activity on EMG.42
testing shows varying abnormalities in the different types. In The congenital myopathies present as a hypotonic and weak
infants with endplate AChE deficiency and slow channel syn- infant. The needle EMG may be normal initially or motor units
dromes there is a repetitive response to a single maximum may show decreased amplitude and duration, and increased
stimulus. These two types of disorders also display a negative polyphasicity (Table 29-10).
Tensilon test. Conversely, the Tensilon test is positive in the Fibrillations are noted in centronuclear (myotubular) myopa-
syndrome in which ACh synthesis or mobilization is defective, thy, but not in the other types of myopathy. Diagnosis is made
and in AChR deficiency. 30 A decremental response of at least by muscle biopsy. 79 Several studies have recently shown that
10% at 2 Hz stimulation is seen in all types, but the type with congenital myopathy is infrequently diagnosed by EMG, with
defective synthesis or ACh mobilization may require more diagnostic accuracy ranging from 10% to 67%.19-62-70 These
prolonged stimulation. 30 This decrement may be noted only in studies compared diagnosis with biopsy outcome. However, two
muscles that are clinically weak. Motor and sensory NCS, as other studies have demonstrated the difficulty in obtaining pre-
well as needle EMG, are normal in these disorders. cise biopsy results, citing difficulties with artifacts and interpre-
Infants whose mothers received intravenous magnesium sultation. 14 Another recent study of 29 patients revealed a 90%
fate during treatment for eclampsia may also develop weakness correlation of needle EMG with myopathy diagnosis.38
and respiratory depression secondary to NMJ presynaptic trans- Consideration must be given to mitochondrial myopathy
mission defects.80 Antibiotics, particularly aminoglycosides, may and glycogen storage metabolic abnormalities in infants with
cause pre- or postsynaptic abnormalities.79 hypotonia. A patient with Pompe's disease (acid maltase defi-
ciency, type II glycogenosis) has cardiomegaly, hepatomegaly,
Muscle Disease macroglossia (large tongue), and hypotonia, along with con-
Myopathies are the second most common peripheral neuro- gestive heart failure. Pompe's disease is a disorder of glyco-
muscular cause of a floppy infant.42-64 The myopathies include gen metabolism with excess glycogen stored in body tissues.
congenital myotonic dystrophy, congenital muscular dystrophy, Needle EMG demonstrates increased fibrillation potentials
the many congenital myopathies, polymyositis, and abnormali- and possibly myotonic discharges along with brief, small,
ties of mitochondrial and enzyme function. abundant polyphasic potentials. Nerve conduction studies are
Infants with congenital myotonic dystrophy often present normal. 64 Mitochondrial myopathies may show an association
with severe hypotonia and difficulty sucking and swallowing, of hypotonia with seizures and developmental delay. Labora-
along with respiratory difficulties. Physical examination may tory studies reveal elevated lactate and pyruvate levels. Needle
show tenting of the upper lip and temporalis muscle wast- EMG demonstrates brief, small, abundant polyphasic MUAPs.
ing.52-64-69-76 There may be a family history of myotonia, but even Muscle biopsy reveals mitochondrial abnormalities. 64
Table 29-10. Congenital Myopathies

Associated Laboratory
Types Genetics Course Findings Biopsy Electrodiagnostics Studies
Central core AD Mild Frequent CDH Type 1 predominance Small-amplitude CK normal
myopathy Chromosome 19 Normal life MH Unstained central polyphasics
span areas
Nemaline AD Slowly progres- Respiratory mus- Small rodlike particles, Small-amplitude CK normal to mild
myopathy Chromosome 1 sive cles abnormal more peripheral polyphasics increase
Cardiomyopathy Type 1 fiber predomi-
nance and atrophy
Myotubular AR AR—varies AR—seizures, Internal nuclei Small-amplitude CK normal to mild
(centronuclear) XLR XLR—early ptosis Type 1 fiber polyphasics, CDRs, increase
myopathy death; 80% XLR—severe predominance fibrillations, posi-
in first year
respiratory tive sharp waves,
disease myotonic discharges
Congenital Varied reports of Improves after Frequent CDH
fiber AD, or sporadic weakness first Short height and Small type 1 fibers Small-amplitude CK normal to mild
disproportion 2 yr low weight Increased percentage polyphasics increase
of type 1 fibers
CDH, congenital' dysplasia of hip; MH, malignant hyperthermia; CK, creatine kinase; CRDs, complex repetitive discharges;AD, autosomal dominanqAR, autosomal re-
cessive; XLR, X-linked recessive.
From Nelson MR: Rehabilitation concerns in myopathy. In Braddom R (ed): Physical Medicine and Rehabilitation. Philadelphia.W.B. Saunders, 1996, with permission.
Systemic Disease children with AIDP described pain as the chief complaint in
A variety of systemic abnormalities may present as infantile hy- 47% of affected children. Early ataxia and abnormalities of
potonia. An infant with Prader-Willi syndrome displays hypotonia equilibrium are reported in 15% of the children, with sensory
and frequently feeding difficulty early in the disease process. disturbance in only 5% of the children.20 In the first week of an
Muscle biopsy and EMG are normal. Down syndrome may also acute illness, if at least two motor and one sensory nerves
present as hypotonia. 79 Metachromatic leukodystrophy and demonstrate signs of demyelination, it is highly suggestive of
Krabbe's leukodystrophy are metabolic diseases that show abnor- AIDP. In week 2, there are even more signs of demyelination of
mal arylsulfatase A and galactocerebrosidase p-galactosidase activ- motor and sensory nerves, with the median sensory NCV abnor-
ity, respectively. Metachromatic leukodystrophy has slowed NCV, mal in 70% of the children. Approximately 60% of the children
decreased CMAP, high stimulation threshold, and slow or absent demonstrate conduction block and temporal dispersion in the
sensory conduction on electrodiagnostic evaluation.79 Refsum's first 2 weeks. Most children do not have an F-wave abnormality,
disease is marked by increased phytanic acid in serum and urine.58 which is thought to be partially due to the fact that the CMAP is
less than 20% of normal in two thirds of those studied. The chil-
Benign Congenital Hypotonia dren showed distal latencies that were extremely prolonged,
Infants with benign congenital hypotonia have normal labo- particularly during the 5th week. Nerve conduction velocity was
ratory values, electrodiagnostic studies, and muscle biopsy. most reduced during week 5 in children, but week 3 in adults.
Family history may be helpful. These children generally im- Sensory amplitude is also reduced to its lowest value at week 5.
prove but may have varying degrees of long-term deficits of Recovery however, was thought to occur sooner in children than
muscle tone, strength, and coordination.6-42 adults. The children's CMAPs returned to normal amplitude at
4 months after onset of illness. This is attributed to either a more
severe axonal injury in adults than children, or faster recovery
OTHER DIAGNOSTIC CONSIDERATIONS in children due to the shorter length of nerve to recover or better
IN CHILDREN regenerative potential. At week 5, when the electrical signs of
demyelination of the children were at the worst, the majority of
Poliomyelitis is uncommon in the United States, but it is occa- the children had demonstrated some clinical recovery.20
sionally seen in infants in this country post-immunization and in
children from other parts of the world. In children with polio, the CRITICAL ILLNESS POLYNEUROPATHY
CMAP amplitude is decreased in proportion to weakness severity.
In a study of children with involvement of only one leg, the H-reflex Critical illness polyneuropathy (CIPN) has been described
latency is prolonged in both the involved and uninvolved limb, in the adult literature. Approximately 70% of adults with sepsis
though slower on the weak side. The CMAP, distal motor latency, have abnormalities on peripheral nerve electrical studies,
and H-reflex amplitude were decreased only in the involved limb.67 whereas corresponding numbers in children are unknown. 73
There are increasing reports of neuromuscular abnormalities in
ACUTE INFLAMMATORY DEMYELINATING children with sepsis, including flaccid quadriplegia and inability
POLYRADICULOPATHY to wean from the ventilator despite recovery of cardiovascular
and respiratory function. Etiologies that should be considered
Older children with GBS or AIDP tend to have some clini- are CIPN, neuromuscular transmission abnormalities, my-
cal features not frequently described in adults. One study of 40 opathies, and steroids. In CIPN there is hypotonic quadriplegia
and the inability to wean from ventilation. Weakness generally for patient cooperation in performing this study, it has been de-
begins 11-20 days after onset of sepsis, which is shorter than the scribed that infants, young children, and others who for any
lag time for adults, which is usually several weeks. Multiorgan reason cannot cooperate are unable to undergo this evaluation.
failure is noted in all children. Recovery is expected, but the SFEMG is difficult because infants and children cannot con-
degree of recovery is not yet well-defined. Serum CK is normal stantly maintain a level of muscle contraction.13 A technique for
or mildly increased. Nerve conduction studies show decreased stimulated SFEMG may allow this useful diagnostic exam to be
motor and sensory amplitudes with needle EMG findings of fib- employed in infants and children as well. A stimulating monopo-
rillations, positive sharp waves, and polyphasic MUAPs with de- lar electrode is used at the motor point to obtain a muscle twitch
creased recruitment. 73 Quadriparesis and the inability to wean with maximum response at the lowest voltage. This technique has
from the ventilator may also be noted as a possible late effect of a smaller jitter than voluntary SFEMG due to variation in tech-
pancuronium neuromuscular blockade. This has been found fol- niques. The stimulated SFEMG represents the variability in one
lowing discontinuation of medication following ventilating for endplate as opposed to two endplates. The stimulated SFEMG
status asthmaticus. Corticosteroids are generally used in these technique also examines both large and small motor units as op-
patients at high or low doses. Steroid myopathy is also a consid- posed to the smaller units studied with voluntary contractions.40
eration as an etiology. In this group, creatine kinase is elevated
or normal. The needle EMG may show polyphasic MUAPs and BIRTH BRACHIAL PLEXUS PALSY
decreased recruitment. A full recovery is expected.73 Hopkins
syndrome has been described in children after status asthmati- Infants with birth brachial plexus palsy (BBPP) are also re-
cus with progressive and permanent mono- or diplegia. This has ferred for electrodiagnostic evaluation. Nerve recovery patterns in
been described as similar to polio but with no known exposure, BBPP are described in 78 infants. Denervation activity was pre-
including vaccination. Electrodiagnostic findings reveal segmen- sent from day 10 through day 60, with abnormal motor unit poten-
tal anterior horn cell disease. Steroids may play a role in predis- tials beginning at day 30. Nerve regeneration began at week 9 and
posing to Hopkins syndrome.61 all infants had MUAPs abnormalities by week 13. When there are
electrodiagnostic findings earlier than expected along with atro-
HUMAN IMMUNODEFICIENCY VIRUS (HIV) phy of muscles, intrauterine etiology must be considered. 63 A
follow-up of 149 infants with BBPP over time shows that 72% had
Children with HIV have rarely been reported to have periph- similar motor grades on initial and final exam, 4% deteriorated,
eral nervous system abnormalities. 31 It is unknown if children and 28% improved. Of those who improved, 31 (76%) improved
with HIV have a resistance to the peripheral nerve abnormali- by one grade and only two children (5%) improved by two or
ties that affect adults, or if they are present, but underreported. more grades.29 An investigation of 105 5-year-old children who
In a study of 50 children with HIV referred for electrodiagnos- had incurred a BBPP showed a decrease in function that was more
tic evaluation for suspected peripheral neuropathy, only 12 had complex than had been predicted. Further, children with only
abnormal findings. Forty of these children were referred for C5-C6 motor deficits showed decreased hand grip strength and
paresthesias in their hands or feet, eight for loss of motor mile- function, at least partially due to shoulder and arm positioning ab-
stones or weakness, and two for decreased reflexes. Nineteen of normalities.75 However, for most BBPP children spontaneous re-
the children were described as having decreased reflexes or a covery is favorable: 70% show a good to excellent and 22% a
focal sensory loss on physical exam, and only 10 of these had moderate recovery. In 8% a severe handicap remains.28 Well de-
abnormal nerve conduction studies. Seven of the children re- scribed nerve grafting procedures are available to increase the
portedly had sensory or sensorimotor axonal polyneuropathy, chance of recovery for strength and function in infants who do not
but all in this group had received two or more antiretroviral show improvement by approximately 4-6 months of age.34
agents. These children were also found to be older than the chil- Electrodiagnostic studies, including evoked potentials, are useful
dren tested who did not have findings indicative of polyneu- in guiding nerve grafting procedures intraoperatively.54
ropathy. The children did display the most common patterns
also found in adults, which was sensory or sensorimotor DERMATOMYOSITIS
polyneuropathy. Most children who were treated with nucleo-
side analogues did not develop peripheral neuropathy, which is Children with dermatomyositis may be referred for electrodi-
a frequent finding in adults. It is hypothesized that the regenera- agnostic evaluation. Common presenting complaints are pain,
tive capacity may decrease as children get older and approach arthralgias, fever, and weight loss. Physical examination frequently
adolescence. This study demonstrates more adolescents with demonstrates Gottron's papules, a heliotrope rash, an erythematous
abnormalities that are similar to those in adults. Three of the malar rash, muscle weakness, arthritis, and calcinosis.72 There is an
children were found to have median nerve compression at the increase in creatine kinase. The classic electrodiagnostic findings
wrist, which is very uncommon in children but not uncommon in dermatomyositis/polymyositis include positive sharp waves,
in adults with HIV.31 In the general population, 59% of children fibrillation potentials, complex repetitive discharges, and small
with median mononeuropathy, are reported to have a proxi- polyphasic MUAPs. The rash may be the first diagnostic clue.56
mal lesion, most commonly due to elbow trauma.21
MYASTHENIA GRAVIS ILLUSTRATIVE CASE
Myasthenia gravis is found in infants and children as well as FLOPPY BABY
in adults. Single-fiber electromyography (SFEMG) has been de-
scribed as an extremely useful diagnostic study in the diagnosis Reason for Referral. Floppy infant since birth.
of neuromuscular disease. Increased jitter on SFEMG is one of History. A five-month-old male baby is reported as being
the earliest abnormalities reported. Because of the requirement floppy since he was born. The mother, upon questioning, does
recall that there were decreased fetal movements during the last Clinical Course. The baby made some developmental
trimester. The baby has had some difficulty with feeding, al- progress, including rolling over at 7 months of age. He re-
though his cry has been good and there have been no severe res- mained unable to sit. He improved in his vocalizations, but
piratory infections. There is no family history of early infant swallowing remained difficult. He had multiple respiratory in-
death or of neuromuscular problems. There is no consanguinity. fections and subsequently died of pneumonia at 20 months of
Physical Examination. Hypotonia and profound weakness age.
are present. Head circumference (FOC) is 40 cm. He has an
alert facial expression with active, symmetric facial movement Comment
and tongue fasciculations. Minimal movement is noted in the The etiology of hypotonia in an infant can arise anywhere
bilateral upper and lower limbs. He is hyporeflexic throughout. along the neural axis from the brain to the muscle. This includes
Sensation is intact to pinprick. Muscle tone is symmetrically de- damage or disease of the cerebral cortex or cerebellum; spinal
creased. There are no contractures. The child is lying with hips cord maldevelopment or damage; or anterior horn cell disease,
fully abducted and arms at his sides. most frequently spinal muscular atrophy, as well as poliomyelitis.
Laboratory Studies. Laboratory studies show normal lactate, Hypotonia also may arise from abnormalities of the peripheral
ammonia, and amino acid levels. Creatine kinase (CK) is elevated. nerve, including Guillain-Barre syndrome, polyneuropathies,
Nerve Conduction Studies. Nerve conduction studies are hereditary motor sensory neuropathies, and congenital hy-
performed on the right upper limb and bilateral lower limbs. pomyelinating disease. The etiology can be neuromuscular junc-
Temperatures are 33.1°C on the right midpalm and 31.0°C on tion disease, including myasthenia gravis and botulism; or muscle
both lateral malleoli. disease, including congenital myopathies or myotonic dystrophy.
Nerve DSL S Amp DML M Amp NCV Hypotonia may be due to systemic disease, including metabolic
(ms) (jiV) (ms) (mV) (m/s) abnormalities and systemic connective tissue disease, or due to
R median 2.0 15.9 2.2 3.0 34 benign congenital hypotonia. The abnormality most commonly
R ulnar 1.8 16.5 2.3 3.3 36 arises from the level of the brain, in approximately 80% of
R peroneal 2.1 11.5 2.3 1.5 35 cases. 42 The etiology is determined by evaluating the history of
L peroneal 2.2 12.3 2.1 1.2 34 the disease process, family history, physical exam, pertinent labo-
DSL, distal sensory latency; S Amp, sensory amplitude; DML, ratory studies, electrodiagnostic evaluation, and muscle and nerve
distal motor latency; M Amp, motor amplitude; NCV, nerve biopsy (Table 29-6).
conduction velocity; ms, milliseconds; uV, microvolts; m/s, The significant features of an infant's disease course include
meters per second. Motor and sensory amplitudes are measured onset, which may be prenatal, as indicated by decreased fetal
baseline to peak. Sensory latencies are measured to peak, and movement, at birth, or later. Hypotonia may cause difficulty with
motor latencies are measured to initial negative onset. the birth process. Onset may be sudden or gradual, and severity
Needle Electromyography. A needle electromyographic in- may worsen, improve, or stabilize. The hypotonia may be asso-
vestigation is performed on the right upper limb and bilateral ciated with systemic problems including congenital anomalies,
lower limbs with a disposable monopolar needle. or with feeding or respiratory difficulties. Family history may in-
Muscle Rest Activity Recruitment clude consanguineous parents or a previous infant with weak-
R deltoid 2+ fibs/PSW Markedly reduced ness or early death due to an unknown cause. Significant factors
R biceps 1 + fibs/PSW Mildly reduced in the physical exam include muscle tone, reflexes, and strength.
R triceps 1 + fibs/PSW Mildly reduced Also critical are facial movement, head size, primitive reflexes,
R abductor pollicus 1+fibs/PSW Markedly reduced posture, and sensation, including anal wink. Observation of res-
brevis piratory effort and feeding are helpful. Laboratory evaluation
R extensor digitorum 1+ fibs/PSW Mildly reduced commonly includes creatine kinase, amino acids, ammonia, lac-
communis tate, and in infants with congenital anomalies or suspicious
R vastus medialis 2+ fibs/PSW Markedly reduced family history, chromosomal analysis. Electrodiagnostic evalua-
R tibialis anterior 2+ fibs/PSW Markedly reduced tion includes sensory and motor (including F-waves) NCS,
R gastrocnemius 1+fibs/PSW Mildly reduced needle EMG, and frequently, repetitive nerve stimulation stud-
L vastus medialis 2+ fibs/PSW Markedly reduced ies. Muscle and nerve biopsies may be indicated.
L gastrocnemius 2+ fibs/PSW Mildly reduced
Comment. There is 15 Hz spontaneous motor unit activity
seen at rest in the right deltoid and tibialis anterior. An increase CONCLUSION
in polyphasicity is noted in the right arm and leg muscles stud-
ied. The right deltoid, biceps brachii, triceps, tibialis anterior, Electrodiagnostic medicine evaluation in children, as in
and vastus medialis motor units show increased amplitude and adults, is an important part of the diagnostic work-up in patients
duration. with weakness, hypotonia, and sensory changes. Abnormalities
Summary of Findings. Normal NCS is found with the ex- may have brain, spinal cord, anterior horn cell, peripheral nerve,
ception of decreased CMAP amplitudes throughout. There are neuromuscular junction, muscle, or systemic or connective
diffuse abnormalities of needle EMG examination including tissue origin. As in adults, electrodiagnosis should be consid-
fibrillations, positive sharp waves, and increased polyphasicity. ered together with a careful patient history, family history, phys-
There is also 15 Hz spontaneous motor unit activity noted. ical examination, particularly including strength, reflexes, and
Electrodiagnostic Medicine Impression. The findings in sensation, and laboratory studies, including nerve or muscle
this baby are classic for spinal muscular atrophy (SMA). The biopsy. A logical and organized approach is critical in obtaining
infant's history and physical exam also point to the diagnosis of a successful electrodiagnostic medicine evaluation in infants
SMA, specifically SMA I, or Werdnig-Hoffmann disease and young children. Knowledge of developmental changes with
(Fig. 29-7). age must be considered. Obtaining maximal trust and comfort
with the parents and child prior to onset of the study results in 34. Gilbert A: Long-term evaluation of brachial plexus surgery in obstetrical palsy.
the best possibility for useful results and an accurate diagnosis. Hand Clin 1995;11,583-594.
35. Gutrecht JA, Dyck PJ: Quantitive teased-fiber and histologic studies of human
sural nerve during postnatal development. J Comp Neurol 1970; 138:117-129.
36. Hausmanowa-Petrusewicz I, Karwanska A: Electromyographic findings in dif-
ferent forms of infantile and juvenile proximal spinal muscular atrophy. Muscle
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AAEM Glossary of Terms
in Electrodiagnostic Medicine
and Illustrations of Selected
Waveforms
CONTENTS
Section I: Alphabetical List o f Terms w i t h Definitions 1450
Section II: Illustrations o f Selected W a v e f o r m s 1468
Section III: A b b r e v i a t i o n s o f Units o f M e a s u r e m e n t 1488
AAEM Nomenclature Committee

Lawrence H. Phillips, II, M D , Chair
William J. Litchy, M D , Chair
Raymond G. Auger, M D
Ernest M. Baran, M D , M S B M E
Francis J. Bonner Jr., M D
M. E. Brandstater, M B B S , PhD, FRCP
Daniel Dumitru, M D , P h D
Bjorn Falck, M D , P h D
Andrew J. Gitter, M D
Andrew J. Haig, M D
Mark Hallett, M D
Charles K. Jablecki, M D
Dale J. Lange, M D
Janice M. Massey, M D
Lawrence R. Robinson, M D
Margaret A . Turk, M D
Jacqueline J. Wertsch, M D
A s a J. Wilbourn, M D
This chapter is reproduced from the AAEM Glossary of Terms in Electrodiagnostic Medicine. Muscle & Nerve 2001 (in press). Reproduced with permission of the
American Association of Electrodiagnostic Medicine, Rochester, Minnesota. Approval for inclusion of the glossary in this book in no way implies endorsement by the
AAEM of material contained in the book.
1449
1450 — AAEM GLOSSARY OF TERMS
SECTION I:
ALPHABETICAL LIST O F TERMS W I T H DEFINITIONS
*A wave A compound muscle action potential that follows the afterdischarge 1) The continuation of action potentials in a
M wave, evoked consistently from a muscle by submaximal neuron, axon or muscle fiber following the termination of an
electric stimuli and frequently abolished by supramaximal applied stimulus. 2) The continuation of firing of muscle
stimuli. Its amplitude is similar to that of an F wave, but the action potentials after cessation of voluntary activation, for
latency is more constant. Usually occurs before the F wave, example in myotonia.
but may occur afterwards. Thought to be due to extra dis- afterpotential The membrane potential between the end of the
charges in the nerve, ephapses, or axonal branching. This spike and the time when the membrane potential is restored
term is preferred over axon reflex, axon wave, or axon re- to its resting value. The membrane during this period may be
sponse. Compare with the F wave. depolarized or hyperpolarized at different times.
absolute refractory period See refractory period. akinesia Lack or marked delay of intended movement, often
accommodation In neuronal physiology, a rise in the threshold observed in patients with Parkinson's disease. Often used
transmembrane depolarization required to initiate a spike, synonymously with bradykinesia.
when depolarization is slow or a subthreshold depolari- amplitude With reference to an action potential, the maximum
zation is maintained. In the older literature, the observation voltage difference between two points, usually baseline-to-
that the final intensity of current applied in a slowly rising peak or peak-to-peak. By convention, the amplitude of poten-
fashion to stimulate a nerve was greater than the intensity of tials which have an initial negative deflection from the
a pulse of current required to stimulate the same nerve. The baseline, such as the compound muscle action potential and
latter may largely be an artifact of the nerve sheath and the antidromic sensory nerve action potential are measured
bears little relation to true accommodation as measured from baseline to the most negative peak. In contrast, the am-
intracellularly. plitude of a compound sensory nerve action potential, motor
accommodation curve See strength-duration curve. unit potential, fibrillation potential, positive sharp wave, fas-
acoustic myography The recording and analysis of sounds pro- ciculation potential, and most other action potentials is mea-
duced by contracting muscle. The muscle contraction may be sured from the most positive peak to the most negative peak.
produced by stimulation of the nerve supply to the muscle or amplitude decay The percent change in the amplitude of the M
by volitional activation of the muscle. wave or the compound sensory nerve action potential be-
action potential (AP) The brief regenerative electric potential tween two different stimulation points along the nerve. Decay
that propagates along a single axon or muscle fiber mem- = 100* (amplitude dista , - amp!itude proximal ) / amplitude distal .
brane. An all-or-none phenomenon; whenever the stimulus is Useful in the evaluation of conduction block. Abnormal
at or above threshold, the action potential generated has a decay without increased temporal dispersion may indicate a
constant size and configuration. See also compound action conduction block.
potential, motor unit action potential. anodal block A local block of nerve conduction caused by
activation 1) In physiology, a general term for the initiation of a membrane hyperpolarization under a stimulating anode.
process. 2) The process of motor unit action potential firing. Does not occur in routine clinical studies, since it is possible
The force of muscle contraction is determined by the number for the anode to routinely result in nerve depolarization if
of motor units and their firing rate. sufficient current intensities are used.
activation procedure A technique used to detect defects of anode The positive terminal of an electric current source. See
neuromuscular transmission during repetitive nerve stimula- stimulating electrode.
tion testing. Most commonly a sustained voluntary contrac- antidromic Propagation of a nerve impulse in the direction op-
tion is performed to elicit facilitation or postactivation posite to physiologic conduction; e.g., conduction along
depression. See also tetanic contraction. motor nerve fibers away from the muscle and conduction
active electrode Synonymous with exploring electrode. See along sensory fibers away from the spinal cord. Contrast with
recording electrode. orthodromic.
acute inflammatory neuropathy An acute, monophasic poly- AP Abbreviation for action potential.
neuropathy. Characterized by a time course of progression to artifact (also artefact) A voltage change generated by a bio-
maximum deficit within 4 weeks of onset of symptoms. Most logic or nonbiologic source other than the ones of interest.
common clinical presentation is an ascending sensory-motor The stimulus artifact (or shock artifact) represents cutaneous
neuropathy. Electrodiagnostic studies most commonly reveal spread of stimulating current to the recording electrode and
evidence for demyelination, but axonal degeneration also the delay in return to baseline which is dependent on the abil-
occurs. Distinguish from chronic inflammatory demyelinat- ity of filters to respond to high voltage. Stimulus artifacts
ing polyradiculoneuropathy (CIDP). See also Guillain-Barre may precede or overlap the activity of interest. Movement ar-
syndrome. tifact refers to a change in the recorded activity caused by
adaptation A decline in the frequency of the spike discharge as movement of the recording electrodes.
typically recorded from sensory axons in response to a main- asterixis A quick involuntary movement caused by a brief lapse
tained stimulus. in tonic muscle activation. It can be appreciated only during
ADEMG Abbreviation for automatic decomposition elec- voluntary movement. Is usually irregular, but can be rhythmic
tromyography. and confused with action tremor.
AEP Abbreviation for auditory evoked potential. ataxia Clumsiness of movement. Specific features include
dysmetria (incorrect distance moved) and dysdiadochokine-
* Illustration in Section II sis (irregularity of attempted rhythmic movements). Most
AAEM GLOSSARY OF TERMS — 1451
commonly due to a disorder of the cerebellum or propriocep- bizarre repetitive discharge See preferred term, complex
tive sensory system. Referred to, respectively, as cerebellar repetitive discharge.
ataxia or sensory ataxia, bizarre repetitive potential See preferred term, complex repet-
auditory evoked potential (AEP) Electric waveforms of bio- itive discharge.
logic origin elicited in response to sound stimuli. Classified blink reflex See blink responses.
by their latency as short-latency brainstem auditory evoked *blink responses Compound muscle action potentials evoked
potential (BAEP) with a latency of up to 10 ms, middle- from orbicularis oculi muscles as a result of brief electric or
latency with a latency of 10 to 50 ms, and long-latency with mechanical stimuli applied to the cutaneous area innervated
a latency of over 50 ms. See brainstem auditory evoked by the supraorbital (or less commonly, the infraorbital)
potential. branch of the trigeminal nerve. Typically, there is an early
automatic decomposition EMG (ADEMG) computerized compound muscle action potential (Rl wave) ipsilateral to
method for extracting individual motor unit action potentials the stimulation site with a latency of about 10 ms and a bilat-
from an interference pattern. eral late compound muscle action potential (R2 wave) with a
averager See signal averager. latency of approximately 30 ms. Generally, only the R2 wave
averaging A method for extracting time-locked potentials from is associated with a visible contraction of the muscle. The
random background noise by sequentially adding traces and configuration, amplitude, duration, and latency of the two
dividing by the total number of traces. components, along with the sites of recording and stimula-
axon reflex Use of term discouraged as it is incorrect. No reflex tion, should be specified. The Rl and R2 waves are oligosy-
is thought to be involved. See preferred term, A wave. naptic and polysynaptic brainstem reflexes, respectively.
axon response See preferred term, A wave. Together they are called the blink reflex. The afferent arc is
axon wave See A wave. provided by the sensory branches of the trigeminal nerve and
axonal degeneration Degeneration of the segment of a nerve the efferent arc is provided by facial nerve motor fibers.
distal to the cell body with preferential distal pathology. blocking Term used in single fiber electromyography to de-
axonotmesis Nerve injury characterized by axon and myelin scribe dropout of one or more components of the potential
sheath disruption with supporting connective tissue preserva- during sequential firings. If more than one component drops
tion, resulting in axonal degeneration distal to the injury site. out simultaneously it is described as concomitant blocking.
Compare neurapraxia, neurotmesis. Usually seen when jitter values exceed 80 to 100 ps. A sign
backaveraging Averaging a signal which occurs in a time of abnormal neuromuscular transmission, which may be due
epoch preceding a triggering event. Often used to extract a to primary neuromuscular transmission disorders, such as
time-locked EEG signal preceding voluntary or involuntary myasthenia gravis and other myasthenic syndromes. Also
movement, usually triggered by the onset of the EMG activity seen as a result of degeneration and reinnervation in neu-
of the movement. An example is the Bereitschaftspotential. ropathies or myopathies. Concomitant blocking may be gen-
backfiring Discharge of an antidromically activated motor erated by a split muscle fiber or failure of conduction at an
neuron. axon branch serving several muscle fibers.
BAEP Abbreviation for brainstem auditory evoked potential. BP Abbreviation for Bereitschaftspotential.
BAER Abbreviation for brainstem auditory evoked response. brachial plexus An anatomical structure which is formed by
See preferred term, brain stem auditory evoked potential. the spinal roots from C5 to Tl, traverses the shoulder region,
baseline 1) The potential recorded from a biologic system and culminates in the named peripheral nerves in the arm. It
while the system is at rest. 2) a flat trace on the recording in- is composed of roots, trunks, divisions, cords, and terminal
strument; an equivalent term, isoelectric line, may be used. nerves.
benign fasciculation potential A firing pattern of fasciculation bradykinesia Slowness of movement, often observed in pa-
potentials occurring in association with a clinical syndrome tients with Parkinson's disease. Often used synonymously
of fasciculations in an individual with a nonprogressive neu- with akinesia.
romuscular disorder. Use of term discouraged. ^brainstem auditory evoked potential (BAEP) Electric wave-
BER Abbreviation for brainstem auditory evoked responses. forms of biologic origin elicited in response to sound stimuli.
See preferred term, brainstem auditory evoked potentials. Normally consists of a sequence of up to seven waves, desig-
Bereitschaftspotential (BP) A component of the movement-re- nated I to VII, which occur during the first 10 ms after the
lated cortical potential. The slowly rising negativity in the onset of the stimulus and have positive polarity at the vertex
EEG preceding voluntary movement. The German term of the head.
means "readiness potential". Has two phases called BP1 and brainstem auditory evoked response (BAER, BER) See pre-
BP2 or BP and NS' (negative slope). See backaveraging. ferred term, brainstem auditory evoked potentials.
biphasic action potential An action potential with one base- BSAP Abbreviation for brief, small, abundant potentials. (See
line crossing, producing two phases. BSAPP). Use of term is discouraged.
biphasic end-plate activity See end-plate activity (biphasic). BSAPP Abbreviation for brief, small, abundant, polyphasic po-
^bipolar needle electrode Recording electrode that measures tentials. Used to describe a recruitment pattern of brief dura-
voltage between two insulated wires cemented side-by-side tion, small amplitude, overly abundant, polyphasic motor unit
in a steel cannula. The bare tips of the electrodes are flush action potentials, with respect to the amount of force gener-
with the level of the cannula which may serve as a ground. ated; usually a minimal contraction. Use of term discouraged.
bipolar stimulating electrode See stimulating electrode. Quantitative measurements of motor unit action potential du-
bizarre high-frequency discharge See preferred term, com- ration, amplitude, numbers of phases, and recruitment fre-
plex repetitive discharge. quency are preferred. See motor unit action potential.
carpal tunnel syndrome A mononeuropathy affecting the
* Illustration in Section II median nerve at the wrist. As the nerve passes through the
carpal tunnel, a space bounded dorsally by the bones of the adjacent muscle fibers in a cyclic fashion. This term is pre-
wrist, laterally by the forearm flexor tendons, and volarly by ferred to bizarre high frequency discharge, bizarre repetitive
the transverse carpal ligament, it is subject to compression by discharge, bizarre repetitive potential, pseudomyotonic dis-
any of these structures. Repetitive hand and wrist movement charge, and synchronized fibrillation. See also ephapse and
is thought to contribute to the compression. ephaptic transmission.
C reflex An abnormal reflex response representing the electro- compound action potential A potential or waveform resulting
physiologic correlate of sensory evoked myoclonus. The term from the summation of multiple individual axon or muscle
"C" was chosen to indicate that the reflex might be mediated fiber action potentials. See compound mixed nerve action po-
in the cerebral cortex. This is sometimes, but not always, true. tential, compound motor nerve action potential, compound
c/s (also cps) Abbreviation for cycles per second. See preferred nerve action potential, compound sensory nerve action po-
term, Hertz (Hz). tential, and compound muscle action potential.
cathode The negative terminal of an electric current source. See compound mixed nerve action potential A compound nerve
stimulating electrode. action potential recorded from a mixed nerve when an elec-
center frequency The mean or median frequency of a wave- tric stimulus is applied to a segment of the nerve that contains
form decomposed by frequency analysis. Employed in the both afferent and efferent fibers. The amplitude, latency, du-
study of muscle fatigue. ration, and phases should be noted.
central electromyography Use of electrodiagnostic recording compound motor nerve action potential (compound motor
techniques to study reflexes and the control of movement by NAP) A compound nerve action potential recorded from ef-
the spinal cord and brain. See electrodiagnosis. ferent fibers of a motor nerve or a motor branch of a mixed
central motor conduction The time taken for conduction of nerve. Elicited by stimulation of a motor nerve, a motor
action potentials in the central nervous system from motor branch of a mixed nerve, or a ventral nerve root. The ampli-
cortex to alpha motoneurons in the spinal cord or brainstem. tude, latency, duration, and number of phases should be
Calculated from the latencies of the motor evoked potentials noted. Distinguish from compound muscle action potential.
produced by transcranial magnetic stimulation or transcra- compound muscle action potential (CMAP) The summation
nial electrical stimulation, subtracting the time for peripheral of nearly synchronous muscle fiber action potentials
conduction. recorded from a muscle, commonly produced by stimulation
chorea Clinical term used to describe irregular, random, brief, of the nerve supplying the muscle either directly or indirectly.
abrupt, involuntary movements of the head or limbs due to a Baseline-to-pQak amplitude, duration, and latency of the neg-
disorder of the basal ganglia. Most commonly observed in ative phase should be noted, along with details of the method
patients with Huntington's disease and Sydenham's chorea. of stimulation and recording. Use of specific named poten-
chronaxie (also chronaxy) See strength-duration curve. tials is recommended, e.g., M wave, F wave, H wave, Twave,
chronic inflammatory demyelinating polyradiculoneuropa- A wave, and Rl or R2 wave (blink responses).
thy (CIDP) A polyneuropathy or polyradiculoneuropathy compound nerve action potential (compound NAP) The
characterized by generalized demyelination of the peripheral summation of nearly synchronous nerve fiber action poten-
nervous system. In most cases there is also a component of tials recorded from a nerve trunk, commonly produced by
axonal degeneration. Some cases are associated with a mon- stimulation of the nerve directly or indirectly. Details of the
oclonal gammopathy of undetermined significance (MGUS). method of stimulation and recording should be specified, to-
Distinguish from acute inflammatory neuropathy. gether with the fiber type (sensory, motor, or mixed nerve).
clinical electromyography Term used commonly to describe *compound sensory nerve action potential (compound SNAP)
the scientific methods of recording and analysis of biologic A compound nerve action potential recorded from the afferent
electrical potentials from human peripheral nerve and fibers of a sensory nerve, a sensory branch of a mixed nerve or
muscle. See preferred term, electrodiagnostic medicine. in response to stimulation of a sensory nerve or a dorsal nerve
CMAP Abbreviation for compound muscle action potential. root. May also be elicited when an adequate stimulus is ap-
coaxial needle electrode See synonym, concentric needle plied synchronously to sensory receptors. The amplitude, la-
electrode. tency, duration, and configuration should be noted. Generally,
collision When used with reference to nerve conduction studies, the amplitude is measured as the maximum peak-to-peak
the interaction of two action potentials propagated toward voltage when there is an initial positive deflection or from
each other from opposite directions on the same nerve fiber b<35£///2<?-to-peak when there is an initial negative deflection.
so that the refractory periods of the two potentials prevent The latency is measured as either the time to the initial de-
propagation past each other. flection or the negative peak, and the duration as the interval
complex motor unit action potential A motor unit action po- from the first deflection of the waveform from the baseline to
tential that is polyphasic or serrated. See preferred terms, its final return to the baseline. Also referred to by the less pre-
polyphasic action potential or serrated action potential. ferred terms sensory response, sensory potential, or SNAP.
^complex repetitive discharge A type of spontaneous activity. :i concentric needle electrode Recording electrode that mea-
Consists of a regularly repeating series of complex polyphasic sures an electric potential difference between a centrally in-
or serrated potentials that begin abruptly after needle elec- sulated wire and the cannula of the needle through which it
trode movement or spontaneously. The potentials have a uni- runs.
form shape, amplitude, and discharge frequency ranging conditioning stimulus See paired stimuli.
from 5 to 100 Hz. The discharge typically terminates abruptly. conduction block Failure of an action potential to propagate
May be seen in both myopathic and neurogenic disorders, past a particular point in the nervous system whereas conduc-
usually chronic. Thought to be due to ephaptic excitation of tion is possible below the point of the block. Documented by
demonstration of a reduction in the area of a compound
* Illustration in Section II muscle action potential greater than that normally seen with
stimulation at two different points on a nerve trunk; anatomic neuropathy caused by compression of the nerve as it passes
variations of nerve pathways and technical factors related to through the aponeurosis (the cubital tunnel) of the two heads
nerve stimulation must be excluded as the cause of the reduc- of the flexor carpi uinaris approximately 1.5 to 3.5 cm distal
tion in area. to the medial epicondyle of the elbow. The mechanism of en-
conduction distance The length of nerve or muscle over which trapment is presumably narrowing of the cubital tunnel
conduction is determined, customarily measured in centime- during elbow flexion. See also tardy ulnar palsy and ulnar
ters or millimeters. neuropathy at the elbow.
conduction time See conduction velocity. cutaneous reflex A reflex produced by cutaneous stimulation.
conduction velocity (CV) Speed of propagation of an action There are several phases to cutaneous reflexes, and, if the
potential along a nerve or muscle fiber. The nerve fibers stud- muscle has a background contraction, the phases can be seen
ied (motor, sensory, autonomic, or mixed nerve) should be to be inhibitory as well as excitatory.
specified. For a nerve trunk, the maximum conduction veloc- CV Abbreviation for conduction velocity.
ity is calculated from the latency of the evoked potential cycles per second (c/s, cps) Unit of frequency. See preferred
(muscle or nerve) at maximal or supramaximal intensity of term hertz (Hz).
stimulation at two different points. The distance between the decomposition EMG Synonym for automatic decomposition
two points (conduction distance) is divided by the difference EMG.
between the corresponding latencies (conduction time). The decremental response See preferred term, decrementing
calculated result is the conduction velocity of the fastest response.
fibers and is usually expressed as meters per second (m/s). As *decrementing response A reproducible decline in the ampli-
commonly used, refers to the maximum conduction velocity. tude and/or area of the M wave of successive responses to
By specialized techniques, the conduction velocity of other repetitive nerve stimulation. The rate of stimulation and the
fibers can also be determined and should be specified, e.g., total number of stimuli should be specified. Decrementing re-
minimum conduction velocity. sponses with disorders of neuromuscular transmission are most
congenital myasthenia A heterogeneous group of genetic dis- reliably seen with slow rates (2 to 5 Hz) of nerve stimulation.
orders of the neuromuscular junction manifest by muscle A decrementing response with repetitive nerve stimulation
weakness and fatigue. commonly occurs in disorders of neuromuscular transmission,
contraction A voluntary or involuntary reversible muscle short- but can also be seen in some neuropathies, myopathies, and
ening that may or may not be accompanied by action poten- motor neuron disease. An artifact resembling a decrementing
tials from muscle. Contrast the term contracture. response can result from movement of the stimulating or
contraction fasciculation Clinical term for visible twitching of recording electrodes during repetitive nerve stimulation (see
a muscle with weak voluntary or postural contraction which pseudodecrement). Contrast with incrementing response.
has the appearance of a fasciculation. More likely to occur in delay 1) The time between the beginning of the horizontal
neuromuscular disorders in which the motor unit territory is sweep of the oscilloscope and the onset of an applied stimu-
enlarged and the tissue covering the muscle is thin, but may lus. 2) A synonym for an information storage device (delay
also be observed in normal individuals. line) used to display events occurring before a trigger signal.
contracture 1) Fixed resistance to stretch of a shortened muscle delay line An information storage device used to display events
due to fibrous connective tissue changes and loss of sarcom- which occur before a trigger signal. A method for displaying
eres in the muscle. Limited movement of a joint may be due a waveform at the same point on a sweep from a free-running
to muscle contracture or to fibrous connective tissue changes electromyogram.
in the joint. Contrast with contraction, which is a rapidly re- demyelination Disease process affecting the myelin sheath of
versible painless shortening of the muscle. 2) The prolonged, central or peripheral nerve fibers, manifested by conduction
painful, electrically silent, and involuntary state of temporary velocity slowing, conduction block, or both.
muscle shortening seen in some myopathies (e.g. muscle denervation potential Sometimes used as a synonym for fibril-
phosphorylase deficiency). lation potential. Use of this term is discouraged, since fibril-
coupled discharge See preferred term, satellite potential. lation potentials can occur in the absence of denervation. See
cps (also c/s) Abbreviation for cycles per second. See preferred preferred term, fibrillation potential.
term, Hertz (Hz). depolarization A change in the existing membrane potential
*cramp discharge Involuntary repetitive firing of motor unit to a less negative value. Depolarizing an excitable cell from
action potentials at a high frequency (up to 150 Hz) in a large its resting level to threshold typically generates an action
area of a muscle usually associated with painful muscle con- potential.
traction. Both discharge frequency and number of motor unit depolarization block Failure of an excitable cell to respond to
action potentials activated increase gradually during develop- a stimulus due to pre-existing depolarization of the cell
ment, and both subside gradually with cessation. See muscle membrane.
cramp. depth electrodes Electrodes which are inserted into the sub-
crossed leg palsy Synonym for peroneal neuropathy at the knee. stance of the brain for electrophysiological recording. Most
cross talk 1) A general term for abnormal communication be- often inserted using stereotactic techniques.
tween excitable membranes. See ephapse and ephaptic trans- dermatomal somatosensory evoked potential (DSEP) Scalp
mission. 2) Term used in kinesiologic EMG for signals picked recorded waveforms generated from repeated stimulation of a
up from adjacent muscles. specific dermatome. Different from typical somatosensory
cubital tunnel syndrome A mononeuropathy involving the evoked potentials which are recorded in response to stimula-
ulnar nerve in the region of the elbow. An entrapment tion of a named peripheral nerve.
discharge The firing of one or more excitable elements (neu-
* Illustration in Section II rons, axons, or muscle fibers); as conventionally used,
refers to all-or-none potentials only. Synonymous with action electrocorticography Electrophysiologic recording directly
potential. from the surface of the brain. In the intraoperative setting,
discharge frequency The rate at which a potential discharges recordings are made of ongoing spontaneous electro-
repetitively. When potentials occur in groups, the rate of re- encephalogram activity, or potentials evoked by stimulation
currence of the group and rate of repetition of the individual of peripheral sensory pathways.
components in the groups should be specified. See also firing electrode A conducting device used to record an electric poten-
rate. tial {recording electrode) or to deliver an electric current
discrete activity See inteiference pattern. (stimulating electrode). In addition to the ground electrode
distal latency The interval between the delivery of a stimulus to used in clinical recordings, two electrodes are always re-
the most distal point of stimulation on a nerve and the onset quired either to record an electric potential or to deliver a
of a response. A measure of the conduction properties of the stimulus. See ground electrode, recording electrode, and
distal most portion of motor or sensory nerves. See motor la- stimulating electrode. Also see specific needle electrode con-
tency and sensory latency. figurations: monopolar, unipolar, concentric, bifilar record-
double discharge Two sequential firings of a motor unit action ing, bipolar stimulating, multilead, single fiber, and
potential of the same form and nearly the same amplitude, macro-EMG needle electrodes.
occurring consistently in the same relationship to one another electrodiagnosis (EDX) The scientific methods of recording
at intervals of 2 to 20 ms. See also multiple discharge, triple and analyzing biologic electrical potentials from the central,
discharge. peripheral, and autonomic nervous systems and muscles. See
doublet Synonym for the preferred term, double discharge. also clinical electromyography, electromyography, elec-
DSEP Abbreviation for dermatomal somatosensory evoked troneurography, electroneuromyography, evoked potentials,
potential. electrodiagnostic medicine, electrodiagnostic medicine con-
duration The time during which something exists or acts. 1) sultation, and electrodiagnostic medicine consultant.
The interval from the beginning of the first deflection from electrodiagnostic medicine A specific area of medical practice
the baseline to its final return to the baseline of an action po- in which a physician integrates information obtained from the
tential or waveform, unless otherwise specified. If only part clinical history, observations from physical examination, and
of the waveform is measured, the points of the measurement scientific data acquired by recording electrical potentials
should be specified. For example, the duration of the M wave from the nervous system and muscle to diagnose, or diagnose
may be measured as the negative phase duration and refers to and treat diseases of the central, peripheral, and autonomic
the interval from the deflection of the first negative phase nervous systems, neuromuscular junctions, and muscle. See
from the baseline to its return to the baseline. 2) The interval also electrodiagnosis, electrodiagnostic medicine consulta-
of the applied current or voltage of a single electric stimulus. tion, and electrodiagnostic medicine consultant.
3) The interval from the beginning to the end of a series of re- electrodiagnostic medicine consultant A physician specially
curring stimuli or action potentials. trained to obtain a medical history, perform a physical exami-
dynamic EMG See kinesiologic EMG. nation, and to record and analyze data acquired by recording
dyskinesia An abnormal involuntary movement of a choreic or electrical potentials from the nervous system and muscle to
dystonic type. The term is nonspecific and is often used in as- diagnose and/or treat diseases of the central, peripheral, and
sociation with a modifier that describes its etiology, e.g. tar- autonomic nervous systems, neuromuscular junction, and
dive dyskinesia or L-DOPA dyskinesia. muscle. See also electrodiagnosis, electrodiagnostic medi-
dystonia A disorder characterized by involuntary movements cine, and electrodiagnostic medicine consultation.
caused by sustained muscle contraction, producing pro- electrodiagnostic medicine consultation The medical evalua-
longed movements or abnormal postures. tion in which a specially trained physician (electrodiagnos-
E-l Synonymous with input tenninal J. See recording electrode. tic medicine consultant) obtains a medical history, performs
E-2 Synonymous with input terminal 2. See recording electrode. a physical examination, and integrates scientific data ac-
E:I ratio In autonomic testing, the ratio of the longest electro- quired by recording electrical potentials from the nervous
cardiographic R-R interval during expiration to the shortest system and muscle to diagnose and/or treat diseases of the
during inspiration. Primarily a measure of parasympathetic central, peripheral, and autonomic nervous systems, neuro-
control of heart rate. muscular junction, and muscle. See also electrodiagnosis,
early recruitment A recruitment pattern which occurs in asso- electrodiagnostic medicine, and electrodiagnostic medicine
ciation with a reduction in the number of muscle fibers per consultant.
motor unit or when the force generated by the fibers is re- electromyogram The record obtained by electromyography.
duced. At low levels of muscle contraction more motor unit electromyograph Equipment used to activate, record, process,
action potentials are recorded than expected, and a. full inter- and display electrical potentials for the purpose of evaluating
ference pattern may be recorded a relatively low levels of the function of the central, peripheral, and autonomic nervous
muscle contraction. Most often encountered in myopathy. systems, neuromuscular junction, and muscles.
earth electrode Synonymous with ground electrode. electromyographer See preferred term, electrodiagnostic med-
EDX Abbreviation for electrodiagnosis. Can also be used for icine consultant.
electrodiagnostic and electrodiagnostic medicine. electromyography (EMG) Strictly defined, the recording and
electric inactivity See preferred term, electric silence. study of insertion, spontaneous, and voluntary activity of
electric silence The absence of measurable electric activity due muscle with a recording electrode (either a needle elec-
to biologic or nonbiologic sources. The sensitivity and signal- trode for invasive EMG or a surface electrode for kinesio-
to-noise level of the recording system should be specified. logic studies). The term is also commonly used to refer to an
electrodiagnostic medicine consultation, but its use in this
* Illustration in Section II context is discouraged.
electroneurography (ENG) The recording and study of the a discrete area of the brain, spinal cord, or muscle. See audi-
action potentials of peripheral nerve. Synonymous with tory evoked potential, brainstem auditory evoked potential,
nerve conduction studies. spinal evoked potential, somatosensory evoked potential,
electroneuromyography (ENMG) The combined studies of visual evoked potential, compound muscle action potential,
electromyography and electroneurography. Synonymous and compound sensoiy nerve action potential.
with clinical electromyography. See preferred term electro- evoked potential studies Recording and analysis of electric
diagnostic medicine consultation. waveforms of biologic origin elicited in response to electri-
EMG Abbreviation for electromyography. cal, magnetic, or physiological stimuli. Stimuli are applied
*end-plate activity Spontaneous electric activity recorded with to specific motor or sensory receptors, and the resulting
a needle electrode close to muscle end plates. These poten- waveforms are recorded along their anatomic pathways in the
tials may have several different morphologies. peripheral and central nervous system. A single motor or sen-
1. Monophasic: Low-amplitude (10 to 20 uV), short-dura- sory modality is typically tested in a study, and the modality
tion (0.5 to 1.0 ms), negative potentials occurring in a studied is used to define the type of study performed. See au-
dense, steady pattern, the exact frequency of which cannot ditory evoked potentials, brainstem auditory evoked poten-
be defined. These nonpropagated potentials are probably tials, visual evoked potentials, and somatosensory evoked
miniature end-plate potentials recorded extracellularly. potentials.
Referred to as end-plate noise or sea-shell sound (sea evoked response Tautology. Use of term discouraged. See pre-
shell roar or noise). ferred term, evoked potential.
2. Biphasic: Moderate-amplitude (100 to 300 uV), short-du- excitability Capacity to be activated by or react to a stimulus.
ration (2 to 4 ms), initially negative spike potentials occur- excitatory postsynaptic potential (EPSP) A local, graded de-
ring irregularly in short bursts with a high frequency (50 polarization of a neuron in response to activation by a nerve
to 100 Hz). These propagated potentials are generated by terminal. Contrast with inhibitory postsynaptic potential.
muscle fibers excited by activity in nerve terminals. These exploring electrode Synonymous with active electrode. See
potentials have been referred to as biphasic spike poten- recording electrode.
tials, end-plate spikes, and, incorrectly, nerve potentials. F reflex An incorrect term for F wave.
May also have a biphasic initially positive morphology. F response Synonymous with F wave. See preferred term, F
3. Triphasic: Similar to biphasic potentials, but the waveforms wave.
have three phases with an initial positive deflection. Fire *F wave An action potential evoked intermittently from a
in an irregular fashion; contrast with fibrillation potential. muscle by a supramaximal electric stimulus to the nerve due
end-plate noise See end-plate activity (monophasic). to antidromic activation of motor neurons. When compared
end-plate potential (EPP) The graded nonpropagated mem- with the maximal amplitude of the M wave, it is smaller (1 to
brane potential induced in the postsynaptic membrane of a 5% of the M wave) and has a variable configuration. Its la-
muscle fiber by release of acetylcholine from the presynaptic tency is longer than the M wave and is variable. It can be
axon terminal in response to an action potential. evoked in many muscles of the upper and lower extremities,
end-plate spike See end-plate activity (biphasic). and the latency is longer with more distal sites of stimulation.
end-plate zone The region in a muscle where neuromuscular Named " F ' wave by Magladery and McDougal in 1950, be-
junctions are concentrated. cause it was first recorded from foot muscles. Compare with
ENG Abbreviation for electroneurography. the H wave and the A wave. One of the late responses.
ENMG Abbreviation for electroneuromyography. facial neuropathy Clinical diagnosis of facial weakness or
entrapment neuropathy A mononeuropathy caused by com- paralysis due to pathology affecting the seventh cranial nerve
pression of a nerve as it passes through an area of anatomical (facial nerve). Bell's palsy refers to a facial neuropathy due
narrowing. to inflammation of the facial nerve.
ephapse A point of abnormal communication where an action * facilitation An increase in an electrically measured response
potential in one muscle fiber or axon can cause depolariza- following identical stimuli. Occurs in a variety of circum-
tion of an adjacent muscle fiber or axon to generate an action stances: 1) Improvement of neuromuscular transmission re-
potential. sulting in activation of previously inactive muscle fibers.
ephaptic transmission The generation of a nerve fiber action May be identified in several ways: Incrementing response—a
potential from one muscle fiber or axon to another through an reproducible increase in the amplitude and area of successive
ephapse. Postulated to be the basis for complex repetitive dis- M waves during repetitive nerve stimulation. Postactivation
charges, myokymic discharges, and hemifacial spasm. or posttetanic facilitation—Nerve stimulation studies per-
EPSP Abbreviation for excitatory postsynaptic potential. formed within a few seconds after a brief period (2 to 60 s) of
Erb's point The site at the anterolateral base of the neck where nerve stimulation producing tetanus or after a strong volun-
percutaneous nerve stimulation activates the axons compris- tary contraction may show changes in the configuration of
ing the upper trunk of the brachial plexus. the M wave(s) compared to the results of identical studies of
Erb's point stimulation Percutaneous supraclavicular nen>e the rested muscle as follows: a) repair of the decrement—A
stimulation during which the upper trunk of the brachial diminution of the decrementing response with slow rates (2
plexus is activated. See the more general and preferred term, to 5 Hz) of repetitive nerve stimulation; b) increment after ex-
supraclavicular nerve stimulation. ercise—an increase in the amplitude and area of the M wave
evoked potential Electric waveform elicited by and temporally elicited by a single supramaximal stimulus. Distinguish from
related to a stimulus, most commonly an electric stimulus pseudofacilitation, which occurs in normal individuals in re-
delivered to a sensory receptor or nerve, or applied directly to sponse to repetitive nerve stimulation at high rates (20 to 50
Hz) or after strong volitional contraction. It probably reflects
* Illustration in Section II a reduction in the temporal dispersion of the summation of a
constant number of muscle fiber action potentials and is char- roof." In addition to this classic form, positive sharp waves
acterized by an increase in the amplitude of the successive M may also be recorded from fibrillating muscle fibers when the
waves with a corresponding decrease in their duration. There potential arises from an area immediately adjacent to the
is no net change in the area of the negative phase of succes- needle electrode.
sive M waves. 2) An increase in the amplitude of the motor firing pattern Qualitative and quantitative descriptions of the
evoked potential as a result of background muscle activation. sequence of discharge of electric waveforms recorded from
far-field A region of electrical potential where the isopotential muscle or nerve.
voltage lines associated with a current source change slowly firing rate Frequency of repetition of a potential. The relation-
over a short distance. Some use the term far-field potential to ship of the frequency to the occurrence of other potentials
designate a potential that does not change in latency, ampli- and the force of muscle contraction may be described. See
tude, or polarity over infinite distances; alternative designa- also discharge frequency.
tions include "boundary potential" and "junctional potential". flexor reflex A reflex produced by a noxious cutaneous stimu-
The terms near-field and far-field are arbitrary designations lus, or a train of electrical stimuli, that activates the flexor
as there are no agreed-upon criteria defining where the near- muscles of a limb and thus acts to withdraw it from the stim-
field ends and the far-field begins. Compare with near-field. ulus. In humans, it is well-characterized only in the lower
fasciculation The random, spontaneous twitching of a group of extremity.
muscle fibers belonging to a single motor unit. The twitch frequency Number of complete cycles of a repetitive waveform
may produce movement of the overlying skin (if in limb or in 1 second. Measured in hertz (Hz) or cycles per second (cps
trunk muscles) or mucous membrane (if in the tongue). If the or c/s).
motor unit is sufficiently large, an associated joint movement frequency analysis Determination of the range of frequencies
may be observed. The electric activity associated with the composing a waveform, with a measurement of the absolute
twitch is termed & fasciculation potential. See also myokymia. or relative amplitude of each component frequency.
Historically, the term fibrillation was used incorrectly to de- full interference pattern See interference pattern.
scribe fine twitching of muscle fibers visible through the skin *full wave rectified EMG The absolute value of a raw EMG
or mucous membranes. This usage is no longer accepted. signal. Involves inverting all the waveforms below the iso-
^fasciculation potential The electric activity associated with a potential line and displaying them with opposite polarity
fasciculation which has the configuration of a motor unit ac- above the line. A technique used to analyze kinesiologic
tivation potential but which occurs spontaneously. Most EMG signals.
commonly occur sporadically and are termed "single fascicu- functional refractory period See refractory period.
lation potentials." Occasionally the potentials occur as a G l , G 2 Abbreviation for grid 1 and grid 2.
grouped discharge and are termed a "brief repetitive dis- generator In volume conduction theory, the source of electrical
charged The repetitive firing of adjacent fasciculation poten- activity, such as an action potential. See far-field and near-
tials, when numerous, may produce an undulating movement field.
of muscle (see myokymia). Use of the terms benign fascicula- "giant" motor unit action potential Use of term discouraged.
tion and malignant fasciculation is discouraged. Instead, the Refers to a motor unit action potential with a peak-to-peak
configuration of the potentials, peak-to-peak amplitude, du- amplitude and duration much greater than the range found in
ration, number of phases, stability of configuration, and fre- corresponding muscles in normal subjects of similar age.
quency of occurrence, should be specified. Quantitative measurements of amplitude and duration are
fatigue A state of depressed responsiveness resulting from ac- preferable.
tivity. Muscle fatigue is a reduction in contraction force fol- giant somatosensory evoked potential Enlarged somatosen-
lowing repeated voluntary contraction or electric stimulation. sory evoked potentials seen as a characteristic of cortical
fiber density 1) Anatomically, a measure of the number of reflex myoclonus and reflecting cortical hyperexcitability.
muscle or nerve fibers per unit area. 2) In single fiber elec- grid 1 Synonymous with Gl, input terminal 1 (E-l), or active
tromyography, the mean number of muscle fiber action po- or exploring electrode. Use of the term Gl is discouraged.
tentials fulfilling amplitude and rise time criteria belonging See recording electrode.
to one motor unit within the recording area of a single fiber grid 2 Synonymous with G2, input terminal 2 (E-2), or refer-
needle electrode encountered during a systematic search in a ence electrode. Use of the term Grid 2 is discouraged. See
weakly, voluntarily contracting muscle. See also single fiber recording electrode.
electromyography, single fiber needle electrode. ground electrode A connection from the patient to earth. Used
fibrillation The spontaneous contractions of individual muscle as a common return for an electric circuit and as an arbitrary
fibers which are not visible through the skin. This term has zero potential reference point.
been used loosely in electromyography for the preferred grouped discharge Term used historically to describe three
term, fibrillation potential. phenomena: (1) irregular, voluntary grouping of motor unit
^fibrillation potential The action potential of a single muscle action potentials as seen in a tremulous muscular contrac-
fiber occurring spontaneously or after movement of a needle tion, (2) involuntary grouping of motor unit action potentials
electrode. Usually fires at a constant rate. Consists of biphasic as seen in myokymia, (3) general term to describe repeated
or triphasic spikes of short duration (usually less than 5 ms) firing of motor unit action potentials. See preferred term,
with an initial positive phase and a peak-to-peak amplitude of repetitive discharge.
less than 1 mV. May also have a biphasic, initially negative Guillain-Barre syndrome Eponym for acute inflammatory
phase when recorded at the site of initiation. It has an associ- neuropathy. Also referred to as Landry-Guillain-Barre syn-
ated high-pitched regular sound described as "rain on a tin drome or Landry-Guillain-Barre-Strohl syndrome.
H reflex Abbreviation for Hoffmann reflex. See H wave.
* Illustration in Section II H response See preferred term H wave.
*H wave A compound muscle action potential with a consistent disorders, the configuration of the M wave may change with
latency recorded from muscles after stimulation of the nerve. repetitive nerve stimulation so that the amplitude and the area
Regularly found in adults only in a limited group of physio- of the M wave progressively increase. This phenomenon is
logic extensors, particularly the calf muscles. Compared to termed facilitation. Contrast with decrementing response.
the M wave of the same muscle, has a longer latency and thus indifferent electrode Synonymous with reference electrode.
is one of the late responses (see A and F wave). Most reliably Use of term discouraged. See recording electrode.
elicited with a stimulus of long duration (500 to 1000 ps). A infraclavicular plexus Segments of the brachial plexus infe-
stimulus intensity sufficient to elicit a maximal amplitude M rior to the divisions; includes the three cords and the terminal
wave reduces or abolishes the H wave. Thought to be due to a peripheral nerves. This clinically descriptive term is based on
spinal reflex, with electric stimulation of afferent fibers in the the fact that the clavicle overlies the divisions of the brachial
mixed nerve and activation of motor neurons to the muscle plexus when the arm is in the anatomic position next to the
mainly through a monosynaptic connection in the spinal body.
cord. The latency is longer with more distal sites of stimula- inhibitory postsynaptic potential (IPSP) A local graded hy-
tion. The reflex and wave are named in honor of Hoffman's perpolarization of a neuron in response to activation at a
description (1918). Compare the F wave and A wave. synapse by a nerve terminal. Contrast with excitatory postsy-
habituation Decrease in size of a reflex motor response to an naptic potential.
afferent stimulus when the latter is repeated, especially at reg- injury potential 1) The potential difference between a normal
ular and recurring short intervals. region of the surface of a nerve or muscle and a membrane
hemifacial spasm Clinical condition characterized by frequent, region that has been injured; also called a "demarcation," or
repetitive, unilateral, involuntary contractions of the facial "killed end" potential. Approximates the potential across the
muscles. Electrodiagnostic studies demonstrate brief dis- membrane, because the injured surface has nearly the same
charges of groups of motor unit action potentials occurring potential as the interior of the cell. 2) In electrodiagnostic
simultaneously in several facial muscles. Occasionally high medicine, the term is also used to refer to the electrical activ-
frequency discharges occur. ity associated with needle electrode insertion into muscle.
hertz (Hz) Unit of frequency. Synonymous with cycles per See preferred terms fibrillation potential, insertion activity,
second. and positive sharp wave.
Hoffmann reflex See H wave. input terminal 1 The input terminal of a differential amplifier at
hyperekplexia Clinical condition characterized by exaggerated which negativity, relative to the other input terminal, produces
startle reflexes. Startle reflexes can be exaggerated by being an upward deflection. Synonymous with active or exploring
more extreme than expected (larger amplitude or more wide- electrode, E-l or less preferred term, grid 1. See recording
spread) or by lack of normal habituation to repeated similar electrode.
stimuli. Can be either genetic or acquired. input terminal 2 The input of a differential amplifier at which
hyperpolarization A change in the existing membrane poten- negativity, relative to the other input terminal, produces a
tial to a more negative value. downward deflection. Synonymous with reference electrode,
hypertonia See tone. E-2 or less preferred term, grid 2. See recording electrode.
hypotonia See tone. insertion activity Electric activity caused by insertion or
Hz Abbreviation for hertz. movement of a needle electrode within a muscle. The amount
impulse blocking See blocking. of the activity may be described as normal, reduced, or in-
inching A nerve conduction study technique consisting of ap- creased (prolonged), with a description of the waveform and
plying stimuli at multiple short distance increments along the repetition rate. See also fibrillation potential and positive
course of a nerve. This technique is used to localize an area sharp wave.
of focal slowing or conduction block. integrated EMG Mathematical integration of the full wave rec-
incomplete activation Motor unit action potentials firing, on tified EMG signal. Reflects the cumulative EMG activity of a
requested maximal effort, in decreased numbers at their muscle over time. See also linear envelope EMG.
normal physiological rates, within the basal firing range of 5 interdischarge interval Time between consecutive discharges
to 10 Hz. Causes include upper motor neuron syndrome, pain of the same potential. Measurements should be made be-
on muscle contraction, hysteria/conversion reaction and ma- tween the corresponding points on each waveform.
lingering. Contrast with reduced recruitment. interference Unwanted electric activity recorded from the sur-
increased insertion activity See insertion activity. rounding environment.
increment after exercise See facilitation. interference pattern Electric activity recorded from a muscle
incremental response See preferred term, incrementing re- with a needle electrode during maximal voluntary effort. A
sponse. full interference pattern implies that no individual motor unit
încrementing response A reproducible increase in amplitude action potentials can be clearly identified. A reduced interfer-
and/or area of successive M waves to repetitive nerve stimula- ence pattern (intermediate pattern) is one in which some of the
tion. The rate of stimulation and the number of stimuli should individual motor unit action potentials may be identified while
be specified. Commonly seen in two situations. First, in normal others cannot due to superimposition of waveforms. The term
subjects the configuration of the M wave may change in re- discrete activity is used to describe the electric activity
sponse to repetitive nerve stimulation so that the amplitude recorded when each of several different motor unit action po-
progressively increases as the duration decreases, leaving the tentials can be identified in an ongoing recording due to lim-
area of the M wave unchanged. This phenomenon is termed ited superimposition of waveforms. The term single unit
pseudofacilitation. Second, in neuromuscular transmission pattern is used to describe a single motor unit action potential,
firing at a rapid rate (should be specified) during maximum
* Illustration in Section II voluntary effort. The force of contraction associated with the
interference pattern should be specified. See also early re- kinesiologic E M G The muscle electrical activity recorded
cruitment, recruitment pattern, reduced recruitment pattern. during movement. Gives information about the timing of
interference pattern analysis Quantitative analysis of the in- muscle activity and its relative intensity. Either surface elec-
terference pattern. This can be done either in the frequency trodes or intramuscular fine wire electrodes are used. Synon-
domain using fast Fourier transformation (FFT) or in the time ymous with dynamic EMG.
domain. Can be done using a fixed load (e.g. 2 kg), at a given kinesiology The study of movement. See kinesiologic EMG.
proportional strength (e.g. 30% of maximum) or at random kinetics The internal and external forces affecting the moving
strengths. The following are measured in the time domain: a) v body. See kinesiologic EMG.
the number of turns per second and b) the amplitude, defined late component (of a motor unit action potential) See pre-
as the mean amplitude between peaks. ferred term, satellite potential.
intermediate interference pattern See interference pattern. late response A general term used to describe an evoked poten-
international 10-20 system A system of electrode placement tial in motor nerve conduction studies having a longer la-
on the scalp in which electrodes are placed either 10% or tency than the M wave. Examples include A wave, F wave,
20% of the total distance on a line on the skull between the and H wave.
nasion and inion in the sagittal plane and between the right latency Interval between a stimulus and a response. The onset
and left preauricular points in the coronal plane. latency is the interval between the onset of a stimulus and the
interpeak interval Difference between the peak latencies of onset of the evoked potential. The peak latency is the interval
two components of a waveform. between the onset of a stimulus and a specified peak of the
interpotential interval Time between two different potentials. evoked potential.
Measurement should be made between the corresponding latency of activation The time required for an electric stimulus
parts of each waveform. to depolarize a nerve fiber (or bundle of fibers as in a nerve
intraoperative monitoring The use of electrophysiological trunk) beyond threshold and to initiate an action potential in
stimulating and recording techniques in an operating room the fiber(s). This time is usually of the order of 0.1 ms or less.
setting. The term is usually applied to techniques which are An equivalent term, now rarely used, is the "utilization time".
used to detect injury to nervous tissue during surgery or to latent period See preferred term, latency.
guide the surgical procedure. linear envelope E M G Moving average of the full wave recti-
involuntary activity Motor unit action potentials that are not fied EMG. Obtained by low pass filtering the full wave recti-
under volitional control. The condition under which they fied EMG. See also integrated EMG.
occur should be described, e.g., spontaneous or reflex poten- linked potential See preferred term, satellite potential.
tials. If elicited by a stimulus, its nature should be described. lipoatrophy Pathologic loss of subcutaneous fat and connective
Contrast with spontaneous activity. tissues overlying muscle which mimics the clinical appear-
IPSP Abbreviation for inhibitory postsynaptic potential. ance of atrophy of the underlying muscle.
irregular potential See preferred term, serrated action potential. long-latency reflex A reflex with many synapses (polysynaptic)
isoelectric line In electrophysiologic recording, the display of or a long pathway (long-loop) so that the time to its occur-
zero potential difference between the two input terminals of rence is greater than the time of occurrence of short-latency
the recording apparatus. See baseline. reflexes. See also long-loop reflex.
iterative discharge See preferred term, repetitive discharge. long-loop reflex A reflex thought to have a circuit that extends
jiggle Shape variability of motor unit action potentials recorded above the spinal segment of the sensory input and motor
with a conventional EMG needle electrode. A small amount output. May involve the cerebral cortex. Should be differenti-
occurs normally. In conditions of disturbed neuromuscular ated from reflexes arising from stimulation and recording
transmission, including early reinnervation and myasthenic within a single or adjacent spinal segments (i.e., a segmental
disorders, the variability can be sufficiently large to be easily reflex). See also long-latency reflex.
detectable by eye. Quantitative methods for estimating this M response See preferred term, M wave.
variability are not yet widely available. *M wave A compound muscle action potential evoked from a
*jitter The variability of consecutive discharges of the inter- muscle by an electric stimulus to its motor nerve. By conven-
potential interval between two muscle fiber action potentials tion, the M wave elicited by a supramaximal stimulus is used
belonging to the same motor unit. Usually expressed quan- for motor nerve conduction studies. Ideally, the recording
titatively as the mean value of the difference between the in- electrodes should be placed so that the initial deflection of
terpotential intervals of successive discharges (the mean the evoked potential from the baseline is negative. Common
consecutive difference, MCD). Under certain conditions, it is measurements include latency, amplitude, and duration. Also
expressed as the mean value of the difference between inter- referred to as the motor response. Normally, the configura-
potential intervals arranged in the order of decreasing inter- tion is biphasic and stable with repeated stimuli at slow rates
discharge intervals (the mean sorted difference, MSD). See (1 to 5 Hz). See repetitive nerve stimulation.
single fiber electromyography. macro motor unit action potential The average electric activity
Jolly Test A technique named for Friedrich Jolly, who applied of that part of an anatomic motor unit that is within the record-
an electric current to excite a motor nerve repetitively while ing range of a macro-EMG electrode. Characterized by it con-
recording the force of muscle contraction. Use of the term is sistent appearance when the small recording surface of the
discouraged. Inappropriately used to describe the technique macro-EMG electrode is positioned to record action potentials
of repetitive nerve stimulation. from one muscle fiber. The following characteristics can be
kinematics Technique for description of body movement with- specified quantitatively: (1) maximal peak-to-peak amplitude,
out regard to the underlying forces. See kinesiologic EMG. (2) area contained under the waveform, (3) number of phases.
macro MUAP Abbreviation for macro motor unit action
Illustration in Section II potential.
AAEM GLOSSARY OF TERMS — I4S9
*macroelectromyography (macro-EMG) General term refer- cathode in nerve conduction studies with another electrode
ring to the technique and conditions that approximate record- serving as an anode.
ing of all muscle fiber action potentials arising from the same motor evoked potential (MEP) A compound muscle action po-
motor unit. See macro motor unit action potential. tential produced by either transcranial magnetic stimulation
macro-EMG Abbreviation for macroelectromyography. or transcranial electrical stimulation.
macro-EMG needle electrode A modified single fiber elec- motor latency Interval between the onset of a stimulus and the
tromyography electrode insulated to within 15 mm from the onset of the resultant compound muscle action potential (M
tip and with a small recording surface (25 urn in diameter) wave). The term may be qualified, as proximal motor latency
7.5 mm from the tip. or distal motor latency, depending on the relative position of
malignant fasciculation Used to describe large, polyphasie/as- the stimulus.
ciculation potentials firing at a slow rate. This pattern has motor nerve A nerve containing axons which innervate extra-
been seen in progressive motor neuron disease, but the rela- fusal and intrafusal muscle fibers. These nerves also contain
tionship is not exclusive. Use of this term is discouraged. See sensory afferent fibers from muscle and other deep structures.
fasciculation potential. motor nerve conduction velocity (MNCV) The speed of prop-
maximal stimulus See stimulus. agation of action potentials along a motor nerve. See conduc-
maximum conduction velocity See conduction velocity. tion velocity.
MCD Abbreviation for mean consecutive difference. See jitter. motor neuron disease A clinical condition characterized by de-
mean consecutive difference (MCD) See jitter. generation of motor nerve cells in the brain, brain stem, and
mean sorted difference (MSD) See jitter. spinal cord. The location of degeneration determines the clin-
membrane instability Tendency of a cell membrane to depo- ical presentation. Primary lateral sclerosis occurs when de-
larize spontaneously in response to mechanical irritation or generation affects mainly corticospinal tract motor fibers.
following voluntary activation. May be used to describe the Spinal muscular atrophy occurs when degeneration affects
occurrence of spontaneous single muscle fiber action poten- lower motor neurons. Amyotrophic lateral sclerosis occurs
tials such as fibrillation potentials during needle electrode when degeneration affects both corticospinal tracts and lower
examination. motor neurons.
MEP Abbreviation for motor evoked potential. motor point The site over a muscle where its contraction may
MEPP Abbreviation for miniature end-plate potential. be elicited by a minimal intensity short duration electric stim-
microneurography The technique of recording peripheral ulus.
nerve action potentials in humans by means of intraneural motor response 1) The compound muscle action potential (M
electrodes. wave) recorded over a muscle in response to stimulation of
miniature end-plate potential (MEPP) The postsynaptic the nerve to the muscle. 2) The muscle twitch or contraction
muscle fiber potentials produced through the spontaneous re- elicited by stimulation of the nerve to a muscle. 3) The
lease of individual acetylcholine quanta from the presynaptic muscle twitch elicited by the muscle stretch reflex.
axon terminal. As recorded with monopolar or concentric motor unit The anatomic element consisting of an anterior horn
needle electrodes inserted in the end-plate region, MEPPs are cell, its axon, the neuromuscular junctions, and all of the
monophasic, negative, short duration (less than 5 ms), and muscle fibers innervated by the axon.
generally less than 20 uV in amplitude. * motor unit action potential (MUAP) The compound action
minimum conduction velocity The nerve conduction velocity potential of a single motor unit whose muscle fibers lie
measured from slowly conducting nerve fibers. Special tech- within the recording range of an electrode. With voluntary
niques are needed to produce this measurement in motor or muscle contraction, it is characterized by its consistent ap-
sensory nerves. pearance, and relationship to the force of the contraction. The
mixed nerve A nerve composed of both motor and sensory following measures may be specified, quantitatively if possi-
axons. ble, after the recording electrode is placed randomly within
MNCV Abbreviation for motor nerve conduction velocity. See the muscle:
conduction velocity. 1. Configuration
mononeuritis multiplex A disorder characterized by axonal a. Amplitude, peak-to-peak (uV or mV).
injury and/or demyelination affecting nerve fibers in multiple b. Duration, total (ms).
nerves (multiple mononeuropathies). Usually occurs in an c. Number of phases (monophasic, biphasic, triphasic,
asymmetric anatomic distribution and in a temporal sequence tetraphasic, polyphasic).
which is not patterned or symmetric. d. Polarity of each phase (negative, positive).
mononeuropathy multiplex A disorder characterized by e. Number of turns.
axonal injury and/or demyelination affecting nerve fibers ex- f. Variation of shape (jiggle), if any, with consecutive dis-
clusively along the course of one named nerve. charges.
monophasic action potential An action potential with the g. Presence of satellite (linked) potentials, if any.
waveform entirely on one side of the baseline. h. Spike duration, including satellites.
monophasic end-plate activity See end-plate activity 2. Recruitment characteristics
(monophasic). a. Threshold of activation (first recruited, low threshold,
^monopolar needle electrode A solid wire electrode coated high threshold).
with Teflon™, except at the tip. Despite the term monopolar, b. Onset frequency.
a separate surface or subcutaneous reference electrode is re- c. Recruitment frequency (Hz) or recruitment interval
quired for recording electric signals. May also be used as a (ms) of individual potentials.
Descriptive terms implying diagnostic significance are not
* Illustration in Section 11 recommended, e.g. myopathic, neuropathic, regeneration,
nascent, giant, BSAP and BSAPP. See polyphasic action po- muscle fiber action potential Action potential recorded from a
tential, serrated action potential. single muscle fiber.
motor unit fraction See scanning EMG. muscle fiber conduction velocity The speed of propagation of
motor unit number counting See the preferred term motor a single muscle fiber action potential, usually expressed as
unit number estimate (MUNE). meters per second. Usually less than most nerve conduction
motor unit number estimate (MUNE) A quantitative tech- velocities, varies with the rate of discharge of the muscle
nique for determining the number of functioning motor units fiber, and requires special techniques for measurement.
in a muscle. A variety of methods, including spfe-triggered muscle hypertrophy Increase in the size of a muscle due to an
averaging, incremental motor nerve stimulation, F-wave increase in the size of the muscle fibers or replacement or dis-
measurement, or a Poisson statistical technique can be used. placement of muscle fibers by other tissues. The latter is also
Synonyms can include motor unit number estimation and referred to by the term pseudohypertrophy, because the
motor unit number estimating. muscle is enlarged but weak. Muscle fibers increase in size as
motor unit number estimating (MUNE) See motor unit a physiologic response to repetitive and forceful voluntary
number estimate (MUNE). contraction or as a pathologic response to involuntary elec-
motor unit number estimation (MUNE) See motor unit tric activity in a muscle, for example, myotonic discharges or
number estimate (MUNE). complex repetitive discharges.
motor unit potential (MUP) See synonym, motor unit action muscle stretch reflex Activation of a muscle which follows
potential. stretch of the muscle, e.g. by percussion of a muscle tendon.
motor unit territory The area of a muscle cross-section within See stretch reflex, T wave.
which the muscle fibers belonging to an individual motor unit muscle tone See tone.
are distributed. myasthenia gravis A disease characterized by muscle weak-
movement artifact See artifact. ness which increases with repetitive muscle activation. Most
movement-related cortical potential Electroencephalogram commonly, an autoimmune disease caused by the presence of
activity associated with (before and after) a voluntary antibodies to the acetylcholine receptors at the neuromuscu-
movement. There are several components including the lar junction.
Bereitschaftspotential before the movement and the motor myoclonus A quick jerk of a body part produced by a brief
potential at about the time of the movement. See also muscle contraction typically originating from activity in the
Bereitschaftspotential. central nervous system. Based on the anatomic location of the
MSD Abbreviation for mean sorted difference. See jitter. pathology, may be classified as spinal, segmental, brainstem,
MUAP Abbreviation for motor unit action potential. or cortical.
multi MUP analysis A template matching, decomposition myoedema Focal muscle contraction produced by muscle per-
EMG method used for MUAP analysis. cussion. Not associated with propagated electric activity.
multielectrode See multilead electrode. May be seen in hypothyroidism (myxedema) and chronic
multifocal motor neuropathy A disease characterized by se- malnutrition.
lective focal block of motor nerve conduction in multiple myokymia Continuous quivering or undulating movement of
nerves. Motor nerve conduction studies may permit identifi- surface and overlying skin and mucous membrane associated
cation and localization of the segments of nerve affected by with spontaneous, repetitive discharge of motor unit action
the underlying pathology. potentials. See myokymic discharge, fasciculation, and fasci-
multilead electrode Three or more insulated wires inserted culation potential.
through apertures in a common metal cannula with their *myokymic discharge A form of involuntary activity in which
bared tips flush with the cannula's outer circumference. The motor unit action potentials fire repetitively and may be asso-
arrangement of the bare tips relative to the axis of the cannula ciated with clinical myokymia. Two firing patterns have been
and the distance between each tip should be specified. See described: (1) Commonly, the discharge is a brief, repetitive
electrode. firing of single motor unit action potentials for a short period
multiple discharge Four or more motor unit action potentials (up to a few seconds) at a uniform rate (2 to 60 Hz) followed
of the same form and nearly the same amplitude occurring by a short period (up to a few seconds) of silence, with repeti-
consistently in the same relationship to one another and gen- tion of the same sequence for a particular potential at regular
erated by the same axon. See double and triple discharge. intervals. (2) Rarely, the potential recurs continuously at a
multiplet See multiple discharge. fairly uniform firing rate (1 to 5 Hz). Myokymic discharges
MUNE Abbreviation for motor unit number estimate, motor are a subclass of grouped discharges and repetitive dis-
unit number estimation, and motor unit number estimating. charges. See also ephapse and ephaptic transmission.
MUP Abbreviation for motor unit potential. See preferred term, myopathic motor unit potential Low amplitude, short dura-
motor unit action potential. tion, polyphasic motor unit action potentials. Use of term dis-
muscle action potential Term commonly used to refer to a couraged. It incorrectly implies specific diagnostic
compound muscle action potential. significance of a motor unit action potential configuration.
muscle atrophy Decrease in size of a muscle that may be due See motor unit action potential.
to disease of nerve or muscle, or to disuse. myopathic recruitment Used to describe an increase in the
muscle cramp An involuntary, painful muscle contraction as- number and firing rate of motor unit action potentials com-
sociated with electrical activity. Cramp discharges are most pared with normal for the strength of muscle contraction. Use
common, but other types of repetitive discharges can also be of term discouraged.
seen. myopathy Disorder affecting the structure and/or function of
muscle fibers. Etiologies include hereditary, congenital, mi-
* Illustration in Section II tochondrial, inflammatory, metabolic, infectious, neoplastic,
vascular, and traumatic diseases. Most, but not all of these in the peripheral nervous system, whereas evoked potential
disorders show abnormalities on needle electromyography. studies refers to studies of waveforms generated in both the
myotonia Delayed relaxation of a muscle after voluntary con- peripheral and central nervous systems. Synonymous with
traction or percussion. Associated with propagated electric electroneurography.
activity, such as myotonic discharges, complex repetitive dis- nerve conduction velocity (NCV) The speed of action poten-
charges or neuromyotonic discharges. tial propagation along a nerve fiber or nerve trunk. Generally
^myotonic discharge Repetitive discharge which occurs at assumed to refer to the maximum speed of propagation
rates of 20 to 80 Hz. There are two types: 1) biphasic (posi- unless otherwise specified. See conduction velocity.
tive-negative) spike potentials less than 5 ms in duration re¬ nerve fiber action potential Action potential recorded from a
sembling fibrillation potentials. 2) positive waves of 5 to 20 single axon.
ms duration resembling positive sharp waves. Both potential nerve potential Equivalent to nerve action potential. Also com-
forms are recorded after needle electrode insertion, after vol- monly, but inaccurately, used to refer to the biphasic form of
untary muscle contraction or after muscle percussion, and are end-plate activity observed during needle electrode examina-
due to independent, repetitive discharges of single muscle tion of muscle. The latter use is incorrect, because muscle
fibers. The amplitude and frequency of the potentials must fibers, not nerve fibers, are the source of these potentials.
both wax and wane. This change produces a characteristic nerve trunk action potential See preferred term, compound
musical sound in the audio output of the electromyograph nerve action potential.
due to the corresponding change in pitch, which has been neurapraxia Clinical term used to describe the reversible motor
likened to the sound of a "dive bomber". Contrast with and sensory deficits produced by focal compressive or trac-
waning discharge. tion lesions of large myelinated nerve fibers. It is due to con-
myotonic potential See preferred term, myotonic discharge. duction block, most often caused by focal demyelination, but,
NAP Abbreviation for nerve action potential. See compound when very short lived, presumably caused by focal ischemia.
nen'e action potential. The axon is not injured at the lesion site. Compare with
nascent motor unit potential From the Latin nascens, "to be axonotmesis and neurotmesis.
born". Refers to very low amplitude, short duration, highly neuromuscular transmission disorder Clinical disorder asso-
polyphasic motor unit action potentials observed during early ciated with pathology affecting the structure and function of
states of reinnervation. Use of term is discouraged, as it incor- the neuromuscular junction and interfering with synaptic
rectly implies diagnostic significance of a motor unit action transmission at that site. Specific diseases include myasthenia
potential configuration. See motor unit action potential. gravis, Lambert-Eaton myasthenic syndrome, and botulism.
NCS Abbreviation for nerve conduction study. neuromyopathy Clinical disorder associated with pathology
NCV Abbreviation for nerve conduction velocity. See conduc- affecting both nerve and muscle fibers.
tion velocity. neuromyotonia Clinical syndrome of continuous muscle fiber
near-field A region of electrical activity where the isopotential activity manifested as continuous muscle rippling and stiff-
voltage lines associated with a current source change rapidly ness. It may be associated with delayed relaxation following
over a short distance. The terms near-field and far-field are voluntary muscle contraction. The accompanying electric ac-
arbitrary designations, as there are no agreed-upon criteria tivity may be intermittent or continuous. Terms used to de-
defining where the near-field ends and the far-field begins. scribe related clinical syndromes are continuous muscle fiber
Compare with far-field. activity syndrome, Isaac syndrome, Isaac-Merton syndrome,
*needle electrode An electrical device used for recording or quantal squander syndrome, generalized myokymia, pseudo-
stimulating that is positioned near the tissue of interest by myotonia, normocalcemic tetany and neurotonia. Distinguish
penetration of the skin. See specific electrodes: bifilar (bipo- from myotonia.
lar) needle recording electrode, concentric needle electrode, ^neuromyotonic discharge Bursts of motor unit action poten-
macro-EMG needle electrode, monopolar needle electrode, tials that fire at high rates (150 to 300 Hz) for a few seconds,
multilead electrode, single fiber needle electrode, and stimu- often starting or stopping abruptly. The amplitude of the wave-
lating electrode. forms typically wanes. Discharges may occur spontaneously
nerve action potential (NAP) Strictly defined, refers to an or be initiated by needle electrode movement, voluntary
action potential recorded from a single nerve fiber. The term effort, ischemia, or percussion of a nerve. The activity origi-
is commonly used to refer to the compound nen'e action po- nates in motor axons. Distinguish from myotonic discharges
tential. See compound nerve action potential. and complex repetitive discharges. One type of electrical ac-
nerve conduction study (NCS) Recording and analysis of elec- tivity recorded in patients who have clinical neuromyotonia.
tric waveforms of biologic origin elicited in response to elec- neuropathic motor unit potential Abnormally high-
tric or physiologic stimuli. The waveforms are compound amplitude, long-duration, polyphasic motor unit action po-
sensory nerve action potentials, compound muscle action potential. Use of term discouraged. Incorrectly implies a
tentials, or mixed nerve action potentials. The compound specific diagnostic significance of a motor unit action poten-
muscle action potentials are generally referred to by letters tial configuration. See motor unit action potential.
which have historical origin: M wave, F wave, H wave, T neuropathic recruitment A recruitment pattern characterized
wave, A wave, and Rl, R2 waves. It is possible under stan- by a decreased number of motor unit action potentials firing
dardized conditions to establish normal ranges for amplitude, at a rapid rate. Use of term discouraged. See preferred terms,
duration, and latency of the waveforms and to calculate the reduced interference pattern, discrete activity, single unit
maximum conduction velocity of sensory and motor nerves. pattern.
The term generally refers to studies of waveforms generated neuropathy Disorder of the peripheral nerves. May be classi-
fied by the anatomical structure of the nerve most affected by
Illustration in Section II the disease: cell body (neuronopathy), the axon (axonopathy)
or the myelin sheath (demyelinating neuropathy). May selec- *p o s i t i v e s h a r p w a v e A biphasic, positive then negative action
tively affect motor or sensory nerves or both simultaneously. potential of a single muscle fiber. It is initiated by needle
The etiology may be hereditary, metabolic, inflammatory, electrode movement (insertional or unsustained positive
toxic, or unknown. sharp wave) or occurs spontaneously. Typically discharge in
n e u r o t m e s i s Partial or complete nerve severance including the a uniform, regular pattern at a rate of 1 to 50 Hz; the discharge
axons, associated myelin sheaths, and supporting connective frequency may decrease slightly just before cessation of dis-
tissues, resulting in axonal degeneration distal to the injury charge. The initial positive deflection is rapid (<1 ms), its du-
site. Compare with axonotmesis, neurapraxia. "ration is usually less than 5 ms, and the amplitude is up to 1
n e u r o t o n i c d i s c h a r g e s Repetitive motor unit action potentials mV. The negative phase is of low amplitude, and its duration
recorded from intramuscular electrodes during intraopera- is 10 to 100 ms. A sequence of positive sharp waves is com-
tive monitoring. Thought to arise from irritation or injury of monly referred to as a train ofpositive sharp waves. Assumed
nerves supplying the muscle from which the recording is to be recorded from a damaged area of a muscle fiber. This
made. configuration may result from the position of the needle elec-
n o i s e Electric activity not related to the signal of interest. In trode which is believed to be adjacent to the depolarized seg-
electrodiagnostic medicine, waveforms generated by elec- ment of a muscle fiber injured by the electrode. Note that the
trodes, cables, amplifier, or storage media and unrelated to positive sharp waveform is not specific for muscle fiber
potentials of biologic origin. The term has also been used damage. May occur in association with fibrillation potentials
loosely to refer to one form of end-plate activity. and are thought by some to be equivalent discharges. Motor
o n s e t f r e q u e n c y The lowest stable firing rate for a single motor unit action potentials and potentials in myotonic discharges
unit action potential that can be voluntarily maintained by a may have the configuration of positive sharp waves.
subject. p o s i t i v e w a v e Loosely defined, the term refers to a positive
o r d e r o f a c t i v a t i o n The sequence of appearance of different sharp wave. See preferred term positive sharp wave.
motor unit action potentials with increasing strength of vol- p o s t a c t i v a t i o n The period following voluntary activation of a
untary contraction. See recruitment. nerve or muscle. Contrast with posttetanic.
o r t h o d r o m i c Propagation of a nerve impulse in the same direc- * p o s t a c t i v a t i o n d e p r e s s i o n A reduction in the amplitude and
tion as physiologic conduction; e.g. conduction along motor area of the M wave(s) in response to a single stimulus or train
nerve fibers towards the muscle and conduction along sen- of stimuli which occurs within a few minutes following a 10
sory nerve fibers towards the spinal cord. Contrast with an- to 60 second strong voluntary contraction. Postactivation ex-
tidromic. haustion refers to the cellular mechanisms responsible for the
p a i r e d s t i m u l i Two consecutive stimuli delivered in a time- observed phenomenon of postactivation depression. Also used
locked fashion. The time interval between the two stimuli and to describe reduction of the M wave following a tetanus, which
the intensity of each stimulus can be varied but should be should more logically be termed posttetanic depression.
specified. The first stimulus is called the conditioning stimu- p o s t a c t i v a t i o n e x h a u s t i o n A reduction in the safety factor
lus and the second stimulus is the test stimulus. The condi- (margin) of neuromuscular transmission after sustained acti-
tioning stimulus may modify tissue excitability, which is then vation at the neuromuscular junction. The changes in the con-
evaluated by the response to the test stimulus. figuration of the M wave due to postactivation exhaustion are
p a r a s i t e p o t e n t i a l See preferred term, satellite potential. referred to as postactivation depression.
p e a k l a t e n c y Interval between the onset of a stimulus and a p o s t a c t i v a t i o n f a c i l i t a t i o n See facilitation.
specified peak of an evoked waveform. p o s t a c t i v a t i o n p o t e n t i a t i o n An increase in the force of con-
p e r o n e a l n e u r o p a t h y a t t h e k n e e A mononeuropathy involv- traction (mechanical response) after a strong voluntary con-
ing the common peroneal nerve as it passes around the head traction. Contrast postactivation facilitation.
of the fibula. The presumed mechanism is compression of the p o s t t e t a n i c The period following tetanus. Contrast with post-
nerve against the fibula. See also crossed leg palsy. activation.
p h a s e That portion of a waveform between the departure from, p o s t t e t a n i c d e p r e s s i o n See postactivation depression.
and the return to, the baseline. p o s t t e t a n i c f a c i l i t a t i o n See facilitation, potentiation.
p l e x o p a t h y Axonal and/or demyelinating disorder affecting the p o s t t e t a n i c p o t e n t i a t i o n 1) The incrementing mechanical re-
nerve fibers exclusive to the cervical, brachial, lumbar, or sponse of muscle during and after repetitive nerve stimula-
sacral rearrangement of spinal nerve roots into peripheral tion. 2) In central nervous system physiology, enhancement
nerves. of excitability or reflex outflow of neuronal systems follow-
p o l a r i z a t i o n The presence of an electric potential difference ing a long period of high-frequency stimulation. See facilita-
usually across an excitable cell membrane. tion, potentiation.
p o l y n e u r o p a t h y Axonal and/or demyelinating disorder affect- p o t e n t i a l 1) A difference in charges, measurable in volts, that
ing nerve fibers, usually in a symmetrical fashion. The distal exists between two points. Most biologically produced poten-
segments of the longer nerves in the lower extremities are tials arise from the difference in charge between two sides of
usually the most severely affected. May be classified as sen- a cell membrane. 2) A term for a physiologically recorded
sory, motor, or sensorimotor depending on the function of waveform.
nerve fibers affected. p o t e n t i a t i o n Physiologically, the enhancement of a response.
p o l y p h a s i c a c t i o n p o t e n t i a l An action potential with four or The convention used in this glossary is to use the term poten-
more baseline crossings, producing five or more phases. See tiation to describe the incrementing mechanical response of
phase. Contrast with serrated action potential. muscle elicited by repetitive nerve stimulation, e.g., post-
p o l y r a d i c u l o n e u r o p a t h y See radiculopathy. tetanic potentiation, whereas the term facilitation is used to
describe the incrementing electrical response elicited by
* Illustration in Section II repetitive nerve stimulation, e.g., postactivation facilitation.
prolonged insertion activity See insertion activity. electrode close to the source of the activity to be recorded is
propagation velocity of a muscle fiber The speed of transmis- called the active or exploring electrode, and the other record-
sion of a muscle fiber action potential. ing electrode is called the reference electrode. Active elec-
pseudodecrement An artifact produced by movement of the trode is synonymous with input terminal 1, or E-l (or older
stimulating or recording electrodes during repetitive nerve terms whose use is discouraged, grid 1, and Gl). Reference
stimulation. The amplitude and area of the M wave can vary electrode is synonymous with input terminal 2, or E-2 (or
in a way that resembles a decrementing response, however older terms whose use is discouraged grid 2, and G2). In
the responses are generally irregular and not reproducible. some recordings it is not certain which electrode is closer to
*pseudofacilitation See facilitation. the source of the biologic activity, e.g. recording with a bifi-
pseudohypertrophy See muscle hypertrophy. lar needle recording electrode, or when attempting to define
pseudomyotonic discharge Formerly used to describe complex far-field potentials. In this situation, it is convenient to refer
repetitive discharges. Use of term discouraged, to one electrode as input electrode 1, or E-1, and the other as
i pseudopolyphasic action potential Use of term discouraged. input electrode 2, or E-2. By present convention, a potential
See preferred term, serrated action potential. difference that is negative at the active electrode (input termi-
QEMG Abbreviation for quantitative electromyography. nal 1, E-l) relative to the reference electrode (input terminal
QSART Abbreviation for quantitative sudomotor axon reflex 2, E-2) causes an upward deflection on the display screen.
test. The term "monopolar recording" is not recommended, be-
QST Abbreviation for quantitative sensory testing. cause all recordings require two electrodes; however, it is
1 quantitative electromyography (QEMG) A systematic commonly used to describe the use of one type of intramus-
' method for measuring the recordings made by an intramuscu- cular needle electrode. A similar combination of needle elec-
lar needle electrode. Measurements include motor unit action trodes has been used to record nerve activity and also has
potential characteristics such as amplitude, duration, and been referred to as "monopolar recording."
phases, or interference pattern characteristics. See turns and recruitment The successive activation of the same and addi-
amplitude analysis. tional motor units with increasing strength of voluntary
quantitative sensory testing (QST) An instrumented method muscle contraction. See motor unit action potential.
for measuring cutaneous sensation. recruitment frequency Firing rate of a motor unit action po-
quantitative sudomotor axon reflex test (QSART) Test of tential (MUAP) when a different MUAP first appears during
post-ganglionic sympathetic sudomotor axons function by gradually increasing voluntary muscle contraction. This pa-
measuring sweat output following activation of axon termi- rameter is essential to assessment of recruitment pattern.
nals by local application of acetylcholine. Antidromic trans- recruitment interval The interdischarge interval between two
mission of the impulse from the nerve terminals reaches a consecutive discharges of a motor unit action potential
branch point, then travels orthodromically to release acetyl- (MUAP) when a different MUAP first appears during gradu-
choline from the nerve terminals, inducing a sweating really increasing voluntary muscle contraction. The reciprocal
sponse. In small fiber polyneuropathy, the response may be of the recruitment interval is the recruitment frequency. See
reduced or absent. In painful neuropathies, and in reflex sym- also interdischarge interval.
pathetic dystrophy, the response may be excessive and persis- ^recruitment pattern A qualitative and/or quantitative descrip-
tent or reduced. tion of the sequence of appearance of motor unit action po-
Rl, R2 waves See blink responses. tentials during increasing voluntary muscle contraction. The
radiculopathy Axonal and/or demyelinating disorder affecting recruitment frequency and recruitment interval are two quan-
the nerve fibers exclusive to one spinal nerve root or spinal titative measures commonly used. See interference pattern,
nerve. May affect the anterior (motor) or posterior (sensory) early recruitment, reduced recruitment for qualitative terms
spinal nerve roots, or both, at one spinal cord segment level. commonly used.
The resulting clinical syndrome may include pain, sensory recurrent inhibition Decreased probability of firing of a motor
loss, parethesia, weakness, fasciculations, and muscle atro- neuron pool mediated by Renshaw cells. Renshaw cells are
phy. If more than one spinal root is involved, the term activated by recurrent collaterals from the axons of alpha-mo-
polyradiculopathy may be used as a descriptor. toneurons. Such inhibition influences the same cells that
raster A method for display of a free-running sweep in elec- originate the excitatory impulses and their neighbors.
tromyography. Sweeps are off-set vertically so that each suc- reduced insertion activity See insertion activity.
cessive sweep is displayed below the one preceding it. reduced interference pattern See interference pattern.
raw EMG Unprocessed EMG signal recorded with surface or reduced recruitment pattern A descriptive term for the inter-
intramuscular electrodes. ference pattern when the number of motor units available to
reciprocal inhibition Inhibition of a motor neuron pool sec- generate a muscle contraction are reduced. One cause for a
ondary to the activation of the motor neuron pool of its antag- reduced interference pattern. See interference pattern, re-
onist. It is one of several important spinal mechanism of motor cruitment pattern.
control that help to make movements smoother and utilize reference electrode See recording electrode.
less energy. There are multiple mechanisms for reciprocal in- reflex A stereotyped motor response elicited by a sensory stim-
hibition, including one mediated by the la inhibitory inter- ulus and a response. Its anatomic pathway consists of an af-
neuron that activates la afferents and disynaptically inhibits ferent, sensory input to the central nervous system, at least
the muscle that is antagonist to the source of the la afferents. one synaptic connection, and an efferent output to an effector
recording electrode Device used to record electric potential organ. The response is most commonly motor, but reflexes
difference. All electric recordings require two electrodes. The involving autonomic effector organs also occur. Examples in-
clude the H reflex and the sudomotor reflex. See H wave,
* Illustration in Section II quantitative sudomotor axon reflex test.
refractory period General term for the time following an action pipe" or constant quality. It is a cardinal feature of central
potential when an excitable membrane cannot be stimulated nervous system disorders affecting the basal ganglia. Con-
to produce another action potential. The absolute refractory trast with spasticity.
period is the time following an action potential during which rise time The interval from the onset of a polarity change of a
no stimulus, however strong, evokes a further response. The potential to its peak. The method of measurement should be
relative refractory period is the time following an action po- specified.
tential during which a stimulus must be abnormally large to ^satellite potential A small action potential separated from the
evoke a second response. The functional refractory period is main motor unit action potential by an isoelectric interval
the time following an action potential during which a second which fires in a time-locked relationship to the main action
action potential cannot yet excite the given regionr potential. It usually follows, but may precede, the main action
refractory period of transmission Interval following an action potential. Less preferred terms include late component, para-
potential during which a nerve cannot conduct a second one. site potential, linked potential, and coupled discharge.
Distinguish from refractory period, as commonly used, scanning EMG A technique by which a needle electrode is ad-
which deals with the ability of a stimulus to produce an action vanced in defined steps through muscle while a separate
potential. SFEMG electrode is used to trigger both the display sweep
regeneration motor unit potential Use of term discouraged. and the advancement device. Provides temporal and spatial
See motor unit action potential. information about the motor unit. Distinct maxima in the
relative refractory period See refractory period. recorded activity are considered to be generated by muscle
* repair of the decrement See facilitation. fibers innervated by a common branch of an axon. These
repetitive discharge General term for the recurrence of an groups of fibers form a motor unit fraction.
action potential with the same or nearly identical form. May sea shell sound (sea shell roar or noise) Use of term discour-
refer to recurring potentials recorded in muscle at rest, during aged. See end-plate activity, monophasic.
voluntary contraction, or in response to a single nerve stimu- sensory latency Interval between the onset of a stimulus and
lus. See double discharge, triple discharge, multiple dis- the onset of the negative deflection of the compound sensory
charge, myokymic discharge, complex repetitive discharge, nerve action potential. This term has been used loosely to
neuromyotonic discharge, and cramp discharge. refer to the sensory peak latency. May be qualified as proxi-
Repetitive nerve stimulation The technique of repeated supra- mal sensory latency or distal sensory latency, depending on
maximal stimulation of a nerve while recording successive M the relative position of the stimulus.
waves from a muscle innervated by the nerve. Commonly sensory nerve A nerve containing only sensory fibers, com-
used to assess the integrity of neuromuscular transmission. posed mainly of axons innervating cutaneous receptors.
The number of stimuli and the frequency of stimulation should sensory nerve action potential (SNAP) See compound sensory
be specified. Activation procedures performed as a part of the nerve action potential.
test should be specified, e.g. sustained voluntary contraction sensory nerve conduction velocity The speed of propagation
or contraction induced by nerve stimulation. If the test in- of action potentials along a sensory nerve.
cludes an activation procedure, the time elapsed after its com- sensory peak latency Interval between the onset of a stimulus
pletion should also be specified. For a description of specific and the peak of the negative phase of the compound sensory
patterns of responses, see incrementing response, decrement- nerve action potential. Contrast with sensory latency.
ing response, facilitation, and postactivation depression. sensory potential Synonym for the more precise term, com-
repolarization A return in membrane potential from a depolar- pound sensory nerve action potential.
ized state toward the normal resting level. sensory response Synonym for the more precise term, com-
residual latency The calculated time difference between the pound sensory nerve action potential.
measured distal latency of a motor nerve and the expected la- SEP Abbreviation for somatosensory evoked potential.
tency, calculated by dividing the distance between the stimu- serrated action potential A waveform with several changes in
lating cathode and the active recording electrode by the direction (turns) which do not cross the baseline. Most often
maximum conduction velocity measured in a more proximal used to describe a motor unit action potential. The term is
segment of the nerve. It is due in part to neuromuscular trans- preferred to complex motor unit action potential and pseudo-
mission time and to slowing of conduction velocity in termi- polyphasic action potential. See also turn and polyphasic
nal axons due to decreasing diameter and the presence of action potential.
unmyelinated segments. SFEMG Abbreviation for single fiber electromyography.
response An activity elicited by a stimulus. shock artifact See artifact.
resting membrane potential Voltage across the membrane of an short-latency reflex A reflex with one (monosynaptic) or few
excitable cell in the absence of a stimulus. See polarization. (oligosynaptic) synapses. Used in contrast to long-latency
rheobase See strength-duration curve. reflex.
rigidity A velocity independent increase in muscle tone and *short-Iatency somatosensory evoked potential (SSEP) That
stiffness with full range of joint motion as interpreted by the portion of the waveforms of a somatosensory evoked poten-
clinical examiner from the physical examination. Often asso- tial normally occurring within 25 ms after stimulation of the
ciated with simultaneous low-grade contraction of agonist median nerve in the upper extremity at the wrist, 40 ms after
and antagonist muscles. Like muscle spasticity, the involuntary stimulation of the common peroneal nerve in the lower ex-
motor unit action potential activity increases with activity or tremity at the knee, and 50 ms after stimulation of the poste-
passive stretch. Does not seem to change with the velocity of rior tibial nerve at the ankle.
stretch, and, on passive stretch, the increased tone has a "lead signal averager A digital device that improves the signal-to-
noise ratio of an electrophysiological recording by adding
* Illustration in Section II successive time-locked recordings to preceding traces and
computing the average value of each data point. A signal spike 1) A short-lived (1 to 3 ms), all-or-none waveform that
! acquired by this method is described as an "averaged" arises when an excitable membrane reaches threshold. 2) The
waveform. electric record of a nerve or muscle impulse.
silent period A pause in the electric activity of a muscle that spinal evoked potential Electric waveforms of biologic origin
may be produced by many different stimuli. Stimuli used recorded over the spine in response to electric stimulation or
commonly in clinical neurophysiology include rapid unload- physiologic activation of peripheral sensory fibers. See pre-
ing of a muscle, electrical stimulation of a peripheral nerve or ferred term, somatosensory evoked potential.
transcranial magnetic stimulation. spontaneous activity Electric activity recorded from muscle at
*single fiber electromyography (SFEMG) The technique and rest after insertion activity has subsided and when there is not
conditions that permit recording of single muscle fiber action voluntary contraction or an external stimulus. Compare with
potentials. See single fiber needle electrode, blocking, and involuntary activity.
jitter. SSEP Abbreviation for short-latency somatosensory evoked po-
single fiber EMG See single fiber electromyography. tential.
single fiber needle electrode A needle electrode with a small staircase phenomenon The progressive increase in muscle
recording surface (usually 25 urn in diameter) which permits contraction force observed in response to continued low rates
the recording of single muscle fiber action potentials be- of muscle activation.
tween the recording surface and the cannula. See single fiber startle (reflex) A response produced by an unanticipated stimu-
electromyography. lus that leads to alerting and protective movements such as
single unit pattern See interference pattern. eye lid closure and flexion of the limbs. Auditory stimuli are
SNAP Abbreviation for sensory nerve action potential. See typically most efficacious.
compound sensory nerve action potential. stiffman syndrome A disorder characterized by continuous
snap, crackle, and pop A benign type of increased insertion muscle contraction giving rise to severe stiffness. Axial mus-
j activity that follows, after a very brief period of electrical si- cles are typically affected most severely. Patients have diffi-
lence, the normal insertion activity generated by needle elec- culty moving. Walking and voluntary movements are slow.
trode movement. It consists of trains of potentials that vary in Sensory stimulation often induces severe spasms. Electro-
length, however, they can persist for a few seconds. Each myography demonstrates continuous activity of motor unit
train consists of a series of up to 10 or more potentials in action potentials in a normal pattern that cannot be silenced
which the individual components fire at irregular intervals. by contraction of the antagonist muscle. It is often associated
The potentials consistently vary in amplitude, duration, and with circulating antibodies to glutamic acid decarboxylase
configuration. Individual potentials may be mono-, bi-, tri-, (GAD), and the resulting deficiency of GABA may play a
or multiphasic in appearance; they often have a positive role in its pathophysiology. Since women are affected in
waveform. The variation on sequential firings produces a dis- equal or greater numbers than men, the term stiffperson syn-
tinctive sound, hence the name. See most often in those with drome may be preferable.
mesomorphic builds, especially young adult males. Found stiffperson syndrome Synonym for stiffman syndrome.
most often in lower extremity muscles, especially the medial stigmatic electrode A term of historic interest. Used by
gastrocnemius. Sherrington for active or exploring electrode.
somatosensory evoked potential (SEP) Electric waveforms of stimulated SFEMG See preferred term stimulation SFEMG.
biologic origin elicited by electric stimulation or physiologic stimulating electrode Device used to deliver electric current.
activation of peripheral sensory nerves and recorded from pe- All electric stimulation requires two electrodes; the negative
ripheral and central nervous system structures. Normally is a terminal is termed the cathode, and the positive terminal is the
complex waveform with several components which are speci- anode. By convention, the stimulating electrodes are called
fied by polarity and average peak latency. The polarity and bipolar if they are encased or attached together and are called
latency of individual components depend upon 1) subject monopolar if they are not. Electric stimulation for nerve con-
variables, such as age, gender, and body habitus, 2) stimulus duction studies generally requires application of the cathode
characteristics, such as intensity and rate of stimulation, and in the vicinity of the neural tissue to produce depolarization.
3) recording parameters, such as amplifier time constants, stimulation single fiber electromyography (stimulation
electrode placement, and electrode combinations. See short- SFEMG) Use of electrical stimulation instead of voluntary
latency somatosensory evoked potentials. activation of motor units for the analysis of single fiber elec-
jpasticity A velocity-dependent increase in muscle tone due to tromyography. The method is used in patients who are unable
a disease process that interrupts the suprasegmental tracts to to produce a steady voluntary muscle contraction. The stimu-
the alpha motor neurons, gamma motor neurons, or segmen- lation can be delivered to intramuscular axons, nerve trunks,
tal spinal neurons. May be elicited and interpreted by the or muscle fibers.
clinical examiner during the physical examination by brisk stimulus Any external agent, state or change that is capable of
passive movement of a limb at the joint. Almost uniformly influencing the activity of a cell, tissue, or organism. In clini-
accompanied by hyperreflexia, a Babinski sign, and other cal nerve conduction studies, an electric stimulus is applied
signs of upper motor neuron pathology, including clonus and to a nerve. It may be described in absolute terms or with re-
the clasp-knife phenomenon. The clasp-knife phenomenon is spect to the evoked potential of the nerve or muscle. In ab-
a rapid decrease of tone following a period of increased tone solute terms, it is defined by a duration (ms), a waveform
during passive rotation of the joint. The pathophysiology is (square, exponential, linear, etc.), and a strength or intensity
not certain and may include more than dysfunction of the measured in voltage (V) or current (mA). With respect to
corticospinal tracts. the evoked potential, the stimulus may be graded as sub-
threshold, threshold, submaximal, maximal, or supramaxi-
Illustration in Section II mal. A threshold stimulus is one just sufficient to produce a
detectable response. Stimuli less than the threshold stimulus tardy ulnar palsy A type of mononeuropathy involving the
are termed subthreshold. The maximal stimulus is the stimu- ulnar nerve at the elbow. The nerve becomes compressed or
lus intensity after which a further increase in intensity causes entrapped due to deformity of the elbow from a previous
no increase in the amplitude of the evoked potential. Stimuli injury. See also cubital tunnel syndrome and ulnar neuropa-
of intensity below this level but above threshold are submaxi- thy at the elbow.
mal. Stimuli of intensity greater than the maximal stimulus template matching An automated method used in quantitative
are termed supramaximal. Ordinarily, supramaximal stimuli electromyography for selecting motor unit action potentials
are used for nerve conduction studies. By convention, an for measurement by extracting only potentials which resem-
electric stimulus of approximately 20% greater voltage/cur- ble an initially identified potential.
rent than required for the maximal stimulus is used for supra- temporal dispersion Relative desynchronization of compo-
maximal stimulation. The frequency, number and duration of nents of a compound muscle action potential due to different
a series of stimuli should be specified, rates of conduction of each synchronously evoked component
stimulus artifact See artifact. from the stimulation point to the recording electrode. It may
strength-duration curve Graphic presentation of the relation- be due to normal variability in individual axon conduction ve-
ship between the intensity (Y axis) and various durations (X locities, especially when assess over a long nerve segment, or
axis) of the threshold electric stimulus of a nerve or muscle. to disorders that affect myelination of nerve fibers.
The rheobase is the intensity of an electric current of infinite terminal latency Synonymous with preferred term, distal la-
duration necessary to produce a minimal action potential. tency. See motor latency and sensory latency.
The chronaxie is the time required for an electric current TES Abbreviation for transcranial electrical stimulation.
twice the rheobase to elicit the first visible action potential. test stimulus See paired stimuli.
Measurement of the strength-duration curve is not a common tetanic contraction The contraction produced in a muscle
practice in modern electrodiagnostic medicine. through repetitive maximal direct or indirect stimulation at a
stretch reflex A reflex produced by passive lengthening of a sufficiently high frequency to produce a smooth summation
muscle. The principal sensory stimuli come from group la of successive maximum twitches. The term may also be ap-
and group II muscle spindle afferents. It consists of several plied to maximum voluntary contractions in which the firing
phases. The earliest component is monosynaptic and is also frequencies of most or all of the component motor units are
called the myotatic reflex, or tendon reflex. There are also sufficiently high that successive twitches of individual motor
long-latency stretch reflexes. See also muscle stretch reflex, T units fuse smoothly. Their combined tensions produce a
wave. steady, smooth, maximum contraction of the whole muscle.
submaximal stimulus See stimulus. tetanus 1) The continuous contraction of muscle caused by
subnormal period A time interval that immediately follows the repetitive stimulation or discharge of nerve or muscle.
supernormal period of nerve which is characterized by re- Contrast with tetany. 2) A clinical disorder caused by circu-
duced excitability compared to the resting state. Its duration lating tetanus toxin. Signs and symptoms are caused by loss
is variable and is related to the refractory period. of inhibition in the central nervous system and are character-
subthreshold stimulus See stimulus. ized by muscle spasms, hyperreflexia, seizures, respiratory
supernormal period A time interval that immediately follows spasms, and paralysis.
the refractory period which corresponds to a very brief period tetany A clinical syndrome manifested by muscle twitching,
of partial depolarization. It is characterized by increased cramps, and carpal and pedal spasm. These clinical signs are
nerve excitability and is followed by the subnormal period. manifestations of peripheral and central nervous system
supraclavicular plexus That portion of the brachial plexus nerve irritability from several causes. In these conditions,
which is located superior to the clavicle. repetitive discharges (double discharge, triple discharge,
supraclavicular stimulation Percutaneous nerve stimulation at multiple discharge) occur frequently with voluntary activa-
the base of the neck which activates the upper, middle, and/or tion of motor unit action potentials or may appear as sponta-
lower trunks of the brachial plexus. This term is preferred to neous activity. This activity is enhanced by systemic alkalosis
Erb 's point stimulation. or local ischemia.
supramaximal stimulus See stimulus. tetraphasic action potential Action potential with three base-
surface electrode Conducting device for stimulating or recording line crossings, producing four phases.
placed on the skin surface. The material (metal, fabric, etc.), thermography A technique for measuring infrared emission
configuration (disk, ring, etc.), size, and separation should be from portions of the body surface. The degree of emission de-
specified. See electrode (ground, recording, stimulating). pends upon the amount of heat produced by the region that is
^sympathetic skin response Electrical potential resulting from studied. Its use in the diagnosis of radiculopathy, peripheral
electrodermal activity in sweat glands in response to both nerve injury, and disorders of the autonomic nervous system
direct and reflex peripheral or sympathetic trunk stimulation is controversial.
of autonomic activity. thermoregulatory sweat test A technique for assessing the in-
synkinesis Involuntary movement made by muscles distant tegrity of the central and peripheral efferent sympathetic
from those activated voluntarily. It is commonly seen during pathways. It consists of measuring the sweat distribution
recovery after facial neuropathy. It is due to aberrant reinner- using an indicator powder while applying a controlled heat
vation and/or ephaptic transmission. stimulus to raise body temperature sufficient to induce
*T wave A compound muscle action potential evoked from a sweating.
muscle by rapid stretch of its tendon, as part of the muscle thoracic outlet syndrome An entrapment neuropathy caused
stretch reflex. by compression of the neurovascular bundle as it traverses the
shoulder region. Compression arises from acquired or con-
* Illustration in Section II genital anatomic variations in the shoulder region. Symptoms
can be related to compression of vascular structures, portions entrapped just distal to the elbow as it passes through the cu-
of the brachial plexus, or both. bital tunnel. Anatomic variations or deformities of the elbow
threshold The level at which a clear and abrupt transition may contribute to nerve injury. See also cubital tunnel syn-
occurs from one state to another. The term is generally used drome and tardy ulnar palsy.
to refer to the voltage level at which an action potential is ini- unipolar needle electrode See synonym, monopolar needle
tiated in a single axon or muscle fiber or a group of axons or recording electrode.
muscle fibers. upper motor neuron syndrome A clinical condition resulting
threshold stimulus See stimulus. from a pathological process affecting descending motor path-
tic Clinical term used to describe a sudden, brief, stereotyped, ways including the corticospinal tract or its cells of origin.
repetitive movement. When associated with vocalizations, Signs and symptoms include weakness, spasticity, and slow
may be the primary manifestation of Tourette syndrome. and clumsy motor performance. On electromyographic ex-
tilt table test A test of autonomic function that is performed by amination of weak muscles, there is slow motor unit action
measuring blood pressure and heart rate before and a speci- potential firing at maximal effort.
fied period of time after head up tilt. The duration of record- utilization time See preferred term, latency of activation.
ing and amount of tilt should be specified. Valsalva maneuver A forcible exhalation against the closed
TMS Abbreviation for transcranial magnetic stimulation. glottis which creates an abrupt, transient elevation of in-
tone The resistance to passive stretch of a joint. When the resis- trathoracic and intra-abdominal pressure. This results in a
tance is high, this is called hypertonia, and when the resis- characteristic pattern of heart rate and blood pressure changes
tance is low, this is called hypotonia. Two types of hypertonia that can be used to quantify autonomic function. See Val-
are rigidity and spasticity. salva ratio.
train of positive sharp waves See positive sharp wave. Valsalva ratio The ratio of the fastest heart rate occurring at the
train of stimuli A group of stimuli. The duration of the group end of a forced exhalation against a closed glottis {phase II of
or the number of stimuli as well as the stimulation frequency the Valsalva maneuver), and the slowest heart rate within 30
should be specified. seconds after the forced exhalation (phase IV). In patients
transcranial electrical stimulation (TES) Stimulation of the with disorders of the autonomic nervous system, the ratio
cortex of the brain through the intact skull and scalp by may be reduced.
means of a brief, very high voltage, electrical stimulus. VEP Abbreviation for visual evoked potential.
Activation is more likely under the anode rather than the VER Abbreviation for visual evoked response. See visual
cathode. Because it is painful, this technique has largely been evoked potential.
replaced by transcranial magnetic stimulation. *visual evoked potential (VEP) Electric waveforms of bio-
transcranial magnetic stimulation (TMS) Stimulation of the logic origin recorded over the cerebrum and elicited in re-
cortex of the brain through the intact skull and scalp by sponse to visual stimuli. They are classified by stimulus rate
means of a brief magnetic stimulus. In practice, a brief pulse as transient or steady state, and they can be further divided by
of strong current is passed through a coil of wire in order to stimulus presentation mode. The normal transient VEP to
produce a time-varying magnetic field in the order of 1 to 2 checkerboard pattern reversal or shift has a major positive oc-
Tesla. Contrast with transcranial electrical stimulation. cipital peak at about 100 ms (PI00), often preceded by a neg-
tremor Rhythmical, involuntary oscillatory movement of a ative peak (N75). The precise range of normal values for the
body part. latency and amplitude of PI00 depends on several factors: 1)
triphasic action potential Action potential with two baseline subject variables, such as age, gender, and visual acuity, 2)
crossings, producing three phases. stimulus characteristics, such as type of stimulator, full-field
•triple discharge Three motor unit action potentials of the same or half-field stimulation, check size, contrast and lumines-
form and nearly the same amplitude, occurring consistently cence, and 3) recording parameters, such as placement and
in the same relationship to one another and generated by the combination of recording electrodes.
same axon. The interval between the second and third action visual evoked response (VER) Synonym for preferred term,
potentials often exceeds that between the first two, and both visual evoked potential.
are usually in the range of 2 to 20 ms. See also double dis- volitional activity Synonymous with voluntary activity.
charge, multiple discharge. voltage Potential difference between two recording sites usu-
triplet Synonym for the preferred term, triple discharge. ally expressed in volts (V) or millivolts (mV).
turn Point of change in polarity of a waveform and the magni- volume conduction Spread of current from a potential source
tude of the voltage change following the turning point. It is through a conducting medium, such as body tissues.
not necessary that the voltage change pass through the base- voluntary activity In electromyography, the electric activity
line. The minimal excursion required to constitute a change recorded from a muscle with consciously controlled contrac-
should be specified. tion. The effort made to contract the muscle may be specified
turns and amplitude analysis See preferred term interference relative to that of a corresponding normal muscle, e.g. mini-
pattern analysis. Refers to the interference pattern analysis mal, moderate, or maximal. If the recording remains isoelec-
developed by Robin Willison in the 1960s. tric during the attempted contraction and equipment
ulnar neuropathy at the elbow A mononeuropathy involving malfunction has been excluded, it can be concluded that there
the ulnar nerve in the region of the elbow. At least two sites is no voluntary activity.
of entrapment neuropathy have been recognized. The nerve wake-up test A procedure used most commonly in spinal
may be entrapped or compressed as it passes through the surgery. During critical portions of an operation in which the
retrocondylar groove at the elbow. Alternatively, it may be spinal cord is at risk for injury, the level of general anesthesia
is allowed to decrease to the point where the patient can re-
•• Illustration in Section II spond to commands. The patient is then asked to move hands
and feet, and a movement in response to commands indicates wave A transient change in voltage represented as a line of dif-
the spinal cord is intact. This procedure is used routinely in fering directions over time.
some centers. Somatosensory evoked potential monitoring waveform The shape of a wave. The term is often used synony-
has supplanted its use in most centers, except sometimes in mously with wave.
the situation where they indicate the possibility of spinal cord wire electrodes Thin wires that are insulated except for the tips,
injury. which are bared. The wire is inserted into muscle with a
wallerian degeneration Degeneration of the segment of an needle. After the needle is withdrawn, the wire remains in
axon distal to nerve injury that destroys its continuity. place. Wire electrodes are superior to surface electrodes for
waning discharge A repetitive discharge that gradually de- kinesiologic EMG, because they are less affected by cross
creases in frequency or amplitude before cessation. Contrast talk from adjacent muscles. They also record selectively from
with myotonic discharge. the muscle into which they are inserted.
SECTION II:
ILLUSTRATIONS OF SELECTED WAVEFORMS
FIGURE 1 COMPOUND SENSORY FIGURE 17 REPETITIVE NERVE STIMULATION

NERVE ACTION POTENTIALS FIGURE 18 INSERTION ACTIVITY
FIGURE 2 SHORT-LATENCY SOMATOSENSORY EVOKED
POTENTIALS MEDIAN NERVE FIGURE 19 END-PLATE ACTIVITY
FIGURE 3 SHORT-LATENCY SOMATOSENSORY EVOKED FIGURE 20 FIBRILLATION POTENTIAL
POTENTIALS COMMON PERONEAL NERVE FIGURE 21 POSITIVE SHARP WAVE
FIGURE 4 SHORT-LATENCY SOMATOSENSORY FIGURE 22 MYOTONIC DISCHARGE
EVOKED POTENTIALS
FIGURE 5 VISUAL EVOKED POTENTIAL FIGURE 23 COMPLEX REPETITIVE DISCHARGE
FIGURE 6 BRAINSTEM AUDITORY EVOKED POTENTIAL FIGURE 24 FASCICULATION POTENTIAL
FIGURE 7 M WAVE FIGURE 25 MYOKYMIC DISCHARGE
FIGURE 8 FWAVE FIGURE 26 NEUROMYOTONIC DISCHARGE
FIGURE 9 HWAVE FIGURE 27 CRAMP DISCHARGE
FIGURE 10 A WAVE FIGURE 28 MOTOR UNIT ACTION POTENTIALS
FIGURE 11 TWAVE FIGURE 29 SATELLITE POTENTIAL
FIGURE 12 BLINK RESPONSES FIGURE 30 RECRUITMENT PATTERN
FIGURE 13 REPETITIVE NERVE STIMULATION FIGURE 31 SINGLE-FIBER ELECTROMYOGRAPHY
FIGURE 14 REPETITIVE NERVE STIMULATION FIGURE 32 MACROELECTROMYOGRAPHY
DECREMENTING RESPONSE FIGURE 33 NEEDLE ELECTRODES
FIGURE 15 REPETITIVE NERVE STIMULATION FIGURE 34 FULL WAVE RECTIFIED EMG
FIGURE 16 REPETITIVE NERVE STIMULATION FIGURE 35 SYMPATHETIC SKIN RESPONSE
Each illustration is accompanied by a complete explanation that is, in most cases, the same as that given in the alphabetic
section. The definitions have been repeated in full with the illustrations so that readers do not need to refer back and forth
between the illustration and definition.
The illustrations have been modified and adapted from materials submitted by AAEM members. The illustrations of the
short-latency somatosensory evoked potentials were reprinted from the Journal of Clinical Neurophysiology (1978;1:41-53)
with permission of the journal editor and the authors.
COMPOUND SENSORY NERVE ACTION POTENTIALS
Stimulate Record MEDIAN NERVE ULNAR NERVE
J^SOnV J~20^.V
1 ms 1 ms
Figure I. Compound sensory nerve action potentials recorded with surface electrodes in a normal subject. A compound nerve action potential is con-
sidered to have been evoked from afferent fibers if the recording electrodes detect activity only in a sensory nerve or in a sensory branch of a
mixed nerve, or if the electric stimulus is applied to a sensory nerve or a dorsal nerve root, or an adequate stimulus is applied synchronously to sen-
sory receptors.The amplitude, latency, duration, and configuration should be noted. Generally, the amplitude is measured as the maximum peak-to-
peak voltage when there is an initial positive deflection or from bose//ne-to-peak when there is an initial negative deflection. The latency is
measured as either the latency to the initial deflection or the peak latency to the negative peak, and the duration as the interval from the first de-
flection of the waveform from the baseline to its final return to the baseline. The compound sensory nerve action potential is also referred to by
the less preferred terms sensory response, sensory potential, or SNAP.
SHORT-LATENCY SOMATOSENSORY EVOKED POTENTIAL (SSEP)

MEDIAN NERVE
N=1024 i I i I i I - I i I
0 10 20 30 40 ms
Figure 2. Short-latency somatosensory evoked potentials evoked by stimulation of the median nerve in a normal subject. Recordings were made
from the scalp to a cephalic reference (C4'-Fz), the scalp to contralateral Erb's point (C4'-EP2), cervical spine to a frontal reference (C5S-Fz), and
ipsilateral Erb's point to the contralateral Erb's point (EP I-EP2). Short-latency somatosensory evoked potentials elicited by electric stimulation of
the median nerve at the wrist occur within 25 ms of the stimulus in normal subjects. Normal short-latency response components to median nerve
stimulation are designated P9, P11, P13, P14, N20, and P23 in records taken between scalp and noncephalic reference electrodes, and N9, N11, N13,
and N I 4 in cervical spine-scalp derivation. It should be emphasized that potentials having opposite polarity but similar latency in spine-scalp and
scalp-noncephalic reference derivations do not necessarily have identical generator sources.The C4' designation indicates that the recording scalp
electrode was placed 2 cm posterior to the International 10-20 C4 electrode location.

COMMON PERONEAL NERVE
Cz' - Fpz'
T12S-4cm
rostral ] ~ 0 . 2 »xV
L3S - 4 cm. y J \ - S
rostral
N = 2048 L -L
1020 30
JL.
40 ms
Figure 3. Short-latency somatosensory evoked potentials evoked by stimulation of the common peroneal nerve in a normal subject. Recordings
were made from the scalp (Cz'-Fpz'), the mid-thoracic spine (T6S-4 cm rostral), the lower thoracic spine (TI2S-4 cm rostral), and the lumbar
spine (L3S-4 cm rostral). Short-latency somatosensory evoked potentials elicited by stimulation of the common peroneal nerve at the knee occur
within 40 ms of the stimulus in normal subjects. It is suggested that individual response components be designated as follows: (I) Spine compo-
nents: L3 andTI2 spine potentials. (2) Scalp components: P27 and N35.The Cz' and Fpz' designations indicate that the recording scalp electrode
was placed 2 cm posterior to the International 10-20 Cz and Fpz electrode locations.

POSTERIOR TIBIAL NERVE
Cz' - Fpz'
T12S-4cm
rostral
L3S - 4 cm
rostral
PF - medial
surface
of knee
1 2jtV
I 1 I i l l
Figure 4. Short-latency somatosensory evoked potentials evoked by stimulation of the posterior tibial nerve at the ankle. Recordings were made
from the scalp (Cz'-Fpz'),The lower thoracic spine (TI2S-4cm rostral), the lumbar spine (L3S-4cm rostral), and the popliteal fossa (PF-medial sur-
face of knee). Short-latency somatosensory evoked potentials elicited by electric stimulation of the posterior tibial nerve at the ankle occur
within 50 ms of the stimulus in normal subjects. It is suggested that individual response components be designated as follows: (I) Nerve trunk
(tibial nerve) component in the popliteal fossa: PF potential. (2) Spine components: L3 andTI2 potentials. (3) Scalp components: P37 and N45
waves.The Cz' and Fpz' designations indicate that the recording scalp electrode was placed 2 cm posterior to the International 10-20 system Cz and
Fpz electrode locations.
VISUAL EVOKED POTENTIAL (VEP)

BRAINSTEM AUDITORY EVOKED
POTENTIAL (BAEP)
N175
I II III IV V
P100
0 100 200 250 ms

1 I » \ I I I I I t I
Figure 5. Normal occipital visual evoked potential to checkerboard _ J I I i I I I—I—I—
pattern reversal stimulation recorded between occipital (01) and 0 5 10 ms
vertex (Cz) electrodes showing N75, PI00 and N I 7 5 peaks.Visual
evoked potentials are electric waveforms of biologic origin recorded Figure 6. Normal brainstem auditory evoked potential to stimula-
over the cerebrum and elicited by visual stimuli.VEPs are classified by tion of the left ear, recorded between left ear (AI) and vertex (Cz)
stimulus rate as transient or steady state, and can be further divided electrodes. Brainstem auditory evoked potentials are electric wave-
by stimulus presentation mode.The normal transient VEP to checker- forms of biologic origin elicited in response to sound stimuli. The
board pattern reversal or shift has a major positive occipital peak at normal BAEP consists of a sequence of up to seven waves, designated I
about 100 ms (PI00), often preceded by a negative peak (N75).The to VII, which occur during the first 10 ms after the onset of the stimu-
precise range of normal values for the latency and amplitude of PI00 lus and have positive polarity at the vertex of the head. In this record-
depends on several factors: (I) subject variables, such as age, gender, ing, negativity in input terminal I or positivity in input terminal 2
and visual acuity, (2) stimulus characteristics, such as type of stimulator, causes an upward deflection.
full-field or half-field stimulation, check size, contrast and lumines-
cence, and (3) recording parameters, such as placement and combina-
tion of recording electrodes.
M WAVE
Stimulate
Wrist
Below elbow
Above elbow
Axilla
Supraclavicular fossa
10 mV
5 ms
Figure 7. M waves recorded with surface electrodes over the abductor digiti quinti muscle elicited by electric stimulation of the ulnar nerve at
several levels.The M wave is a compound muscle action potential evoked from a muscle by an electric stimulus to its motor nerve. By convention, the
M wave elicited by a supramaximal stimulus is used for motor nerve conduction studies. Ideally, the^recording electrodes should be placed so that the
initial deflection of the evoked potential from the baseline is negative.The latency, commonly called the motor latency, is the time from stimulation
(ms) to the onset of the first phase (positive or negative) of the M wave.The amplitude (mV) is the baseline-to-peak amplitude of the first negative
phase, unless otherwise specified.The duration (ms) refers to the duration of the first negative phase, unless otherwise specified. Normally, the con-
figuration of the M wave (usually biphasic) is quite stable with repeated stimuli at slow rates (1-5 Hz). See repetitive nerve stimulation.
F WAVE
F waves F waves
10 mV 1 mV
10 ms 10 ms
Figure 8. F waves recorded with surface electrodes over the abductor digiti quinti muscle elicited by electric stimulation of the ulnar nerve at the
wrist with two different gain settings.The F wave is an action potential evoked intermittently from a muscle by a supramaximal stimulus to the
nerve. Compared with the maximal amplitude M wave of the same muscle, the F wave has a smaller amplitude (I-5% of the M wave), variable con-
figuration and a longer, more variable latency.The F wave can be found in many muscles of the upper and lower extremities, and the latency is
longer with more distal sites of stimulation.The F wave is due to antidromic activation of motor neurons. It was named by Magladery and McDougal
in 1950. Compare with the H wave and the A wave. One of the late responses.
H WAVE
H wave
i 1
•• » +
10 ms
Figure 9. H waves recorded with surface electrodes over the soleus muscle elicited by electric stimulation of the posterior tibial nerve at the
knee.The stimulus intensity was gradually increased (top tracing to bottom tracing).The H wave is a compound muscle action potential having a con-
sistent latency evoked regularly, when present, from a muscle by an electric stimulus to the nerve. It is regularly found in adults only in a limited
group of physiologic extensors, particularly the calf muscles.The H wave is most easily obtained with the cathode positioned proximal to the
anode. Compared with the maximum amplitude M wave of the same muscle, the H wave has a smaller amplitude, a longer latency, and a lower opti-
mal stimulus intensity. The latency is longer with more distal sites of stimulation. A stimulus intensity sufficient to elicit a maximal amplitude M
wave reduces or abolishes the H wave.The H wave is thought to be due to a spinal reflex, the Hoffmann reflex, with electric stimulation of afferent
fibers in the mixed nerve to the muscle and activation of motor neurons to the muscle mainly through a monosynaptic connection in the spinal
cord.The reflex and wave are named in honor of Hoffmann's description in I9I8. Compare with the F wave.
A WAVE
10 ms
Figure 10. A waves (under arrow markers) recorded with surface electrodes over the abductor hallucis brevis elicited by electric stimulation of
the posterior tibial nerve at the level of the ankle (top four traces) and at the level of the knee (bottom four traces).The A wave is a compound
muscle action potential evoked consistently from a muscle by submaximal stimuli to the nerve and frequently abolished by supramaximal stimuli.The
amplitude of the A wave is similar to that of the F wove, but the latency is more constant.The A wave usually occurs before the F wave, but may
occur afterwards. It is thought to be due to extra discharges in the nerve, ephapses between adjacent nerve fibers, or axonal branching. Compare
with the F wave.
T WAVE
Tendon Tendon J1 mV
tap tap
20 ms
Quadriceps femoris Triceps surae
Figure II. T waves produced by triggering a microswitch in the handle of a reflex hammer by striking the patellar tendon (quadriceps femoris) or
the Achilles tendon (triceps surae).The T wave is a compound muscle action potential evoked by rapid stretch of a tendon, as part of the muscle
stretch reflex.
BLINK RESPONSES
R1 R2
Right Right
Left
J l m V
Stimulation on right side Stimulation on left side 10 ms
Figure 12. Blink responses recorded with surface electrodes over the right orbicularis oculi (upper tracings) and left orbicularis oculi (lower trac-
ings) elicited by electric stimulation of the supraorbital nerve on the right (left tracings) and on the left (right tracings).The blink responses are
compound muscle action potentials evoked from orbicularis oculi muscles as a result of brief electric or mechanical stimuli to the cutaneous area in-
nervated by the supraorbital (or less commonly, the infraorbital) branch of the trigeminal nerve.Typically, there is an early compound muscle
action potential (Rl wave) ipsilateral to the stimulation site with a latency of about 10 ms and a bilateral late compound muscle action potential (R2
wave) with a latency of approximately 30 ms. Generally, only the R2 wave is associated with a visible twitch of the orbicularis oculi.The configura-
tion, amplitude, duration, and latency of the two components, along with the sites of recording and the sites of stimulation, should be specified. RI
and R2 waves are oligosynaptic and polysynaptic brainstem reflexes, respectively, together called the blink reflex.The afferent arc is provided by the
sensory branches of the trigeminal nerve, and the efferent arc is provided by facial nerve motor fibers.
REPETITIVE NERVE STIMULATION

NORMAL RESPONSE
2 ms
Figure 13. Repetitive nerve stimulation study in a normal subject.The successive M waves are displayed to the right.The M waves were recorded
with surface electrodes over the hypothenar eminence (abductor digiti quinti) during ulnar nerve stimulation at a rate of 3 Hz. Note the configura-
tion of the successive M waves is unchanged. Repetitive nerve stimulation is a technique of repeated supramaximal stimulation of a nerve while
recording M waves from the muscle innervated by the nerve. It is commonly used to assess the integrity of neuromuscular transmission.The
number of stimuli and the frequency of stimulation should be specified. Activation procedures performed prior to the test should be specified, e.g.,
sustained voluntary contraction or contraction induced by nerve stimulation. If the test was performed after an activation procedure, the time
elapsed after it was completed should also be specified.The technique is commonly used to assess the integrity of neuromuscular transmission.
For a description of specific patterns of responses, see incrementing response, decrementing response, facilitation, and postactivation depression.
DECREMENTING RESPONSE
Figure 14. Repetitive nerve stimulation study in a patient with myasthenia gravis. Successive M waves were recorded with surface electrodes over the
rested nasalis muscle during repetitive facial nerve stimulation at a rate of 2 Hz, with a display to permit measurement of the amplitude and dura-
tion of the negative phase (left) or peak-to-peak amplitude (right). A decrementing response is a reproducible decline in the amplitude and/or area of
the M wave of successive responses to repetitive nerve stimulation.The rate of stimulation and the total number of stimuli should be specified.
Decrementing responses with disorders of neuromuscular transmission are most reliably seen with slow rates (2 to 5 Hz) of nerve stimulatiOn.A
decrementing response with repetitive nerve stimulation commonly occurs in disorders of neuromuscular transmission, but can also be seen in
some polyneuropathies, myopathies, and motor neuron disease. An artifact resembling a decrementing response can result from movement of the
stimulating or recording electrodes during repetitive nerve stimulation (pseudodecrement). Contrast with incrementing response.
REPETITIVE NERVE S T I M U L A T I O N
INCREMENTING RESPONSE
Figure 15. Repetitive nerve stimulation study in a patient with Lambert-Eaton myasthenic syndrome (LEMS). An incrementing response was
recorded with surface electrodes over the hypothenar eminence (abductor digiti quinti) during repetitive ulnar nerve stimulation at a rate of 50 Hz
with a display to permit measurement of the peak-to-peak amplitude (top) or amplitude and duration of the negative phase (bottom). An increment-
ing response is a reproducible increase in amplitude and/or area of successive responses (M waves) to repetitive nerve stimulation.The rate of stim-
ulation and the number of stimuli should be specified. An incrementing response is commonly seen in two situations. First, in normal subjects the
configuration of the M wave may change with repetitive nerve stimulation so that the amplitude progressively increases as the duration decreases,
but the area of the M wave remains the same.This phenomenon is termed pseudofacilitation. Second, in disorders of neuromuscular transmission,
the configuration of the M wave may change with repetitive nerve stimulation so that the amplitude progressively increases as the duration re-
mains the same or increases, and the area of the M wave increases.This phenomenon is termed facilitation. Contrast with decrementing response.

NORMAL (N), MYASTHENIA GRAVIS (MG), LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)
Rested Exercise T l m e AfterExercise

Muscle Time 3s 2 min 10 min
Figure 16. Repetitive nerve stimulation studies in a normal subject (N) and patients with myasthenia gravis (MG) and Lambert-Eaton myasthenic
syndrome (LEMS).Three successive M waves were elicited by repetitive nerve stimulation at a rate of 2 Hz.The three responses were superimposed.
This method of display emphasizes a change in the configuration of successive responses, but does not permit identification of their order. In each
superimposed display of three responses where the configuration did change, the highest amplitude response was the first, and the lowest amplitude
response was the third.After testing the rested muscle, the muscle was maximally contracted for 10 to 30 seconds (exercise time). Repetitive nerve
stimulation was carried out again 3 s, 2 min, and 10 min after the exercise ended.The results illustrate facilitation and postactivation depression.
j
PSEUDOFACILITATION
2 ms
Figure 17. Repetitive nerve stimulation study in a normal subject.The successive M waves were recorded with surface electrodes over the hy-
pothenar eminence (abductor digiti quinti) during ulnar nerve stimulation at a rate of 30 Hz. Pseudofacilitation may occur in normal subjects with
repetitive nerve stimulation at high (20—50 Hz) rates or after strong volitional contraction, and probably reflects a reduction in the temporal disper-
sion of the summation of a constant number of muscle fiber action potentials due to increases in the propagation velocity of muscle cell action po-
tentials with repeated activation. Pseudofacilitation should be distinguished from facilitation. The recording shows an incrementing response
characterized by an increase in the amplitude of the successive M waves with a corresponding decrease in the duration, resulting in no change in the
area of the negative phase of successive M waves.
INSERTION ACTIVITY
Figure 18. Insertion activity recorded by an intramuscular needle electrode in a normal subject. Insertion activity is the electric activity caused by
insertion or movement of a needle electrode within a muscle.The amount of the activity may be described as normal, reduced, or increased (pro-
longed), with a description of the waveform and repetitive rate.
END PLATE ACTIVITY
100 ms +
20 ms
Figure 19. Spontaneous activity recorded by an intramuscular needle electrode close to muscle end-plates. May be either of two forms:
1. Monophasic end-plate activity (upper and lower traces): Low amplitude (10 to 20 uV), short-duration (0.5 to I ms), monophasic (negative) poten¬
tials that occur in a dense, steady pattern and are restricted to a localized area of the muscle. Because of the multitude of different potentials oc-
curring, the exact frequency, although appearing to be high, cannot be defined.These nonpropagated potentials are probably miniature end-plate
potentials recorded extracellularly.This form of end-plate activity has been referred to as end-plate noise or sea shell sound (sea shell noise or roar).
2. Biphasic end-plate activity (upper trace): Moderate amplitude (100 to 300 uV), short-duration (2 to 4 ms), biphasic (negative-positive) spike po-
tentials that occur irregularly in short bursts with a high frequency (50 to 100 Hz), restricted to a localized area within the muscle.These
propagated potentials are generated by muscle fibers excited by activity in nerve terminals.These potentials have been referred to as end-
plate spikes, and, incorrectly, nerve potentials.
FIBRILLATION POTENTIAL
\—L—-4—i—i—i—i—j—L— [ 100 ms
50 ixV
Figure 20. Fibrillation potentials recorded by an intramuscular needle electrode.The top trace shows the waveform of a single fibrillation potential.The
bottom trace shows the pattern of discharge of two other fibrillation potentials which differ with respect to amplitude and discharge frequency. A fib-
rillation potential is the electric activity associated with a spontaneously contracting (fibrillating) muscle fiber. It is the action potential of a single muscle
fiber.The action potentials may occur spontaneously or after movement of the needle electrode.They usually fire at a constant rate, although a small
proportion fire irregularly. Classically, the potentials are biphasic spikes of short duration (usually less than 5 ms) with an initial positive phase and a
peak-to-peak amplitude of less than I mV.When recorded with concentric or monopolar needle electrodes, the firing rate has a wide range (I to 50 Hz)
and often decreases just before cessation of an individual discharge. A high-pitched regular sound is associated with the discharge of fibrillation poten-
tials and has been described in the older literature as "rain on a tin roof". In addition to this classic form of fibrillation potentials, positive sharp waves
may also be recorded from fibrillating muscle fibers when the action potentials arise from an area immediately adjacent to the needle electrode.
POSITIVE SHARP W A V E
POSITIVE SHARP WAVE
^ J 100 M-V
/ 10 ms
TRAIN OF POSITIVE SHARP WAVES
—*y; . i y i v ^ ^ ^ — r
^ j 200 jiV
10 ms
Figure 21. Positive sharp waves recorded by an intramuscular needle e/ectrode.The top trace shows a single positive sharp wave.The bottom trace
shows the pattern of initial discharge of a number of different positive sharp waves after movement of the needle electrode in a denervated
muscle. A positive sharp wave is a biphasic, positive-negative action potential initiated by needle movement and recurring in a uniform, regular pat-
tern at a rate of I to 50 Hz.The discharge frequency may decrease slightly just before cessation.The initial positive deflection is rapid (<l ms), its
duration is usually less than 5 ms, and the amplitude is up to I mV.The negative phase is of low amplitude, with a duration of 10 to 100 ms.A se-
quence of positive sharp waves is commonly referred to as a train of positive sharp waves. Positive sharp waves can be recorded from the damaged
area of fibrillating muscle fibers.Their configuration may result from the position of the needle electrode which is believed to be adjacent to the
depolarized segment of a muscle fiber injured by the electrode. Note that the positive sharp waveform is not specific for muscle fiber damage.
Motor unit action potentials and potentials in myotonic discharges may have the configuration of positive sharp waves.
MYOTONIC DISCHARGE
10 m s
Figure 22. Myotonic discharge recorded by an intramuscular needle electrode. A myotonic discharge is a repetitive discharge which fires at rates of 20
to 80 Hz.There are two types: (I) biphasic (positive-negative) spike potentials less than 5 ms in duration resembling fibrillation potentials,and (2) positive
waves of 5 to 20 ms duration resembling positive sharp waves. Both potential forms are recorded after needle electrode insertion, voluntary muscle con-
traction or muscle percussion, and are due to independent, repetitive discharges of single muscle fibers.The amplitude and frequency of the potentials
must both wax and wane to be identified as a myotonic discharge.This change produces a characteristic musical sound in the audio display of the
electromyograph due to the corresponding change in pitch, which has been likened to the sound of a "dive bomber". Contrast with waning discharge.
COMPLEX REPETITIVE DISCHARGE
Figure 23. Complex repetitive discharges recorded by an intramuscular needle electrode. A complex repetitive discharge is a polyphasic or serrated
action potential that may begin spontaneously or after needle movement.The discharges have a uniform frequency, shape, and amplitude, with abrupt
onset, cessation, or change in configuration. Amplitudes range from 100 uV to I mV and the frequency of discharge from 5 to 100 Hz.This term is
preferred to bizarre high frequency discharge, bizarre repetitive discharge, bizarre repetitive potential, or pseudomyotonic discharge.
FASCICULATION POTENTIAL
Figure 24. Fasciculation potentials recorded by an intramuscular needle electrode. Six different fasciculation potentials are displayed in the top
traces, on a time scale which permits characterization of the individual waveforms.The bottom two traces display fasciculation potentials on a time
scale which demonstrates the random discharge pattern. A fasciculation potential is an action potential which is often associated with a visible fasci-
culation. It has the configuration of a motor unit action potential but occurs spontaneously. Most commonly these potentials occur sporadically and
are termed "single fasciculation potentials". Occasionally, the potentials occur as a grouped discharge and are termed a "brief repetitive discharge!'
The repetitive firing of adjacent fasciculation potentials, when numerous, may produce an undulating movement of muscle (see myokymia). Use of
the terms benign fasciculation and malignant fasciculation is discouraged. Instead, the configuration of the potentials, peak-to-peak amplitude, duration,
number of phases, and stability of configuration, in addition to the frequency of occurrence, should be specified.
MYOKYMIC DISCHARGE
Figure 25. Tracings of two different myokymic discharges recorded with an intramuscular needle electrode are displayed on a time scale (left)
which illustrates the firing pattern and with a different time scale (right) which illustrates that the individual potentials have the configuration of a
motor unit action potential.A myokymic discharge is a group of motor unit action potentials that fire repetitively and may be associated with clinical
myokymia.lwo firing patterns have been described. (I) Commonly, the discharge is a brief, repetitive firing of single motor unit action potentials for
a short period (up to a few seconds) at a uniform rate (2 to 60 Hz) followed by a short period (up to a few seconds) of silence, with repetition of
the same sequence for a particular potential. (2) Rarely, the potential recurs continuously at a fairly uniform firing rate (I to 5 Hz). Myokymic dis-
charges are a subclass of grouped discharges and repetitive discharges.
NEUROMYOTONIC DISCHARGE
First dorsal interosseous
1
fjipBHP^*
II! ! llli llillllli i llllill

Abductor digiti quinti
II llil III llll ill il II1 111 IlllllllllBimMM
l l mV
i 1+
1s
Figure 26. Neuromyotonic discharges recorded by an intramuscular needle electrode are shown on a time scale which illustrates the characteristic
firing pattern. A neuromyotonic discharge is a burst of motor unit action potentials which originates in motor axons firing at high rates (150 to 300
Hz) for a few seconds.They often start and stop abruptly.The amplitude of the waveforms typically wanes. Discharges may occur spontaneously or be
initiated by needle electrode movement, voluntary effort, ischemia, or percussion of a nerve.These discharges should be distinguished from myotonic
discharges and complex repetitive d/schorges.They are one type of electrical activity that may be recorded in patients who have clinical neuromyotonia.
CRAMP DISCHARGE
1 mV
1s
Figure 27. Cramp discharges recorded by an intramuscular needle electrode.A cramp discharge arises from the involuntary repetitive firing of
motor unit action potentials at a high frequency (up to 150 Hz) in a large area of muscle, usually associated with painful muscle contraction. Both the
discharge frequency and the number of motor unit action potentials firing increase gradually during development, and both subside gradually with
cessation. See muscle cramp.
MOTOR UNIT A C T I O N POTENTIALS
10 ms
Figure 28. A selection of different motor unit action potentials recorded with an intramuscular needle electrode. A motor unit action potential is a
potential which reflects the electrical activity of a single motor unit. It is the compound action potential of those muscle fibers within the recording
range of an electrode. When it is produced by voluntary muscle contraction, the potential is characterized by its consistent appearance and rela-
tionship to the force of contraction.The following parameters may be specified, quantitatively if possible, after the recording electrode is placed ran-
domly within the muscle.
1. Configuration
a. Amplitude, peak-to-peak (uV or mV).
b. Duration, total (ms).
c. Number of phases (monophasic, biphasic, triphasic, tetraphasic, polyphasic).
d. Sign of each phase (negative, positive).
e. Number of turns.
f. Variation of shape (jiggle), if any, of consecutive discharges.
g. Presence of satellite (linked potentials), if any.
h. Spike duration, the duration of the spike including satellites.
2. Recruitment characteristics
a. Threshold of activation (first recruited, low threshold, high threshold).
b. Onset frequency.
c. Recruitment frequency (Hz) or recruitment interval (ms) of individual potentials.
Descriptive terms implying diagnostic significance are not recommended, e.g., myopathic, neuropathic, regeneration, nascent, giant, BSAP and BSAPP.
See polyphasic action potential, serrated action potential.
SATELLITE POTENTIAL
10 ms
Figure 29. Four discharges of the same motor unit action potential with satellite potentials are indicated by the arrows. A satellite potential is a
small action potential separated from the main motor unit action potential by an isoelectric interval which fires in a time-locked relationship to the
main action potential.These potentials usually follow, but may precede, the main action potential. Less preferred terms include late component, par-
asite potential, \inked potential, and coupled discharge.
RECRUITMENT PATTERN/INTERFERENCE PATTERN
Rest j Voluntary Contraction •
Weak Strong
500 piV
i , J +
0.5 s
Figure 30. Recordings made with an intramuscular needle electrode at five different levels of force of voluntary contraction. Recruitment refers to
the successive activation of the same and new motor units with increasing strength of voluntary muscle contraction.The recruitment pattern is a
qualitative and/or quantitative description of the sequence of appearance of motor unit action potentials during increasing voluntary muscle con-
traction.The recruitment frequency and recruitment interval are two quantitative measures commonly used.The interference pattern is the electric ac-
tivity recorded from a muscle with a needle electrode during maximal voluntary effort. A full interference pattern implies that no individual motor
unit action potentials can be clearly identified (see tracing on far right). A reduced interference pattern (intermediate interference pattern) is one
in which some of the individual motor unit action potentials may be identified while others cannot due to superimposition of waveforms.The term
discrete activity is used to describe the electric activity recorded when each of several different motor unit action potentials can be identified due
to limited superimposition of waveforms.The term single unit pattern is used to describe a single motor unit action potential, firing at a rapid rate
(should be specified) during maximum voluntary effort The force of contraction associated with the interference pattern should be specified.
SINGLE FIBER ELECTROMYOGRAPHY
A B C
Figure 31. Schematic representation of the location of the recording surface of a single fiber needle electrode recording from two muscle fibers
innervated by the same motor neuron (row I). Consecutive discharges of a potential pair are shown in a superimposed display (row 2) and in a
raster display (row 3).The potential pairs were recorded from the extensor digitorum communis of a patient with myasthenia graWs.They show
normal jitter (column A), increased jitter (column B),and increased jitter and impulse blocking (column C, arrows). Jitter is synonymous with "single
fiber electromyographic jitter". It is the variability of the interpotential interval between two muscle fiber action potentials belonging to the same motor
unit on consecutive discharges. It is usually expressed quantitatively as the mean value of the difference between the interpotential intervals of suc-
cessive discharges (the mean consecutive difference, MCD). Under certain conditions, jitter is expressed as the mean value of the difference between
interpotential intervals arranged in the order of decreasing interdischarge intervals (the mean sorted difference, MSD).
I486 — AAEM GLOSSARY OF TERMS
MACROELECTROMYOGRAPHY (MACRO-EMG)
•— *+
20 ms
Figure 32. Schematic representation of the location of the recording surface of the macro-EMG needle electrode recording from all the muscle
fibers innervated by the same motor neuron (upper diagram). Macro motor unit potentials recorded by the technique of macroelectromyography
(lower traces) from a healthy subject (column A) and from a patient with amyotrophic lateral sclerosis (column B). Macroelectromyography is a gen-
eral term referring to the technique and conditions that approximate recording of all muscle fiber action potentials arising from the same motor unit.
NEEDLE ELECTRODES
General purpose Special purpose
E1 E2 E1 E2 E1 E2 E1 E2 E1 E2 E1 E2
CCF
©2000
1. Concentric 2. Monopolar 3. Bipolar 4. Single Fiber 5. Macro
Figure 33. Schematic representation of five different types of needle electrodes. (I) The concentric needle electrode consists of a hollow, stainless
steel cannula (light gray) containing a centrally located wire (black) from which it is insulated.The latter serves as the active electrode (El), while the
entire barrel of the needle serves as the reference electrode (E2). (2) The monopolar needle electrode consists of a solid stainless steel needle coated
with insulation except for its distal tip, which serves as the cone-shaped recording surface (EI).The reference electrode (E2) consists of either an-
other monopolar needle electrode or a surface electrode. (3) The bipolar needle electrode consists of a stainless steel hollow cannula which contains
two wires, insulated from each other and from the cannula itself.The exposed distal tips of these wires on the bevel surface serve as the active (EI)
and reference (E2) electrodes. (4) Single fiber needle electrode. Similar to the concentric needle electrode, the proximal portion of this electrode con-
sists of a hollow cannula, which contains a central wire from which it is insulated.This wire, instead of ending on the bevel tip, is exposed through
a side port in the cannula opposite the bevel tip.The bared area serves as the active electrode (El) while the surface of the cannula serves as the
reference electrode (E2). (5) The macro-EMG needle electrode consists mainly of a modified single fiber needle electrode.Two different potentials are
recorded.The first is recorded from the single fiber EMG needle electrode.The recording surface opposite the bevel of the needle serves as the
active electrode (El), and the uninsulated portion of the cannula (light gray) serves as the reference electrode (E2).The potential recorded from
this electrode is used to trigger the sweep for recording the macro motor unit potential from the second electrode.The second electrode consists
of the uninsulated portion of the cannula, which serves as the active electrode (El).A surface electrode serves as the reference electrode (E2).
FULL WAVE RECTIFIED EMG
Figure 34. Motor unit action potentials recorded normally (top sweep) and simultaneously as a full wave rectified EMG signal (bottom sweep).A full
wave rectified EMG signal is the absolute value of the raw EMG signal. Full wave rectification involves inverting all the waveforms below the isopo-
tential line and displaying them with opposite polarity above the line. A technique used to analyze kinesiologic EMG signals.
1488 — AAEM GLOSSARY OFTERMS
SYMPATHETIC SKIN RESPONSE
Figure 35. Sympathetic skin response recorded from the palm following stimulation of the contralateral median nerve.The sympathetic skin re-
sponse is an electric potential resulting from electrodermal activity in sweat glands in response to both direct and peripheral or sympathetic trunk
stimulation of autonomic activity.
SECTION III: ABBREVIATIONS

The Glossary follows the recommendations of the Council of Biology Editors Style Manual (6th edition)1 for abbreviations of units
of measurement. The abbreviations are as follows:
meter m millivolt mV
centimeter cm microvolt
millimeter mm ampere A
hour h milliampere mA
minute min microampere uA
second s ohm O
millisecond |IS hertz Hz
volt V cycles per second cps or c/s
1. CBE Style Manual Committee. Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers, 6th ed. Council of Biology Editors, 1994.
Index
Page numbers in boldface type indicate complete chapters.
A Acoustic neuroma, 463 Adenocarcinoma

A bands, 23-24 Acquired immunodeficiency syndrome (AIDS), gastrointestinal, 1401
Abductor digiti minimi muscle conditions associated with pulmonary, 990
compound motor action potentials of, 66-67, distal symmetric polyneuropathy, 975 Adenoma, parathyroid, 1396
175 meningeal fungal infections, 769 Adenosine diphosphate, role in muscle
innervation of, 721, 722 multiple mononeuropathies, 977 contraction, 25
ulnar nerve conduction recordings from, neuropathy associated, 433 Adenosine triphosphatase, myofibrillar, pH of,
196-198 Acrodermatitis chronica atrophies, 974 1236-1237, 1238
Abductor hallucis muscle Acromegaly, 984, 1238, 1398-1399 Adenosine triphosphate
compression-induced evoked muscle action Acrylamide, as neuropathy cause, 1006 as active transport energy source, 5
potentials in, 133, 134 Actin, 22-23,25, 1269 role in muscle contraction, 25
innervation of, 722 acromegaly-related increase in, 1399 Adenosine triphosphate-binding cassette (ABC)
Abductor muscles, of hip, weakness of, 1233 Actin filaments, 22-24 transporter, 918
Abductor pollicis brevis muscle oc-Actin gene mutations, in nemaline myopathy, Adenovirus infections, as myositis cause, 1391
compound motor action potentials of, 65-66 1321 Adhalin, 1278
innervation of, 721 a-Actinin, 1269 Adie's pupils, in Sjogren's syndrome, 968
magnetic stimulation of, 422 deficiency of, 1283 Adrenal disorders, as myopathy cause, 1397-1398
Abductor pollicis longus muscle, innervation of, Action potentials, 8-10, 1450 Adrenal hypoplasia congenita, Duchenne muscular
721 intracellular, in denervated muscle fibers, 57-60 dystrophy-related, 1277-1278
Abscess intramuscular nerve, 46 Adrenal insufficiency, 1398
appendiceal, 867 intraoperative monitoring of, 463 Adrenoleukodystrophy, 917-918
psoas, 864 isopotential lines of, 263 Adrenomyeloneuropathy, 917-918
renal, 867 magnitude of, 71 Adynamia episodica hereditaria. See Periodic
retroperitoneal, 861-862 propagation of, 12-17, 18-19,24, 262-263 paralysis, hyperkalemic
Accessory process, of lumbar spine, 715, 717 all-or-none principle of, 14-15 Afterdepolarization, 24
Accommodation, 15,236, 1450 effect of demyelination on, 141-143 Afterdischarge, 1450
Acetabulum, fractures of, as sciatic nerve injury local circuit currents in, 30-31 Afterpotential, 1450
cause, 871-872 in myelinated muscle, 15-16 Alcoholics
Acetazolamide-responsive myotonia congenita, in myelinated nerve fibers, 167-169 myopathies in, 1405, 1414-1415
1306-1307 myelinated nerve optimization in, 16-17 neuropathies in, 987, 1014-1015
Acetyl-carnitine deficiency, 1004 passive current potentials in, 12-14 quantitative testing of, 433
Acetylcholine resting membrane potential in, 29-30 thiamine deficiency in, 1011
quantum of, 19 in unmyelinated muscle, 14-15 Alendrenate, 952
release and synthesis of in unmyelinated nerves, 30 Alendronate, as chronic inflammatory
effect of botulinum toxin on, 480, 481 effect of temperature on, 188 demyelinating polyneuropathy treatment,
in familial infantile myasthenia, 1195-1196 in Wallerian degeneration, 128 952
in neuromuscular transmission, 19-20 Activation, 1450 Alfentanil, effect on intraoperative
effect of organophosphates on, 1007 Activation procedures, 1450 neurophysiologic monitoring, 450
in tick paralysis, 1194 Active transport, 5, 6 Aliasing, 87, 110, 337, 338
Acetylcholine receptor-binding antibodies, 1165, Acute axonal motor-sensory neuropathy, 944-945 "All-median hand," 566
1183 differentiated from acute motor axonal "All-or-none principle," of action potential
Acetylcholine receptor-blocking antibodies, 1165 neuropathy, 845 propagation, 14-15
Acetylcholine receptor-modulating antibodies, Acute inflammatory demyelinating "All-ulnar hand," 561,566
1165-1166 polyradiculoneuropathy. See Guillain-Barre Alternating current (AC), 70-71, 106-107, 108
Acetylcholine receptors, 19 syndrome Alzheimer-characteristic proteins, inclusion body
in neuromuscular disorders Acute motor axonal neuropathy, 945-946 myositis-associated, 1381, 1382
abnormal response to depolarization by, 1148 Acute quadriplegic myopathy, 988 Amblyomma maculatum, 1193
decreased number of, 1147 Acyclovir, as herpes varicella zoster virus infection Ambulation. See also Gait
in myasthenia gravis, 1167-1168, 1199 treatment, 979 footdrop-related impairment of, 927-928
with short channel-open time, 1199 Acyl-coenzyme A, 1339 misonidazole-related impairment of, 1000
structure of, 20 Acyl-coenzyme A dehydrogenase deficiency, positive Trendelenburg sign during, 1233
Acetylcholinesterase, congenital deficiency of, 1341-1342 American Academy of Neurology, chronic
1196-1197 Adductor brevis muscle, innervation of, 722, 841 inflammatory demyelinating polyneuropathy
Acetylcholinesterase inhibitors, as myasthenia Adductor hallucis muscle, in sciatic nerve injury diagnostic criteria of, 947
gravis treatment, 1173 evaluation, 873 American Electroencephalographic Society,
Achalasia, botulinum toxin therapy for, 506 Adductor longus gracilis muscle, innervation of, somatosensory evoked potential recording
Acid maltase deficiency. See also Glycogenosis 841 recommendations of, 362, 372, 376
type 2; Pompe's disease Adductor longus muscle, innervation of, 722 4-Aminopyridine
myotonic potentials in, 1246 Adductor magnus muscle, innervation of, 722, 841 as botulism treatment, 1190
Acidosis, as osteomalacia cause, 1396 Adductor muscles potassium channel-blocking action of, 138
Acidosis, lactate, mitochondrial myopathy- femoral needle electromyography of, 868-869 Amiodarone, as neuropathy cause, 1001
associated, 1347 in obturator nerve injury, 870 Amish, limb-girdle muscular dystrophy in, 1279
Acoustic myography, 1450 Adductor pollicis muscle, innervation of, 721 Amoxicillin, as Lyme disease treatment, 974
1489
1490 — INDEX
Amphetamines Analog-to-digital (A/D) conversion (cont.) Antebrachial cutaneous nerves (com.)
as hypersensitivity vasculitis cause, 966 dwell time in, 85 lateral (cont.)
as myopathy cause, 1405 epoch or sweep in, 85 segmental somatosensory evoked potentials
Amphipathic substances, as plasma membrane horizon resolution in, 86-88 of, 390-391
component, 3 . latency measurement in, 87-88 sensory nerve conduction studies of, 206
Amphotericin, as myopathy cause, 1405 Nyquist frequency in, 87, 110, 338 median, 781
Amplification, 77 sampling frequency in, 85 sensory nerve conduction studies of,
central, effect on somatosensory evoked vertical resolution in, 85-86 206-207
potential waveforms, 574 • Anal sphincter muscles, external posterior, anatomic course of, 784
differential, 78-79 innervation of, 849 Anterior horn cell disease, 1205-1206
electrodiagnostic problems associated with, needle electromyographic evaluation of, 874 as infant hypotonia cause, 1439-1440
553-554 in radiculopathies, 538, 753 Anterior horn cells
gain in, 77 Anal wink, 753 in motor neuron disease, 531
effect on nerve conduction studies, 182 Anatomic knowledge, of electrodiagnostic muscle fiber innervation by, 267
effect on onset latency, 183 medicine practitioners, 566 Anterior tarsal tunnel syndrome, 1100-1101
sensitivity of, 77 Anconeus muscle, innervation of, 721 Anterior tibial compartment syndrome,
Amplifiers, 77-79, 112-113, 553 Anderson's disease. See Glycogenosis, type 4 1096
common-mode rejection ratio of, 79 Anesthesia Anticholinesterase drugs
common-mode signals of, 78 effect on brainstem auditory evoked potentials, as congenital myasthenic syndrome treatment,
difference-mode signals of, 78 448, 450,451 1200
differential amplification quality of, 78-79, 258 effect on intraoperative neurophysiologic as Lambert-Eaton myasthenic syndrome
gain by, 112 monitoring, 446-453 treatment, 1182
input impedance of, 77-78, 258 as malignant hyperthermia cause, 1313-1314 Anticipation phenomenon, in spinocerebellar
preamplification by, 112 effect on motor evoked potentials, 466 ataxia, 924
sensitivity of, 186 as musculocutaneous nerve injury risk factor, Antiepileptic medication, as diabetic neuropathy
in sensory nerve conduction studies, 553-554 809 treatment, 980
settings of, in routine electromyography, 260 as myopathy cause, 1405, 1413-1414 Antiganglioside antibodies
Amplitude, 1450 as peripheral nerve injury risk factor, 825 in acute axonal motor-sensory neuropathy, 944,
Amplitude decay, 1450 effect on somatosensory evoked potentials, 945
Amputees, upper-limb, axillary nerve injuries in, 384 in Guillain-Barre syndrome, 939
808 Aneurysm in Miller-Fisher syndrome, 946
Amyloid, beta-pleated sheets of, 995 of anterior cerebral artery, 460-461 in multifocal acquired demyelinating sensory
Amyloid deposition. See Amyloidosis of internal carotid artery, 459-460 and motor neuropathy, 959
Amyloidosis pelvic arterial, 855 in multifocal motor neuropathy, 957
acquired, primary and secondary, 994-995 Aneurysm surgery, intraoperative Antigliadin antibodies, in celiac disease, 986
familial, 994 neurophysiologic monitoring during, Anti-Hu antibodies, 887
polyneuropathies associated with, 914—915 458-461,464-465 in paraneoplastic neuronopathy/ganglionopathy,
in hemodialysis patients, 985 Angier disease. 919 990
histologic detection of, 1236 Angiitis, allergic. See Churg-Strauss syndrome in small-cell lung cancer, 966
immunohistochemistry of, 995 Angiofollicular lymph node hyperplasia Anti-Hu antibodies-associated encephalomyelitis-
in inclusion body myositis, 1381-1382 (Castleman's disease), 949, 955, 993, 994 neuropathy syndrome, 990
light-chain immunoglobulin, 1401-1402 Angiokeratoma corporis difTusum (Fabry's Anti-Hu syndromes, 990, 1401
in multiple myeloma-associated neuropathy, 993 disease), 917 Anti-mitochondrial antibodies, in primary biliary
in myopathies, 1401-1402 Angiotrophic large-cell lymphoma, neuropathy cirrhosis, 987
Amyotrophic lateral sclerosis associated with, 991 Anti-neuronal antibodies, in sensory neuropathies,
differentiated from multifocal motor neuropathy, Anhidrosis 961
956-957 idiopathic sensory Anti-neutrophil antibodies, in Churg-Strauss
edrophonium testing in, 1165 neuronopathy/ganglionopathy-related, syndrome, 965
El Escorial diagnostic criteria for, 532-533 962 Anti-nuclear antibodies, in rheumatoid vasculitis,
fasciculation potentials in, 280 leprosy-related, 971 969
hyperparathyroidism associated with, 1396 Sjogren's sydrome-related, 968 Anti-nuclear antibody assay, 1235
Lambert's electrodiagnostic criteria for, 532 Anhidrosis, hereditary sensory and autonomic Antiretroviral agents, neurotoxicity of, 976
macro electromyographic studies of, 1256 neuropathy-associated, 914 Anti-ribonucelar protein antibodies, in systemic
needle electromyographic studies of, 534 Anions, 27-28 lupus erythematosus, 1376-1377
nerve conduction studies of, 533-534 anodal attraction of, 91 Anti-striatal antibodies, 1164-1165, 1166
neurotransmission junction disorders in, definition of, 6 Anti-tubulin antibodies, in chronic inflammatory
1205-1206 Anismus, botulinum toxin therapy for, 506 demyelinating polyneuropathy, 949
quantitative electromyographic studies of, 349 Ankle, sprain of, as common peroneal nerve injury Anus, imperforate, 874
spasticity associated with, 887 cause, 1095 Apolipoprotein A1 gene mutations, 915
ulnar neuropathy associated with, 1086 Annulus fibrosus, 715, 716 Aponeurosis (lacertus fibrosus), bicipital, 1055,
Amyotrophy in spinal stenosis, 756 1056
diabetic, 754, 769, 857-859, 981, 983 Anodal block, 49-50, 91, 173, 183, 552, 1450 Ara-c (cytosine arabinoside), as neuropathy cause,
neuralgic. 803-804, 815-817 Anodal break excitation, 173 997, 1000
hereditary, 910-911 Anodes Arachnoiditis, as radiculopathy cause, 769
suprascapular nerve in, 806 definition of, 91, 101 Arbovirus infections, as myositis cause, 391
Amytal testing, 464 in peripheral nervous system depolarization. Arcade of Frohse, 1091, 1092
Anabolic steroids, as muscle hypertrophy cause, 172,173 Arcade of Struthers
1238 reversal with cathode position, 552-553, 896 ulnar nerve location in, 1071
Anal fissures, botulinum toxin therapy for, 506 rotation of, 546, 547 as ulnar neuropathy site, 1076
Analgesic agents, intravenous, as total intravenous stability of, 553 Arcuate ligament, as ulnar neuropathy site,
anesthetic (TIVA), 450, 451, 452-453 in volume conduction, 27-28 1079
Analog-to-digital (A/D) conversion, 85-89, 90, Anoxia, 132 Areflexia
258,337-338 Antabuse, as neuropathy cause, 1002-1003 chronic inflammatory demyelinating
aliasing in, 87, 110, 337, 338 Antebrachial cutaneous nerves neuropathy-related, 949
averaging in, 88-89, 173, 182-183, 341, 554 lateral, 809 Guillain-Barre syndrome-related, 937, 938
bins or sample points in, 85 injuries to, 809 Miller-Fisher syndrome-related, 946-947
INDEX — 1491
Arm Autosomal recessive hereditary inclusion body Azathioprine (cont.)
cutaneous nerves of myopathy, 1294 as multifocal motor neuropathy treatment, 959
lower, 1088 Averaging, 88-89, 173, 182-183, 554, 1451 as myasthenia gravis treatment, 1174-1175
lower lateral, 810-811 needle electromyographic spike-triggered, 341 phosphodiesterase-inhibiting effect of, 1202
medial, 783 A-wave, 251-252, 1450, 1474 as systemic vasculitis treatment, 967
posterior, 810, 1088 Axilla as vasculitic neuropathy treatment, 967
median nerve anatomy in, 1047-1059 arteriographic procedures in, as plexopathy Azidothymidine. See Zidovudine
proximal weakness in, 1233 cause, 824-825
radial nerve injuries in, 1089-1090 innervation of, 781 B
right, numbness and weakness in, 928-930 as median and ulnar nerves' stimulation site, Backaveraging, 1451
Aromatic monocarboxylic acids, as myotonia 227 Backpack (rucksack) paralysis, 822-823
cause, 1316-1317 as median nerve injur}' site, 811 Bacterial infections. See also specific bacteria
Arrhythmias as nerve stimulation site, 227 as inflammatory myopathy cause, 1372
acute motor axonal neuropathy-related, 945 Axillary artery, needle injuries to, 824 myositis associated with, 1391
dermatomyositis-related. 1375 Axillary F-loop latency, 242 Bacteriophage, of Clostridium botulinum, 1186
Guillain-Barre syndrome-related, 939 Axillary nerve, 781 Balanced bridge electrical circuits, 103, 104
Arsenic anatomic course of, 784, 805, 808, 809 Bands of Bungner, 117, 121, 122
as neuropathy cause, 1010-1011 injuries to, 808 Barbiturates, effect on intraoperative
screening for exposure to, 887 needle electromyographic examination of, 809 neurophysiologic monitoring, 451-452
Arteriography stimulation of, 228, 229 Barnhardt-Roth syndrome, 865
axillary, 824-825 upper-limb muscle innervation by, 721 Basal lamina, 162
for median nerve injury evaluation, 811 Axillary vein, spontaneous occlusion of, 818 Basement membrane, 22
Arteriovenous malformation surgery, Axis, cervical, 717 Batteries
intraoperative monitoring during, 461-462, Axolemma, 15, 138, 160 constant voltage maintenance by, 99, 100-101
464-465 resistive and capacitive components of, 139, 140 electronic circuits of, 69-71
Arteritis, 964 . Axonal chronic inflammatory demyelinating Beevor's sign, 1285
Arthralgia, polyarteritis nodosa-related, 965 polyneuropathy, 955 Behcet's disease, 966, 1386
Arthritis, Sjogren's syndrome-related, i 376 Axonal degeneration/reaction, 116, 119 Bell's palsy
Arthroplasty, of the hip Axonal loss aberrant facial nerve regeneration in, 496
as sciatic nerve injury cause, 872 brachial plexopathy-reiated, 786, 789-790 absence of facial wrinkles in, 506
sciatic nerve monitoring during, 468,469 electrodiagnostic determination of, 793, 794 facial nerve dysfunction in, 974
Articular processes, inferior and superior, 714 peripheral neuropathy-related, 530-531, facial nerve side-to-side amplitude in, 232
Artifact, 1450 1043-1044 Benediction sign, 1052, 1055, 1086
Arylsulfatase A gene, mutations of, 916 radiculopathy-related, 538,729-730 Bent spine/dropped head syndrome, 1290-1291
Asian patients, thyrotoxic periodic paralysis in, 1383 with structural damage, 786 Benzodiazepines
Asthenia, 1231 without structural damage, 786 effect on intraoperative neurophysiologic
Asthma, Churg-Strauss syndrome-related, 965 Axonal motor-sensory neuropathy, acute, 944-945 monitoring, 452
Asterixis, 1450 Axon hillock, 160, 239-241 as tetanus treatment, 1193
Ataxia, 1450 Axonopathies, 889 Beriberi, 1011
acrylamide-related, 1006 Axonotmesis, 125,786, 1457 Bernstein, Julius, 7
chronic inflammatory demyelinating Axon reflex, 251-252 Bethlem myopathy, 1290
polyneuropathy-related, 949 in brachial plexopathies, 799-800 Biceps brachii muscle
of gait, celiac disease-related, 986 Axons, 137 biopsy of, in giant-cell myositis, 1165
hereditary, 920-924 action potentials of. See Action potentials compound motor action potentials of, 229
abetalipoproteinemia-related, 920, 922-923 collateral sprouting of, 120, 281 innervation of, 721
Friedreich's, 920-921 in chronic inflammatory demyelinating macro-electromyographic recordings in, 1256
Marinesco-Sjogren-Garland syndrome- polyneuropathy, 951 as musculocutaneous nerve stimulation site,
related, 924 effect of botulinum toxins on, 480, 481 228, 229
spinocerebellar, 920, 923-924 in motor nerve injuries, 743 Biceps femoris muscle, innervation of, 722, 841
vitamin E deficiency-related, 920, 921-922 in polymyositis, 1378 Biceps muscle, motor unit reinnervation of, 282
hereditary episodic, 971 diameter of, injury-related decrease in, 127 Bile duct cancer, 966
human immunodeficiency virus infection- equivalent circuit diagram of, 139-140 Binary (digital) signals, 69, 70
related, 977 growth rate of, 120-121 Biopsy
idiopathic sensory neuropathy/ganglionopathy- myelinated, current flow in, 167 of brachial plexus, in multifocal acquired
related, 960-961 nodal, 165 demyelinating sensory and motor
sensory, 887 optimal ratio with myelin, 16 neuropathy, 960
Ataxins, 924 regeneration of, age factors in, 1433 of liver, 1235
Atlas, cervical, 716 resistive and capacitive components of, 139, 140 of muscle, 294
Atony, 1235 in segmental demyelination, 122-123 contraindication in diabetic thigh infarction,
Atorvastatin, as myopathy cause, 1404, 1405-1406 selective permeability of, 7-8 1399
Auditory evoked potentials, 1451 in severe nerve injuries, 17, 118 in critical illness/acute quadriplegic
effect of anesthetic agents on, 450, 452 structure of, 160-161 myopathy, 1403
Autoimmune connective tissue diseases, 968-969 transport mechanisms of, 162 in dermatomyositis, 1375
Autonomic dysfunction, chronic inflammatory Axon terminal, 17 in diabetic thigh infarction, 1399
demyelinating polyneuropathy-related, 949 Axoplasm, 160-161 false-negative results in, 1237-1238
Autonomic nervous system, effect of botulinum resistive and capacitive components of, 140 following or prior to needle
toxins on, 482 Axoplasm streaming, 162 electromyography, 287-288
Autonomic neuropathy, 960-962 Azathioprine in giant-cell myositis, 1165. 1385
diabetic, 981 as chronic inflammatory demyelinating in inclusion body myositis, 1381
human immunodeficiency virus infection- polyneuropathy treatment, 953 in myofibrillar myopathy, 1241
related, 977 inefficacy as multifocal motor neuropathy needle, 1235
Autonomic sensory testing treatment, 959 in neonatal hypotonia, 1439
in Guillain-Barre syndrome, 943 as inflammatory myopathy treatment, 1387, open, 1235
in peripheral neuropathies, 890, 892 1388 in sarcoid myopathy, 1385
Autosomal dominant hereditary inclusion body as Lambert-Eaton myasthenic syndrome of nerves, in peripheral neuropathies, 888
myopathy, 1280 treatment, 1183 renal, in microscopic polyangiitis, 966
1492 — INDEX
Biopsy (cont.) Botulinum neurotoxins (cont.) Brachial plexopathies (cont.)
of skin, in peripheral neuropathies, 888 therapeutic uses of (cont.) incomplete, 785
of superficial peroneal nerve, in nonsystemic contraindications to, 484 infraclavicular, 806-812
vasculitis, 967 in gastrointestinal disorders, 506 of axillary nerve, 808-809
of sural nerve, in vasculitis, 965 in hemifacial spasm, 482, 484, 495, 496-497 of lateral cord, 807
Birth brachial plexus palsy, 1444 in hyperfunctional facial lines, 506 of medial cord, 806-807
Bisphosphonates, as systemic vasculitis treatment, in hyperhydrosis, 507 of musculocutaneous nerve, 809-810
967 " in limb dystonia, 498-500,508-509 of peripheral nerves, 807-808
Black widow spider bites, 1202 with needle electromyography, 484—486 of posterior cord, 807
Bladder, neurogenic, idiopathic sensory in nondystonic tremor, 500-501 of radial nerve, 810-812
neuronopathy/ganglionopathy-related, 962 in oromandibular dystonia, 497-498 of ulnar nerve, 812
Bladder cancer, paclitaxei treatment for, 998 in pain, 507-508 ischemia-related, 787
Blanket principle, of low-frequency filters, 336, pharmacology of, 482-483 laceration-related, 785, 786-787
337 resistance to, 483-484 motor nerve conduction studies of, 790,
Blepharospasm, botulinum toxin therapy for, 482, in spasmodic dysphonia, 489-493 792-794
484, 496 in spasticity, 501-505 needle electromyographic studies of, 791, 792,
Blink reflex, 232-234, 1244, 1451 in strabismus and ocular motility disorders, 796-798
in idiopathic sensory 494-496 spontaneous activity in, 796-797
neuronopathy/ganglionopathy, 961 toxicity of, 484 voluntary motor unit action potential activity
in infants and children, 1436 in voice tremor and stuttering, 493 in, 797-798
latencies and amplitudes of, 234 Botulism, 479,482, 1183-1190 needle-induced, 824-825
in Lyme disease, 974 clinical forms of neoplastic, 821-822
in Miller-Fisher syndrome, 947 classic or food-borne, 1183-1184, 1195 nerve root avulsion-related, 787-788
neural pathway of, 232, 233 hidden, 1184 nerve root stimulation studies of, 794-795
in paraneoplastic sensory inadvertent, 1185 as neuralgia amyotrophy, 815-817
neuronopathy/ganglionopathy, 990 infantile, 1184, 1187, 1440, 1441-1442 of obstetric origin, 784-785, 814-815,
in sarcoidosis, 970 wound, 1184, 1185 1444
in Sjogren's sydrome, 968 diagnosis of, 1189-1190 open, 785
waveforms associated with, 552 edrophonium testing in, 1165 as partial lesions, 749
Blocking, 329, 330, 331, 332, 333, 334, 336, 1148, histopathology of, 1185-1186 pathophysiology of, 785-788
1451 as infant hypotonia cause, 1440, 1441-1442 perioperative, 823-824
Blood, resistivity of, 100 intravenous drug abuse-related, 1184 postanesthetic, 824
Blood flow, cerebral motor nerve conduction studies of, 1169, postganglionic, 785, 786
effect on electroencephalogram, 455 1187- 1188 preganglionic, 785, 786, 789-790
during intraoperative neurophysiologic needle electromyographic studies of, 1169, progression of, 788
monitoring, 453-454 1188- 1189 retroclavicular, 806
effect on somatosensory evoked potentials, pathogenesis and pathophysiology of, scapular winging associated with, 802,
455^156 1186- 1187 803-804
Body temperature, effect on electrodiagnostic repetitive nerve stimulation studies of, sensory nerve conduction studies of, 790-792
examination results 1187- 1188 somatosensory evoked potentials studies of,
in brachial plexopathies, 825 sensory nerve conduction studies of, 1169, 1187 795-796
documentation of, 517 single-fiber electromyographic studies of, 1169, sports-related (burners/stingers), 820-821
in Lambert-Eaton myasthenic syndrome, 1182 1189 stretch or traction-related, 786, 787-788
in nerve conduction studies, 188-191, 536, treatment of, 1189-1190 supraclavicular, 800-806
558-560, 563, 896 Brachial artery, association with median nerve, as C5 and C6 root lesions, 800-801
effect on nerve conduction velocity, 188-191 1048 as C8 and Tl root lesions, 801
in demyelinated nerves, 141 Brachialis muscle, innervation of, 721 as C7 root lesions, 801
in neuromuscular junction disorders, 536, Brachial ligament, internal, 1071 as peripheral nerve lesions, 801-804,
1156-1157 Brachial plexopathies, 777-863 805-806
effect on somatosensory evoked potentials, age factors in, 784-785 as trunk lesions, 804-805
383-384 anatomic and physiologic correlates of, 798-800 surgical treatment of, intraoperative
Boltzmann's constant, 108 axon reflex, 799-800 neurophysiologic monitoring during,
Bone computed tomography, 798 467-468
cancellous, 714 magnetic resonance imaging, 798-799 as thoracic outlet syndrome, 817-820
cortical, 714 myelography, 798, 799 thoracic polyradiculopathy-associated, 982
resistivity of, 100 plain radiography, 798 traction-related, 798
Bone density, osteomalacia-related decrease in, backpack (rucksack) paralysis, 822-823 Brachial plexus, 1451
1396 cancer-related, 991-992 anatomy of, 777, 778-784
Bone marrow transplantation, neuropathies classification of, 785 cervical and thoracic roots, 778-779, 780
associated with, 996 closed, 785 communicating branches, 780-783
Borrelia burgdorferi, 966, 973 complete, 785 cords, 778, 780, 783-784
Botulinum neurotoxins compression-related, 787 major upper limb peripheral nerves, 778, 780,
commercial preparations of, 482-484 differential diagnosis of, 812-814, 1086 783-784
immunologically distinct types of. 1183 direct plexus stimulation evaluation of, 795 terminal nerve branches, 808-810
as inadvertent botulism cause, 1185 electrodiagnostic medicine pitfalls in trunks and divisions, 778, 779-780, 783
pathogenic mechanisms of, 1186-1187 false-negative investigations, 825-826 biopsy of, in multifocal acquired demyelinating
physiology and pharmacology of, 479-482 false-positive investigations, 826 sensory and motor neuropathy, 960
cell intoxication, 479-480 electrophysiologic correlates of, 788-790 as post-fixed plexus, 779
postsynaptic neurophysiologic effects, 481 axonal loss, 786, 789-790 as pre-fixed plexus, 779
presynaptic neurophysiologic effects, conduction block, 786, 788-790 stimulation of, in neuromuscular junction
480-481 demyelination, 786, 789 disorders, 1159
structure and activation, 479 F-wave in, 794 Brachial plexus palsy, birth, 1444
therapeutic uses of, 486-489 gender differences in, 784-785 Brachioradialis muscle, innervation of, 721
in blepharospasm, 482, 484, 496 H-reflex in, 794 Brain, celiac disease-related degeneration of,
in cervical dystonia, 483-484, 486-489 illustrative cases of, 826-830 986
in eervicopharyngeal dysphagia, 493 incidence/prevalence of, 784 Brain stem, myelination of, 1436
INDEX — 1493
Brainstem auditory evoked potentials (BAEPs), Campylobacter jejuni infections, Guillain-Barre Carpal tunnel syndrome (cont.)
1451, 1471 syndrome-associated, 938, 939-940, 944, "inching" technique in, 1062
as far-field potentials, 35-36 945, 946, 996 indications for electrodiagnostic consultation in,
intraoperative monitoring of, 443 Cancer. See also Paraneoplastic syndromes; 1067-1070
effect of anesthetic agents on, 448, 450, 451 specific types of cancer intermediate, 1059
in arteriovenous malformation surgery, brachial plexopathies associated with, 821-822 Lyme disease-related, 974
461-462 dermatomyositis associated with 1375 Martin-Gruber anastomosis associated with,
effect of elevated intracranial pressure on, 454 of lumbosacral plexus, 859-860 560-561, 1068-1069
in posterior fossa and cranial nerve surgeries, myopathies associated with, 1401 microvascular compression hypothesis of, 1061
461,463 neuropathies associated with, 989-996 motor nerve conduction studies of, 1062,
recording techniques in, 469, 470 acquired amyloidosis, 994-995 1065-1066
effect of ventilation on, 454 bone marrow transplantation-related, 996 needle electromyographic studies of, 1066-1067
waveform peaks of, 443 chronic inflammatory deyelinating orthodromic techniques in, 1062
Brain tumors, neuropathies and radiculopathies polyneuropathy, 949 prevalence of, 1058-1059
associated with, 991 cryptogenic sensory or sensorimotor quantitative sensory testing of, 434
Brain tumor surgery, intraoperative monitoring polyneuropathy, 990-991 radial nerve in, 526
during, 462-463 graft-versws-host disease-related, 996 renal failure-associated, 985, 986
Branching enzyme deficiency. See Glycogenosis, lymphoproliferative disorders-related, in renal failure patients, 985
type 4 992-994 ring finger electrodiagnostic technique in, 1062
Breast cancer, 989, 990 monoclonal gammopathies-related, 992-994 risk factors for, 1059, 1060
metastatic, 821, 991 monoclonal gammopathy of uncertain sensory nerve conduction studies of, 1061,
paclitaxel treatment for, 998 significance-related, 995-996 1062, 1063-1065
Brief small abundant polyphasic potentials paraneoplastic neuropathies, 989-990 severity grading of, 1070
(BSAPPs), 284 tumor infiltration-related, 991-992 ulnar nerve injuries associated with, 1068-1069
British anti-Lewisite, as lead neuropathy treatment, vasculitis associated with, 966 Castleman's disease
1009 Capacitance, 70, 104-106 chronic inflammatory demyelinating
Brody's disease, 1248, 1315 as biological signal distortion cause, 106 neuropathy-related, 949
Brown recluse spider bites, 1202 definition of, 104 Castleman's disease (angiofollicular lymph node
Bulbocavernosus reflex, 211, 753, 874 Capacitance resistance (X c ), 71 hyperplasia), 949,955, 993,994
(3-Bungarotoxin, 1202 Capacitive reactance, of needle electrodes, 73-74 chronic inflammatory demyelinating
Burners, 820-821 Capacitors, 70, 80-81, 1004-1006 neuropathy-related, 949
Burn injury patients, critical illness components of, 14 Catabolism, increase of
polyneuropathy in, 988 definition of, 14 cancer-related, 1401
Burn patients, sensorimotor peripheral neuropathy impedance of, 105, 106 myopathies associated with, 1412-1413
in, 988 time constant of, 105 Cataracts, corticosteroids-related, 952
Burns-Garland syndrome, 981 Cap disease, 1319, 1325 Cathode ray tubes (CRTs), 90, 113, 258
Buttocks, lumbosacral plexopathy-related pain in, Capsaicin, as postherpetic neuralgia treatment, 979 Cathodes
877-878 Capsaicin cream, as painful sensory neuropathy definition of, 91, 101, 1452
Bytes, 85 treatment, 976 orientation with E-1 recording electrodes, 183
Carbamazepine in peripheral nervous system depolarization,
C as painful sensory neuropathy treatment, 976 172-173
Cachexia as postherpetic neuralgia treatment, 979 reversal with anode position, 552-553, 896
diabetic neuropathic, 981 Carbohydrates, as plasma membrane component, 3 stability of, 553
myoedema associated with, 1234 Carbon dioxide, transport through cell membranes, in volume conduction, 27-28
Calcaneal nerves 4 Cations, 27-28
anatomy and anatomic course of, 848, Carbon disulfide exposure, as neuropathy cause, definition of, 6
1101-1102 1006 Cauda equina
inferior, isolated compromise of, 1105 Carbon monoxide exposure, as neuropathy cause, anatomy of 723
somatosensory evoked potential studies of, 1008 compression of, in acromegaly, 984
402-403 Cardiomyopathy, autosomal recessive, with intraneural edema of, 728
Calcification, subcutaneous, dermatomyositis- ophthalmoplegia, 1348 nerve root involvement in, 724
related, 1375 Carnitine deficiency, 1339-1341 Caveolin-3 gene, 1267, 1269
Calciphylaxis, 1395 Carnitine palmityltransferase 2, 1339, 1341 mutations of, 1281
Calcium Carnitine transporter protein gene, 1340-1341 Caveolins, 1269
homeostasis of, 1395 Carotid artery, internal, aneurysm of, 459-460 Celiac disease, 986
release from sarcoplasmic reticulum, 24-25 Carotid balloon test occlusion, 465 as folic acid deficiency cause. 1013
Calcium channelopathies, 1202, 1309-1313 Carpal tunnel Cellubrevin, 1187
Calcium channels anatomy of, 1049, 1059 Center frequency, 1452
in neuromuscular transmission, 18-19 median nerve in, 1050-1051 "Centimetering" technique. See "Inching"
voltage-dependent, 1307 surgical decompression of, 1068 technique
a - 1 A subunit of, 924 Carpal tunnel syndrome, 524-525, 1058-1070, Central conduction time
Calcium disodium ethylenediamine tetraacetate, as 1243,1433, 1451-1452 aging-related changes in, 575
lead neuropathy treatment, 1009 acromegaly-associated, 984 of F-wave latency, 242
Calcium ions, in neuromuscular transmission, acute/subacute, 1067 Central core disease, 333, 1240-1241. 1313, 1317,
18-19 advanced, 1059 1318,1319-1320
Calcium supplementation, as osteomalacia-related amyloid myopathy-related, 1401 Central electromyography, 1452
myopathy treatment, 1396 amyloidosis-associated, 995 Central motor conduction, 1452
Calf, innervation of, 841, 848, 1094, 1099 antidromic techniques in, 1062 Centrally-acting medications, as myopathy cause,
Calf, lateral cutaneous nerve of, 848, 1094 cervical radiculopathy-associated, 750 1413_1414
compression of, 1099 in children and adolescents, 1061 Central nervous system
Calipers, obstetric, use in nerve measurement, definition of, 1058 aging-related changes in, 187
186-187, 199 in diabetic patients, 983 H-reflex elicitation from, 249-253
Calpain-3, 1267 diagnostic testing for, 1059 sarcoidosis of, 969-970
limb-girdle muscular dystrophy-related early, 1059 Centronuclear myopathy, 1318, 1322-1323
deficiency of, 1279 electrodiagnostic medicine techniques in, 1062 Cerebellopontine surgery, 463
Calpains, in critical illness myopathy, 1402 hypothyroidism-related, 984 Cerebral artery, anterior, aneurysm of, 460-461
1494 — INDEX
Cerebral cortex, magnetic stimulation of, 417-422, Children (cont.) Clofibrate, as myopathy cause, 1404
424 nerve conduction velocity in, 562 Clostridial spores, as honey contaminant, 1184
Cerebrospinal fluid, resistivity of, 100 neural physiology of, 1433-1436 Clostridium botulinum, 1186
Cerebrotendinous xanthomatosis (cholestanolosis), pudendal nerve examination in, 874 Clostridium botulinum toxins. See Botulinum
919-920 sciatic nerve injury in, 872 neurotoxins
Cerivastatin, as myopathy cause, 1404 sedation of, 1437 Clostridium species, 1186
Cervical nerve root stimulation, 225-227 tick paralysis in, 1194 CMAP. See Compound motor action potentials
Cervical spine toxic myopathies in, 1403 Coat's disease, 1285
anatomy of, 716-717 Chinese paralytic syndrome, 945 Cobalamin. See Vitamin B ] 2
magnetic stimulation of, 423, 424 Chlorambucil Cocaine
radiculopathies of, 747-750 as inflammatory myopathy treatment, 1387, as hypersensitivity vasculitis cause, 966
as somatosensory evoked potential recording 1389 as myopathy cause, 1405
site, 366, 367 as systemic vasculitis treatment, 967 nasal sniffing of, 1184
Cestodes, as myositis cause, 1392 Chloramphenicol, neuropathies associated with, Coccyx, anatomy of, 714, 718
Chagas'disease, 1392-1393 1004 Cockayne's syndrome, 924-925
Channelopathies Chloride anions, passive distribution of, 8 Coenurosis, 1392
calcium, 1202, 1309-1313 Chloride channelopathies, 24, 1301-1302 Cogan's sign, 1163
chloride, 24, 1301-1302 Chloride ions, plasma membrane lipid bilayer Colchicine
diffuse abnormal insertional activity in, permeability of, 4, 5 as amyloidosis treatment, 995
1315-1316 Chloroquine as folic acid deficiency cause, 1013
potassium, 1313 as myopathy cause, 1405, 1407-1408 as myopathy cause, 1405, 1408
Schwartz-Jampel syndrome (chondrodystrophic as neuropathy cause, 1000-1001 as neuropathy cause, 1001-1002
myotonia), 1297, 1316 Cholangiocarcinoma, 949 Colitis, ulcerative, 987
sodium, 1302-1313 Cholestanolosis (cerebrotendinous xanthomatosis), Collagen, type VI, in Bethlem myopathy, 1290
cardiac, 1313 919-920 Collision, 1452
hyperkalemic periodic paralysis as, Cholesterol, as plasma membrane component, 3 Collision technique, 235-236
1303-1305, 1308-1309 Cholesterol-lowering drugs, as myopathy cause, Collodion, 72
Chaperones, for pudendal nerve examinations, 874 1404-1406 Colon cancer, 949
Charcot-Marie-Tooth disease, 886, 899-910 Cholesterol-lowering drugs, as myopathy cause, Coma, somatosensory evoked potential-based
classification of, 900 1405 prognostic evaluation of, 405-407
as syndrome, 899 Cholinergic crisis, 1173 Common mode rejection ratio, 112-113
type 1,900-905 Chromatolysis, central, 119 Compartment syndromes
type 2, 900, 906-907,910 Chronic idiopathic sensory polyneuropathy, anterior tibial, 1096
type 3, 900, 903, 907-908 1015-1016 pathophysiology of, 728
type 4, 900, 908-909 Chronic inflammatory demyelinating peroneal, 1096, 1098
X-linked, 900, 909-910 polyneuropathy, 939, 956, 976, 977, 1452 retroperitoneal, 861
Cheiralgia paresthetica, 1094 axonal variant of, 955 Complement activation
Chelation therapy in children, 954 in acute motor axonal neuropathy, 946
for arsenic-related neuropathy, 1011 diagnostic criteria for, 947, 948 in Guillain-Barre syndrome, 939
for lead-related neuropathy, 1009 human immunodeficiency virus infection- Complex repetitive discharges, 276-277, 1452,
for thallium-related neuropathy, 1010 associated, 976, 977, 978-979 1481
Chemical denervation, with botulinum neurotoxin. laboratory evaluation of, 887 in amyloid myopathy, 1402
See Botulinum neurotoxins myasthenia gravis-associated, 1164 in brachial plexopathies, 796-797
Chemotherapy paraprotein-related neuropathies associated in peripheral neuropathies, 892
for leukemia, 991 with, 954-955 in polymyositis and dermatomyositis, 1378
for lymphoma, 991 relationship with multifocal acquired in radiculopathies, 740
neuropathies associated with, 996-1005 demyelinating sensory and motor Compound motor action potentials (CMAP)
Childbirth neuropathy, 959, 960 in acromegaly, 984
as brachial plexopathy cause, 784-785, relationship with symmetric, painless diabetic in acrylamide-related neuropathy, 1006
814-815, 1444 polyradiculopathy, 982-983 in acute axonal motor-sensory neuropathy, 945
as femoral nerve injury cause, 867 symmetric, painless diabetic in acute motor axonal neuropathy, 945, 946
as lumbosacral plexopathy cause, 862-863 polyradiculoneuropathy-related, 982-983 in alcoholic myopathy, 1414
as neonatal humeral fracture cause, 1089 Chronic obstructive pulmonary disease, in alcoholic neuropathy, 1015
as peroneal nerve injury cause, 1095? neuropathies associated with, 988 amplitude of, 178
Children. See also Infants Churg-Strauss syndrome (allergic interstimulus distance-related variability of,
botulinum toxin dosages in, 501 angiitis/granulomatosis), 965 556-557
brachial plexopathies in, 785 differentiated from polyarteritis nodosa, 965 effect of temperature on, 189, 190, 191
carpal tunnel syndrome in, 1061 Chvostek's sign, 281, 1396, 1401 in amyloidosis, 995
chronic inflammatory demyelinating CIDP. See Chronic inflammatory demyelinating in anomalous innervation, 192-193
polyneuropathy in, 954 polyneuropathy area of, 179
clinical evaluation of, 1232-1233 Ciguatoxin, 1201 in arsenic-related neuropathy, 1011
dermatomyositis in, 1374" Cimetidine, as myopathy cause, 1405, 1412 in asymmetric, painful diabetic
electrodiagnostic evaluation of, 1433-1447 Circuit current flow, 31 polyradiculopathy, 982
needle electromyography in, 320-321, Circuit model, of waveform morphology, 31 biphasic, 45, 46
1438-1439 Circumflex nerve. See Axillary nerve in carbon disulfide-related neuropathy, 1006
nerve conduction studies in, 1438 Cirrhosis, primary biliary, 987-988 in chronic idiopathic sensory polyneuropathy,
of specific disease processes, 1439-1445 Cisplatin, as neuropathy cause, 996, 997, 998 1016
techniques in, 1437 Clarithromycin, as leprosy treatment, 973 in chronic inflammatory demyelinating
Guillain-Barre syndrome in, 943-944, 945 Claudication, neurogenic, 757 polyneuropathy, 951
human immunodeficiency virus infection in, Claw hand, ulnar, 1074-1075, 1083, 1086 in colchicine-related neuropathy, 1002
1444 Clinical evaluation, in electrodiagnostic medicine effect of compression on, 134
Lyme disease treatment in, 974 consultations, 1229-1235, 1242 conduction velocity of, 177-178
median mononeuropathy in, 1444 Clinical impression, in electrodiagnostic medicine correlation with nerve fiber diameter, 169-171
motor unit action potentials in, 571, 572 consultations, 518 in critical illness/acute quadriplegic myopathy.
myasthenia gravis in, 1176 Clinical Neuropathy Disability Score, 955 1403
myositis in, 1390 Clitoris, dorsal nerve of, 850 in critical illness polyneuropathy, 989
INDEX — 1495
Compound motor action potentials (cont.) Compound motor action potentials (cont.) Conduction block (cont.)
in dapsone-related neuropathy, 1003 in paraneoplastic neuronopathy/ganglionopathy, chronic inflammatory demyelinating
of deep peroneal nerve, in distal leg, ankle, and 990 polyneuropathy-related, 951
foot region, 1101 in perhexiline maleate-related neuropathy, 1001 compression-related, 131
in diabetic proximal neuropathy, 858 in peripheral neuropathies, 891, 1043, 1044, definition of, 131
in diphtheritic neuropathy, 975 1045 demyelinating, 786
in disulfiram (antabuse)-related neuropathy, in peroneal nerve neuropathies, 1096, 1097 Guillain-Barre syndrome-related, 941, 942
1003 phase cancellation in, 48 intermediate neural injury-related, 133
in drug-induced neuropathies, 997, 998, 1000, phase of, 176 internodal induction time in, 140-141
1001, 1002, 1003, 1004, 1005 in phenytoin-related neuropathy, 1005 ischemic, 786
in Duchenne muscular dystrophy, 1274-1275 in podophyllin-related neuropathy, 1002 leprosy-related, 973
duration of, 178 in POEMS syndrome, 994 multifocal motor neuropathy-related, 957-958
in eosinophilia myalgia syndrome, 1005 premotor potentials of, 46, 47 peripheral neuropathy-related, 891, 1044-1045
in ethylene oxide-related neuropathy, in pyridoxine-related neuropathy, 1004 prolonged, anatomic basis of, 137
1006-1007 in radial nerve neuropathies, 1090 radiculopathy-related, 730
of facial nerve, 231 in radiation-related lumbosacral plexopathies, rate-dependent, 141
in folic acid deficiency-related neuropathy, 1013 860 severity grading of, 124
in gastrointestinal disease-associated in radiculopathies, 732-733 in vasculitis secondary to essential mixed
neuropathies, 986 recording of, 72, 73, 175-179, 181-182 cryoglobinuria, 967
in gold therapy-related neuropathy, 1011 in recurrent branch of the median nerve, 1070 Counduction velocity, 1453
in Guillain-Barre syndrome, 940-941, 942 relationship with F-wave, 239, 241, 243-244 Congenital fiber type disproportion, 1318, 1323¬
in children, 943-944 rise time of, 178-179 1324
in variant forms, 945. 946, 947 in sarcoidosis, 970 Congenital hypomyelination hereditary
in herpes varicella zoster virus infection, 978 stability of, 179 neuropathy, 907-908, 1441
in hexacarbon-related (glue sniffer's) effect of stimulation site location on, 36 Congenital myasthenic syndromes, 1195-1200
neuropathy, 1008 in suramin-related neuropathy, 999 with abnormal acetylcholine-acetylcholine
high-frequency decrease in, 83-84 surface electrode recordings of, 72, 73 receptor interactions, 1200
in human immunodeficiency virus infection- in symmetric/painful diabetic edrophonium testing in, 1165
related progressive polyradiculopathy, 977 polyradiculopathy, 983 as hypotonia cause, 1442
in hyperparathyroidism, 1396 in tarsal tunnel syndrome, 1104 with mode-switching kinetics, 1199-1200
in hypoglycemia, 984 effect of temperature on, 559 partially characterized, 1200
in hypoglycemia/hyperinsulinemia-related termination latency of, 177 postsynaptic space disorders, 1197-1200
polyneuropathy, 984 in thalidomide-related neuropathy, 1002 presynaptic disorders, 1195-1196
in hypothyroidism, 984 in thallium-related neuropathy, 1010 synaptic space disorders, 1196-1197
in industrial and environmental toxin-induced in thyroid disorders, 1394 treatment of, 1200
neuropathies, 1006-1007, 1008 triphasic, 45, 47 Congenital myotonia dystrophy, as hypotonia
in infants and children, 943-944, 1434, 1438 in ulnar nerve neuropathies cause, 1440, 1442
intramuscular nerve action potentials of, 46 in arm region, 1076 Congenital peripheral neuropathies, as hypotonia
intraoperative recording of, 449, 452, 458 in distal arm and supracondylar region, 1076 cause, 1441
during peripheral nerve surgery, 466-467, in elbow region, 1081 Congenital radial nerve palsy, 1089
468 in forearm region, 1082-1083 Congenital sensory neuropathy with anhidrosis,
during posterior fossa and cranial nerve in wrist region, 1085 914
surgery, 463 in uremic neuropathy, 985, 986 Connectin, 1269
in Kiloh-Nevin syndrome, 1057-1058 in vasculitis secondary to essential mixed Connective tissue, increase in, 1241
latency of cryoglobinuria, 967 Connective tissue disease
of activation, 176 in vincristine-related neuropathy, 998 autoimmune, neuropathies associated with,
errors in measurement of, 558 in vitamin B, 2 deficiency, 1012 968-969
leading/trailing dipole model of, 45 secondary to nitrous oxide inhalation, 1013 inflammatory myopathy associated with, 1232
in leprosy, 973 in vitamin B, deficiency-related neuropathy, vasculitis associated with, 966
in lithium-related neuropathy, 1005 1012 Connexins, 163
low-frequency filter evaluation of, 83 in vitamin E deficiency-related neuropathy, co-Conotoxin, 1202
in lumbosacral plexopathies, 853-854 1014 Consecutive amplitude difference, 337
in Lyme disease, 974 in Wallerian degeneration, 129 Constipation
in Martin-Gruber anastomosis, 1068-1069 waveforms of, 80 anti-Hu antibodies-associated
measurement of, 175-179 low-frequency subcomponent, 895-896 encephalomyelitis-neuropathy syndrome-
in median nerve neuropathies morphology of, 45-47 related, 990
at bicipital aponeurosis (lactates fibrosus), near-field and far-field component idiopathic sensory
1055 waveforms, 65-67 neuronopathy/ganglionopathy-related, 962
in forearm region, 1058 negative waveform/spike, 178 vincristine-related, 998
in pronator teres syndrome, 1056 Compression Consultations, in electrodiagnostic medicine,
in mercury poisoning, 1009 as brachial plexopathy cause, 787 515-540
in metronidazole-related neuropathy, 1000 effect on compound motor action potentials, 134 examples of, 517-524
in Miller-Fisher syndrome, 947 as conduction block cause, 131 unacceptable consultations, 522-524
modeling of, 171-172 as intermediate neural injury cause, 132-137 formulating an approach in, 524-539
in monoclonal garrunopathy of uncertain Computed tomography (CT) in diffuse weakness, 531, 532
significance, 996 for brachial plexopathy evaluation, 798 in motor neuron disorders, 531-534
in multifocal motor neuropathy, 957 for carpal tunnel syndrome evaluation, 1060 in neuromuscular junction transmission
in multiple myeloma-associated neuropathy, 993 for pelvic mass evaluation, 855, 859, 860 disorders, 535-538
in neoplastic plexopathies, 859 Computers, use in electrodiagnostic medicine, in painful lower limb and low back region,
in neuralgic amyotrophy of the lumbosacral 113-114, 141-143, 296,298, 299-300, 358, 528-529
plexus, 857 517 in painful upper limb and cervical region,
in nitrofurantoin-related neuropathy, 1003 Concentric needle electrodes, 1452 524-525
in nucleoside-related neuropathy, 1004 Conditioning stimulus, of axonal membrane, 236 in peripheral neuropathies, 529-531
onset latency of, 176-177 Conduction block, 123-125, 1452-1453 in primary muscle disease (myopathy),
amplifier sensitivity in, 77 brachial plexopathy-related, 793, 795 534-535
in organophosphates-related neuropathy, 1007 carpal tunnel syndrome-related, 1067, 1068 in radiculopathy/polyradiculopathy, 538-539
1496 — INDEX
Consultations (cont.) Creatine kinase, serum levels of (cont.)
medical history in, 515-516, 541 as idiopathic inflammatory myopathy marker, DADS (distal acquired demyelinating symmetric)
physical examination in, 516, 541 1373-1374 neuropathy, 955-956
report generation in, 515-518 as inflammatory myopathy marker, 1386, 1387, Danon disease, 1337
recommendations section of, 518 1388 Dapsone
Contiguous gene syndrome, 1277 needle electromyography-related increase in, as leprosy trearment, 973
Contraction fasciculation, 1453 288 as neuropathy cause, 1003
Contractures Creatine monohydrate, 1281 Davidenkow syndrome, 1288
definition of, 1248 as muscular dystrophy treatment, 1277 Debranching enzyme deficiency. See
Emery-Dreifuss muscular dystrophy-associated, Cremaster muscle, innervation of, 841 Glycogenosis, type 3
1288 CREST syndrome, 969, 1376 Deceleration injuries, to lumbosacral plexus, 860
McArdle's disease-associated, 281 Cricoarythenoid muscle, posterior Decomposition technique, in interference pattern
Volkmann's, 1058 action of, 490 analysis, 324-325
Conus medullaris, 723 as botulinum toxin injection site, 493 Decrementing response, 1453
Coprophyria, hereditary, 925, 926 Critical illness myopathy, 1402-1403 Deflazacort, as Becker muscular dystrophy
Coracobrachialis muscle, innervation of, 721 Critical illness polyneuropathy, 988-989, treatment, 1276
Cori-Forbes disease. See Glycogenosis, type 3 1443_1444 Dehydroepiandrosterone, as myotonic dystrophy
Cornea reflex, 234 Critical interval of conduction, 237 treatment, 1299
Corporotransverse ligaments, 720 Crohn's disease, 987 Dejerine-Sottas disease. See Charcot-Marie-Tooth
Corticosteroids Crow-Fukase syndrome. See POEMS syndrome disease, type 3
adverse effects of, 952, 1174, 1388, 1397-1398 Crush injury Delay, 1453
as chronic inflammatory demyelinating endoneurial tubes in, 121, 126 Delay line, 1453
polyneuropathy treatment, 952 nerve conduction velocity in, 126-127 Deltoid muscle, innervation of, 721
as eosinophilia myalgia syndrome treatment, neural changes in, 117 Dementia
1005 Cryoglobulinemia, essential mixed, vasculitis celiac disease-related, 986
as generalized necrotizing myopathy treatment, associated with, 966-967 Whipple's disease-related, 987
1401 Cryptogenic sensory polyneuropathy, 433-434 Demyelinating polyneuropathies, acquired
as Graves' disease treatment, 1394 cancer-associated, 990-991 chronic, 947-960
as herpes varicella zoster virus infection aB-Crystallin, 1269 chronic inflammatory demyelinating
treatment, 979 expression in inclusion body myositis, 1381, polyneuropathy, 947-955
as idiopathic inflammatory myopathy treatment, 1382 distal acquired demyelinating symmetric
1386-1387 Cubital tunnel syndrome, 526, 1079, 1453 neuropathy, 955-956
as Lambert-Eaton myasthenic syndrome Cumulative trauma disorder, 1067 multifocal acquired demyelinating sensory and
treatment, 1183 Curare testing, in neuromuscular junction motor neuropathy, 955, 959-960
as myasthenia gravis treatment, 1173-1174 disorders, 1160-1162 multifocal motor neuropathy, 956-959
as myopathy cause, 1397-1398 Current (I), 70 Demyelinating polyradiculoneuropathies
as myopathy cause, 1405 Current sink, 31, 262-263 inflammatory, human immunodeficiency virus
as polymyalgia rheumatica treatment, 1417 in large-volume conductors, 32, 33 infection-related, 976-977
as systemic vasculitis treatment, 967 in restricted-volume conductors, 32 sensorimotor, suramin-related, 999
as vasculitic neuropathy treatment, 967 Current source, 31 Demyelination
Corynebacterium diphtherial as diphtheritic Cushingoid appearance, 1174 in acute axonal motor-sensory neuropathy, 944
neuropathy causal organism, 974 Cushing's syndrome, 1397-1398 anatomic/electrical aspects of, 140-141
Costotransverse lamella, 715, 717 Cutaneous reflex, 1453 in brachial plexopathy, 786, 789
Coulomb, 99 Cyclophosphamide in chronic inflammatory demyelinating
Coxsackie virus infection, myositis associated as chronic inflammatory demyelinating neuropathy, 949
with, 1391 polyneuropathy treatment, 953 computer modeling of, 141-143
Cramp discharge, 1483 as inflammatory myopathy treatment, 1387, as conduction block cause, 786, 789
Cramps, 1231 1389 electrodiagnostic medicine criteria for, 940
electromyographic recordings in, 281 as multifocal acquired demyelinating sensory electrophysiologic evidence of, 940-941
hyperparathyroidism-related, 1395 and motor neuropathy treatment, 960 experimental production of, 133-137, 140
hypothyroid myopathy-related, 1395 as multifocal motor neuropathy treatment, 959 focal, 1044-1045
motor unit action potentials in, 1248 as myasthenia gravis treatment, 1175 in radiculopathy, 730
multifocal motor neuropathy-related, 957 as systemic vasculitis treatment, 967 in Guillain-Barre syndrome, 939, 941
physical examination of, 1233 as vasculitic neuropathy treatment, 967 electrodiagnostic criteria for, 940
Cranial nerves Cyclosporine in lymphoma-associated neuropathy, 993
5. See Trigeminal nerve as chronic inflammatory demyelinating merosin gene mutation-related, 1267
7. See Facial nerve polyneuropathy cause, 949 in Miller-Fisher syndrome (Guillain-Barre
11. See Spinal accessory nerve as Graves' disease treatment, 1394 variant), 947
in amyloidosis, 995 as inflammatory myopathy treatment, 1387, in monoclonal gammopathy of uncertain
in diabetic mononeuropathies, 983 1389 significance, 996
in Guillain-Barre syndrome, 939 as myasthenia gravis treatment, 1175 refractory periods in, 237
in human immunodeficiency virus infection- as myopathy cause, 1405 segmental, 122-123
related multiple mononeuropathies, as necrotizing myopathy cause, 1406 in acromegaly, 984
977 Cyst, Baker's, 1105, 1106 in diphtheritic neuropathy, 975
intraoperative monitoring of, 462,463 Cystercercosis, 1392 fibrillation potentials in, 136-137
in motor neuron disease, 534 Cytokines in intermediate neural injury, 132-133
nerve conduction studies of, 230-235 cancer-associated, 1401 in motor and sensory polyneuropathies, 893
in neuralgic amyotrophy, 817 sepsis-associated, 1402 in perhexiline maleate-related neuropathy,
in paraneoplastic neuronopathy/ganglionopathy, Cytomegalovirus infection, 938, 978, 1391 1001
989 human immunodeficiency virus infection- in vitamin B P deficiency-related neuropathv,
in peripheral neuropathies, 890 associated, 977 1012
in sarcoidosis, 969 vasculitis-associated, 966 in sensory polyneuropathy, 892-893, 894
in tick paralysis, 1194 Cytoplasmic body myopathy. See Myofibrillar in Waldenstrom's macroglobulinemia, 994
in Wegener's granulomatosis, 965-966 myopathy Dendrotoxin, 1202
Creatine kinase, serum levels of, 1235 Cytosine arabinoside, as neuropathy cause, 997, Denervated muscle fibers, intracellular action
as dermatomyositis marker, 1375-1376 1000 potentials of, 57-60
INDEX — 1497
Denervation Dielectrics, 70, 100, 104 Dural root sleeve, 723
motor unit reinnervation after, 281-282 Diffusion, 4—5 Duration, 1454
j myopathy-related, 294 facilitated, 5 Dwarfism, 1399
j Dens, 717 simple, 4-5 "Dying back" neuropathy, 529, 889
Deoxyribonucleic acid (DNA) testing, for Digital nerves Dynamo (generator), 108
hereditary myopathies, 1235 palmar, common, 1051 Dysarthria
Depolarization, 9-10, 12, 1453 proper, 1051-1052 acrylamide-related, 1006
definition of, 5 anatomy of, 847, 848 chronic inflammatory demyelinating
in neural stimulation, 49-50 Digital processors. See Computers neuropathy-related 949
of peripheral nervous system, 172-173 Dihydropyridine receptors, 1269, 1270 dermatomyositis-related, 1374
effect of volume conduction on, 547-552 in hypokalemic periodic paralysis, 1310-1311 Miller-Fisher syndrome-related, 946
zone of, 547-552 1,25-Dihydroxy-vitamin D, 1395, 1396 Dysautonomia
Dermatitis, acrylamide-related, 1006 Dinoflagellates, lethal toxins of, 1201 anti-Hu antibodies-associated
Dermatocentor andersoni, 1193 Diodes, 111, 112 encephalomyelitis-neuropathy syndrome-
Dermatomal somatosensory evoked potentials, Diphtheria toxin-antitoxin, demyelination- related, 990
398-400, 738, 1453 inducing activity of, 140 familial, 912, 913-914
L5,398-399 Diphtheritic neuropathy, 974-975 Dysesthesia
SI, 399-400 Diplopia, myasthenia gravis-related, 1163 asymmetric, painful diabetic polyradiculopathy-
Dermatomes, 726, 727 Dipole, 28 related, 982
Dermatomyositis, 969, 1374-1376, 1444 Direct current (DC), 71 paraneoplastic syndromes-related, 989
amyopathic, 1375 Direct muscle stimulation, 551-552 Dysferlin, 1267, 1269
clinical features of, 1300 in critical illness polyneuropathy, 989 Dysferlin gene mutations, 1280, 1294
differentiated from polymyositis, 1374-1375 Direct nerve stimulation, in brachial plexopathy, Dysphagia
electrodiagnostic findings in, 1377-1379 795 chronic inflammatory demyelinating
inflammatory bowel disease-associated, 987 Discoid lupus erythematosus, thalidomide neuropathy-related 949
with ischemic induced muscle fiber necrosis, treatment for, 1002 cricopharyngeal, botulinum toxin therapy for,
1401 Distal acquired demyelinating symmetric 493
overlap syndromes of, 1376-1377 neuropathy,' 955-956 dermatomyositis-related, 1374
sarcoid myopathy-associated, 1385 Distal latency, 1454 inclusion body myositis-related, 1380
Desflurane, effect on intraoperative Distal myopathies, 1291-1295 Miller-Fisher syndrome-related, 946
neurophysiologic monitoring, 447 Laing myopathy, 1292, 1293, 1295 myasthenia gravis-related, 1163
Desmin, 1269 Markesbery-Griggs-Udd myopathy, 1292-1293 polymyositis-related, 1373
Desmin myopathy. See Myofibrillar myopathy Miyoshi myopathy, 1279-1280, 1292, 1293, Dysphonia, spasmodic, botulinum toxin therapy
Desmin storage myopathy. See Myofibrillar 1294-1295 for, 489-493
myopathy Monaka myopathy, 1292, 1293-1294, 1295 Dysplasia, cerebro-ocular. See Walker-Warburg
Dehusor-sphincter-dyssnergia, botulinum toxin with vocal cord paralysis and pharyngeal syndrome
therapy for, 505 weakness, 1295 Dystonia, botulinum toxin treatment for, 481-482
Diabetes mellitus Welander myopathy, 1292-1293 in cervical dystonia, 483-484, 486-489
amyotrophy associated with, 754, 769, 857-859, Distal symmetric polyneuropathy in limb dystonia, 498-500, 508-509
981 diabetic sensory, 979-981 in oromandibular dystonia, 497-498
carpal tunnel syndrome associated with, 983 human immunodeficiency virus-related, Dystrobrevin, 1266
chronic inflammatory demyelinating 975-976 in Duchenne muscular dystrophy, 1271
polyneuropathy associated with, 949 Disulfiram, neuropathies associated with, a-Dystroglycan, merosin binding by, 1283
lateral cutaneous nerve of the calf compression 1002-1003 |3-Dystroglycan deficiency, muscular dystrophy-
associated with, 1099 Diuretics related, 1284
limb mononeuropathies associated with, 983 as myoglobinuria treatment, 1416 Dystroglycans, 1266-1267
myopathy associated with, 1399 as myopathy cause, 1405 in Duchenne muscular dystrophy, 1271, 1273
nephropathy of, 1399 Docetaxel (Taxotere), neuropathies associated dystrophin-associated, 1266
neuropathies associated with, 979-983, 1399 with, 997, 999 Dystrophic myotonia-protein kinase gene, 1298
asymmetric, painful polyradiculoneuropathy, Dorsal columns, as somatosensory evoked Dystrophin
9 8 1 -982 potential pathway, 359-360, 361-362, 364 deficiency of, 1274
distal symmetric sensory and sensorimotor Dorsal cutaneous nerve, medial/intermediate, in Duchenne muscular dystrophy, 1271, 1273
polyneuropathy, 979-981 lower-limb innervation by, 841 postsynaptic density localization of, 1266
mononeuropathies, 983 Dorsal root, 722 revertant fibers of, 1271
neuropathic cachexia, 981 Dorsal scapular nerve, 781-782 structure of, 1266
polyradiculoneuropathy, 981 upper-limb muscle innervation by, 721 Dystrophin-associated proteins/glycoprotein.
proximal neuropathy, 857-859 Double crush syndrome, 750, 1066-1067, 1086 1266-1267
symmetric, painless polyradiculoneuropathy, Double discharge, 1454 Dystrophin gene, 1274
982-983 Double-step test, 1159, 1160, 1161 Dystrophin gene therapy, for Duchenne muscular
paraspinal muscle instability associated with, Down syndrome, as hypotonia cause, 1443 dystrophy, 1277
742 Doxycycline, as Lyme disease treatment, 974 Dystrophin-glycoprotein complex, 1266-1268
retinopathy of, 1399 Droperidol, effect on intraoperative in Duchenne muscular dystrophy, 1273
4-Diaminopyridine neurophysiologic monitoring, 451 function of, 1268
as congenital myasthenic syndrome treatment. Dropped-head syndrome, 949, 1384, 1395 in y-sarcoglycanopathy, 1273
1200 Drug abuse Dystrophin-related protein. See Utrophin
as Lambert-Eaton myasthenic syndrome intravenous, as botulism cause, 1184
treatment, 1182-1183 maternal, 1435 E
Diaphragm, myasthenia gravis-related weakness as myopathy cause, 1405, 1414-1415 Early growth response 2 (ERG2) gene, mutations
of, 1163 Drugs. See also names of specific drugs of, 904
Diazacholesterol, as myotonia cause, 1317 as hypersensitivity vasculitis cause, 966 Early recruitment, 1454
Dichlorophenoxyacetic acid, as neuropathy cause. as myotonia cause, 1317 Echinococcus, 1392
1008 neuromuscular transmission-modulating effects Echovirus infections, myositis associated with,
Didanosine, as neuropathy cause, 1004 of, 1201-1205 1391
Dideoxycytidine, 433 Duodenojejunal resection, as folic acid deficiency Eclampsia, 1442
neurotoxicity of, 976 cause, 1013 magnesium sulfate treatment of, as
Dideoxyinosine, neurotoxicity of, 976 Dura, in nerve root avulsion, 798, 799 hypermagnesemia cause, 1400
1498 — INDEX
Edema, of nerve roots, 728 Electrodes (cont.) Electromyography (EMG) (cont.)
Edrophonium (Tensilon), as congenital myasthenic surface, 71-73, 572 needle (cont.)
syndrome treatment, 1200 application to skin, 72 in dapsone-related neuropathy, 1003
Edrophonium (Tensilon) test, 1165 cables for, 72 decomposition/multi-motor unit action
Elbow composition of, 71 potential analysis in, 299-300
dislocations of, as median nerve injury cause, continuity of, 72 definition of, 257
1053 for cranial nerve studies, 231-233, 234 in dermatomyositis and polmyositis,
ulnar neuropathy in, 1076-1082 electrode bias potential of, 71 1377-1379
electrodiagnostic evaluation of, 1079-1082 in peripheral nervous system depolarization, in diabetic neuropathies, 980, 981, 982, 983
Elderly patients, toxic myopathies in, 1403 172-174 in diabetic thigh infarction, 1399
Electric silence, 1454 separation of, 72-73 in diffuse weakness, 532
Electrical charge size of, 72 in diphtheritic neuropathy, 975
build-up and discharge of, 99, 100 Electrodiagnostic medicine examination, display gains or sensitivity in, 297
flow of, 99-100 1243-1259, 1454 in disulfiram (antabuse)-related neuropathy,
negative or positive, 98-99 false-negative studies in, 1261 1003
Electrical circuits false-positive studies in, 1259-1260 documentation of results of, 517
alternating current (AC), 70-71, 106-107, 108 needle electromyography in, 1244—1259 in Duchenne muscular dystrophy, 1275
balanced bridge, 103, 104 single-fiber, 1255-1259 electrode positions in, 306, 307
dedicated, 95 spontaneous activity measurement in, electrodiagnostic medicine impression
direct current (DC), 71 1244-1254 formulation in, 261
grounding of, 99, 102, 103 nerve conduction studies in, 1243-1244 endplate spikes in, 265, 266
parallel, 103, 104 Electroencephalography (EEG) in eosinophilia myalgia syndrome, 1005
resistor/capacitor, 106-107 effect of anesthesia on, 446-447, 451 equipment for, 258-259
resistor/inductor, 108 development of, 358 in ethylene oxide-related neuropathy, 1007
series, 101-103 electrode placement in, 10-20 international fasciculation potentials in, 278-279
Electrical injuries, as delayed paraparesis cause, system for, 469-470 of femoral nerve, 868-869
988 intraoperative, 444-445, 446,456-458 fibrillation potentials in, 274-276, 281
Electrical potentials, of muscle, 264-266 in interventional neuroradiologic procedures, in folic acid deficiency-related neuropathy,
Electricity, basic concepts of, 98-114. See also 463-464,465 1013
Electrical circuits Electrolyte assays, 1235 in gold therapy-related neuropathy, 1011
capacitance, 104-106 Electrolyte disorders, myopathies associated with, in Guillain-Barre syndrome, 943, 944, 1441
electronic devices, 111-114 1400-1401 in hemophilic patients, 286
elemental forces, 98-99 Electromyography (EMG) in hereditary neuropathy with liability to
filters, 108-111 needle, 257-291, 1244-1259 pressure palsies, 906
ground, 103 abnormal motor unit action potential in herpes varicella zoster virus infection, 978
inductors, 107-108 recruitment during, 284-286 in hexacarbon-related (glue sniffer's)
resistance, 99-101 in acrylamide-related neuropathy, 1006 neuropathy, 1008
Electrochemical conduction, 18-19 action potential generation during, 262-263, in hyperparathyroidism, 1396
Electrocochleography, 463 264 in hypoglycemia, 984
Electrocorticography, 1454 in acute axonal motor-sensory neuropathy in hypothyrdoism, 984
Electrodes, 1454 (Guillain-Barre syndrome variant), 945 in hypothyroidism, 984
active (E-l), 29, 174,542 in alcoholic neuropathy, 1015 in hypothyroid myopathy, 1395
application to skin, 895 in amyloid myopathy, 1402 in iatrogenic steroid myopathy, 1398
conmac, 347, 348 in amyloidosis, 995 in inclusion body myositis, 1382-1383
distance between, 29 anatomic distribution of abnormalities in, 572 information synthesis in, 261
as electrodiagnostic error source, 895 in arsenic-related neuropathy, 1011 injury potentials of, 260
ground, 174 in asymmetric, painfial diabetic insertional activity in, 260-261, 264-265,
needle, 73-77, 225, 227, 228, 229, 230 polyradiculopathy, 982 274-278, 739
bipolar concentric, 74, 76 in Becker muscular dystrophy, 1275 interference pattern analysis in, 310-325, 517
capacitive reactance of, 73-74 in botulinum toxin therapy, 484-486, 498 decomposition analysis in, 324-325
concentric, 565-566 in brachial plexopathies, 797-798 definition of, 312
impedance of, 73-74 in carbon disulfide-related neuropathy, 1006 expert's quantitative (EQUIP) analysis in,
inductance of, 73-74 in carpal tunnel syndrome, 1066-1067 322-324
as infection cause, 575 in cervical radiculopathy, 1086 at maximal effort, 312-314
insertional pain of, 564 in Charcot-Marie-Tooth disease, 905 mean amplitude in, 319-320, 323
intramuscular, 73 in chloroquine-related neuropathy, 1001 mean amplitude/number turns per second
monopolar, 73, 74-76, 565, 566 in chronic idiopathic sensory polyneuropathy, ratio in, 319-322
near-nerve, 73, 74, 554 1016 at minimal effort, 314-317
in peripheral nervous system depolarization, in chronic inflammatory demyelinating normal cloud analysis in, 321, 322
173-174 polyneuropathy, 952 number of turns per second in, 319-320. 323
placement in lumbosacral multifidi muscles, in chronic liver disease, 987 power spectrum analysis in, 317-318
740 in chronic obstructive pulmonary disease, 988 time dimension measurement, 318-320
as pneumothorax cause, 736 clinical findings in, 305-306 turns and amplitudes-based analytic
recording characteristics of, 564-565 in colchicine-related neuropathy, 1002 techniques in, 318-322
standard concentric, 74, 75-76 complex repetitive discharges in, 276-277 turns and amplitudes measurement al fixed
sterilization of, 287 complications of, 287 force in, 318-320
subdermal electroencephalographic, 73, computerized analysis in, 296, 298, 299-300, turns and amplitudes (TA) method of analysis
76-77 517 in, 320-321
placement of, 29, 542, 566, 895, 896 concentric and monopolar needle electrodes intraoperative use of, 443-444
in sensory nerve action potential recordings, in, 1249-1250 in peripheral nerve surgery, 466
182 in congenital myopathies, 1442 in posterior fossa and cranial nerve surgeries,
reference (E-2), 29, 174, 572 continuous muscle activity in, 280-281 463
single-fiber, 74, 76 contraindications to, 286-287 techniques in, 471
stability of, 545 in critical illness polyneuropathy, 989 "Johnson's five steps" of, 260-261
sterilization of, 575 in cryptogenic sensory or sensorimotor in lead-related neuropathy, 1008
stimulus artifacts of, 183, 545-547, 552 polyneuropathy, 990-991 in leprosy, 973
INDEX — 1499
Electromyography (EMG) (cont.) Electromyography (EMG) (cont.) Electromyography (EMG) (cont.)
in lithium-related neuropathy, 1005 propagation velocity in, 296 spontaneous activity in (cont.)
local circuit model of waveform morphology in, quantitative, 293-356, 517, 1258 in symmetric, painfial diabetic
263 in dermatomyositis and polymyositis, 1379 polyradiculopathy, 983
in lumbosacral plexopathies, 855 disadvantages of, 352 in tarsal tunnel syndrome, 1104, 1105
macro, 328, 346-348, 1256-1257, 1258 insertional activity in, 295 template in, 299-300
conmac technique, 347, 348 interference pattern analysis in, 310-325, temporal dispension in, 296, 307-309
in inclusion body myositis, 1383 1260 in thalidomide-related neuropathy, 1002
as nonselective recording technique, 328 as model for disease process, 348-352 in thallium-related neuropathy, 1010
manual analysis in, 297, 298-299 motor unit pathology in, 294-296 triphasic waveforms in, 266-267
in median nerve neuropathies, 1053, motor unit potential recording in, 295 in ulnar neuropathy, 1076, 1081-1082, 1083,
1054-1055, 1056, 1058, 1066-1067, 1071 routine examinations, 294-295 1085
in metronidazole-related neuropathy, 1000 spontaneous activity in, 295 in uremic neuropathy, 985, 986
in Miller-Fisher syndrome (Guillain-Barre in radial neuropathies, 1090, 1093 in vitamin B 12 deficiency-related neuropathy,
syndrome variant), 947 in radiculopathies, 738-747 1012
miniature endplate potentials of, 265 anatomic/physiologic correlation of, 746-747 in vitamin E deficiency-related neuropathy,
in monoclonal gammopathy of uncertain complex repetitive discharges in, 740 1014
significance, 996 false-negative interpretations of, 760-761 in Waldenstrom's macroglobulinemia,
in motor neuron disease, 533, 534 false-positive interpretations of, 758, 759-760 994
motor unit action potentials in, 270-274, fasciculation potentials in, 740 single-fiber, in alcoholic neuropathy, 1015
297-306 fibrillation potentials in, 739-740, 745-746 surface, 338-346
amplitude of, 306 paraspinal muscle examination in, 740-743 motor unit number estimation (MUNE)
amplitude trigger technique of, 299, 300, 303, positive sharp waves in, 739-740, 745-746 technique of, 338-343
304, 305 spontaneous activity abnormalities in, 738, Electron, definition of, 98
anatomy and physiology of, 267-270 739-740 Electronic circuits, 69-71
architecture of, 306-308 voluntary motor unit action potential Electronic potential, 13
delay line of, 299 abnormalities in, 743-745 Electron microscopy, of muscle fibers, 1236
duration of, 306-307 raster signals*in, 297 Electron transferring flavoprotein (ETF)-coenzyme
extraction and quantification techniques for, reference limits in, 296, 297 Q oxidoreductase, 1339
298-300 scanning, 44, 350, 351-352, 1255, 1257-1258, Electron transferring flavoprotein (ETF)-coenzyme
potential size index of, 298 1259 Q oxidoreductase deficiency, 1339
waveform characteristics of, 298 in sciatic nerve injury, 873-874 Electron transferring flavoprotein (ETF)
in multifocal motor neuropathy, 958-959 serum creatine kinase increase in, 288 deficiency, 1339
multiple discharges in, 281 signal sound of, use in interference pattern Electron-transferring protein, 1339
in multiple myeloma, 993 analysis, 317-318 Electrophoresis
muscle biopsy prior to or following, 287-288 signal-to-noise ratio in, 299, 306 immunofixation, 887, 992, 1235
myokymic discharges in, 279, 280 single-fiber, 326-338, 1255-1259 serum protein, 992, 1235
myotonic discharges in, 277-278, 280 in dermatomyositis and polmyositis, 1379 Electrostatic attraction, 98-99
myotonic-like potentials in, 534 fiber density measurements in, 328-329, 332, Electrotonically declining potential difference, 13,
in necrotizing myopathies, 1404 335-336 14
needle insertion in, 260-261, 1244 in inclusion body myositis, 1383 El Escorial criteria, for amyotrophic lateral
in neuromuscular junction disorders, 284, instrument-associated motor unit action sclerosis diagnosis, 532
1153-1154, 1441-1442 potential analysis in, 1258 Elinafide, as myopathy cause, 1405, 1413
neuromuscular transmission in, 296 jitter measurement in, 327, 329-332, 333-335 Embolia cutis medicamentosa, 862
in nitrofurantoin-related neuropathy, 1003 with muscle biopsy, 1235 Embolization, of arteriovenous malformations,
objective, 293 in muscular dystrophy, 1275-1276 464,465
in organophosphates-related neuropathy, 1007 in myotonia congenita, 1246 Emerin, 1269
outlier approach in, 296-297 in neuromuscular junction disorders, lamin-binding by, 1270
in pacemaker patients, 286 537-538, 1154-1155 Emerin gene, mutations of, 1289
in paclitaxel-related neuropathy, 999 in pediatric myasthenia gravis, 1444 Emetine (ipecac), as myopathy cause, 1405,
pain associated with, 258, 259, 286, 564 in radiculopathies, 745 1412-1413
in painful lower limb and low back pain, relevance to routine electromyographic EMLA cream, use in pediatric patients, 1437
528-529 studies, 335-338 Encephalitis, Lyme disease-related, 974
in painful upper limb and cervical region. scanning, 1255, 1257-1258, 1259 Encephalomyelitis, anti-Hu, 990
527-528 as selective recording technique, 327 Encephalomyelitis-neuropathy syndrome, anti-Hu
in paraneoplastic neuronopath/ganglionopathy. special recording techniques in, 326-348 antibodies-associated, 990
990 in uremic neuropathy, 985-986 Encephalomyopathy, mitochondrial
in paraneoplastic sensory sinusoidal waves in, 286 neurogastrointestinal, 1349-1350
neuronopathy/ganglionopathy, 990 in spinal muscular atrophy, 1440 Encephalopathy, uremic, 984-985
patient anxiety about, 258, 259 spontaneous activity in, 265-266, 738, Endarterectomy, carotid, intraoperative
in pediatric patients, 1437, 1438-1439 1244-1254 neurophysiologic monitoring during, 455,
in perhexiline maleate-related neuropathy, 1001 complex repetitive discharges, 1245, 1246 456-458
in peripheral neuropathies, 530-531, 890, 892. fasciculation potentials, 1248 Endoneurial tubes, 167
1044, 1047 fibrillation potentials, 1244-1246 in nerve injury, 121
in peroneal nerve injury, 1097 motor unit action potential morphology in, Endoneurium, 165-167
in phenytoin-related neuropathy, 1005 1248-1253 Endopeptidases, 967
pitfalls in. 564-572 motor unit action potential recruitment, Endplate, 295
instrumentation-related, 564-565 1253-1254 activity of, 1455, 1479
motor unit action potential parameters, muscle spasms/cramps, 1248 anatomy of, 17, 18
567-572 myokymic discharges, 1248 Endplate acetylcholinesterase deficiency,
physiologic factors-related, 564, 566-567 myotonic discharges, 1245, 1246 1196-1197
in podophyllin-related neuroapthy, 1002 myotonic potentials, 1246-1248 Endplate noise, 738
in POEMS syndrome, 994 positive sharp waves, 1244-1246 Endplate potentials, 40-41, 296, 1455. See also
positive sharp waves in, 275-276, 281 pseudomyotonic discharges, 1246 Endplate spikes; Miniature endplate
preparation for, 257-259 in suramin-related neuropathy, 1000 potentials
in primary muscle disease, 283-284 sweep duration/speed of, 297 definition of, 19
1500 — INDEX
Endplate potentials (cont.) Extensor carpi uinaris muscle, innervation of, 721 Far-field potentials (cont.)
in neuromuscular junction disorders, 1147, Extensor digit minimi muscle, innervation of, 721 leading/trailing dipole model of, 47, 48, 60-65
1148,1149-1150, 1151 Extensor digitorum brevis muscle in muscle, 47, 48
threshold of, in neuromuscular transmission, 20 anomalous innervation of, 193 of peripheral nerves, 37-38
Endplate proteins, effect of botulinum toxins on, 480 compound muscle action potentials of properties of, 39
Endplate spikes, 40-41, 265, 266 effect of botulinum toxin on, 483 of somatosensory evoked potentials, 36-37
characteristics of, 40 • in sciatic nerve injury evaluation, 873 volume conduction theory of, 47, 48
as erroneous diagnoses cause, 571 innervation of, 722 Fasciculation, 1231
firing rate of, 570 in peroneal nerve injury, 1096-1097, 1098 definition of, 278
as positive sharp wave-like potentials, 56, 569, peroneal nerve innervation of, 561, 567, 1095 Fasciculation potentials, 278-279, 569-570, 1456,
570-571 as peroneal nerve stimulation site, 212 1481
triphasic, 41, 570-571 tibial nerve innervation by, 561-562 in brachial plexopathies, 796-797
Endplate zone, 295-296 Extensor digitorum communi muscle, innervation difficulty in detection of, 569-570
Endurance training, as muscle hypertrophy cause, of, 721 firing rate of, 570
1238 Extensor digitorum longus muscle, innervation of, in multifocal motor neuropathy, 959
Enflurane, effect on intraoperative 722 in peripheral neuropathies, 892
neurophysiologic monitoring, 447, 448 Extensor hallucis longus muscle, innervation of, in radiculopathies, 539, 740
p-enolase deficiency, 1337 722 Fasciitis
Enoyl coenzyme A hydratase, 1339 Extensor indicis muscle, innervation of, 721 diffuse, with eosinophilia, 1384-1385
Enteropathy, gluten-induced. See Celiac disease Extensor muscles, relaxation during myalgia associated with, 1232
Entrapment neuropathy, 1455 electromyographic examination, 259 Fas ligand, 1374
Eosinophilia Extensor pollicis brevis muscle, innervation of, Fast-channel syndrome, 1198-1199, 1200
diffuse fasciitis-associated, 1384-1385 721 Fatal infantile myopathy, 1349
polymyositis-associated, 1384 Extensor pollicis longus muscle, innervation of, Fatigability, progression of, 1230
Eosinophilia myalgia syndrome, 1005, 1411 721 Fatigue, 1456
Ephapse, 1455 Extraocular muscles, congenital fibrosis of, 1279 adrenal insufficiency-related, 1398
Ephaptic transmission, 1455 Eyebrows, leprosy-related loss of, 971 clinical evaluation of, 1231
Epicondylitis, lateral, 1091-1092 Eyelashes, leprosy-related loss of, 971 dermatomyositis-related, 1374
Epilepsy differential diagnosis of, 1149
myoclonic, with ragged red fibers, 1346-1347 F motor units' resistance to, 269
pharmacologic treatment of, as neuropathy Fabry's disease (angiokeratoma corporis pituitary failure-related, 1399
cause, 1004-1005 diffusum),917 surface electromyography in, 338
Epineurium, 165-166 Face F chondrodispersion, 242
Epsilon-aminocaproic acid, as myopathy cause, 1407 acute axonal motor-sensory neuropathy-related Femoral cutaneous nerves
Epstein-Barr virus infections weakness of, 944 lateral
as acute inflammatory demyelinating leprosy of, 971 anatomy and anatomic course of, 213,
polyradiculoneuropathy cause, 987 Miller-Fisher syndrome-related weakness of, 841-842, 852, 843, 866
as Guillain-Barre syndrome cause, 938 946 antidromic stimulation of, 865
as idiopathic sensory myasthenia gravis-related weakness of, 1163 injuries to, 865-866
neuronopathy/ganglionopathy cause, 961 Facet joints. See Zygapophyseal joints nerve conduction studies of, 213-214
as myositis cause, 1391 Facial lines, hyperfunctional, botulinum toxin orthodromic stimulation of, 865
as neuropathy cause, 978 therapy for, 506 segmental somatosensory evoked potentials
Equilibrium potential, 6-7 Facial nerve of, 397-398
Erb's palsy, 814-815 aberrant regeneration of, in Bell's palsy, 496 sensory nerve action potentials of, 853
Erb's point stimulation, 225, 227-230, 1455 anatomic course of, 231 in thoracic radiculopathy, 982
in neuromuscular junction disorders, 1158 in Charcot-Marie-Tooth disease, 905 medial
for somatosensory evoked potential generation, Chvostek's sign of, 281, 1396 anatomy and anatomic course of, 843,
362, 363, 367-368, 369. 373-374 function of, 230-231 866-867
Erythema migrans, Lyme disease-related, 973-974 in Guillain-Barre syndrome, 941 injuries to, 866-867
Erythema nodosum leprosum, 973 left, stimulation of, 550 needle electromyography of, 867
Erythrocyte sedimentation rate, 1235 in leprosy, 973 nerve conduction studies of, 867
giant-cell vasculitis-related increase in, 964 myelination of, 1436 posterior
rheumatoid vasculitis-related increase in, 969 palsy of anatomy and anatomic course of, 214. 846
Erythromycin, as Lyme disease treatment, 974 Bell's disease-related, 974 injuries to, 871
Esophagus cancer, 989 Lyme disease-related, 974 nerve conduction studies of, 214
Ethambutol, as neuropathy cause, 1004 stimulation of, 230-232 sensory evoked potentials of, 865-866
Ethylene oxide, neuropathies associated with, in neuromuscular junction disorders, 536, Femora] nerve
1006-1007 537,1158-1159 anatomy and anatomic course of, 209, 843, 844.
I,l'-Ethylidenebis tryptophan, 1005 problems associated with, 551-552 867
Etomidate, effect on intraoperative Facies, "leonine," of leprosy, 971 compound motor action potentials of, 853-854
neurophysiologic monitoring, 452 Facilitation, 1455-1456 in diabetic mononeuropathy, 983
Etopside, neuropathies associated with, 997, 998 of H-reflex, 563-564 injuries to, 867-869
Eulenberg disease, 1297, 1305-1306, 1308 in magnetic cortical stimulation, 418, 419 lower-limb innervation by, 841
myotonic discharges in, 1247-1248 Facioscapulohumeral dystrophy, macro lower-limb muscle innervation by, 722
Evoked potential, 1455 electromyographic evaluation of, 1256 in lumbosacral plexus conduction latency
Evoked response amplitude, 341-342, 343 F-actin, 22-23 evaluation, 229
Excitable cells, nerve and muscle cells as, 30 Familial amyloidosis, 994, 1401 motor nerve conduction studies of, 853-854, 868
Excitable tissue, termination of, 39 Familial cardiomyopathy with subsarcolemmal needle electromyography of, 868-869
Excitation, suprathreshold, 91 vermiform deposits. See Myofibrillar nerve conduction studies of, 209-210, 528
Excitation-contraction coupling, 24-25 myopathy posterior, anatomy of, 846
Excitatory postsynaptic potential, 1455 Familial desminopathy. See Myofibrillar myopathy Femoral plexus stimulation, in neuromuscular
Exercise forearm test, 1334 Familial infantile myasthenia, 1195-1196 junction disorders, 1159
Exercise stimulation test, 1243 Faraday's box, 95 Fentanyl, effect on intraoperative neurophysiologic
Exercise test, 1304 Faraday's constant (F), 6 monitoring, 450
Expert's quantitative interference pattern (EQUIP) Far-field potentials, 35-40, 1456 Fibric acid derivatives, as myopathy cause. 1404,
analysis, 322-324 definition of, 28, 35 1406
INDEX — 1501
Fibrillalion-like potentials, 570-571 Flexor carpi uinaris muscle Frey's syndrome, botulinum toxin therapy for,
Fibrillation potentials, 47-^8, 274-276, 281, 1456, aponeurosis of, as ulnar nerve compression site, 507
1479 1079 Frohse, arcade of, 1091, 1092
in amyloid myopathy, 1402 innervation of, 721 Froment-Rauber nerve, 1088
biphasic, 47-48 Flexor digitorum longus muscle, innervation of, Froment's sign, 1075, 1077
in chronic obstructive pulmonry disease, 988 722, 841 F tacheodispersion, 243
definition of, 47 Flexor digitorum profundus muscle Fukutin, 1283, 1284
in diabetic thigh infarction, 1399 "OK" sign of, 1057 Full wave rectified EMG, 1456, 1487
in docetaxel-related neuropathy, 999 tendon ruptures of, 1058 Fungal infections
in hypokalemia, 1400 Flexor digitorum profundus muscles as inflammatory myopathy cause, 1372
nonreproducible, 570 innervation of, 721 meningeal, 769
in paclitaxel-related neuropathy, 999 Flexor digitorum superficialis muscle, innervation as myositis cause, 1391-1392
in polymyositis and dermatomyositis, of, 721, 1049 Funiculi, of peripheral nerves, 165, 166
1377-1378 Flexor hallucis longus muscle, innervation of, 722, Furcal nerve, 839, 845
in radiculopathies, 538, 739-740, 745-746 841 Furosemide, as myoglobinruia treatment, 1416
in segmental demyelination, 136-137 Flexor pollicis longus muscle F-wave, 238-244, 1244, 1455, 1472
sound of, 47 innervation of, 721 in acute motor axonal neuropathy, 946
in tick paralysis, 1194 median nerve innervation of, 1049 amplitude and persistence of, 243-244
triphasic, 48 "OK" sign of, 1057 in asymmetric, painful diabetic
waveform morphology of, 47-48 tendon ruptures of, 1058 polyradiculopathy, 982
Fibromyalgia, 1417 Flexor reflex, 1456 in brachial plexopathy, 794
botulinum toxin therapy for, 507 "Floppy infants," 1230, 1234. See also Hypotonia, in Charcot-Marie-Tooth disease, 905
Fibrosis in infants in chronic inflammatory demyelinating
necrotizing myopathy-related, 1401 electrodiagnostic evaluation of, 1433, polyneuropathy, 951
perineal, 970, 971 1439_1443 clinical utility of, 244
pulmonary Fluodrocortisone, as idiopathic sensory conduction velocity of, 242-243
amiodarone-related, 1001 neuronopaxthy/ganglionopathy treatment, 962 in dapsone-related neuropathy, 1003
microscopic polyangiitis-related, 966 Fluvastatin, as myopathy cause, 1404, 1405-1406 diagnostic applications of, 241-244
scleroderma-related, 969 F/M ratio, 243-244 differentiated from H-reflex, 244, 245,
Fibrosis, myopathy-related, 294 Focal mitochondrial depletion, 1349 563-564
Fibula, fractures of, as common peroneal nerve Folic acid deficiency, neuropathies associated in Guillain-Barre syndrome, 940, 942, 943
injury cause, 1095 with, 1013 in hypoglycemia, 984
Fibular head, in peroneal neuropathies, 528, 941, Food-borne botulism, 1183-1184, 1195 in hypoglycemia/hyperinsulinemia-related
1095-1099 Foot polyneuropathy, 984
Fibular tunnel, 1095 innervation of, 841, 847 in infants and children, 1435, 1436
Fila radicularia, 722 pain with numbness in, 1114-1115 latency of, 242
Filters, 79-85, 108-111 Footdrop, 1113-1114 in mercury-related neuropathy, 1009
analog, 81, 110 differential diagnosis of 1099 in peripheral neuropathies, 891, 1046-1047
bandpass, 109, 110, 554 with difficulty in ambulation. 927-928 of peroneal nerve, 528
digital, 81, 110-111 evaluation of, 1113-1114 physiology of production of, 239-241
as false-positive diagnoses source, 554 multifocal motor neuropathy-related, 957 in radiculopathies, 538, 539, 732,735,752
high-frequency (low-pass), 29, 80-81, 83-84, peroneal neuropathy-related, 528, 1098-1099 ratio of, 243
85, 106-107, 109, 110, 554, 556 tetanus toxoid-related, 1193 in sacral plexopathy, 854
effect on motor unit action potentials, 565 Forearm as surface-recorded motor unit action potential,
effect on somatosensory evoked potential cutaneous nerves of 344, 345-346
waveforms, 572-573 lateral, 783 in uremic neuropathy, 985
low-frequency (high-pass), 80-81, 82-83, 85, medial, 783 in vasculitis secondary to essential mixed
109, 110, 554 posterior, 811, 1088 cryoblobinuria, 967
blanket principle of, 336, 337 median nerve anatomy in, 1048 in vitamin B l 2 deficiency secondary to nitrous
effect on compound motor action potentials, median nerve lesions in, 1058 oxide inhalation, 1013
182, 555-556 radial nerve injuries in, 1090-1092
as diagnostic error source, 895-896 ulnar neuropathy in, 1082-1083 G
effect on motor unit action potentials. Forearm muscles, relaxation during Gabapentin
565 electromyographic examination, 259 as diabetic distal symmetric sensory and
effect on sensory nerve action potential Foscarnet, 977 sensorimotor polyneuropathy treatment,
parameters, 182 Fourier analysis. 317-318 981
effect on somatosensory evoked potential Fractionation. 351 as diabetic neuropathy treatment, 981
waveforms, 572-573 Fractures as painful sensory neuropathy treatment, 976
notch, 84-85 of acetabulum, as sciatic nerve injury cause. G-actin, 22
settings of, 85 871-872 in muscle contraction, 25
for routine needle electromyography, 260 of hip, as sciatic nerve injury cause, 1099 Gait abnormalities
spatial, 29 of humerus celiac disease-related, 986
Filum terminale, 722 as median nerve injury cause, 1053 Charcot-Marie-Tooth disease-related, 901
Finasteride, as myopathy cause, 1412 as radial nerve injury cause, 1089 clinical evaluation of, 1233
Finger-nose-finger test, 961 as tardy ulnar palsy cause, 1078-1079 hip abductor weakness-related, 1233
Fingerprint body myopathy, 1318, 1324 as median nerve injury cause, 1053, 1058 Gamma-aminobutyric acid receptors, interaction
Fingers Monteggia, 1090 with anesthetic agents, 446
circumference of, gender differences in, of radius, 1090-1091 Ganciclovir, 977
188 as median nerve injury cause, 1053 Ganglion
extensor weakness of, 1112-1113 of scapula, 806 dorsal root, 722, 724, 778
Finkelstein sign, 1094 as tardy ulnar palsy cause, 1078-1079 of sural nerve, 1106
First-degree injury, 786 of ulna, 1090-1091 Ganglionitis
Flexor carpi radialis muscle as median nerve injury cause, 1053 sensory, 949, 960
H-reflex of, 247, 249, 563 of wrist, as carpal tunnel syndrome cause, 1067 human immunodeficiency virus infection-
innervation of, 721 F ratio, 243 related, 975, 977
median nerve innervation of, 1049 Frequency domain analysis, 318 Sjogren's syndrome-related, 968
1502 — INDEX
Ganglionopathy, 889 Glycogenosis (cont.) Gunshot wounds
sensory, ataxia associated with, 887 type 9 (phosphoglycerate kinase deficiency), as axillary nerve injury cause, 808
Gangrene, 862 1336-1337 as brachial plexopathy cause, 785, 786, 787
polyarteritis nodosa-related, 965 type 10 (phosphoglycerate mutase deficiency), as femoral nerve injury cause, 867
Gastrectomy 1336-1337 as radial nerve injury cause, 811
partial, as folic acid deficiency cause, 1013 type 11 (lactate dehydrogenase deficiency), Guyon's canal
sensorimotor peripheral neuropathy associated 1336-1337 anatomy of, 1084
with, 1014 type 12 (p-enolase deficiency\, 1337 as ulnar nerve compression site, 526,
Gastrocnemius muscle, innervation of, 722, 841 Glycogen storage disorders, 1329 1083-1085
Gastrocnemius-soleus muscle complex as infant hypotonia cause, 1440, 1442 ulnar nerve in, 1072
as botulinum toxin injection site, 503 Glycolipids, as plasma membrane component, 3
Charcot-Marie-Tooth disease-related atrophy of, Glygogen storage disease, 1416 H
901 Goldman-Hodgkin-Katz equation, 8, 16,24, 1247 Habituation, 1457
H-reflex of, 244, 247-248, 563, 734, 736 Gold therapy, neuropathies associated with, 1011 Hallucinations, acrylamide-related, 1006
Gastrointestinal cancer, 990, 1401 Gottron's sign, of dermatomyositis, 1375 Halothane, effect on intraoperative
Gastrointestinal disorders Gout, 988 neurophysiologic monitoring, 447, 456
botulinum toxin therapy for, 506 colchicine treatment for, 1001 Hanging leg syndrome, 869
idiopathic sensory Gower's sign, 1234, 1271 Hansen's disease. See Leprosy
neuronopathy/ganglionopathy associated Gracilis muscle, innervation of, 722 Harmonic spectrum analysis, 79
with, 962 Gmft-versus-host disease Headaches
neuropathies associated with, 986-987 neuropathies associated with, 996 botulinum toxin therapy for, 507
Gastroparesis, dermatomyositis-related, 1375 thalidomide treatment for, 1002 cervical radiculopathy-related, 747
GBS. See Guillain-Barre syndrome Granuloma Head and neck cancer, paclitaxel treatment for,
Gemellus inferior and superior muscles, sacral Churg-Strauss syndrome-related, 965 998
plexus nerve branch connection of, 839, sarcoid, 1385 Heart block, Lyme disease-related, 974
845-846 Granulomatosis Heavy metal intoxication, neuropathies associated
Gemfibrozil, as myopathy cause, 1404, 1406 lymphomatoid, neuropathies associated with, 991 with, 1008-1011
General anesthesia, as malignant hyperthermia Wegener's, 965-966 Heavy metal screen, 887
cause, 1313-1314 Graves'disease, 1393, 1394 Height
Generator (dynamo), 108 Gravitational fields, 98 effect on nerve conduction studies, 188, 563
Gene therapy, for Duchenne muscular dystrophy, Grounding, of electrical circuits, 99, 102, 103 effect on somatosensory evoked potentials,
1277 Grouped discharge, 1456 382
Genitofemoral nerve Growth hormone Heliotrope rash, of dermatomyositis, 1374-1375
anatomy of, 840-842 deficiency of, 1399 Hematocrit, intraoperative, effect on evoked
injuries to, 863, 864-865 induced decrease of, as acromegaly treatment, 1399 potentials, 454
lower-limb innervation by, 841 Guanidine Hematoma
Genu recurvatum, 1233 as botulism treatment, 1190 of iliacus compartment, 869
Giant axonal neuropathy, 925 as Lambert-Eaton myasthenic syndrome paraspinal, 743
Giant-cell myositis, 1164, 1165 treatment, 1182 Hemifacial spasm, 1457
Giant-cell vasculitis, 964 as myasthenia gravis-Lambert Eaton overlap Hemodialysis
Gibbs phenomenon, 111 syndrome treatment, 1183 with Cuprophan membrane, as mononeuropathy
Glial cells Guillain-Barre syndrome, 937-938, 1456 cause, 985
potassium channels of, 6 areflexia associated with, 937, 938 as uremic neuropathy treatment, 985, 986
transmembrane equilibrium potential of, 7 autonomic instability assessment in, 943 Hemophiliacs, needle electromyography in, 286
Glioma, pontine, 461 bone marrow transplantation-related, 996 Hemorrhage
Glomerular filtration rate, 985 in children, 943-944, 1443 muscle biopsy-related, in diabetic thigh
Glomerulonephritis, necrotizing, microscopic chronic, 947 infarction, 1399
polyangiitis-related, 966 clinical features of, 938-939 retroperitoneal
Glucose, plasma membrane permeability of, 4, 5 as critical illness, 988 as femoral plexopathy or neuropathy cause,
Glue sniffer's neuropathy, 1007-1008 diagnostic criteria for, 938 867-868
Gluteal nerves differentiated from botulism, 1189 as lumbosacral plexopathy cause, 861-862
anatomy and anatomic course of, 846 differentiated from ciguatera poisoning, 1201 Hepatitis
injuries to, 871 differentiated from tick paralysis, 1194-1195 amiodarone-related. 1001
lower-limb muscle innervation by, 722, 841 electrophysiologic findings in, 940-943 as chronic inflammatory demyelinating
Gluten intolerance, 986 herpes varicella zoster virus infection-related, polyneuropathy cause, 949
Gluteus maximus muscle, innervation of, 722, 841 978-979 Epstein-Barr virus-related, 987
Gluteus medius muscle, innervation of, 722, 841 histopathology of, 939 as myositis cause, 1391
Gluteus minimus muscle, innervation of, 722, 841 human immunodeficiency virus infection- as neuropathy cause, 978
Glycerol, plasma membrane lipid bilayer associated, 976, 977, 978-979 as polyarteritis nodosa cause, 967-968
permeability of, 4, 5 as infant hypotonia cause. 1441 Hepatitis A, as Guillain-Barre syndrome cause,
Glycerol kinase deficiency, 1277-1278 laboratory evaluation of, 887, 939 938
Glycerol kinase deficiency, Duchenne muscular motor conduction studies of, 940-942 Hepatitis B
dystrophy-related, 1277, 1278 motor unit action potentials in, 1253 as Guillain-Barre syndrome cause, 938
Glycogen, metabolism of, 1330 needle electromyographic studies of, 943, 944 as mononeuropathy multiplex cause, 987
Glycogenosis, 1329-1337 pathogenesis of, 939-940 polyarteritis nodosa-associated, 967-968
type 2 (acid maltase deficiency), 1330-1332. radiculopathies associated with, 769 vasculitis-associated, 966
See also Pompe's disease sensory conduction studies of, 942 Hepatitis C
type 3 (debranching enzyme deficiency), 1329, somatosensory evoked potential studies of, 943 as Guillain-Barre syndrome cause, 938
1332-1333 in children, 944 as mononeuropathy multiplex cause, 987
type 4 (branching enzyme deficiency), 1333 treatment of, 943, 944 as myositis cause, 1391
type 5 (myophosphorylase deficiency), 1248, variants of polyarteritis nodosa-associated, 965
1329,1333-1335, 1336 acute axonal motor-sensory neuropathy, 938, polyarteritis nodosa-associated, 967, 968
type 7 (phosphofructokinase deficiency), 1329, 939, 944-945 vasculitis-associated, 966
1335-1336 acute motor axonal neuropathy, 938, 939, Hepatitis virus, as electrode contaminant, 379
type 8 (phosphorylase b kinase deficiency), 945-946 Hernia, surgical repair of, peripheral nerve
1336 Miller-Fisher syndrome. 888, 946-947 monitoring during, 468
INDEX — 1503
Herniated disks HIV infection (cont.) Hyperthyroidism, myopathies associated with,
lumbar, 751-753 conditions associated with (cont.) 1393-1394
physiologic models of, 727-728 Guillain-Barre syndrome, 938 Hypocalcemia, 1396-1397
thoracic, 750 myositis, 1390 toluene abuse-related, 1415
Herniorrhaphy, inguinal, as genitofemoral nerve neuropathies, 433, 1004 Hypocapnia, intraoperative, effect on
injury, 864 in pediatric patients, 1444 somatosensory evoked potentials, 454
Heroin, as myopathy cause, 1405 peripheral neuropathies, 886 Hypoglycemia
Herpes simplex infections, myositis associated polyarteritis nodosa, 965 perhexiline maleate-related, 1001
with, 1391 polyneuropathies, 975-977 as polyneuropathy cause, 983-984
Herpes varicella zoster infection, 978-979 vasculitis, 966 Hypokalemia
vasculitis-associated, 966 needle electromyography-related transmission alcoholism-related, 1414
Herpes zoster oticus, 978 of, 287, 379 drug-related, 952, 1413
Hertz (Hz), 79 pharmacologic treatment of myopathies associated with, 1400
Hexacarbons, as neuropathy cause, 1007-1008 as mitochondrial myopathy cause, 1409-1411 effect on refractory periods, 237
High-density lipoprotein deficiency, as angier as neuropathy cause, 1004 toluene abuse-related, 1415
disease cause, 919 Human T-cell leukemia virus type-1 infection, Hypomagnesemia, myopathies associated with,
Hip 1390 1401
abductor muscle weakness of, 1233 Human T-cell lymphotropic virus type-1, 1014 Hypomyelination, cerebral, 1296
arthroplasty of Human tetanus immunoglobulin, 1193 Hypophosphatemia
as sciatic nerve injury cause, 872 Human T-lymphocyte type-1 infection, 977-978 hyperalimentation-related, 1014
sciatic nerve monitoring during, 468,469 Humerus, fractures of myopathies associated with, 1400
corticosteroid-related avascular necrosis of, 952 as median nerve injury cause, 1053 toluene abuse-related, 1415
fractures or dislocations of, as sciatic nerve as radial nerve injury cause, 1089 Hypotension
injury cause, 1099 as tardy ulnar palsy cause, 1078-1079 Guillain-Barre syndrome-related, 939
Hodgkin's disease, peripheral neuropathies Hunter's canal, 869, 870 idiopathic sensory neuronopathy/ganglionop-
associated with, 993 Hunting, as tick paralysis risk factor, 1194 athy-related, 962
Hoffmann's syndrome, 1394 H wave, 1457, 1473 intraoperative, effect on somatosensory evoked
Homunculus, 360, 361 Hyaline body myopathy/familial myopathy with potentials, 458
Honey, clostridial spore contamination of, 1184 lysis of myofibrils, 1319, 1325 orthostatic
Honeymooner's palsy, 1089 Hydatidosis, 1392 anti-Hu antibodies-associated
Hopkin's syndrome, 1444 Hydrophobic compounds, definition of, 3 encephalomyelitis-neuropathy
Horner's syndrome, 778-779, 821, 1086 3-Hydroxyacyl-CoA dehydrogenase, 1339 syndrome-related, 990
H-reflex, 244-253, 1244 3-Hydroxyacyl-CoA dehydrogenase deficiency, etoposide-related, 998
absence of, 563, 564 1342-1343 in human immunodeficiency virus infection-
aging-related decrease in, 562, 896 Hydroxychloroquine related autonomic neuropathy, 977
in brachial plexopathy, 794 as myopathy cause, 1405, 1408 Sjogren's sydrome-related, 968
in diabetic distal symmetric sensory and as neuropathy cause, 1001 vincristine-related, 998
sensorimotor polyneuropathy, 980 3-Hydroxy-3-methyl-glutaryl-coenzyme A Hypothenar muscle, compound motor action
diagnostic applications of, 246-253 reductase inhibitors, as myopathy cause, potentials of, 1076
in central nervous system, 249-253 1404-1406 Hypothermia
in peripheral nervous system, 247-249 25-Hydroxy-vitamin D, 1395 intraoperative, effect on evoked potentials,
in ethylene oxide-related neuropathy, 1006 Hyperalimentation, as hypophosphatemia cause, 454-455, 458
facilitation of, 563-564 1014 effect on somatosensory evoked potentials,
factors affecting, 246 Hypercalcemia, myopathies associated with, 1400 364
in Guillain-Barre syndrome, 940 Hypereosinophilia, Churg-Strauss syndrome- Hypothyroidism, 984, 1394-1395
in hypoglycemia, 984 related, 965 Hypotonia
in hypoglycemia/hyperinsulnemia-related Hypereosinophilic syndrome, 971, 1384 infantile
polyneuropathy, 984 Hyperglycemia benign congenital, 1443
in idiopathic sensory diabetic distal symmetric sensory and congenital muscular dystrophy-related, 1282
neuronopathy/ganglionopathy, 961 sensorimotor polyneuropathy-related, 980 electrodiagnostic evaluation of, 1433,
in infants and children, 1434-1435, 1436 diabetic neuropathies-associated, 980 1439-1443
in mercury-related neuropathy, 1009 Hyperhidrosis illustrative case of, 1444-1445
in peripheral neuropathies, 891, 1046 acute motor axonal neuropathy-related, 945 rigid spine syndrome-related, 1290
physiology of, 245-246 botulinum toxin therapy for, 507 Hypoxemia, intraoperative, effect on evoked
in piriformis syndrome, 873 Hyperinsulinemia. as polyneuropathy cause, potentials, 454
in poliomyelitis, 1443 983-984 H-zone, 24
in radiculopathies, 538, 539, 733-735 Hyperkalemia. See also Periodic paralysis,
in cervical radiculopathies, 748 hyperkalemic I
relationship with F-wave, 241, 244, 245, myopathies associated with, 1400 I bands, 23
563-564 secondary, 1304 Idiopathic autonomic neuropathy, 961-962
relationship with tendon reflex, 250-251 Hypermagnesemia, myopathies associated with, Idiopathic perineuritis, 970-971
in sacral plexopathy, 854 1400 Idiopathic sensory neuronopathy/ganglionopathv.
S1 central loop of, 248-249 Hyperparathyroidism, 1395-1396 960-961
in tarsal tunnel syndrome, 1105 Hyperpathia, chloramphenicol-related, 1004 Idiopathic sensory polyneuropathy, chronic,
of tibial nerve, 854 Hyperphagia, Whipple's disease-related, 987 1015-1016
in tibial nerve neuropathies Hyperplasia Ifosfamide, neuropathies associated with, 1000
in tarsal tunnel syndrome, 1104 angiofollicular lymph node. See Castleman's Iliac arteries
in uremic neuropathy, 985 disease inadvertent injections into, 862
in vitamin B 12 deficiency secondary to nitrous thymic, 1164 pseudoaneurysm of, 862
oxide inhalation, 1013 Hyperpolarization, 5, 10, 1457 Iliac spine, anterior superior, as lateral femoral
Human immunodeficiency virus (HIV), as in demyelinated nerves, 141 cutaneous stimulation site, 398
electrode contaminant, 379 Hyperreflexia, thallium poisoning-related, 1010 Iliacus muscle, innervation of, 722
Human immunodeficiency virus (HIV) infection Hyperthermia, malignant, 1313-1314 Iliohypogastric nerve
conditions associated with central core disease-related, 1319-1320 anatomy of, 839-840
chronic inflammatory demyelinating drug-induced, 1413 injuries to, 863, 864
polyneuropathy, 949 multicore/minicore myopathy-related, 1320 lower-limb innervation by, 841
1504 — INDEX
Ilioinguinal nerve Infection Instrumentation (cont.)
anatomy of, 840, 842 acquired neuropathies associated with, 971-979 cathode ray tubes, 90, 113, 258
injuries to, 863-864 electrode-related, 378-379 component parts of, 69, 70
intraoperative monitoring of, 468 needle electromyography-related, 287 dedicated electrical circuits, 95
lower-limb innervation by, 841 vasculitis associated with, 966 digital processors (computers), 113-114, 296,
Immunoelectrophoresis, 992 Inferior corporotransverse ligament, 720 298, 299-300, 358,517
Immunofixation, 887, 992, 1235 Inferior gluteal nerve, lower-limb muscle diodes, 111, 112
Immunoglobulins, perineal deposition of, innervation by, 722 electrical interference with, 94-95
970-971 Inferior transforaminal ligament, v 720 electrical safety guidelines for, 95-96
Immunophilins, as myopathy cause, 1406 Inflammation, histologic abnormalities associated Faraday's box, 95
Immunostaining, 1236 with, 1241 inappropriate parameters of, 1260
Immunosuppressed patients. See also Acquired Inflammatory acquired myopathies, 1371-1390 inductors, 106, 107-108
immunodeficency syndrome (AIDS); Human Behcet's disease, 966, 1386 effect on nerve conduction studies recordings,
immunodeficency virus (HIV) infection dermatomyositis, 1374-1376, 1377-1379 182-187
fungal myositis in, 1391-1392 diagnostic evaluation of, 1373, 1386 amplification, 182
Immunosuppressive therapy diffuse fasciitis with eosinophilia, 1384-1385 averaging, 182-183
hepatotoxicity of, 1235 dropped-head syndrome, 1384 electrode separation, 182
for polymyositis, 1373 focal myositis, 1384 filters, 182
for systemic lupus erythematosus, 969 granulomatous and giant-cell myositis, 1385 measurement parameters, 184-187
for vasculitic neuropathy, 967 idiopathic, 1371-1390 stimulators, 182-183
Immunotherapy inclusion body myositis, 1379-1383 sweep speed, 182
for symmetric, painful diabetic infantile myositis/congenital inflammatory sound production by, 85
polyradiculopathy, 982, 983 myopathy, 1383-1384 stimulators, 9-194
for symmetric, painless diabetic overlap syndromes, 1376-1377 artifacts produced by, 93-94
polyradiculoneuropathy, 983 polymyositis, 1372-1374, 1377-1379 as electrodiagnostic error source, 896
Impedance meters, 72 sarcoid myopathy, 1385 errors in placement of, 92-93
Impedance (Z), 70, 71 treatment of, 1386-1390 frequency of, 93
of capacitors, 105, 106 Inflammatory bowel disease, 949, 987 types of, 91-92
of inductors, 108 Inflammatory demyelinating polyneuropathy switches, 111-112
input, of amplifiers, 77-78 chronic, 947-955 Insulin therapy, as peripheral neuropathy cause, 983
mismatch of, 78-79, 143 human immunodeficiency virus infection- Integrated EMG, 1457
of needle electrodes, 73-74 related, 975-977 a7piD-Integrin, 1283
in somatosensory evoked potential myasthenia gravis-related, 1164 Integrins, 1268
examinations, 377-378 Inflammatory disorders, as radiculopathy cause, Intercostal muscles, needle electromyographic
of surface electrodes, 72 769 examination of, 751
Impotence Influenza virus Intercostal segmental nerve, 725
diabetic neuropathic cachexia-related, 981 as Guillain-Barre syndrome cause, 938 Interdigital neuropathy, 1106-1107
idiopathic sensory as myositis cause, 1390-1391 Interdischarge interval, 1457
neuronopathy/ganglionopathy-related, 962 Infraspinatus muscles Interference, electrical, 94-95
vincristine-related, 998 innervation of, 721 Interference pattern, 1457-1458, 1484
"Inching" techniques, 201-203, 548-549, 558, in suprascapular nerve injury, 806 Interferons
1062, 1457 as suprascapular nerve stimulation site, 228 as chronic inflammatory demyelinating
Inclusion body myopathies, hereditary, 1295-1296 Inhalation agents, halogenated, effect on polyneuropathy treatment, 953-954
Inclusion body myositis, 1300, 1373, 1380-1383 intraoperative neurophysiologic monitoring, as hepatitis treatment, 967, 968
clinical features of, 1380-1381 447^50,456 Interleukins
differentiated from polymyositis, 1381 Inhibitory phenomenon, magnetic stimulation- in diabetic distal symmetric sensory and
sarcoid myopathy associated with, 1385 related, 422 sensorimotor polyneuropathy, 980
treatment of, 1386-1387 Inhibitory postsynaptic potential, 1457 in leprosy, 972
Incomplete activation, 1457 Inhibitory presynaptic potentials, 240 Internal oblique muscle, innervation of, 841
Incremental stimulation, 340-341, 345 Injection injuries International Federation of Societies for
Incrementing response, 1457 to axillary nerve, 808 Electroencephalography and Clinical
Inductance as brachial plexopathy cause, 824-825 Neurophysiology, 10-20 International System
definition of, 107 to iliac arteries, 862 of, 368-369, 1458
of needle electrodes, 73-74 as myopathy cause, 1415 Internodal conduction time, 139
Inductive reactance, 71 to sciatic nerve, 872 effect of temperature on, 141
Inductor/resistor filter circuits, 109, 110 Injury potential, 1457 Internode regions, 15
Inductors, 106, 107-108 Innervation, anomalous. See also specific nerves Interossei muscles, innervation of, 841
impedance of, 108 effect on nerve conduction studies, 191-194 Interosseous nerves
Industrial agents, as neuropathy cause, 1005-1008 Innervation ratio, of muscle fibers, 267 anterior
Infantile myositis, 1383-1384 Insertional activity, 1457, 1478 anatomy and anatomic course of, 784, 1049-1050
Infantile neuroaxonal dystrophy, 925 Insomnia, Whipple's disease-related, 987 entrapment syndrome of, 1057-1058
Infants Instrumentation, 69-97. See also Amplifiers; posterior
botulism in, 1184, 1185 Electrodes; Filters anatomy and anatomic course of, 1087
congenital radial nerve palsies in, 1089 analog-to-digital (A/D) conversion of, 85-89, neuropathy of, 1092-1093
hypotonia in 90, 258, 337-338 Interpeak interval, 1458
benign congenital, 1443 aliasing in, 87, 110, 337, 338 Interpotential interval, 329, 331, 332, 334, 1458
congenital muscular dystrophy-related, 1282 averaging in, 88-89 Interspinous ligament, 718, 719
electrodiagnostic evaluation of, 1439-1443 bins or sample points in, 85 Intertransverse ligaments, 719-720
illustrative case of, 1444-1445 dwell time in, 85 Intervertebral disks
nerve conduction studies in, 1438 epoch or sweep in, 85 anatomy and functions of, 715-716, 717
nerve conduction velocity in, 562, 1433-1436 horizon resolution in, 86-88 degeneration of, in spinal stenosis, 756
physical examination of, 1234 latency measurement in, 87-88 herniated, 727
toxic myopathies in, 1403 Nyquist frequency in, 87, 110, 338 lumbar, 751-753
transient autoimmune myasthenia gravis in. sampling frequency in, 85 physiologic models of, 727-728
1176 vertical resolution in, 85-86 thoracic, 750
Infarction, muscular, 1239 basic electronic circuit principles of, 69-71 as low back pain source, 729
INDEX — 1505
Intervertebral foramina, 715, 716 Ischemia (cont.) Knee (cont.)
Intracranial pressure elevation, evoked potentials cerebral (cont.) dislocation of, as common peroneal nerve injury
in, 454 somatosensory evoked potential monitoring cause, 1095
Intramuscular nerve action potentials, 46 of, 460-461 as saphenous nerve stimulation site, 397
Intraoperative neurophysiologic monitoring, effect on somatosensory evoked potentials, weakness of, lumbosacral plexopathy-related,
439-478 458 875-877
anesthesia considerations in, 446-453 as conduction block cause, 786 Kocher-Debre-Semelaigne syndrome, 1394
in aneurysm surgery, 459-461 diabetic mononeuropathies-related, 983 Krabbe's disease (globoid cell leukodystrophy),
in arteriovenous malformation surgery, 461-462 repetitive nerve stimulation during, in 916-917, 1443
artifacts in, 440,441,442 neuromuscular junction disorders,
brain stem auditory evoked potentials in, 441, 1159-1160, 1161 L
443, 448, 450, 451, 454, 461-462, 469, 470 temporary neural, 131-132 Labetalol, as myopathy cause, 1405, 1406
in brain tumor surgery, 462-463 vasculitis-related, 962 Labial nerves, 840, 849-859
in carotid endarterectomy, 456-458 Ischemic monomelic neuropathy, 985 Lactate dehydrogenase deficiency. See
in cerebral ischemia, 455-456 Isoelectric line, 1458 Glycogenosis, type 9
in cranial nerve surgery, 463 Isoflurane, effect on intraoperative Laing myopathy, 1292, 1293, 1295
electroencephalographic, 444-445, 446, neurophysiologic monitoring, 447, 448, 450, Lambert-Eaton myasthenic syndrome, 536, 887,
456-458,463^164, 465 456 891, 987, 989, 990, 1164, 1177-1183, 1401
equipment requirements for, 445 Isoniazid, neuropathies associated with, 1004 clinical features of, 1177
general results and efficacy of, 445-446 Isopotential lines, 28, 29 compound motor action potentials in, 537
in interventional neuroradiologic procedures, Ixodes dammini, 973 edrophonium (Tensilon) test for, 1165
463-465 Ixodes holocyclus, 1193, 1194, 1195 electrodiagnostic medicine evaluation of
in intracranial neurovascular surgery, 458-459 Ixovotoxin, 1194 autonomic neuropathy studies, 1180
intraoperative electromyography technique in, motor nerve conduction studies, 1180
471 needle electromyographic studies, 1181
intraoperative physiologic variables affecting, Jamaican neuropathy, 1014 repetitive nerve stimulation studies,
446-455 Jendrassik maneuver, 246 1180- 1181
with motor cortex stimulation, 421 Jiggle, 298, 337; 338, 1458 sensory nerve conduction studies, 1179
motor evoked potentials in, 444 Jitter, 1458 single-fiber electromyographic studies,
nerve conduction studies in, 444, 470 in alcoholic neuropathy, 1015 1181- 1182
operating room recordings in, 479 in botulism, 1189 effect of temperature on, 560, 1182
in peripheral nerve surgery, 466-468 in idiopathic sensory histopathology of, 1178
in posterior fossa surgery, 463 neuronopathy/ganglionopathy, 962 jitter in, 332, 1182
somatosensory evoked potentials in, 440, in Lambert-Eaton myasthenic syndrome, 332, laboratory features of, 1177-1178
441-442, 444, 4 4 5 ^ 4 6 1182 motor nerve conduction evaluation of, 1169
in spinal surgery, 465^466 in myasthenia gravis, 1171 motor unit action potentials in, 284
technical considerations in, 468-470 in neuromuscular junction disorders, 1155 needle electromyographic evaluation of, 1169
-visual evoked potentials in, 445, 454, 471 temperature-dependent changes in, 1157 overlap with myasthenia gravis, 1165, 1183
Intravenous analgesic agents, as total intravenous in paraneoplastic neuronopath/ganglionopathy, as paraneoplastic syndrome, 989,990, 1401
anesthetic (TIVA), 450, 451, 452-453 with superimposed Lambert-Eaton pathogenesis and pathophysiology of,
Intravenous drug abuse, as botulism cause, 1184 myasthenic syndrome, 990 1178-1179
Intravenous immunoglobulin (IVIG) in polymyositis, 1378 postexercise facilitation in, 1180
as asymmetric, painful diabetic routine electromyographic measurement of, 335 sensory nerve conduction evaluation of, 1169
polyradiculopathy treatment, 982 in single-fiber electromyography, 329-332, single-fiber electromyographic evaluation of,
as chronic inflammatory demyelinating 333-335, 336-337 1169
polyneuropathy treatment, 950, 953 blocking in, 329, 330, 331, 332, 333, 334, 336 Lambert's criteria, for amyotrophic lateral
as Guillain-Barre syndrome treatment, 941, 943, in chronic inflammatory demyelinating sclerosis diagnosis, 532
944 polyneuropathy, 951 Lamin A, 1270
as inflammatory myopathy treatment, 1387, interpotential interval in, 329, 331, 332, 334 Lamin A/C gene mutations, 1289
1389 interspike interval in, 330 Laminae, 714
as Lambert-Eaton myasthenic syndrome mean difference between consecutive Laminae, vertebral, 714
treatment, 1183 potential intervals in, 329, 331 Lamin C, 1270
as multifocal motor neuropathy treatment, 959 mean sorted difference in, 329, 331 Laminin, 1267
as myasthenia gravis treatment, 1175 mean value of the interpotential interval in, cx2-Laminin deficiency, in infantile myositis,
in children, 1176 329 1383-1384
as systemic vasculitis treatment, 967 velocity recovery function in, 333, 334 Lamivudine, neuropathies associated with, 1004
Intussusception, neural, 135-136 in tetanus, 1193 Lamotrigine
"Inverted champagne bottle legs," 901 Joplin's neuroma, 1107 as inflammatory myopathy cause, 1412
Involuntary activity, 1458 Jugular veins, internal, cannulation-related injury as myopathy cause. 1405
Inward rectifier channels, 138 to, 825 Larynx
Ion channels anatomy of. 490
in myelinated nerve fibers, 138 K as botulinum toxin injection site, 490-492
voltage-gated, 10-12 Kearns-Sayre syndrome, 1347-1348 musculature of, in spasmodic dysphonia,
refractory periods of, 11 Kennedy's disease, 910 490-492
Ions Keratitis, Graves' disease-related, 1394 Latency of activation, 557
hydrated, 4 Ketamine, effect on intraoperative Latency potential, 547-549
transport across cell membranes, 4 neurophysiologic monitoring, 450-451 Lateral cutaneous nerve of the calf, 1094
Ipecac, as myopathy cause, 1405, 1412-1413 Kidney cancer, 966, 989, 990 compression of, 1099
Isaacs' syndrome, 280. 971, 1164 Kiloh-Nevin syndrome, 1057-1058 Late responses, in motor nerve conduction studies,
Ischemia Kindling, magnetic stimulation-related, 424 238, 1458. See also Axon reflex; F-wave; H-
as brachial plexopathy cause, 787 Kinesiologic EMG, 1458 reflex
cerebral Klein-Lisak-Andersen syndrome, 1313 Latency, 1458
in aneurysm surgery, 460 Klumpke's paralysis, 814, 815 Latency of activation, 1458
electroencephalographic evaluation of, 456 Knee Latissimus dorsi muscle, innervation of, 721
intraoperative monitoring of, 453-454, arthroplasty of, as sciatic nerve injur)' cause, Laxatives, as myopathy cause, 1405
455-456, 458, 460-461 872 Lead, screening for exposure to, 887
1506 — INDEX
Leading/trailing dipole (L/TD) model, 38 Lordosis, lumbar, physical examination of, 1233 Lymphoma, 989
of compound motor action potentials, 45 Lovastatin, as myopathy cause, 1404-1406 chronic inflammatory demyelinating
of far-field potentials, 47,48 Low-affinity, fast-channel syndrome, 1198-1199 polyneuropathy associated with, 949
of motor unit action potentials, 45 Low back pain, differential diagnosis of, 728-729, etoposide treatment of, 998
of near-field/far-field waveforms, 54-67 756 Hodgkin's, 990
Lead line, 1008 Lower limb peripheral neuropathies associated with,
Lead neuropathy, 1008-1009 -innervation of, 722, 841 992-993
"Learned hand rule," 446 anomalous, 193-194 Lymphomatoid granulomatosis, 991
Leigh's syndrome, 1350 cutaneous nerves, 842 Lymphoproliferative disorders, peripheral
Lemniscal (dorsal column) system, as lumbosacral plexopathy-related pain in, neuropathies associated with, 992-994
somatosensory evoked potential pathway, 877-878 Lymphorrhage, 1166
359-360 nerve conduction studies of, 209-213 Lyon hypothesis, 1274
"Leonine fades," 971 progressive numbness and weakness of,
Lepromin test, 972 1018-1019 M
Leprosy (Hansen's disease), 429, 971-973 segmental somatosensory evoked potential MAC (membrane attack complex), 1376
dapsone treatment for, 1003 studies of, 395-398 Macro motor unit potential, 1458, 1486
thalidomide treatment for, 1002 sensory nerve conduction studies of, 213-217, Madarosis, leprosy-related, 971
treatment of 391-395 MAD deficiency. See Myoadenylate deaminase
reversal reaction in, 973 Lumbarization, 718 deficiency
Leukemia Lumbar puncture, as paraspinal muscle instability MADS AM (multifocal acquired demyelinating
etoposide treatment for, 998 cause, 741-742 sensory and motor neuropathy), 955, 959-960
Leukemia, neuropathy associated with, 991 Lumbar spine Magnesium salts, neuromuscular transmission-
Leukodystrophy anatomy of, 717-718 inhibiting effect of, 1202
globoid cell (Krabbe's disease), 916-917, 1443 as peroneal nerve stimulation site, 394 Magnesium sulfate
metachromatic, 916 as pudendal nerve stimulation site, 400 as eclampsia cause, 1442
as infant hypotonia cause, 1440, 1443 as somatosensory evoked potential recording as hypermagnesemia cause, 1400
Leukopheresis, as inflammatory myopathy site, 365 Magnetic fields
treatment, 1389 as tibial nerve stimulation site, 392 of inductors, 107, 108
Levitation sign, 1415 Lumboinguinal nerve, 864 in magnetic stimulation, 424
Levodopa, as myopathy cause, 1405, 1412 Lumbosacral nerve roots Magnetic resonance imaging (MRI)
Lewis-Sumner syndrome, 960. See also Multifocal anatomy of, 838-839 for brachial plexopathy evaluation, 798-799
motor neuropathy avulsion of, 856, 861 for carpal tunnel syndrome evaluation, 1060
Lhermitte's sign, 141,999, 1003 stimulation of, 229-230 inversion recovery, for radiculopathy evaluation,
Licorice, as myopathy cause, 1405 Lumbosacral plexopathies 747
Lidocaine cream, as painful sensory neuropathy anatomic and physiologic correlation of, 855 for pelvic disease evaluation, 855, 859, 860
treatment, 976 cancer-related, 992 Magnetic stimulation, 172,415-427
Ligament of Struthers, as median nerve classification of, 850 cortical, 417^122,424
compression site, 1054-1055, 1056, 1076 electrodiagnostic medicine evaluation of, of the peripheral nervous system, 422-424
Ligaments, spinal, 718-720 851-855 physical principles of, 415-417
Ligamentum flavum, 718, 719 illustrative cases of, 875-878 transcranial, 466
Ligamentum nuchae, 719 technical and anatomic problems in, 875 Malabsorption
Limb length, effect on nerve conduction studies, electrodiagnotic correlates of, 851 celiac disease-related, 986
563 neuralgic amyotrophy, 856-857 Whipple's disease-related, 987
Limb mononeuropathies, diabetic, 983 painful, 856 Malaria, chloroquine treatment for, 1000
Limbs. See also Lower limb; Upper limb pathophysiology of, 850-851 Malignant fasciculation, 1459
innervation of, 721-726 proximal injury-related, 863-875 Mallory body myopathy. See Myofibrillar
musculature of, 720-721 radiation therapy-related, 859-860 myopathy
weakness of, acute onset of, 1016-1018 radiculopathies, 751-758 Mamillary process, 718
Limb weakness, acute onset of, 1016-1018 regional, 856-863 Mamillo-accessory ligament, 720, 725
Linear envelope EMG, 1458 traumatic injury-related, 860-861 Mamillo-accessory notch, 718
Lipid metabolism disorders, 1339-1343 Lumbosacral plexus Manual muscle testing, 1234
hereditary, 915-920 anatomy of, 723-724, 837-845 Marinesco-Sjogren-Garland syndrome, 924
Lipid-soluble molecules, transport through cell anomalies, 724, 850 Markesbery-Griggs-Udd myopathy, 1292-1293
membranes, 4 lumbar plexus branches, 839-845 Martin-Gruber anastomosis, 191-193, 897, 1047
Lithium, neuropathies associated with, 1005 normal, 850 anterior interosseous nerve injury-associated,
Liver disease, neuropathies associated with, thoracic and lumbar roots, 838-839 1058
987-988 cancer involvement of, 859-860 carpal tunnel syndrome-associated, 560-561,
Liver function testing, 987 nerve conduction latencies of, 229-230 1068-1069
in polymyositis, 1373-1374 neural innervation pathways of, 722, 841 compound motor action potentials of, 560-561
Liver transplantation patients, ulnar nerve injuries traumatic injuries to, 860-861 electrodiagnostic anomalies in, 1107
in, 1079 Lumbosacral trunk, 845 motor nerve conduction velocity in, 1066
Livido reticularis, polyarteritis nodosa-related, 965 Lumbrical muscles, innervation of, 721 needle electromyographic examination of, 566
Local circuit currents, 13-14, 30-31 Lundborg's system, of nerve injury classification. ulnar neuropathy associated with, 1082-1083
in large-current volume conductors, 32-34 125 Mass, 98
in restricted-current volume conductors, 31-32 Lung cancer, 990, 991 Masseter inhibitory reflex, 234
waveform asymmetry in, 34 metastatic, 991 Masseter muscle
Longitudinal ligaments, anterior and posterior, paclitaxel treatment for, 998 activation of, 551-552
718-719 small-cell, 966, 989 electrodiagnostic examination of, in motor
Long-latency reflex, 1458 antibodies in, 990 neuron disease, 534
Long-QT syndrome, 1313 etoposide treatment for, 998 Matrix metalloproteinases, 950, 967
Long thoracic nerve Lung disease, interstitial Maximal stimulus, 173
anatomy and anatomic course of, 781, 782, 802, dermatomyositis-related, 1375 McArdle's disease, 1329. See also Glycogenosis,
803 polymyositis-related, 1373, 1374 type 5
in scapular winging, 802-803 Lyme disease, 769, 887, 966, 973-974 contractures associated with, 281, 1248
stimulation of, 228 Lymphoid radiation, total, as chronic inflammatory histologic diagnosis of, 1236
upper-limb muscle innervation by, 721 demyelinating polyneuropathy treatment, 954 neuromuscular transmission disorders in, 1206
INDEX — 1507
Mean arterial pressure, effect on Median nerve block, as spasticity treatment, 504 Mitochondria
I electroencephalogram, 456 Medical history, in electrodiagnostic medicine within axoplasm, 161
i Measles, myositis associated with, 1391 consultations, 516, 1229-1233, 1242 metabolic processes of, 1338, 1340
Medial antebrachial cutaneous nerve, 781 Medical impression, in electrodiagnostic medicine Mitochondrial ATPase 6 gene, 1350
Medial cutaneous nerve of the arm, 783 consultations, 518 Mitochondrial DNA depletion syndromes, 1349
Median nerve Medical Research Council scale, for manual Mitochondrial myopathy lactic acidosis and
anatomic course of, 194, 811, 1047-1049 muscle testing, 1234 strokes (MELAS), 1347
anatomy of, 783, 784, 1047-1052 Mee's lines, 1010 Mixed connective tissue disease, 969, 1377
neural branching, 1049-1052 Melphalan, as amyloidosis treatment, 995 Mixed nerve somatosensory evoked potential
palmar cutaneous branch, 784, 1050, 1070 Membrane attack complex, 1376 examinations, 385-388
recurrent branch, 784, 1070 Membrane instability, 1459 Mixed nerve stimulation examination
in brachial plexopathy, 783-784 Membrane potential, 5-17 of focal peripheral neuropathies, 1047
complete laceration of, in Riche Cannieu active of radiculopathies, 737
anastomosis, 561, 566 definition of, 8 upper limb, 208-209
compound motor action potentials of, 811-812 ionic hypothesis of, 8-10 Miyoshi myopathy, 1279-1280, 1292, 1293,
in painful upper limb and cervical region, 526 propagation of, 12-17 1294-1295
connection with ulnar nerve, 192 voltage-gated channels in, 10-12 Monaka myopathy, 1292, 1293-1294, 1295
in diabetic mononeuropathy, 983 resting/transmembrane Monoclonal gammopathies
digital branches of, 1070 definition of, 5 benign, 992
focal neuropathies and injuries of, 811-812, generation of, 5-7 chronic inflammatory demyelinating
1052-1070 of nerve cells, 7-8 neuropathy-related, 949
in arm region, 1052-1053 Meningitis, Lyme disease-related, 974 diagnostic tests for, 1235
benediction sign of, 1052, 1055, 1086 Meningocele, traumatic, 798, 799 immunoglobulin A, 949, 954
bicipital aponeurosis-related, 1055, 1056 Meralgia paresthetica, 865 immunoglobulin G, 949, 954
compression by ligament of Struthers, Mercury, neuropathies associated with, 1009 immunoglobulin M, 949, 954, 955
1054-1055 Merosin, 1267 peripheral neuropathies associated with,
in forearm, 1058 deficiency of 992-994
leprosy-related, 971 in congenital muscular dystrophy, 1282-1283 of uncertain significance, 992
near axilla, 811 in infantile myositis, 1383-1384 chronic inflammatory demyelinating
at wrist, 550. See also Carpal tunnel Metabolic disorders, of muscle, 1329-1343 polyneuropathy-associated, 949,
syndrome glycogen metabolism disorders, 1329-1337 954-955
F-wave reference values of, 243 lipid metabolism disorders, 1339-1343 neuropathies associated with, 995-996
growth rate of, 120 purine nucleotide metabolism disorder, Mononeuropathies
"inching" technique for, 201-203 1337-1339 leprosy-associated, 971
mixed-nerve somatosensory evoked potential as radiculopathy cause, 769 limb, 983
studies of, 385-387 Metals, resistivity of, 100 of lumbosacral plexus, 863-875
motor conduction studies of, 194-196 Metatarsalgia, Morton's, 1106-1107 median, in children, 1444
in multifocal motor neuropathy, 958 Methotrexate multiple, 889, 963, 964
nerve conduction studies of as inflammatory myopathy treatment, 1387, critical illness polyneuropathy-associated,
with concomitant radial nerve stimulation, 1388-1389 988
207, 208 as systemic vasculitis treatment, 967 differential diagnosis of, 895
with concomitant ulnar nerve stimulation, /V-Methyl-D-aspartate receptors, 446 hepatitis-related, 987
207-208, 209 Methylprednisone human immunodeficiency virus infection-
in painful upper limb and cervical region , as inflammatory myopathy treatment, 1387 related, 977
525-526 as systemic vasculitis treatment, 967 leprosy-associated, 971
nerve conduction velocity in, in children, 1434, Metronidazole, neuropathies associated with, 1000 paraneoplastic vasculitis-related, 990
1435, 1436 Mevalonate, 1406 perineuritis-associated, 971
in neuromuscular junction disorders. 1159 Mexiletine rheumatoid arthritis-associated, 969
residual latency of, 235 as diabetic distal symmetric sensory and tumor infiltration-related, 991
sensory nerve conduction studies of, 200-203. sensorimotor polyneuropathy treatment, viral infection-related, 966
206-207. 811-812 981 progressive idiopathic, 875
in multifocal motor neuropathy, 958 as diabetic neuropathy treatment, 981 proximal, differentiated from brachial
in pediatric patients, 1436, 1438 as painful sensory neuropathy treatment, 976 plexopathy, 813
somatosensory evoked potentials of, 362, 363, Micelles, 3 uremic, 985
364 Microangiopathy, humorally mediated, 1376 Monophasic action potential, 1459
in coma evaluation, 405-^407 Microfilaments, 161 Monopolar needle electrode, 1459
far-field, 403-404 (32-Microglobulin, in hemodialysis, 985 Monoradiculopathy, diabetic thoracic, 982
montage of, 370 Micrography, diabetes mellitus-related, 979, 980 Morphologic index (MI), 972
segmental, 388-389 Microneurography, 252-253, 1459 Morton's neuroma, 1106-1107
stimulation of, 547, 548 Microscopic polyangiitis, 966 Motor axonal neuropathy, acute, 945-946
antidromic, 200-201, 202 Microtubules, 161 Motor endplate. See Endplate
gender differences in, 562-563 Midazolam, effect on intraoperative Motor evoked potentials, 1459
axillary, 227 neurophysiologic monitoring, 451, 452 intraoperative monitoring of, 421, 444,466
orthodromic, 203 Middle cerebral artery aneurysm, surgical effect of anesthetic agents on, 446-447,
repetitive, 546 treatment of, 459-460 448-449, 451, 452, 453, 466
at wrist, 550 Mid-transforaminal ligament, 720 effect of cerebral blood flow on, 454
in anomalous innervation, 192-193 Miller-Fisher syndrome, 888, 946-947 effect of hypothermia on, 455
coactivation of the ulnar nerve in. 50. Miniature endplate potentials, 1459 after magnetic stimulation, 418-420
183-184 definition of, 19-20 in neuromuscular junction disorders, 1147, 1148
inadvertent, 553 frequency of, 19-20 Motor latency, 1459
in median nerve lesions, 192 in needle electromyography, 265 Motor nerve conduction studies, 174-179, 1243,
sensory nerve action potential waveform Minimata Bay, mercury poisoning incident in, 1459
morphology in, 34—35 1009 of amyloidosis, 995
sympathetic skin response in, 575 Minimum conduction velocity, 1459 of brachial plexopathies, 790, 792-794
thenar branch of, 1051 Minocycline, as leprosy trearment, 973 of carpal tunnel syndrome, 1062, 1065-1066
upper-limb muscle innervation by, 721 Misonidazole, as neuropathy cause, 1000 of Charcot-Marie-Tooth disease, 904
1508 — INDEX
Motor nerve conduction studies (cont.) Motor unit action potentials (cont.) Motor unit action potentials (cont.)
of chronic inflammatory demyelinating in critical illness polyneuropathy, 989 in sarcoidosis, 970
polyneuropathy, 951 in dapsone-related neuropathy, 1003 satellite potentials of, 283
of diabetic neuropathies, 980 definition of, 42 sound of, 85
of diphtheritic neuropathy, 975 denervation-related loss of, 281 stable, 337
false-negative results in, 897 in diabetic thigh infarction, 1399 in suramin-related neuropathy, 1000
of gastrointestinal disease-associated in diphtheritic neuropathy, 975 surface-recorded, 338-343
neuropathies, 986, 987 in disulfiram (Antabuse)-related neuropathy, in thallium-related neuropathy, 1010
of Guillain-Barre syndrome, 940-942 1003 in thyroid disorders, 1394
of herpes varicella zoster virus infection, 978 doublets of, 1397 in toxoplasmosis, 1393
of inclusion body myositis, 1382 duration of, 4 2 ^ 3 , 271-272, 568, 1275 triplets of, 1397
interelectrode separation in, 544-545 in eosinophilia myalgia syndrome, 1005 unstable, 337
of leprosy, 973 failure to measure all parameters of, 1259-1260 in uremic neuropathy, 986
of lumbosacral plexopathies, 852-854 filter effects on, 84 variations in, 272
of paraneoplastic sensory firing rate of, 274 in vasculitis secondary to essential mixed
neuronopathy/ganglionopathy, 990 following denervation/reinnervation, 282-283 cryoblobinuria, 967
of peripheral neuropathies, 890, 891, 1046 in generalized necrotizing myopathy, 1401 in vincristine-related neuropathy, 998
of POEMS syndrome, 994 generation of, 1241-1242 in vitamin B, deficiency-related neuropathy,
proximal, 225-235 in herpes varicella zoster virus infection, 978 1012
cranial nerve conduction studies, 230-235 in hexacarbon-related (glue sniffer's) in Waldenstrom's macroglobulinemia, 994
nerve root stimulation studies, 225-230 neuropathy, 1008 waveform morphology of, 42-45
of radiculopathies, 732-733 effect of high-frequency filters on, 565 blanket principle of, 1251, 1252
stimulation sites in, 557-558 in human immunodeficiency virus infection- nascent potentials of, 1252
of ulnar neuropathy, 1081, 1084 related progressive polyradiculopathy, 977 near-field and far-field component
of uremic neuropathy, 985 in hyperparathyroidism, 1396 waveforms, 60, 63-65
Motor nerves, conduction veloci'.y of, 47 in hypoglycemia, 984 in radiculopathies, 744-745
Motor neuron disease, electrodiagnostic medicine in hypoparathyroidism, 1397 Motor unit counting, in Duchenne muscular
evaluation of, 531-534, 1459 in hypothyroid myopathy, 1395 dystrophy, 1276
compound motor action potentials in, 957-958 in iatrogenic steroid myopathy, 1398 Motor unit density, 344
motor evoked potentials in, 420 in inclusion body myositis, 1382-1383 Motor unit number estimation (MUNE) technique,
refractory periods in, 237 in injection injuries, 1415 338-343
Motor neurons, "backfiring" by, 239, 240 leading/trailing dipole model of, 45 Movement disorders, surface electromyography in,
Motor point, 1459 in lead-related neuropathy, 1008 338
Motor response, 1459 in lithium-related neuropathy, 1005 Movement-related cortical potential, 1460
Motor unit(s), 267, 1459 long-duration, in Duchenne muscular dystrophy, M response, 175
anatomy of, 267-268 1275 MUAP. See Motor unit action potentials
definition of, 42, 294 effect of low-frequency filters on, 565 Multiceps, 1392
electrophysiology of, 268-270, 295-296 in mercury-related neuropathy," 1009 Multicore/minicore myopathy, 1318, 1320
fast-twitch, 269, 270 in Miller-Fisher syndrome, 947 Multifidi muscles, 721
fatigue sensitivity of, 269-270 during minimal-to-moderate muscle Multifocal acquired demyelinating sensory and
firing rate of contractions, 261 motor neuropathy (MADSAM), 955,
antigravity 45° test of, 315, 316 in multifocal motor neuropathy, 957, 958 959-960
central rate, 312 in multiple myeloma, 993 Multifocal motor neuropathy, 888, 956-959,
interdischarge interval of, 314, 315 in myoglobinuria, 1416 1460
onset frequency of, 314 myopathic, 44-45 Multilead electrode, 1460
precision decomposition analysis of, 310-312 "myopathic," in hyperkalemia, 1400 Multiple discharge, 1460
number per muscle, 268 in necrotizing myopathies, 1404 Multiple myeloma, peripheral neuropathies
rate modulation of, 310 needle electromyographic recordings of, 73, associated with, 993
recruitment of. See Recruitment 74-76, 270-274, 295 Multiple sclerosis
reinnervation of, 281-282 in neoplastic plexopathies, 859 body temperature-related weakness associated
remodeling of, 349-350 neurogenic, 44 with, 141
size of, 294, 310, 311 in neuromuscular junction disorders, 284 central motor conduction time in, 420
following reinnervation, 350 in nitrofurantoin-related neuropathy, 1003 myasthenia gravis associated with, 1205
size principle of, 310 in nucleoside-related neuropathy, 1004 neuromuscular transmission disorders
slow-twitch, 269, 270 in organophosphates-related neuropathy, 1007 associated with, 1205
tetanus tension of, 269, 270 in paraneoplastic neuronopathy/ganglionopathy, refractory periods in, 237
Motor unit action potentials (MUAP), 567-572, with superimposed Lambert-Eaton somatosensory evoked potential abnormalities
1459-1460, 1483 myasthenic syndrome, 990 in, 361
aging-related changes in, 571-572, 896 in peripheral neuropathies, 892 Multipoint stimulation, 341
in alcoholic myopathy, 1414-1415 phases of, 42^13, 272 Mumps, as myositis cause, 1382, 1391
in alcoholic neuropathy, 1015 physiology of, 268-270 MUNE (motor unit number estimation) technique,
amplitude of, 42-43, 44, 567 in POEMS syndrome, 994 338-343
amplitude/rise time of. 271 in polymyalgia rheumatica, 1416-1417 Muscle
in amyloid myopathy, 1402 in polymyositis and dermatomyositis, components of, 21 -24
anatomic basis of, 267-268 1378-1379 electrophysiology of, 24-25, 261-264
in arsenic-related neuropathy, 1011 polyphasic potentials of, 43, 567-568 aging-related changes in, 572
in axonal sprouting, 45 in primary muscle diseases, 283-284 evaluation of, 1235-1236
in brachial plexopathies, 797-798 pseudopolyphasic potentials of, 567-568 histology of, 1235-1236
cathode ray tube display of, 90 in radiculopathies, 539 abnormal, 1237-1241
in Charcot-Marie-Tooth disease, 908 recruitment of, 272-274, 284-286 normal, 1236-1237
in chloroquine-related neuropathy, 1001 false-positive interpretations of, 568-569 of limbs, innervation of, 721-726
in chronic idiopathic sensory polyneuropathy, 1016 myogenic, 285-286, 568 primary function of, 20
in chronic obstructive pulmonry disease, 988 neurogenic, 284-285, 568 refractory periods in, 238
in colchicine-related neuropathy, 1002 in radiculopathies, 743-744 spinal, 720-721
in critical illness/acute quadriplegic myopathy, in stroke, 286 tumor invasion of, 1401
1403 rise time of, 42-43, 271 twitch time of, 268-269
INDEX — 1509
Muscle (com.) Muscle stretch reflexes, mvopathy-related loss of, Muscular dystrophies (cont.)
waveform morphology in, 40-49 1234 Duchenne (cont.)
compound muscle action potentials, 45-47 Muscle tissue specimens, stains for, 1235-1236 histopathology of, 1271, 1272
endplate potentials, 40-41 Muscle wasting, surface electromyographic immunohistochemistry of, 1271
far-field potentials, 47 evaluation of, 338 jitter in, 332
fibrillation potentials, 47-48 Muscle weakness. See also Hypotonia laboratory features of, 1271
motor unit potential morphology, 42-45 acromegaly-related, 1399 motor unit action potentials in, 1249
positive sharp waves, 48-49 acute onset of, 1016-1018 treatment of, 1276-1277
in single-muscle fiber, 41-42 adrenal insufficiency-related, 1398 Emery-Dreifuss
Muscle bulk cancer-related, 1401 autosomal dominant, 1281, 1289
acromegaly-related increase in, 1398, 1399 celiac disease-related, 986 autosomal recessive, 1289-1290
progressive loss of, 1231 chloroquine-related, 1000 contractures associated with, 1288
Muscle calcium channel gene, a-1 subunit dapsone-related, 1003 X-linked, 1270, 1288-1289
mutation of, 1310-1311 differential diagnosis of, 1149, 1229, 1230, facioscapulohumeral, 1284-1286
Muscle chloride channel gene, 1302 1232 Beevor's sign of, 1285
Muscle contraction, speed of, 269 diffuse, 531,532 as Coat's disease, 1285
Muscle cramp, 1460 diphtheritic neuropathy-related, 975 "Popeye arms" associated with, 1285
Muscle-eye-brain disease, 1282, 1284, 1442 distal, differential diagnosis of, 1232 scapular winging associated with, 1285
Muscle fascicles, motor units of, 267 distribution pattern of, 1230-1231 "trapezius hump" associated with, 1233,
Muscle fibers generalized 1285
aging-related changes in, 187 during childhood, 1229, 1230 immunostain-based diagnosis of, 1236
atrophy of, 1238, 1261 differential diagnosis of, 1229, 1230 jitter in, 332
capacitance of, 106-107 during early adulthood, 1229, 1230 limb-girdle, 1278-1282
characteristics of, 1236 in infants, 1229, 1230 sarcoglycanopathy-related, 1278-1279
cores and multicores of, 1240-1241 during middle-late adulthood, 1231 treatment of, 1281-1282
cytoplasmic inclusions of, 1240 hypermagnesemia-related, 1400 type IA, 1280
density of hypokalemia-related, 1400 type 2 A, 1279
neighboring, 349 hypophosphatemia-related, 1400 type IB, 1289
reference values for, 327 in idiopathic perineuritis, 970 type IB, with cardiopathy, 1280
single-fiber electromyographic measurements in infants, 1229, 1230, 1234 type2B, 1279-1280
of, 328-329, 332-333, 335-337 myasthenia gravis-related, 1163 type IC, 1281
diameter of, 1237 osteomalacia-related, 1396 type 2C, 1278
extrafusal, 21-24 pituitary failure-related, 1399 type 2D, 1278-1279
fast-twitch, effect of botulinum toxins on, 481 progressive lower limb, 1018-1019 type 2E, 1279
hypertrophy of, 1238-1239, 1242 progressive proximal, 1417-1419, 1420 type2F, 1279
hypotrophy of, 1238 proximal, 1232 type 2G, 1280
intrafusal, 21 differential diagnosis of, 1232 type 2H, 1280
"motheaten," 1241 lower-limb, 1230 type 21, 1280
necrosis of, regeneration after, 1239-1240 scleroderma-related, 1376 molecular genetics of, 1268, 1274
nuclei of, central or internal, 1239 toluene abuse-related, 1415 pathogenesis of, 1274
number per motor unit, 267-268 upper-limb, 1230-1231 refractory periods in, 237
pseudohypertrophy of, 1239 Muscular dystrophies, 1270-1292 scapuloperoneal syndromes of, 1287-1292
regeneration of, 1239-1240 Becker, 1271-1274 autosomal dominant Emery-Dreifuss
segmental necrosis of, 1239 clinical features of, 1271-1271 muscular dystrophy, 1281, 1289
size of differentiated from Duchenne muscular autosomal recessive Emery-Dreifuss
assessment of, 1237 dystrophy, 1271, 1272 muscular dystrophy, 1289-1290
normal, in myopathies, 1261 dystrophin deficiency in, 1266 bent spine/dropped head syndrome,
as polyphasic potential cause, 1251-1252 electrophysiologic findings in, 1275 1290- 1291
variability in, 1239 female carriers of, 1274 Bethlem myopathy, 1290
slow-twitch, effect of botulinum toxins on, 481 histopathology of, 1272 oculopharyngeal muscular dystrophy,
splitting of, 1240 laboratory features of, 1272 1291- 1292
target, 1241, 1242 molecular genetics of, 1274 rigid spine syndrome, 1290
triad of, 24 outlier, 1271, 1274 scapuloperoneal muscular dystrophy, 1287
triphasic waveforms of, 266-267 pathogenesis of, 1274 scapuloperoneal neuropathy (Davidenkow
type 1,294, 1236 treatment of, 1276-1277 syndrome), 1288
type 2, atrophy of, 1261 congenital, 1282 spinal scapuloperoneal atrophy, 1287-1288
type 2A. 294, 1236 with associated integrin mutations, 1283 X-linked Emery-Dreifuss muscular
distribution of, 1237 classic or occidental type, 1282-1283 dystrophy, 1288-1289
type 2B, 294, 1236 Fukuyama-type, 1280, 1282, 1283-1284, severe childhood autosomal recessive
distribution of, 1237 1442 (SCARND), 1278, 1279, 1281
type 2C. 1236 histopathology of, 1282-1284 X-linked, 1270, 1275. 1288-1289
distribution of, 1237 as hypotonia cause, 1442 Musculocutaneous nerve, 781
types of, predominance and preference of, 1239 merosin gene mutation-related, 1267 anatomic course of, 783, 809
ultrastructural changes in, 1241 merosin-positive with a-actinin loss, 1283 anatomy of, 783
vacuoles of, 1240 Santavouri-type (muscle-eye-brain) disease, compound motor action potentials of, 810
Muscle fiber conduction velocity, 1460 1282, 1284, 1442 injury to, 809-810
Muscle hypertrophy, 1460 Walker-Warburg syndrome, 1282, 1284 needle electromyographic studies of, 810
Muscle injury, electrophysiologic correlates of, Duchenne sensory nerve action potential studies of, 810
1241-1243 clinical features of, 1270-1271 stimulation of, 228, 229
Muscle pain, clinical evaluation of, 1231-1232 contiguous gene syndrome of, 1277-1278 in neuromuscular junction disorders,
Muscle relaxants, effect on intraoperative differentiated from Becker muscular 1159
neurophysiologic monitoring, 453 dystrophy, 1271, 1272 upper-limb muscle innervation by, 721
Muscle relaxation time, 269 dystrophin deficiency in, 1266 Musician's cramp, 498-499
Muscle strength dystrophin-glycoprotein complex in, 1273 M waves, 1458, 1472
diurnal fluctuations in, 1231 electrophysiologic findings in, 1274-1276 Myalgia, 1231
functional assessment of, 1234 female carriers of, 1274 polyarteritis nodosa-related, 965
1510 — INDEX
Myasthenia Myelin sheath, 15, 137, 161, 162 Myopathies (cont.)
congenital syndromes of. See Congenital Myelography inflammatory (cont.)
myasthenic syndromes cervical, in brachial plexopathies, 798, 799 polymyositis, 1372-1374, 1377-1379
familial as paraspinal muscle instability cause, 741-742 sarcoid myopathy, 1385
infantile, 1195-1196 as radiculopathy risk factor, 769 treatment of, 1386-1390
limb-girdle, 1200 three-dimensional magnetic, in brachial necrotizing, alcoholism-related, 1414
Myasthenia gravis, 987, 988, 1162-1176, 1460 plexopathies, 799 parathyroid, 1400
association with Graves' disease, 1393 Myeloma, osteosclerotic. See POEMS toxic, 1404-1415
classification of, 1163-1164 (polyneuropathy, organomegaly, amphiphillic, 1405
congenital, with primary acetylcholine receptor endocrinopathy, monoclonal gammopathy, anesthetic agents-related, 1413-1414
deficiency, 1199 skin changes) syndrome antimicrotubular, 1405, 1408-1409
curare testing in, 1160, 1161 Myelopathy, traumatic, somatosensory evoked centrally acting medication-related,
electrodiagnostic medicine evaluation of, potential-based prognosis of, 407 1413-1414
1168- 1176 Myoadenylate deaminase deficiency, 1337-1339 drug-induced hypokalemic, 1413
effect of body temperature on, 560, 1156, histologic diagnosis of, 1236 drug-induced inflammatory, 1411-1412
1157 Myoclonic epilepsy and ragged red fibers drug-induced mitochondrial, 1409-1411
comparison of different techniques in, (MERRF), 1346-1347 drugs of abuse-related, 1414-1415
1172-1173 Myoclonus, 1460 impaired protein synthesis-related,
electrode stabilization in, 1157-1158 Whipple's disease-related, 987 1412-1413
movement artifacts in, 1157-1158 Myoedema, 1234, 1395, 1460 increased metabolism-related, 1412-1413
epidemiology of, 1162-1163 Myofibribillar myopathy, 1280, 1295, 1319, necrotizing, 1404-1408
histopathology of, 1166 1326-1329 of unclear pathogenesis, 1413
hypothyroidism-associated, 1395 muscle biopsy in, 1241 classification of, 1262
as infant hypotonia cause, 1441 Myofibrillar proteins, 1269 critical illness, 1402-1403
jitter in, 331, 332 Myofibrils, 22 electrodiagnostic classification of, 1245, 1259
juvenile, 1176 Myofilaments, 22-24 electrodiagnostic medicine evaluation of,
laboratory features of, 1165-1166 Myoglobinuria, 1416 534-535
maternal, 1176, 1234 hypoparathyroidism-related, 1397 focal, cancer-related, 1401
motor nerve conduction studies of, 1169 hypophosphatemia-related, 1400 hereditary, 1265-1370. See also Muscular
multiple sclerosis associated with, 1205 influenza myositis-associated, 1390-1391 dystrophies
needle electromyographic studies of, 1170-1171 myalgia-associated, 1232 classification of, 1262, 1266
overlap syndrome with Lambert-Eaton myopathy-associated, 1415-1416 congenital myopathies, 1317-1329
myasthenic syndrome, 1165, 1183 recurrent, mitochondrial myopathies-associated, cap disease, 1319, 1325
pathogenesis and pathophysiology of, 1350-1351 central core disease, 1317, 1318,
1166-1168 rhabdomyloysis-associated, 1239 1319-1320
pediatric, 1176, 1441, 1444 serotonin syndrome-related, 1414 centronuclear myopathy, 1318, 1322-1323
post-nerve stimulation exhaustion associated toluene abuse-related, 1415 congenital fiber type disproportion, 1318,
with, 1152 Myoinositol, 980 1323-1324
during pregnancy, 1176 Myokymia, 1460 definition of, 1317
relapse of, differentiated from steroid myopathy, gold therapy-related, 1011 fingerprint body myopathy, 1318, 1324
1174 Myokymic discharges, 279, 280, 1460, 1482 hyaline body myopathy/familial myopathy
repetitive nerve stimulation studies of, in brachial plexopathies, 796-797 with lysis of myofibrils, 1319, 1325
1169- 1170, 1172 in peripheral neuropathies, 892 multicore/minicore myopathy, 1318, 1320
under ischemic conditions, 1159-1160 Myopathic potentials, 284, 1460 myofibrillar myopathy, 1319, 1326-1329
muscle sensitivity in, 1158-1159 Myopathic recruitment, 1460 nemaline myopathy, 1318, 1320-1322
sensory nerve conduction studies of, 1168-1169 Myopathies, 1460-1461 reducing body myopathy, 1318, 1324
single-fiber electromyographic evaluation of, acquired, 1371-1431 sarcotubular myopathy, 1319, 1324-1325
1171-1173 amyloid, 1401-1402 trilaminar myopathy, 1319, 1325
systemic disorders associated with, 1164-1165 cancer-associated, 1401 tubular aggregate myopathy, 1319,
transient neonatal autoimmune, 1176 classification of, 1262 1325-1326
treatment of, 1173-1176 critical illness/acute quadriplegic, 1402-1403 zebra body myopathy, 1319, 1325
Myasthenia Gravis Foundation of America, drug-induced/toxic, 1372 distal myopathies, 1291-1295
myasthenia gravis clinical classification electrolyte imbalance-associated, 1400-1401 Laing myopathy, 1292. 1293, 1295
system of, 1164 endocrine, 1372, 1393-1399 Markesbery-Griggs-Udd myopathy,
Myasthenic crisis, 1173 adrenal disorders-related, 1397-1398 1292-1293
"Myasthenic snarl," 1163 diabetes mellitus-related, 1399 Miyoshi myopathy, 1279-1280, 1292,
Myasthenic syndrome. See Lambert-Eaton parathyroid disorders-related, 1395-1397 1293,1294-1295
myasthenic syndrome pituitary disorders-related, 1398-1399 Monaka myopathy, 1292, 1293-1294, 1295
Mycobacterial infections, needle thyroid disorders-related, 1393-1395 with vocal cord paralysis and pharyngeal
electromyography-related, 287 focal muscle disorder-related, 1415-1417 weakness, 1295
Mycophenylate, as myasthenia gravis treatment, hypokalemic, alcoholism-related, 1414 Welander myopathy, 1292-1293
1175 iatrogenic steroid, 1397-1398 DNA diagnostic testing for, 1235
Mycoplasma pneumoniae infections, Guillain- ill-defined, 1416-1417 dystrophic myotonic, 1296-1300
Barre syndrome-associated, 938, 939-940 inflammatory, 1371-1390 congenital, 1297
Myelin Behcet's disease, 966, 1386 proximal, 1299-1300
composition of, 163 dermatomyositis, 1374-1376, 1377-1379 inclusion body myopathies, 1295-1296
optimal ratio with axon, 16 diagnostic evaluation of, 1373, 1386 metabolic disorders of muscle, 1329-1343
in segmental demyelination, 122-123 diffuse fasciitis with eosinophilia, 1384-1385 glycogen metabolism disorders, 1329-1337
in severe nerve injuries, 117-118 dropped-head syndrome, 1384 lipid metabolism disorders, 1339-1343
Myelin-associated glycoproteins, 163 focal myositis, 1384 purine nucleotide metabolism disorder,
Myelination, 15-16 granulomatous and giant-cell mysitis, 1385 1337-1339
following nerve injury, 121 idiopathic, 1371-1390 mitochondrial, 1343-1351
Myelin basic proteins, 163 inclusion body myositis, 1379-1383 electrodiagnostic findings in, 1346
Myelinopathies, 889 infantile myositis/congenital inflammatory genetics of, 1344-1345
sensory nerve action potentials in, 891 myopathy, 1383-1384 histopathology of, 1345-1346
Myelin protein zero, 163 overlap syndromes, 1376-1377 specific myopathies, 1346-1351
INDEX — 151 I
Myopathies (cont.) Myotonia fluctuans, 1306 Nerve conduction studies (cont.)
hereditary (cont.) Myotonia peramens, 1306 instrumentation factors affecting (cont.)
non-dystrophic myotonias and Myotonic discharges, 277-278, 1461, 1480 averaging, 182-183
channelopathies, 1300-1317 in amyloid myopathy, 1402 biologic variation, 186
chloride channelopathies, 1301-1302 Myotonic dystrophy, 1296-1299 distance between stimulation sites, 184
sodium channelopathies, 1302-1313 congenital, 1234, 1297 limb position and anatomic nerve course,
inflammatory, myasthenia gravis-associated, 1164 myotonic discharges in, 1247 186-187
interference pattern analysis of, 318, 319, proximal, 1299-1330 measurement parameters of, 184-187
322-323, 324 Myotonic-like potentials, 534 onset latencies of proximal and distal
Lyme disease-related, 974 Myotonic myopathy, proximal (PROMM), 1233. responses, 184—185
motor unit action potentials in, 303, 305-306 1299-1300 stimulators, 183-184
muscle pathology processes in, 294 Myotonic potentials, 1298-1299 intraoperative, 444
myofibribillar, 1280, 1295, 1319, 1326-1329 in chloroquine-related neuropathy, 1001 in peripheral nerve surgery, 466,468
muscle biopsy in, 1241 Myotonin protein kinase gene, 1298 techniques in, 470
necrotizing Myotubes, in muscle regeneration, 1240 in pediatric patients, 1438
paraneoplastic, 1401 Myotubularin gene mutations, 1323 physiologic factors affecting, 187-194
needle electromyographic evaluation of, Myxedema, 1234 aging, 187-188
534-535 anomalous innervation, 191-194
nerve conduction studies of, 534 N digit circumference, 188
neuropathy-associated, 927 NARP (neuropathy, ataxia, and retinitis gender, 187, 188
power spectrum analysis of, 318 pigmentosa) disorder, 1350 height, 188
progression rate of, 1229-1330 Near field, definition of, 28 temperature, 188-191
proximal myotonic (PROMM), 1233, Near-field potentials, definition of, 28, 1461 special techniques, 225-256
1299-1300 Near-field waveforms, leading/trailing dipole collision technique, 235-236
recruitment ratio in, 316 model of, 54-67, 81 late responses, 238-253, 1244
sarcotubular, 1319, 1324-1325 in denervated muscle fibers, 57-60 proximal motor nerve conduction, 225-235
Myophosphorylase deficiency. See Glycogenosis, in innervated muscle fibers, 54—57 collision technique, 235-236
type 5 Near-nerve sensory studies, of peripheral residual latency, 235
Myophosphorylase gene mutations, 1334 neuropathies, 889 refractory period measurement, 236-238
Myosin, 22, 1269 Nebulin, 1269 repetitive stimulation, 1243-1244
acromgealy-related increase in, 1399 Nebulin gene, 1321 residual latency measurement, 235
Myositis, 987 Neck. See also Cervical spine effect of temperature on, 558-560
acquired, associated with infections, 1390-1393 innervation of, 781 Nerve conduction velocity. See also under specific
focal, 1384 musculature of, 486-489 nerves
giant-cell (granulomatous), 1164, 1165, 1385 pain in, differential diagnosis of, 728 aging-related changes in, 187-188,562, 896
granulomatous, inflammatory bowel disease- weakness in, 1231 as basis for nerve fiber classification, 169
associated, 987 Necrosis in children, 1433-1436
inclusion body, 1300, 1380-1383 in critical illness/acute quadriplegic myopathy, definition of, 177
clinical features of, 1380-1381 1403 differential slowing of, 730
differentiated from polymyositis, 1381 diabetic thigh infarction-related, 1399 error curves in, 184
electrodiagnostic findings in, 1382-1383 myopathy-associated, 1401 experimental error curves in, 184—185, 186
sarcoid myopathy associated with, 1385 toxin-induced, 1404-1408 measurement of, 177-178
treatment of, 1386-1387 segmental first description of, 159-160
infantile/congenital inflammatory, 1383-1384 acromegaly-related, 1398-1399 of motor nerves, 47
inflammatory, systemic lupus erythematosus- motor unit fiber density in, 283 optimal axommyelin ratio required for, 16
related, 1376 in myogenic disorders, 1276 relationship with nerve fiber density, 16-17
myalgia associated with, 1232 Needle electrode, 1461, 1487 in sectioned nerves, 127-128
sporadic inclusion body, 1295 Needle myopathy, 287 effect of temperature on, 190-191
Myositis ossificans, sciatic nerve compression in, Needlestick injuries. See also Injection injuries in Wallerian degeneration, 126-127
873 to femoral nerve, 867 Nerve excitability test, of facial muscles, 232
Myotilin, 1280 as myopathy cause, 1415 Nerve fibers
Myotomes, 720-721 Negligence, "learned hand rule" of, 446 classification of, 17, 169
Myotonia, 1231, 1461 Nemaline myopathy. 1318, 1320-1322 myelinated, 160-167
acetazolamide-responsive. 1306-1307 Nematodes, as myositis cause, 1392 aging-related changes in, 187
acquired, 1297 Nephropathy, diabetic, 1399 axon of, 160-162
action, 1296 Nernst equation, 6-7 ion channels of, 138
definition of, 277 Nerve conduction, ephaptic, 141 periaxonal region of, 162
chemical induction of, 1246-1247 Nerve conduction studies, 159-223, 1243-1244, sodium and potassium channels of, 167-169
chondrodystrophic. See Schwartz-Jampel 1461. See also under specific disorders sensory, Lloyd classification system of, 359
syndrome basic principles of, 172-182 unmyelinated, 160
myotonic dystrophy-related. 1296-1299 patient considerations in, 172 Nerve Growth Factor Study Group, 433
warm-up phenomenon of, 1296 recordings, 173-174 Nerve injuries. See also specific nerves
percussion, 1233, 1296, 1305 stimulation, 172-173 classification of, 123, 126
definition of, 277-278 comparison with quantitative sensory testing, Lundborg's system, 125
potassium-aggravated, 1306 430 Seddon's system, 123-125
toxin/drug-induced, 1316-1317 definition of, 172 Sunderland's system, 124, 125-126
Myotonia congenita diagnostic pitfalls in, 556-563 third- through fifth-degree injuries, 786
abnormal compound motor action potentials in, amplitude variability, 556-557 Nerve roots
1206 number of stimulation sites, 557-558 avulsion of, as brachial plexopathy cause,
autosomal dominant form (Thomsen's disease), short interstimulus distances, 558 787-788, 798, 794,799, 801
1297, 1301 documentation of results of, 516-517 lesions of. See Radiculopathies
autosomal recessive form, 1301-1302 of dual-innervated digits, 207-208 lumbar, anomalies of, 724
differentiated from myotonic dystrophy, 1246 historical aspects of, 159-172 spinal, 722-724
as muscle hypertrophy cause, 1238 instrumentation factors affecting, 182-187 Nerve root stimulation, 225-230. See also Nerve
myotonic potential generation in, 1246-1247 amplification, 182 stimulation
"transient paresis" of, 1233-1234 amplifier sensitivity, 186 in brachial plexopathies, 794-795
1512 — INDEX
Nerve root stimulation (cont.) Neuromuscular junction disorders (cont.) Neuropathies (cont.)
cervical, 225-227 drug/toxin-related, 1201-1205 acquired (cont.)
of cervical nerve roots, 735-736 postsynaptic disorders, 1204-1205 immune-mediated neuropathies (cont.)
of lumbar nerve roots, 735-736 presynaptic disorders, 1201-1204 sarcoidosis, 969-971
of lumbosacral nerve root, 854 electrodiagnostic medicine evaluation of, sensory neuronopathies and autonomic
magnetic stimulation, 423-424 535-537 neuropathies, 960-962
proximal, 225-230 • curare-testing in, 1160—1162 vasculitic neuropathies, 962-968
purpose of, 225 false-positive results in, 535-536 nutritional deficiencies-related, 1011-1015
Nerves needle electromyographic studies, 538 sensorimotor polyneuropathy, 1015-1016
growth rates of, 120-121 nerve conduction studies of, 537-538 systemic disease-associated, 984-989
myelinated technical factors in, 1155-1162 toxic
active currents in, 15-17 effect-of temperature on, 560 chemotherapy-related, 996-1005
structure of, 137-138 electrophysiologic correlates of, 1148-1162 industrial and environmental agents-
unmyelinated, active currents in, 14-15 history and physical examination, 1148-1149 related, 1005-1008
waveforms of, 34-40 nerve conduction studies, 1149-1162 alcoholic, quantitative sensory testing in, 433
Nerve stimulation as infant hypotonia cause, 1441-1442 ataxia, and retinitis pigmentosa (NARP)
combined with botulinum toxin therapy, needle electromyographic studies of, 1150, disorder, 1350
485-486 1153- 1154 autonomic, 960-962
error sources in, 49-50 nerve conduction studies of, 537-538, diabetic, 981
inadvertent, 549-551 1149-1162 human immunodeficiency virus infection-
mechanisms of, 49-50 motor nerve conduction studies, 1149, 1150 related, 977
of peripheral nervous system, 172-173 repetitive stimulation assessment, 1149-1153 diabetic
rate of, effect on somatosensory evoked sensory nerve conduction studies, 1149, 1150 nerve conduction testing in, 432
potential waveforms, 574 pathophysiology of proximal, 857-859
repetitive, 1476-1478 in postsynaptic region, 1147-1148 quantitative sensory testing in, 432-433
in neuromuscular junction disorders, in presynaptic region, 1145-1147 diabetic, 1399
1149-1153 in synaptic space, 1145-1147 gouty, 988
sites of, 557-558 postexercise exhaustion associated with, hereditary, 899-936
distance between, 184 1151-1153 congenital hypomyelination. See Charcot-
transcranial, 466 single-fiber electromyographic studies of, 1150, Marie-Tooth disease, type 3
Neural arch, 714 1154- 1155 familial amyloid polyneuropathies, 914-915
Neuralgia, postherpetic, treatment of, 979 axonal-stimulated, 1155 hereditary ataxias, 920-924
Neural physiology, in children, 1433-1436 Neuromuscular transmission, 17-20, 1461 illustrative cases of, 927-930
Neural tissue, anatomy and physiology of, in presynaptic region, 19 with liability to pressure palsies, 905-906
3-5 safety factor in, 19, 139-140 lipid metabolism disorders-related, 915-920
Neurapraxia, 123-125, 132-133, 786, 1461 effect of temperature on, 559 miscellaneous, 924-927
Neurilemma, 167 in Wallerian degeneration, 128-129 motor and sensory neuropathies, 899-911
Neuritis Neuromyotonia, 971 Charcot-Marie-Tooth disease and related
brachial acquired. See Isaacs' syndrome disorders, 899-910
acute. See Amyotrophy, neuralgic Neuromyotonic discharges, 280, 1461, 1482 classification of, 899-900
idiopathic, 525 Neuronopathy, definition of, 889 with deafness, 910
progressive hypertrophic, 947 Neurontin as infant hypotonia cause, 1441
Neuroaxonal dystrophy, infantile, 925 as human immunodeficiency virus infection- neuralgic amyotrophy, 910911
Neurofibrillar brushes, 120 related distal symmetric polyneuropathy proximal hereditary motor and sensory
Neurofibromatosis, type 1, 821 treatment, 976 neuropathy/neuronopathy, 910
Neurofilaments, 161 as postherpetic neuralgia treatment, 979 type 1, 900-905
Neurofilamin, 161 Neuropathies, 1461-1462. See also type 2, 900, 906-907
Neurogenic block, 744 Polyneuropathies type 3, 900, 907-908
Neuroleptic malignant syndrome, 1413-1414 acquired, 937-1041 type 4,918-919
Neurologic examination, 1233-1235, 1242 associated with infections, 971-979 myopathic disorders associated with, 927
Neuroma cytomegalovirus, 978 sensory and autonomic neuropathies,
acoustic, 463 diphtheritic neuropathy, 974-975 911-914
Joplin's, 1107 Epstein-Barr virus, 978 type 1,911,912
Morton's, 1106-1107 hepatitis, 978 type 2,911-913
Neuromuscular block, 744 herpes varicella zoster, 978-979 type 3, 912
Neuromuscular junction human immunodeficiency virus infection, type 4,912
anatomy of, 17-18 975-977 type 5, 912
definition of, 17 human T-lymphocyte-1 infection, 977-978 spastic paraplegias, 927
effect of botulinum toxins on, 480-481 leprosy (Hansen's disease), 971-973 tomaculous, 905
in tick paralysis, 1194 Lyme disease, 973-974 Wartenberg's migrant, 911
unmyelinated nerves adjacent to, 160 chronic idiopathic sensory polyneuropathy, human immunodeficiency virus infection-
Neuromuscular junction disorders, 535-538 1015-1016 related, quantitative sensory testing in,
acquired. 1162-1195 electrodiagnostic medicine findings in, 1419 433
postsynaptic disorders, 1162-1176 endocrinopathies-associated, 979-984 hypertrophic, 902
presynaptic disorders, 1176-1195 heavy metal intoxication-associated, interference pattern analysis of, 318, 320, 321
compound motor action potentials in, 535 1008-1011 motor unit action potentials in, 303, 305-306
congenital myasthenic syndromes, 1195-1200 illustrative cases of, 1016-1019, 1417-1420 motor unit firing rate in, 316
with abnormal acetylcholine-acetylcholine immune-mediated neuropathies, 937-971 muscle fiber density in, 328-329
receptor interactions, 1200 acquired chronic demyelinating painful sensory, treatment of, 976
edrophonium testing in, 1165 polyneuropathies, 947-960 peripheral, 885-897
as hypotonia cause, 1442 Guillain-Barre" syndrome and associated absence of somatosensory nerve action
partially characterized, 1200 disorders, 937-947 potentials in, 553-554
postsynaptic space disorders, 1197-1200 hypereosinophilic syndrome, 971 autoantibodies in, 887-888
presynaptic disorders, 1195-1196 Isaac's syndrome, 971 axonal loss in, 530-531
synaptic space disorders, 1196-1197 neuropathies associated with autoimmune classification of, 892-897
treatment of, 1200 connective tissue diseases, 968-969 congenital, as hypotonia cause, 1441
INDEX — 1513
Neuropathies (cont.) Noise, 1462 Orchitis, polyarteritis nodosa-related, 965
peripheral (cont.) thermal electric, 108-109 Organophosphates
electrodiagnostic medicine evaluation of. Nonconductors, 100 as delayed polyneuropathy cause, 1007
529-531 Nonpolar compounds, definition of, 3 as neuropathy cause, 1007
electrodiagnostic pitfalls in, 895-897 Notochord, 715 Osserman criteria, for myasthenia gravis
electrophysiologic patterns in, 892-895 Nuclear lamina-associated protein family, classification, 1163-1164
false-negative diagnoses of, 896-897 1269-1270, 1289 Osteoarthritis, ulnar nerve injuries associated with,
false-positive diagnoses of, 895-896 Nuclear membrane proteins, 1269-1270 1079
focal, 1043-1126 Nucleoside reverse transciptase inhibitors, as Osteomalacia, 1395-1396
anatomic variations in, 1107-1108 neuropathy cause, 1004 treatment of, 1396
axonal loss in, 1043-1044 Nucleosides, as neuropathy cause, 1004 Osteoporosis, corticosteroids-related, 952, 1174,
electrical stimulation intensity in, 1109 Nucleus cuneate, 359, 360 1388
electrodiagnostic correlates of, 1043-1045 lesions of, 364 Osteotomy, tibial, as common peroneal nerve
electrodiagnostic evaluation of, 1045-1047 Nucleus gracilis, 359, 360 injury cause, 1095
electrodiagnostic medicine consultation Nucleus pulposus, 715, 716 Ovarian cancer, 989, 990
pitfalls in, 1107-1109 Nucleus Z, 360 paclitaxel treatment for, 998
illustrative cases of, 1109-1115 "Numb chin syndrome," 991 Overlapping mononeuropathy multiplex, 969
inadequate electrodiagnostic studies of, Numbness Overlap syndromes, dermatomyositis and
1109 chronic idiopathic sensory polyneuropathy- poly myositis-associated, 1376-1377
of lower limb, 1094-1109 related, 1015 Oxandrolone, as Becker muscular dystrophy
median nerve lesions, 1047-1070 cryptogenic sensory or sensorimotor treatment, 1276
medical history of, 1045 polyneuropathy-related, 990-991 Oxygen molecules, transport through cell
peroneal nerve lesions, 1094-1101 in foot, with pain, 1114-1115 membranes, 4
physical examination of, 1045-1046 in hand
radial nerve lesions, 1087-1094 with arm pain, 1109-1110 P
reference values in, 1108 with elbow pain, 1110-1112 Pacemaker patients
temperature effects in, 1108-1109 ifosfamide-related, 1000 needle electromyographic waveforms in, 286
tibial nerve lesions, 1101-1107 monoclonal gammopathy of uncertain peripheral nerve stimulation in, 95-96
ulnar nerve lesions, 1070-1086 significance-related, 995 Paclitaxel, as neuropathy cause, 997, 998-999
of upper limb, 1047-1094 paraneoplastic syndromes-related, 989 Paget's disease, ulnar nerve injuries associated
hereditary, differentiated from acquired progressive lower limb, 1018-1019 with, 1079
neuropathies, 885-886 Nutritional deficiencies Pain
laboratory evaluation of, 887-888 as alcoholic neuropathy cause, 1014, 1015 amyloid myopathy-related, 1401
medical history of, 885-886, 890 as neuropathies cause, 1011-1015 in arm, cancer-related, 991-992
needle electromyographic studies of, 530-531 as osteomalacia cause, 1396 botulinum toxin therapy for, 507-508
nerve biopsy in, 888 Nyquist frequency, 87, 110, 338 in chest wall, thoracic radiculopathy-related,
nerve conduction studies of, 529-530 Nystagmus, Whipple's disease-related, 987 982
nutritional deficiencies-related, 1396 chronic idiopathic sensory polyneuropathy-
onset of, 886 O related, 1015
physical examination in, 886-887, 890 Oblique muscle, internal, innervation of, 841 congenital indifference to, 914
quantitative sensory testing in, 429, 432-435 Obturator internus nerve, sacral plexus nerve diabetic distal symmetric sensory and
refractory periods in, 237 branch connection of, 845-846 sensorimotor polyneuropathy-related, 979,
skin biopsy in, 888 Obturator nerve, 838 980-891
uremic, 984-985 accessory, 843 as diabetic distal symmetric sensory and
power spectrum analysis of, 318 anatomy and anatomic course of, 842-843, 844 sensorimotor polyneuropathy treatment,
recruitment in, 316 injuries to, 870-871 980
sensory nerve action potentials in, 891 lower-limb muscle innervation by, 722, 841 epicritic, 885
uremic, quantitative sensory testing in, 433 Obturator nerve block, as spasticity treatment, 504 in lower limb and low back region, 528-529
vitamin B ) 2 deficiency-related, quantitative Ocular motility disorders, botulinum toxin therapy muscular, evaluation of, 1231-1232
sensory testing in, 433 for, 494-496 myofascial pain syndrome-related, 1417
Neuropathy target esterase, 1007 Ocular muscles, myasthenia gravis-related polymyalgia rheumatica-related, 1416
Neuroradiologic procedures, intraoperative weakness of, 1163 postherpetic, 978, 979
monitoring during, 463-465 Ofloxacin, as leprosy trearment. 973 protopathic, 885
Neurosarcoidosis, 970 Ohm's law. 69-70, 77, 78, 100, 101, 102 psychosomatic. 1232
Neurotmesis, 125 "OK" sign, 1057 radicular differentiated from non-radicular,
Neurotonic discharges, 443. 444, 1462 Olivopontocerebellar atrophy, 923 728-729
Neurovascular surgery, intracranial, intraoperative Omeprazole, as neuromyopathy cause. 1413 repetitive peripheral nerve stimulation-related.
monitoring during. 458-459 Oncherciasis, suramin treatment for. 999 535
Niacin, as necrotizing myopathy cause, 1404, 1406 "Onion bulbs," 889 thallium poisoning-related, 1009
Niclosamide, as tapeworm treatment, 1392 Onset latency tumor-related, 1401
Nissl bodies, 119-120 effect of amplification on. 183, 553 in upper limb and cervical region, 524-528
Nitrofurantoin, neuropathies associated with, 1003 of proximal and distal responses, 184-185 Paired stimuli, 1462
Nitrogen, transport through cell membranes, 4 Ophthalmoparesis, supranuclear, Whipple's Palm, neuromuscular structures of, 1051
"Nitrous-narcotic" anesthetic technique, 450 disease-related, 987 Palmar/dorsal interossei muscles, innervation of.
Nitrous oxide Ophthalmoplegia 721
effect on intraoperative neurophysiologic autosomal recessive cardiomyopathy with. 1348 Palmaris brevis sign, 1084
monitoring, 448, 449-450 Miller-Fisher syndrome-related, 946 Palmaris longus muscle, innervation of, 721,
as vitamin B, 2 deficiency cause, 1013 neuromuscular cause of, 1233 1049
Node of Ranvier, 15, 160, 161, 164-165 progressive external, 1348 Palpation, in infants, 1234
in action potential propagation, 16, 17, 139 Opioids Pancoast rumors, 991
anatomy of, 138 effect on intraoperative neurophysiologic Pancreatic cancer, 990
in regenerated nerves, 121 monitoring, 450 Pancreatic islet cell tumors. 983
resistive and capacitive components of, 139. 140 as hypersensitivity vasculitis cause, 966 Pancreatic transplantation, as diabetic neuropathy
sodium and potassium channels within, 168 Opponens pollicis muscle, innervation of, 721 treatment, 980, 981
Nodules, subcutaneous, polyarteritis nodosa- Orbicularis oris muscle, as botulinum toxin Panhypopituitarism, 1399
related, 965 injection site. 496-497 Parainfluenza infection, as myositis cause, 1391
1514 — INDEX
Paralysis. See also Periodic paralysis Pelvis, traumatic injuries to, lumbosacral plexus Peroneal nerves
acute ascending, 937 involvement in, 860-861 accessory, 567
normokalemic periodic, 1305 Penicillamine anatomy and anatomic course of, 211-212,
obstetric, brachial plexopathy associated with, as lead neuropathy treatment, 1009 872-873
784-785 as myopathy cause, 1405, 1412 common
tick bite-induced, 1193-1195 Penicillin, as Lyme disease treatment, 974 anatomy and anatomic course of, 848,
Paralysis periodica paramyotonica, 1303, 1305 Penis, dorsal nerve of, 850 1094-1095
Paramyotonia, physical examination of, 1233 Pentazocine, as myopathy cause, 1405 injuries to, 1095-1099
Paramyotonia congenita (Eulenberg disease), Percussion, muscular, 1233-1234 lower-limb innervation by, 841
1297,1305-1306, 1308 Perfloxacin, as leprosy treatment, 973 conduction velocity in, 238
myotonic discharges in, 1247-1248 Perhexiline maleate, as neuropathy cause, 1001 in children, 1436
Paraneoplastic syndromes, 1401 Pericarditis, Lyme disease-related, 974 deep
autonomic neuropathy, 990 Perifascicular atrophy, 1376 accessory, 193,561, 1098
chronic inflammatory demyelinating Perineal nerve, anatomy of, 849-850 anatomic course of, 1095
polyneuropathy, 949 Perineuritis, idiopathic, 970-971 anterior tarsal tunnel syndrome of,
definition of, 989 Perineurium, 165-166 1100-1101
Lambert-Eaton myasthenic syndrome, 1182 Periodic paralysis in anterior tibial nerve compartment
neuropathy, 887, 989-990 hyperkalemic, 1303-1305, 1308-1309 syndrome, 1096
sensorimotor polyneuropathy, 990 neuromuscular transmission disorders in, lower-limb innervation by, 841
sensory neuronopathy/ganglionopathy, 989-990 1206 distal motor latency of, Duchenne muscular
Paranodal region, 164, 165 hypokalemic, 1309, 1400 dystrophy-related absence of, 1275
Paraparesis familial, 1310 F-wave of, 528
electrical injury-related, 988 neuromuscular transmission disorders in, reference values of, 243
tropical spastic, 1014 1206 lower-limb muscle innervation by, 722
Paraplegia primary, 1309-1310 nerve conduction studies of, 211-212, 528
hereditary spastic, 927 secondary, 1313 in peripheral neuropathies, 529
scoliosis surgery-related, 465 thyrotoxic, 1393 neuropathies of
Paraprotein-related neuropathies, chronic Klein-Lisak-Andersen syndrome of, 1313 at fibular head, 528, 1095-1099
inflammatory demyelinating polyneuropathy thyrotoxic, 1313 sensory nerve conduction studies of, 393-395
associated with, 954—955 Peripheral myelin protein-22, 163 strawberry pickers' palsy of, 1095
Parasitic infections Peripheral myelin protein-22 gene, 903-904, superficial
as inflammatory myopathy cause, 1372 908 anatomy and anatomic course of, 848, 849,
as myositis cause, 1392-1393 Peripheral nerves 1095, 1099
Paraspinal muscles far-field potentials of, 37-38 electrodiagnostic medicine evaluation of,
membrane instability of, 570 focal neuropathies of, differentiated from 528
in myopathies, 535 cervical radiculopathy, 749-750 injuries to, 1099-1100
in polyradiculoneuropathies, 531 stimulation of, 91 lower-limb innervation by, 841
in radiculopathies, 740 in pacemaker patients, 95-96 in lumbosacral radiculopathies, 752
relaxation of, 259 structure of, 165-167 nerve conduction studies of, 216
Parathyroid disorders, as endocrine myopathy Peripheral nerve surgery, intraoperative monitoring in nonsystemic vasculitis, 967
cause, 1395-1397 during, 466-469 in peroneal neuropathies, 889-890, 1096
Parathyroidectomy, 1396 Peripheral nervous system in sciatic nerve injury, 873
Parents, involvement in children's clinical aging-related changes in, 187-188 segmental somatosensory evoked potential
evaluation, 1232-1233 effect of cancer on. See Paraneoplastic examination of, 396
Paresthesia syndromes sensory nerve action potentials of, 853
amiodarone-related, 1001 depolarization of, 172-173 in thoracic radiculopathy, 982
celiac disease-related, 986 injury response of, 115-156, 888-889 Peroneal plexus, stimulation of, in neuromuscular
hyperparathyroidism-related, 1395 action potential conduction slowing and junction disorders, 1159
ifosfamide-related, 1000 blockade, 137-148 Peroneus brevis muscle, innervation of, 722, 841
Lyme disease-related, 974 in chronic nerve compression, 148-152 Peroneus longus muscle, innervation of, 722, 841
misonidazole-related, 1000 electrical aspects of, 139-140 Peroneus tertius muscle, innervation of, 722
paraneoplastic syndromes-related, 989 electrophysiologic correlates of, 889-892 Persian Gulf War syndrome, 1417
Parkinson's disease in intermediate injuries, 132-137 Pes cavus, 913
levodopa treatment for, as inflammatory in minimal injuries, 131-132 Petechiae, polyarteritis nodosa-related, 965
myopathy cause, 1412 neuromuscular transmission disorders, 1206 Pharynx, distal myopathy-related weakness of,
tremor treatment in, 500 in severe injuries, 116-131 1295
Parotid gland, amiodarone-related hypertrophy of, clinical correlates of, 129-131 Phase cancellation, in sensory nerve action
1001 nerve injury classification of, 123-126 potentials, 35, 36
Parsonage-Turner syndrome, 910-911 neural regeneration in, 120-122 Phenobarbital
Patellar plexus, 842 neurophysiologic correlates of, 126-128 as folic acid deficiency cause, 1013
Peak latency, 896, 1462 segmental demyelination in, 122-123 effect on intraoperative neurophysiologic
Pectoralis major muscle, innervation of, 721 Wallerian degeneration in, 116-120. monitoring, 451
Pectoralis minor muscle, innervation of, 721 128-129 3-Phenylamino alanine, 1005
Pectoral nerves magnetic stimulation of, 422-424 Phenytoin
anatomic course of, 781, 782 sarcoidosis of, 969 as folic acid deficiency cause, 1013
anatomic variations of, 782 somatosensory evoked potentials of. 358-359 as inflammatory myopathy cause, 1412
in brachial plexopathies, 807 structure of, 160-172 as myopathy cause, 1405
upper-limb muscle innervation by, 721 myelinated nerve fibers, 160-167 neuropathies associated with, 1004-1005
Pedicles, anatomy of, 714, 716 relationship with action potential propagation, as painful sensory neuropathy treatment, 976
Pedicle screws, misplacement of, 444 167-169 Phosphate, depletion of, as osteomalacia cause,
Pelvic structures, anatomic relationship with relationship with compound nerve action 1396
lumbosacral plexus, 840 potential propagation, 169-172 Phosphatidylcholine, structure of, 4
Pelvic tumors unmyelinated nerve fibers, 160 Phosphodiesterase, azathioprine-induced inhibition
as femoral nerve lesion cause, 867 Perixonal region, of myelinated nerve fibers, 162 of, 1202
lumbosacral plexopathy associated with. 855, Peroneal muscular atrophy, Charcot-Marie-Tooth Phosphofructokinase deficiency. See
859-860 disease-related, 901 Glycogenosis, type 7
INDEX — 1515
Phosphoglycerate kinase deficiency. See Plexopathies, 1462 Plexopathies (cont.)
Glycogenosis, type 9 botulinum toxin therapy for. 484 brachial (cont.)
Phosphoglycerate mutase deficiency. See brachial, 777-863 supraclavicular, 800-806
Glycogenosis, type 10 age factors in, 784-785 as C5 and C6 root lesions, 800-801
Phospholipase A,, inflammatory response to, anatomic and physiologic correlates of, as C8 and Tl root lesions, 801
729 798-800 as C7 root lesions, 801
Phospholipids, as plasma membrane component, axon reflex, 799-800 as peripheral nerve lesions, 801-804,
3,4 computed tomography, 798 805-806
Phosphor, as cathode ray tube screen coating, 90 magnetic resonance imaging, 798-799 as trunk lesions, 804-805
Phosphorus, homeostasis of, 1395 myelography, 798, 799 surgical treatment of, intraoperative
Phosphorylase b kinase deficiency. See plain radiography, 798 neurophysiologic monitoring during,
Glycogenolysis, type 8 backpack paralysis, 822-823 467-^168
Phrenic nerve cancer-related, 991-992 as thoracic outlet syndrome, 817-820
accessory, 782 classification of, 785 thoracic polyradiculopathy-associated, 982
anatomic course of, 782 closed, 785 traction-related, 798
in Charcot-Marie-Tooth disease, 904-905 complete, 785 lumbosacral
connection with brachial plexus, 781 compression-related, 787 anatomic and physiologic correlation of, 855
in Guillain-Barre syndrome, 941 differential diagnosis of, 812-814, 1086 cancer-related, 992
in herpes varicella zoster virus infection, 978 direct plexus stimulation evaluation of, 795 classification of, 850
in leprosy, 973 electrodiagnostic medicine consultations electrodiagnostic medicine evaluation of,
motor conduction studies of, 200 pitfalls related to 851-855
Physical examination, in electrodiagnostic false-negative investigations, 825-826 illustrative cases of, 875-878
medicine consultations, 516, 1233-1235, false-positive investigations, 826 technical and anatomic problems in, 875
1242 electrodiagnostic medicine pitfalls in electrodiagnotic correlates of, 851
Phytanoyl-coenzyme A a-hydroxylase gene, false-negative investigations, 825-826 neuralgic amyotrophy, 856-857
mutations of, 918 false-positive investigations, 826 painful, 856
Piriformis muscle electrophysiologic correlates of, 788-790 pathophysiology of, 850-851
innervation of, 841 axonal loss, 786, 789-790 proximal injury-related, 863-875
sacral plexus connection of, 846 conduction block, 786, 788-790 radiation therapy-related, 859-860
Piriformis syndrome, 873 demyelination, 786, 789 radiculopathies, 751-758
Pitfalls, in electrodiagnostic medicine, 541-577 F-wave in, 794 regional, 856-863
amplification, 553-554 gender differences in, 784-785 traumatic injury-related, 860-861
anodal block, 552 H-reflex in, 794 sacral, F-wave and H-reflex in, 654
cathode/anode reversal, 552-553 illustrative cases of, 826-830 P loop, 12
cathode/anode stability, 553 incidence/prevalence of, 784 Pneumothorax, needle electromyography-related,
electrode stability, 545 incomplete, 785 287, 566, 736
filters-related, 554-556 infraclavicular, 806-812 Podophyllin, neuropathies associated with, 1002
in focal peripheral neuropathies, 1107-1109 of axillary nerve, 808-809 POEMS (polyneuropathy, organomegaly,
in motor nerve conduction studies, 544-545 of lateral cord, 807 endocrinopathy, monoclonal gammopathy,
in nerve conduction studies, 556-558 of medial cord, 806-807 skin changes) syndrome
electrode location-related, 562 of musculocutaneous nerve, 809-810 chronic inflammatory demyelinating
instrumentation-related, 541-564 of peripheral nerves, 807-808 polyneuropathy-associated, 949, 955
recording electrodes-related, 562 of posterior cord, 807 peripheral neuropathies-associated, 993-994
physiologic factors, 558-563 of radial nerve, 810-812 Polar compounds, definition of, 3
stimulus artifacts, 545-547, 552 of ulnar nerve, 812 Polarization, 1462
volume conduction, 547-552 ischemia-related, 787 Poliomyelitis, 1442
Pituitary disorders, as myopathy cause, 1398-1399 laceration-related, 785, 786-787 neuromuscular transmission disorders
Plantar/dorsal interossei muscle, innervation of, motor nerve conduction studies of, 790, associated with, 1205-1206
722 792-794 quantitative electromyography in, 348
Plantar nerves needle electromyographic studies of, 791, POLIP syndrome, 1349-1350
interdigital, neuropathy of, 1106-1107 792,796-798 Poly(A)binding protein 2 gene, 1291, 1292
lower-limb innervation by, 841 spontaneous activity in, 796-797 Polyangiitis, microscopic, 966
medial and lateral voluntary motor unit action potential Polyarteritis nodosa, 964—965
anatomic course of, 847, 848, 1102 activity in, 797-798 hepatitis associated with, 967-968
anatomy of, 1101 needle-induced, 824-825 Polydipsia, Whipple's disease-related, 987
lesions of, 1102-1103 neoplastic, 821-822 Polygiucosan body disease. See Glycogenosis,
motor conduction studies of, 1104 nerve root avulsion-related, 787-788 type 4
in peripheral neuropathies, 891 nerve root stimulation studies of, 794-795 Polymyalgia rheumatica, 1416-1417
somatosensory evoked potential studies of, as neuralgia amyotrophy, 815-817 Polymyositis, 1372-1376
402-^03 of obstetric origin, 784-785, 814-815, 1444 clinical features of, 1300
nerve conduction studies of, 216-217 open, 785 differentiated from dermatomyositis, 1374-1375
in peripheral neuropathies, 529-530 as partial lesions, 749 differentiated from inclusion body myositis,
Plasmacytoma, POEMS syndrome-associated, pathophysiology of, 785-788 1381
993, 994 perioperative. 823-824 electrodiagnostic findings in, 1377-1379
Plasma membrane postanesthetic, 824 eosinophilic, 1384
lipid bilayer of, 3-4 postganglionic, 785, 786 giant-cell (granulomatous), 1385
molecular permeability of, 5 preganglionic, 785, 786, 789-790 inflammatory bowel disease-associated, 987
transport through, 4-5 progression of, 788 as mixed connective tissue disease component,
Plasmapheresis treatment retroclavicular, 806 969
for chronic inflammatory demyelinating scapular winging associated with, 802, 803¬ overlap syndromes of, 1376-1377
polyneuropathy, 950, 952-953 804 steroid-resistant/refractory, 1380-1381
for Guillain-Barre syndrome, 943, 944 sensory nerve conduction studies of, 790-792 toxoplasmosis-related, 1393
for inflammatory myopathy, 1389 somatosensory evoked potentials studies of, Polyneuritis, recurrent, 947
for Lambert-Eaton myasthenic syndrome. 795-796 Polyneuropathies, 1462
1183 sports-related (burners/stingers), 820-821 chronic idiopathic sensory, 1015-1016
for myasthenia gravis, 1175 stretch or traction-related. 786, 787-788 critical illness, 988-989, 1443-1444
1516 — INDEX
Polyneuropathies (cont.) Popliteal fossa (cont.) Prenatal diagnosis
cryptogenic sensory, 433-434 as superficial sensory peroneal nerve stimulation of limb-girdle muscular dystrophy, 1279
cancer-associated, 990-991 site, 396 of spinal muscular atrophy, 1440
demyelinating as sural nerve stimulation site, 395 Probenecid, as Lyme disease treatment, 974
acquired chronic, 947-960 as tibial nerve stimulation site, 392 Procainamide, as myopathy cause, 1405, 14—12
chronic inflammatory demyelinating Porphyria, 925-927 Progressive external ophthalmoplegia, 1348
polyneuropathy, 947-955 Positive sharp wave-like potentials, 569 Progressive polyradiculopathy, human
distal acquired demyelinating symmetric Positive sharp waves, 48^*9, 275-276, 281, 1462, immunodeficiency virus infection-related,
neuropathy, 955-956 1480 977
multifocal acquired demyelinating sensory in brachial plexopathies, 796-797 Pronator quadratus muscle, innervation of, 721,
and motor neuropathy, 955, in chronic obstructive pulmonary disease. 1049-1050
959-960 98"8 Pronator teres muscle, innervation of, 721, 1049
multifocal motor neuropathy, 956-959 definition of, 48 Pronator teres syndrome, 1055-1056
chronic inflammatory, 939, 956 in diabetic thigh infarction, 1399 Propagation velocity, 1463
axonal variant of, 955 distorted, 571 Propofol
in children, 954 endplate spikes appearing as, 56 effect on intraoperative neurophysiologic
human immunodeficiency virus infection- in hypokalemia, 1400 monitoring, 452-453
associated, 978-979 nonreproducible, 570 as myopathy cause, 1406-1407
laboratory evaluation of, 887 in polymyositis, 1377-1378 Propranolol, as thyrotoxicosis treatment, 1394
myasthenia gravis-associated, 1164 in polymyositis and dermatomyositis, Proprioception, 359-360
paraprotein-related neuropathies associated 1377-1378 Lyme disease-related reduction in, 974
with, 954-955 in radiculopathies, 739-740, 745-746 Prosaposin gene mutations, 916
relationship with multifocal acquired sound of, 49 Prostate cancer, 966
demyelinating sensory and motor in tick paralysis, 1194 Protein
neuropathy, 960 volume conduction theory of, 48-49 carrier, 4
relationship with symmetric, painless Postactivation, 1462 in facilitated diffusion, 4, 5
diabetic polyradiculopathy, 982-983 Postactivation depression, 1462 channel, 4
distal symmetric Postactivation exhaustion, 1462 as plasma membrane component, 3 , 4
diabetic sensory, 979-981 Postactivation potentiation, 1462 synthesis impairment of, myopathies associated
human immunodeficiency virus-related, Postcondylar groove, ulnar nerve in, 1071 with, 1412-1413
975-976 Posterior fossa surgery, 461,463 transport, 4
human immunodeficiency virus infection- Postgastrectomy syndromes, 1014 Protein channels
related, 975 Posttetanic potentiation, 1462 ligand or voltage gating of, 5
immune-mediated, 937-971 Posture, evaluation of, 1233 transmembrane, 4
acquired chronic demyelinating Potassium channels, 6 Protozoal infections, as myositis cause, 1392-1393
polyneuropathies, 947-960 of demyelinated nerves, 141 Provastatin, as myopathy cause, 1404, 1405-1406
Guillain-Barre syndrome and associated drug/toxin-induced dysfunction of, 1201-1202 Proximal diabetic neuropathy, 981
disorders, 937-947 of myelinated nerve fibers, 138, 167, 168-169 Proximal hereditary motor and sensory
hypereosinophlic syndrome, 971 pharmacologic blockage of, 138, 143 neuropathy/neuronopathy, 910
Isaacs' syndrome, 971 voltage-gated, 10-12 Proximal motor nerve conduction, 225-235
neuropathies associated with autoimmune autoantibodies against, in Isaac's syndrome, Proximal myotonic myopathy (PROMM), 1233,
connective tissue diseases, 968-969 971 1299-1300
sarcoidosis, 969-971 Potassium conductance, in myotonia congenita, Proximal nerves, inadvertent stimulation of,
sensory neuronopathies and autonomic 1247 549-551
neuropathies, 960-962 Potassium ions Prurigo nodularis, thalidomide treatment for, 1002
vasculitic neuropathies, 962-968 effect on resting membrane potential, 29, 30 Pseudoaneurysm, 824
sensorimotor, 1015-1016 selective permeability of, 7-8 Pseudoclaudication, 757
cancer-associated, 990-991 transmembrane equilibrium potential of, 6, 7 Pseudoclaw, 1092
diabetic, 979-981 Potential, 1462 Pseudodecrement, 1463
mixed, 892-893 Potentiation, 1462 Pseudofacilitation, 179
uniform demyelinating, 892 Potentiometers, 102, 104 Pseudomyotonia, 534
Polyphasic potentials, 1462 Power spectrum analysis, 317-318 Pseudomyotonic potentials, in polymyositis and
brief small (BSAPPs), 284 Prader-Willi syndrome, 1443 dermatomyositis, 1377
in radiculopathies, 745 Praziquantel, as tapeworm treatment, 1392 Psoas muscles
Polyposis, nasal, Churg-Strauss syndrome-related, Precision decomposition analysis, 310-312 hemorrhage into, 861-862
965 Prednisone treatment innervation of, 722, 841
Polyradiculoneuropathies for amyloidosis, 995 Ptosis
cervical, thoracic polyradiculopathy-associated, for asymmetric, painful diabetic myasthenia gravis-related, 1163
982 polyradiculopathy, 982 neuromuscular cause of, 1233
chronic inflammatory, 947 for Becker muscular dystrophy, 1276 Pudendal nerve
definition of, 889 for chronic inflammatory demyelinating anatomic course of, 849-850
diabetic, 981 polyneuropathy, 952 inferior, anatomy and anatomic course of, 846
asymmetric, painful, 981 -982 for facioscapulohumeral muscular dystrophy, injuries to, 874-875
symmetric, painless, 982-983 1286 differentiated from lumbosacral
thoracic, 982 for human immunodeficiency virus infection- radiculopathy, 755
Polyradiculopathies associated chronic inflammatory nerve conduction studies of, 211
definition of, 889 demyelinating polyneuropathy, 977 somatosensory evoked potential examination of,
electrodiagnostic medicine evaluation of, for inclusion body myositis, 1381 400
537-538 for inflammatory myopathy, 1386-1388 terminal motor latency of, 874-875
Pompe's disease, 1329, 1330, 1442 for myasthenia gravis, 1173-1174 Pulse duration, in peripheral nerve studies, 173
"Popeye arms," 1285 for POEMS syndrome, 994 Pulse width, in peripheral nerve studies, 173
Popliteal fossa for systemic vasculitis, 967 Purine nucleotide metabolism disorder, 1337-1339
lateral, peroneal nerve entrapment syndrome of, Pregnancy Purkinje cells, celiac disease-related loss of, 986
1099 drug abuse during, 1435 Pyomyositis, 1391
as somatosensory evoked potential recording myasthenia gravis during, 1176 Pyramidal tract, as somatosensory evoked potential
site, 369-370 Premotor potentials. 46, 47 pathway. 361
INDEX — 1517
Pyridostigme bromide, as myasthenia gravis Radial nerve (cont.) Radiculoplexopathy, diabetic lumbosacral, 981
treatment, 1173 superficial (cont.) Radiocircumflex nerve trunk, 784
in children, 1176 injuries to, 1093-1094 Radios, as source of electrical interference,
Pyridoxine in painful upper limb and cervical region, 526 988-989
deficiency of, neuropathies associated with, segmental somatosensory evoked potential Radius, fractures of, 1053, 1090-1091
1012 studies of, 390 Ragged red fibers, 1241
excess of, neuropathies associated with, 1012 sensory conduction studies of, 205-206 in bent head/dropped spine syndrome, 1291
isoniazid-related deficiency of, 1004 upper-limb muscle innervation by, 721 in inclusion body myositis, 1373, 1382
neuropathies associated with, 1003-1004 Radial tunnel, anatomy of, 1091 in myoclonic epilepsy, 1346-1347
toxicity of, 1003-1004 Radial tunnel syndrome, 1090, 1091-1092 in zidovudine-related mitochondrial myopathy,
Radiation therapy 1409, 1410, 1411
as brachial plexopathy cause, 821-822, 992 Rami
Quadrangular space, 784 for leukemia, 991 anterior and posterior, 778
Quadratus femoris muscle, sacral plexus nerve as lumbosacral plexopathy cause, 859-860, 992 anterior primary, 721-722
branch connection of, 839, 845 for lymphoma, 991 dorsal, 724-725
Quadriceps muscle to pelvic area, as femoral nerve injury cause, posterior primary, 719
biopsy of, in diabetic thigh infarction, 1399 867 ventral, 725-726
H-reflex of, 249 for POEMS syndrome, 994 ventral primary, 841
Quadriceps myopathy, 1271-1272 Radiculopathies, 713-776, 1463 Ramsay-Hunt syndrome, 978
Quadrilateral space, 784 axonal loss in, 538 Rash, dermatomyositis-related, 1374
Quadriplegia, H-reflex of, 563 botulinum toxin therapy for, 484 Raster, 1463
Quadriplegic myopathy, acute, 988, 1402 brain tumor-associated, 991 Raw EMG, 1463
Quantitative sensory testing, 429-435, 1463 cervical, 747-750 Real-time (analog) signals, 69, 70. See also
in chronic idiopathic sensory polyneuropathy, carpal tunnel syndrome associated with, Analog-to-digital (A/D) conversion
1016 1066-1067 Reciprocal inhibition, 1463
clinical applications of, 432-435 as hand weakness cause, 1086 Recruitment, 212-21 A, 284-286, 314-315,
equipment for, 430 ulnar neuropathy associated with, 1086 732-744, 1463
4-2-1 stepping algorithm of, 431-432 computed tomographic evaluation of, 746 in brachial plexopathies, 797
historical background of, 429 differentiated from brachial plexopathy, 813-814 contraindication as sole electrodiagnostic
"just noticeable differences (JNDs)" in, 430, electrodiagnostic medicine evaluation of, criterion, 1259-1260
431 537-539, 730-747 definition of, 270, 310
in nucleoside-related neuropathy, 1004 dermatomal somatosensory evoked potential false-positive interpretations of, 568-569
of peripheral neuropathies, 890, 891, 892 examination in, 738 myogenic, 285-286, 568
physical properties of, 429-430 F-waves, 538, 539, 732, 735 neurogenic, 284-285, 568
rationale for, 430 H-reflex, 538, 539, 732, 733-735, 736 precision decomposition of, 310-312
reference data in, 431-432 medical history in, 730 in stroke, 286
stimulus intensity units in, 430 mixed nerve stimulation studies in, 737 Recruitment frequency, 1253-1254, 1463
test algorithms for. 430-431 motor nerve conduction studies in, 732-733 Recruitment interval, 315-316, 1463
Quantitiative sudomotor axon reflex test (QSART), needle electromyographic examination in, Recruitment pattern, 1463, 1484
962,1463 538-539, 734, 738-747 Recruitment ratio, 315, 316, 1254
Quinidine, as congenital myasthenic syndromes nerve conduction studies in, 538, 539,731-738 Rectal nerves, inferior, 849
treatment, 1200 nerve root stimulation studies in, 735-736 Rectifiers, 112
physical examination in, 730 Recurrent inhibition, 1463
R segmental stimulation studies in, 737-738 Red tide, 1201
Radial nerve sensory conduction studies in, 731-732 Reduced recruitment pattern, 1463
anatomic course of, 781, 784, 810-811, 1087 somatosensory evoked potential examination Reducing body myopathy, 1318, 1324
anatomy of, 784, 810-811, 1087-1089 in, 736-738 Reflex, 1463
anatomic variations, 1088-1089 electrodiagnostic medicine pitfalls in Reflex sympathetic dystrophy, following sciatic
branches, 1088 false-negative investigations, 760-761 nerve injection injury, 872
antidromic somatosensory nerve action false-positive investigations, 758-760 Refractory period, 236-238, 1464
potentials of, gender differences in, electrophysiologic correlates of, 729-730 absolute, 236
562-563 fasciculation potentials in, 539 clinical utility of, 237
in carpal tunnel syndrome, 526 illustrative cases of, 761-768 relative, 236, 237
compound motor action potentials of, 811 lumbar sensory and motor nerve, 238
congenital palsy of, 1089 differentiated from genitofemoral nerve effect of temperature on, 189
focal neuropathies of, 811 injury, 864 Refsum's disease, 918-919, 1443
in arm region, 1089-1090 differentiated from ilioinguinal nerve injury, Regeneration, neural, in peripheral nervous
in forearm region, 1090-1092 864 system, 120-122
posterior interosseous nerve compromise, differentiated from obturator injuries, Reinnervation, 281-283
1092-1093 870-871 jitter and blocking during, 336
as tardy radial palsy, 1090-1091 lumbosacral, 751-758 Remifentanil, effect on intraoperative
growth rate of, 120 quantitative sensory testing of, 434 neurophysiologic monitoring, 450
motor conduction studies of, 198-200 Lyme disease-related, 974 Remyelination, 143
in proximal segment, 199-200 motor unit action potentials in. 539 intercalated segments in, 136
needle electromyographic studies of, 811 as neck and back pain cause, 728-729 in intermediate nerve injuries, 136
nerve conduction studies of, in painful upper needle electromyographic studies of by Schwann cells, 889
limb and cervical region , 526-527 false-negative interpretations of. 760-761 Renal cancer, 989, 990
sensory nerve action potential studies of, 811 false-positive interpretations of, 758, 759-760 Renal failure, uremic neuropathy of, 984-985
stimulation of, 547, 548 nerve conduction studies of Renal transplantation, in uremic neuropathy
superficial false-negative interpretations of, 760-761 patients, 985, 986
anatomic course of, 1087 false-positive interpretations of, 758-760 Renal tubular disorders
anatomy of, 784 nondiscogenic, 768—769 as osteomalacia cause, 1396
cheiralgia paresthetica of, 1094 pathophysiology of, 726-728 toluene abuse-related, 1415
far-field potentials of, 37-38 progression of, 538 Renshaw cells, 240, 241, 267
Finkelstein sign of, 1094 spinal anatomy in, 713-726 inhibition of, 563
focal versus generalized cooling of, 559 thoracic, 750-751 Repetitive discharge, 1464
1518 — INDEX
Repetitive nerve stimulation, 1464 S Scalp (cont.)
Repolarization, 1464 Sacralization, 718 as sural nerve stimulation site, 395
Residual latency, 235, 558, 1464 Sacral plexopathy, F-wave and H-reflex in, 654 as tibial nerve stimulation site, 392
in carpal tunnel syndrome, 1062, 1066 Sacral plexus, 837 as trigeminal nerve stimulation site, 401
Resistance, 99-101 anatomy of, 839, 845-850 Scanning EMG, 1464
as thermal electric noise source, 108-109 nerve conduction studies of, 852 Scapula, fractures of, 806
Resistor/capacitor circuits, 106-107, 109, 110 .neural innervation pathways of, 841 Scapular nerve, dorsal
Resistor/inductor circuits, 108 sensory nerve conduction studies of, 853 anatomy of, 801-802
Resistors, 70, 80-81 Sacrum, anatomy of, 718 v injury to, 802
in parallel circuits, 103, 104 Safety factor, in neuromuscular transmission, 19, Scapular winging, 802, 803-804
Respiratory chain complex, 1340 139-140 Scapulohumeroperoneal syndromes, 1287
Respiratory failure Safety guidelines, for electrodiagnostic medicine, Scapuloperoneal syndromes, of muscular
amyloid myopathy-related, 1401 95-96 dystrophy, 1287-1292
hypermagnesemia-related, 1400 Saltatory conductance, 16, 162 autosomal dominant Emery-Dreifuss muscular
Respiratory syncytial virus infections, myositis Sample, 337 dystrophy, 1281, 1289
associated with, 1391 Sampling interval, 337 autosomal recessive Emery-Dreifuss muscular
Resting membrane potentials, 24, 29-30, 1464 Sampling rate, 337 dystrophy, 1289-1290
Retinopathy, diabetic, 1399 Santavouri-type muscular dystrophy (muscle-eye- bent spine/dropped head syndrome, 1290-1291
Retroperitoneal space, hemorrhage into, 867-868 brain disease), 1282, 1284, 1442 Bethlem myopathy, 1290
Reversal reaction, in leprosy treatment, 973 Saphenous nerve oculopharyngeal muscular dystrophy,
Revertants, 1271 anatomic course of, 214, 396, 843-845, 869 129-11292
Rhabdomyolysis, 1239 compound motor action potential modeling of, rigid spine syndrome, 1290
human immunodeficiency virus infection- 171 scapuloperoneal muscular dystrophy, 1287
related, 1390 entrapment of, 869-870 scapuloperoneal neuropathy (Davidenkow
hypophosphatemia-related, 1400 injuries to, 869-870 syndrome), 1288
immunophilins-related, 1406 nerve conduction studies of, 214-216 spinal scapuloperoneal atrophy, 1287-1288
myalgia associated with, 1232 in peripheral neuropathies, 529 X-linked Emery-Dreifuss muscular dystrophy,
myopathy-associated, 1415-1416 segmental somatosensory evoked potential 1288-1289
neuroleptic malignant syndrome-related, 1413 studies of, 396-397 Schmidt-Lanterman inclusions, 122, 162, 163-164
serotonin syndrome-related, 1414 sensory nerve action potentials of, 853 Schwann cells, 160, 161, 167
Rheumatoid arthritis, 968-969 Sarcocytosis, 1392-1393 in chronic inflammatory demyelinating
chloroquine treatment for, 1000 a-Sarcoglycan, 1267, 1273 polyneuropathy, 950-951
dermatomyositis and, polymyositis associated deficiency of, 1278, 1279 in Guillain-Barre syndrome, 939-940
with, 1377 P-Sarcoglycan, 1267, 1273 internal structure of, 162, 163
tendon ruptures in, 1058, 1086 5-Sarcoglycan, 1267, 1273 length of, 138
ulnar nerve injuries in, 1079 gene mutations of, 1279 in myelination, 138
vasculitis associated with, 966, 969 Y-Sarcoglycan, 1267, 1273 in neural regeneration, 120, 121
Vaughan-Jackson syndrome of, 1086 Sarcoglycan complex, 1267 in remyelination, 15, 889, 902, 903
Rhinitis, allergic, Churg-Strauss syndrome-related, y-Sarcoglycanopathy, 1273 in segmental demyelination, 122
965 Sarcoglycans structure of, 137
Rhomboid major and minor muscles, innervation in Duchenne muscular dystrophy, 1271 in uremic neuropathy, 985
of, 721 dystrophin-associated, 1266 Schwartz-Jampel syndrome (chondrodystrophic
Rib, cervical, 717 Sarcoidosis, 969-970, 1385 myotonia), 1297, 1316
Riche-Cannieu anastomosis, 192-193, 561, 566, chloroquine treatment for, 1000 Sciatica, catamenial, 872
1047,1107-1108 Sarcolemma, 21-22, 24 Sciatic nerve
Rickets, 1396 in myopathies, 1261 anatomy and anatomic course of, 210, 846-847
Rifampin, as leprosy trearment, 973 Sarcolemmal proteins, 1269 in diabetic mononeuropathy, 983
Rigid spine syndrome, 1290 dystrophin-associated, 1266 injuries to, 871-874
Rigidity, 1464 Sarcomere, 22, 23 classification of, 871-872
Rigor mortis, 25 definition of, 1269 differentiated from lumbosacral
Riley-Day syndrome, 912, 913-914 Sarcoplasm. 24 radiculopathy, 755
Ring apophysis, 714 composition of, 1269 footdrop associated with, 1099
Rippling muscle disease, 1164, 1234, 1314-1315 Sarcoplasmic reticulum, 24 needle electromyographic studies of, 873-874
Rise time, 34, 1464 calcium release from, 24-25 intraoperative monitoring of, 468, 469
of motor unit action potentials, 42-43 triad junctions of, 1269, 1270 lower-limb innervation by, 841
of sensory nerve action potentials, 35, 180 Sarcoplasmic reticulum calcium ATPase (SERCA lower-limb muscle innervation by, 722
Rochester Diabetic Neuropathy Study, 433 1), 1269, 1315 nerve conduction studies of, 210-211
Romberg sign Sarcospan, in Duchenne muscular dystrophy, 1271 as peroneal nerve stimulation site, 393-394
in acrylamide-related neuropathy, 1006 Sarcotubular myopathy, 1319, 1324-1325 stimulation of, 854
in celiac disease, 986 Sartorius muscle, innervation of, 722 tumors of, 1105
in chronic idiopathic sensory polyneuropathy, Satellite potential, 1464. 1484 Scleroderma, 969, 1376
1015 Saturday night palsy, 1089 chloroquine treatment for, 1000
in hereditary sensory and autonomic Saxitoxin. 1201 Sclerosis, systemic, vasculitis associated with, 966
neuropathies. 912 Scalp Scoliosis, Duchenne muscular dystrophy-related,
in idiopathic sensory as lateral femoral cutaneous stimulation site, 1277
neuronopathy/ganglionopathy, 961 398 Scoliosis surgery
in monoclonal gammopathy of uncertain as peroneal nerve stimulation site, 395 electrophysiologic monitoring during, 440,
significance, 996 as pudendal nerve stimulation site, 400 441-443, 445, 446, 465-466
in tick paralysis, 1194 as saphenous nerve stimulation site, 397 as paraplegia cause, 465
Romberg test, 887 as somatosensory evoked potential recording Scorpion bites, 1201
Root sheaths, 722 site, 365, 366-367, 369 Scrotal nerves, 840, 849-850
Roussy-Levy syndrome, 901-902 10-20 International System of, 368-369 "Sea shell murmur." See Endplate noise
Ryanodine receptor gene mutations, 1317, 1318 nomenclature of, 367 Second-degree injur}', 786
Ryanodine receptor model, of hypokalemic reference data for, 382 Sedation, of pediatric patients, 1437
periodic paralysis, 1310 as superficial sensory peroneal nerve stimulation Sedative-hypnotics, effect on intraoperative
Ryanodine receptors, 1269 site, 396 neurophysiologic monitoring, 451
INDEX — 1519
Seddon's system, of nerve injury classification, Sensory nerve action potentials (SNAP) (cont.) Sensory nerve action potentials (SNAP) (cont.)
123-125 in gastrointestinal disease-associated in uremic neuropathy, 985, 986
Segmental sensory nerve somatosensory evoked neuropathies, 986, 987 in vasculitis secondary to essential mixed
potentials, 388-391 gender differences in, 562-563 cryoglobinuria, 967
Segmental stimulation examination in gold therapy-related neuropathy, 1011 in vincristine-related neuropathy, 998
central amplification in, 737 in hexacarbon-related (glue sniffer's) in vitamin B, 2 deficiency, 1012
of radiculopathies, 737-738 neuropathy, 1007-1008 secondary to nitrous oxide inhalation, 1013
Seizures, magnetic stimulation-selated, 424 in human immunodeficiency virus infection- in vitamin B, deficiency-related neuropathy,
Semimembranous muscle, innervation of, 722, 841 related distal symmetric polyneuropathy, 976 1012
Semitendinous muscle, 722, 841 in human immunodeficiency virus infection- in vitamin E deficiency-related neuropathy,
Semmes-Weinstein monofilaments, 429 related progressive polyradiculopathy, 977 1013
Sensorimotor polyneuropathy, 1015-1016 in hyperparathyroidism, 1396 waveform morphology of, 34—35
cancer-associated, 990-991 in hypothyrdoism, 984 Sensory nerve conduction studies, 179-181, 1243
diabetic, 979-981 in industrial and environmental toxin-induced amplifier sensitivity in, 553-554
mixed, 892-893 neuropathies, 1006, 1007-1008 antidromic, 179
uniform demyelinating, 892 in infants, 1435 anodal rotation in, 94
Sensory fibers, quantitative sensory test evaluation in Kiloh-Nevin syndrome, 1057 of carpal tunnel syndrome, 1061, 1062,
of, 429, 430 in leprosy, 973 1063-1065
Sensory latency, 1464 in lithium-related neuropathy, 1005 of Charcot-Marie-Tooth disease, 904
Sensory loss effect of low-frequency filters on, 554-555, 556 of chronic inflammatory demyelinating
amiodarone-related, 1001 low-frequency subcomponent waveform of, polyneuropathy, 951-952
asymmetric, painful diabetic polyradiculopathy- 895-896 of diabetic neuropathies, 980
related, 982 in lumbosacral plexopathies, 852, 853 of gastrointestinal disease-associated
cervical sponydylosis-related, 361 in Lyme disease, 974 neuropathies, 987
hypothyroidism-related, 984 in median nerve neuropathies of Guillain-Barre syndrome, 942
monoclonal gammopathy of uncertain in forearm region, 1058 in children, 944
significance-related, 995-996 near ligament of Struthers, 1054, 1055 of inclusion body myositis, 1382
myopathy-related, 1234 in pronater teres syndrome, 1056 of lumbosacral plexopathies, 852-853
symmetric, painful diabetic polyradiculopathy- * in metronidazole-related neuropathy, 1000 orthodromic, 179, 180
related, 982 in monoclonal gammopathy of uncertain of peripheral neuropathies, 890-891, 1046
Sensory motor studies, of lumbosacral significance, 996 pitfalls in, 542-544
plexopathies, 859 in multifocal motor neuropathy, 958 in antidromic versus orthodromic studies,
Sensory nerve action potentials (SNAP) in multiple myeloma-associated neuropathy, 993 543-544
in abnormal or with absent dorsal ulnar negative waveform/spike of, 181 interelectrode separation-related, 542-543
cutaneous nerve, 1086 nerve conduction velocity of, 180-181 of POEMS syndrome, 994
in acromegaly, 984 aging-related decrease in, 187-188 of radiculopathies, 731-732
in acrylamide-related neuropathy, 1006 in nucleoside-related neuropathy, 1004 stimulation sites in, 557
aging-related decrease in, 896 parameters of, 180-181 in ulnar neuropathy, 1075, 1076, 1079-1080,
in alcoholic myopathy, 1414 in paraneoplastic neuropathies, 990 1083, 1084
in alcoholic neuropathy, 1015 in perhexiline maleate-related neuropathy, 1001 Sensory neuropathies, 960-962
amplifier sensitivity of, 77 in peripheral neuropathies, 553-554, 890-891, Sensory neuropathy/ganglionopathy. human
amplitude of, 181 1043-104, 1045 immunodeficiency virus infection-related,
gender differences in, 188 in peroneal nerve neuropathies 977
interstimulus distance-related variability of. differential diagnostic use of, 1099 Sensory peak latency, 1464
556 in thigh and knee region, 1096, 1097 Series circuits, 101-103
effect of temperature on, 189, 190, 191 in Persian Gulf War syndrome, 1417 Serotonin syndrome, 1414
in amyloidosis, 995 phase cancellation of, 35, 36 Serrated action potential, 1464
antidromic, 73, 179 phase of, 180 Serratus anterior muscle
high-frequency decrease in, 83, 84 in phenytoin-related neuropathy, 1005 in brachial plexopathy evaluation, 228
low-frequency filter evaluation of, 82-83 in podophyllin-related neuropathy, 1002 innervation of, 721
median, 542 in POEMS syndrome, 994 Serum protein electrophoresis, 992
area of, 181 in primary biliary cirrhosis, 988 Sevoflurane, effect on intraoperative
in asymmetric, painful diabetic in pyridoxine-related neuropathy, 1004 neurophysiologic monitoring, 447,450
polyradiculopathy, 982 in radial nerve neuropathies, 1089-1090 Shawl sign, of dermatomyositis, 1375
in carbon disulfide-related neuropathy, 1006 rise time of, 35, 181 Shingles. See Herpes varicella zoster virus
in chronic idiopathic sensory polyneuropathy. in sarcoidosis, 970 Short-latency reflex, 1464
1016 of sciatic nerve, 874 Short-latency somatosensory evoked potential,
in chronic inflammatory demyelinating stability of, 181 1464
polyneuropathy, 951-952 effect of stimulation site location on, 35, 36 Shoulder, traumatic injuries to, suprascapular
in chronic liver disease, 987 of superficial peroneal nerve, 1099-1100 nerve in, 806
clinical recordings of, 34 in superficial radial nerve neuropathies, 1094 Shoulder girdle weakness
in colchicine-related neuropathy, 1002 in symmetric, painful diabetic clinical evaluation of, 1230-1231. 1233
compound, 1468 polyradiculopathy, 983 sensory nerve conduction studies of, 1243
in critical illness polyneuropathy, 989 effect of temperature on, 559 suprascapular nerve lesion-related, 805
of deep peroneal nerve, in distal leg, ankle, and termination latency of, 180 Shoulder surgery, as brachial plexopathy cause,
foot region, 1100-1101 in thalidomide-related neuropathy, 1002 823-824
in diabetic distal symmetric sensory and in tibial nerve neuropathies Shulman's syndrome, 1411
sensorimotor polyneuropathy, 980 in knee region, 1101 Sicca complex, 968
in disulfiram (Antabuse)-related neuropathy, in tarsal tunnel syndrome, 1104 Sicca syndrome, 1376
1002 in ulnar neuropathies S ignal averager, 1464-1465
in drug-induced neuropathies, 997, 998, 1000, in arm region, 1075, 1076 Silent areas, electrical, 3531, 1395
1001, 1002, 1003, 1004, 1005 differential diagnostic use of, 1086 Silent periods, motor cortex stimulation-related.
duration of, 181 in distal arm and supracondylar region, 1076 422
in eosinophilia myalgia syndrome, 1005 in elbow region, 1080-1081 Simvastatin, as myopathy cause, 1404, 1405-1406
in ethambutol-related neuropathy, 1004 in forearm region, 1083 Single fiber electromography, 1485
in folic acid deficiency-related neuropathy, 1013 in wrist region, 1084 Single-muscle-fiber potentials, 41-42
1520 — INDEX
Sinusitis, cocaine sniffing-related, 1184 Somatosensory evoked potentials (cont.) Spasticity, 1465
Sjogren's syndrome, 887, 968, 376 neural generators of (cont.) botulinum toxin therapy for, 501-505
dermatomyositis associated with, 1376 upper-limb, 362-365 celiac disease-related, 986
polymyositis associated with, 1376 onset latency of, aging-related increase in, 575 ethyl alcohol neurolysis treatment for, 504
vasculitis associated with, 966 short-latency, 362, 364, 1469-1470 phenol neurolysis treatment for, 504
Skin, impedance of, 71 Somatosensory evoked potential studies, 357-413 surgical treatment of, 504
Sleep, effect on somatosensory evoked potential •anatomical basis of, 358-362 Spectrum analysis, harmonic, 79
examination results, 384 central nervous system pathways, 359-360 Speech arrest, magnetic stimulation-related,
Slimmer's paralysis, 1095 peripheral nervous system pathways, 358-359 422
Slow-channel syndrome, 1197-1198, 1200 spinal system pathways, 360-361 Speech delay, dermatomyositis-related, 1374
Small-fiber sensory neuropathies, 1015 applications of, 403-405 Spheroid body myopathy. See Myofibrillar
Smooth endoplasmic reticulum/vesicles, 161-162 of brachial plexopathy, 790-792, 795-796 myopathy
Snake venom, neuromuscular transmission- for central nervous injury prognosis, 405-407 Sphincter muscles
inhibiting effect of, 1202 of Charcot-Marie-Tooth disease, 905 innervation of, 849
SNAP. See Sensory nerve action potentials of chronic inflammatory demyelinating needle electromyographic evaluation of, 874
Snap, crackle, and pop, 1465 polyneuropathy, 952 in radiculopathies, 538, 753
SNARE proteins, 1187 clinical interpretations of, 373, 374 Sphygmomanometer cuff, temporary neural
Sodium bicarbonate, as myoglobinruia treatment, diagnostic errors in ischemia induction with, 131-132
1416 instrumentation-related, 572-573 Spider bites, neuromuscular transmission-
Sodium channels physiological factors-related, 574-575 inhibiting effect of, 1201, 1202
in demyelinated nerves, 141 electrodes for, 377-380 Spinal accessory nerve, stimulation of, 234-235
drug/toxin-induced dysfunction of, 1201 application to skin, 378, 379 in myasthenia gravis, 1158
in hyperkalemic periodic paralysis, 1309 comparison of needle and surface electrodes, in neuromuscular junction disorders, 1159
inactivation gating of, 12 378-379 in neuromuscular junction transmission disorder
of myelinated nerve fibers, 138, 167-168 composition of, 377 evaluation, 536. 537
voltage-gated, 10-12, 1303, 1307 impedance to, 377-378 Spinal canal
Ploop of, 12 as infection cause, 378-379 stenosis of, 755-758
in sodium channelopathies, 1307-1309 needle-type, 378 tumors of, as radiculopathy cause, 768-769
Sodium conductance, in myotonia congenita, 1247 safety guidelines for, 379-380 Spinal column, anatomy of, 713-718
Sodium ions sensory threshold of, 380 Spinal cord
balanced, 99 surface-type, 377-378 compression of, in acromegaly, 984
local circuit currents of, 30-31 factors affecting, 381-384 injuries to
plasma membrane lipid bilayer permeability of, far-field, 403^105 as infant hypotonia cause, 1439, 1440
4,5 of focal peripheral neuropathies, 1047 motor cortex mapping in, 422
effect on resting membrane potential, 29-30 of Guillain-Barre syndrome, 943 motor evoked potentials in, 420
selective permeability of, 7-8 historical aspects of, 358 somatosensory evoked potential-based
transmembrane permeability of, 10 instrumentation for, 375-377 prognosis of, 407-408
Sodium-potassium adenosine triphosphate pump, 8 lumbosacral, limitations of, 875 length discrepancy with vertebral column,
Soleus muscle. See also Gastrocnemius-soleus of lumbosacral plexopathies, 852-853, 722-723
muscle complex 854-855 segmental innervation of, 722-724, 778-779,
Charcot-Marie-Tooth disease-related atrophy of, of Miller-Fisher syndrome (Guillain-Barre 780
901 syndrome variant), 947 Spinal cord evoked potentials (SCEPs),
innervation of, 722, 841 patient cooperation in, 381-382 intraoperative monitoring of, 442
Somatosensory cortex, as somatosensory evoked of peripheral neuropathies, 891 Spinal motor neurons, recurrent collaterals of,
potential recording site, 365 of radiculopathies, 736-738 240
Somatosensory evoked potentials, 1465 recording electrode sites in Spinal muscular atrophy
aging-related changes in, 575 bipolar montage of, 367 facioscapulohumeral, 1286-1287
amplitude of, 71 cephalic reference montage of, 367, 369 as infant hypotonia cause, 1439-1440, 1441.
effect of anesthesia on, 446-447 lower-limb, 369-370 1445
central conduction time of, 453,459, 460 nonhalic reference montage of, 367 Spinal nerve, 724, 778
definition of, 357 upper-limb, 367-369 stimulation of, in brachial plexopathies,
dermatoma! reference data for, 380-381 794-795
intraoperative monitoring of, 441-442 short-latency Spinal nerve root, 722-724
in thoracic radiculopathies, 751 recommended standards for, 367 Spinal potentials, 573, 575
far-field potentials of, 36-37 recording electrode sites for, 362-370 Spinal stenosis, 755-758
intraoperative monitoring of, 441-443, 445 techniques in, 384-403 Spinal surgery, intraoperative neurophysiologic
effect of anesthetic agents on, 447, 449, 450, dermatomal, 398-400 monitoring during, 465-466
451,452, 453 lower-limb, 391-395 Spine. See also Cervical spine; Iliac spine; Lumbar
in aneurysm surgery, 459-461 mixed-nerve, 385-388 spine; Thoracic spine
in arteriovenous malformation surgery, segmental, 388-391, 395-398 anatomy of. 713-726
461-462 upper-limb, 369, 373-374. 385 ligamentous, 718-720
in brain tumor surgery, 462-463 waveforms in, 370-375 muscular, 720-721
in carotid endarterectomy, 457-458 amplitude measurement of, 371, 374-375 neural, 721-726
effect of cerebral blood flow on, 453, 454 interpeak latency of, 373-374 skeletal, 713-718
effect of hematocrit on, 454 peak amplitude of. 375 magnetic stimulation of, 423-424
effect of hypothermia on. 454-455 peak latency of, 371, 372-373 three joint complex of, 756
in peripheral nerve surgery, 466, 467, 468 peak nomenclature of. 371-372 Spinocerebellar degeneration, 923
recording techniques in. 469-470 peak-to-peak amplitude of, 371, 375 Spinoglenoid ligament, 805
in scoliosis surgery, 465-466 polarity of, 371 Spinoglenoid notch, 805, 806
effect of ventilation on, 454 Sorbitol metabolism, in diabetic distal symmetric Spinomedullothalamic tract, 360
neural generators of, 362-367 sensory and sensorimotor polyneuropathy, Spinous process, 714
definition of, 362 980 Spiral of Perroncito, 120, 121
lower-limb, 362. 364 365-367 Sparfloxacin, as leprosy trearment. 973 Spiwmetra mansonoides, 1392
recording electrode placement in, 362 Sparganosis. 1392 Spondylosis, cervical
as stationary waves, 362 Spasms, hemifacial, botulinum toxin therapy for, motor evoked potentials in, 420
as traveling waves, 362, 363-364 482, 484, 495, 496-497 somatosensory evoked potentials in, 361
INDEX — 1521
Sports-related injuries Superior sulcus tumors, 1086 Switches, electronic, 111-112
to axillary nerve, 808 Superior transforaminal ligament, 720 Sympathetic skin response, 252-253, 575. 1466,
brachial plexopathies (burners/stingers), 806, Supernormal period, 1466 1488
820-821 Supinator muscle, anatomy of, 1092 Synaptic clefts, 17-18
as ulnar neuropathy cause, 1079 Supinator syndrome, 1090, 1092 Synaptic vesicles, acetylcholine content of, 17, 19
Sprue, nontropical. See Celiac disease Supracondylar region, ulnar neuropathies of, 1076 Synaptobrevin, 483
Stab wounds Supracondylar spur, as median and ulnar nerve Synaptogamin, 480
as brachial plexopathy cause, 785, 786, 787 compression site, 1054-1055, 1076 Synaptosomal-associated protein of 25kDa, 480,
as femoral nerve injury cause, 867 Supramaximal stimulus, 173, 183, 549 481, 1187
Stains, for muscle tissue specimens, 1235-1236 cathode displacement in, 553 Syndrome of continuous muscle fiber activity. See
Staircase phenomenon, 1465 in neuromuscular junction transmission disorder Isaac's syndrome
Statins, as myopathy cause, 1404-1406 evaluation, 537 Synkinesis, 1466
Status epilepticus, 1415 "virtual cathode" effect of, 50 Synovial joints. See Zygapophyseal joints
Stavudine, neurotoxicity of, 976 Supraorbital nerve Syntaxin, 481, 1187
Sterilization, of needle electrodes, 287 location of, 232 a-Syntrophin, 1266
Sternotomy, median, as brachial plexopathy cause, stimulation of, 232-234 P,-Syntrophin, 1266
823 Suprascapular nerve, 781 p 2 -Syntrophin, 1266
Steroids. See also Corticosteroids anatomic course of, 782-783, 805 Syntrophin complex, 1266
as Becker muscular dystrophy treatment, 1277 injuries to, 805-806 Syringomyelia, posttraumatic, 420
as Duchenne muscular dystrophy treatment, stimulation of, 228-229 Systemic lupus erythematosus, 969
1276-1277 upper-limb muscle innervation by, 721 chloroquine treatment for, 1000
as myopathy cause, 1174, 1412 Suprascapular notch, 805 chronic inflammatory demyelinating
Sterol 27 hydroxylase gene, mutations of, 919 Supraspinatus muscles polyneuropathy-associated, 949
Stiffness, 1231 innervation of, 721 dermatomyositis and polymyositis associated
Stiff-persons' syndrome, 1164, 1465 in suprascapular nerve injury, 806 with, 1376-1377
Stimulating electrode, 1465 as suprascapular nerve stimulation site, 228 vasculitis associated with, 966
Stimulation single fiber electromyography, 1465 Supraspinous ligament, 718, 719 Systemic sclerosis (scleroderma), 969, 1376
Stimulators, 91-94 Sural nerve chloroquine treatment for, 1000
artifacts produced by, 93-94, 183, 545-547, 552 aging-related changes in, 186
as electrodiagnostic error source, 896 anatomy and anatomic course of, 216, 853, 1105 T
errors in placement of, 92-93 biopsy of Tacrolimus
frequency of, 93 in amiodarone-induced neuromyopathy, 1001 as inflammatory myopathy treatment, 1389
types of, 91-92 in hereditary neuropathy with liability to as necrotizing myopathy cause, 1406
Stimulus, 1465-1466 pressure palsies, 906 as systemic vasculitis treatment, 967
Stimulus artifacts, 93-94, 183,545-547,552 in hereditary sensory and autonomic Taenia solium, 1392
Stimulus lead, 547 neuropathies, 913 Takayasu arteritis, 964
Stingers, 820-821 in lymphoma, 993 Tangier disease, 919
Stomach cancer, 966 in POEMS syndrome, 994 Tapeworms, 1392
Strabismus, botulinum toxin therapy for, 494-496 in vasculitis, 965 Tardy ulnar palsy, 1078-1079, 1466
Strawberry picker's palsy, 1095 in chronic idiopathic sensory polyneuropathy, Tarsal tunnel
Strength-duration curve, 1466 1016 anatomy of, 1102
Stretch reflex, 1466 compound motor action potentials of, 169, anterior, 1100
Stroke 170-171 tibial nerve in, 1101
mitochondrial myopathy-associated, 1347 cutaneous, 847 Tarsal tunnel syndrome, 1101-1105
motor evoked potentials in, 420 focal neuropathies of, 1106 Tarui's disease. See Glycogenosis, type 7
motor unit action potentials in, 286 in leprosy, 971 Taxanes, neuropathies associated with, 996, 997,
Stuttering, botulinum toxin therapy for, 493 in hexane neuropathy, 1008 998-999
Styrene, as neuropathy cause, 1008 histogram of, in hereditary motor sensory Taxol. See Paclitaxel
Styrene, neuropathies associated with, 1008 neuropathy, 902 Taxotere. See Docetaxel
Subclavian artery, cannulation-related injury to, 825 injuries to, 1105 Telethonin, 1269
Subclavian nerves, 781 lower-limb innervation by, 841 Telethonin gene mutations, 1280
Subclavian vein, spontaneous occlusion of, 818 misonidazole-related dgeneration of, 1000 Televisions, as source of electrical interference,
Sublimus bridge, as median nerve compression nerve conduction studies of, 216, 528 988-989
site, 1055-1056 in peripheral neuropathies, 529 Template matching, 1466
Submaximal stimulus, 173, 549 nerve conduction velocity in Temporal arteritis, 964
Subneural clefts, 17-18 aging-related changes in, 562 Temporal artery, giant-cell vasculitis-related
Subnormal period, 1466 in children, 1436 tenderness of, 964
Subsartorial canal, 869, 870 in peripheral neuropathies, 889-890, 891 Temporal dispersion, 1466
Subscapular nerve segmental somatosensory evoked potential Temporalis muscle, in motor neuron disease, 534
needle electromyographic examination of, studies of, 395-396 Tendonitis, deQuervain's, 1094
807-808 sensory nerve action potentials of, 853 Tendon reflex, relationship with H-reflex, 250-251
upper-limb muscle innervation by, 721 sensory nerve conduction studies of, 853 Tensilon. See Edrophonium
Subthreshold stimulus, 173 in sciatic nerve injury, 873 Tensor fascia lata muscle, innervation of. 722, 841
Succinate dehydrogenase deficiency, 1351 suramin-related degeneration of, 999 Teres major muscle
Sudden infant death syndrome, botulism-related, Suramin, neuropathies associated with, 997, innervation of, 721
1184 999-1000 weakness of, 808
Sufentanil, effect on intraoperative Surgery. See also Intraoperative neurophysiologic Teres minor muscle, innervation of, 721
neurophysiologic monitoring, 450 monitoring Terminal cisternae, 24, 1269
Sulfasalazine, as folic acid deficiency cause, 1013 abdominal, as lumbosacral plexus injury cause, Terminal innervation ratio, 17
Sunderland's system, of nerve injury classification, 863-865 Terminal latency index
124, 125-126 as brachial plexopathy cause, 823-824 in carpal tunnel syndrome, 1062, 1066
Superior articular recess, 719-720 pelvic, as femoral nerve injury cause, 867 in monoclonal gammopathy of uncertain
Superior corporotransverse ligament, 720 as ulnar nerve injury cause, 1078, 1079 significance, 996
Superior gluteal nerve Sweating, gustatory, botulinum toxin therapy for, Termination latency, of sensory nerve action
lower-limb innervation by, 841 507 potentials, 180
lower-limb muscle innervation by, 722 Sweep speed, 182 Testicular cancer, 990
1522 — INDEX
Test stimulus, of anoxal membrane, 236 Thymus gland, in myasthenia gravis, 1166-1167 Tramadol (cont.)
Tetanic contraction, 1466 Thyroarytenoid muscle, as botulinum toxin as diabetic neuropathy treatment, 981
Tetanus, 1190-1193, 1466 injection site, 492 as painful sensory neuropathy treatment, 976
clinical features of, 1190-1191 Thyroid disorders Transcranial electrical stimulation, 466
electromyographic studies of, 1193 amiodarone-related, 1001 Transcranial magnetic stimulation, 466
motor nerve conduction studies of, 1192-1193 as endocrine myopathy cause, 1393-1395 Transcutaneous electrical nerve stimulation, as
pathogenesis and pathophysiology of, Thyroid function tests, 1235 postherpetic neuralgia treatment, 979
1191-1192 Thyrotoxicosis, 1394 Transforaminal ligaments, 720
sensory nerve conduction studies of, 1192 Tibia, osteotomy of, as common peroneal nerve Transformers, 108
treatment of, 1193 injury cause, 1095 Transistors, 112
Tetanus tension, of muscle motor units, 269,2 70 Tibialis anterior muscle Transmembrane currents, 58
Tetanus toxoid, adverse reaction to, 1193 innervation of, 722 Transport, through cell membrane
Tetany, 281, 1466 as peroneal nerve stimulation site, 212 by active transport, 4, 5
hypomagnesemia-related, 1401 Tibialis muscle, innervation of, 841 by diffusion, 4-5
Tethered cord surgery, 444 Tibialis posterior muscle, innervation of, 722 Transverse foramina, 715, 717
Tetraphasic action potential, 1466 Tibial nerve Transverse process, 714
Tetrodotoxin, 10, 1201 anatomy and anatomic course of, 212, 847 Transverso-articulaire ligament, 720
Thalamocortical fibers, 360 conduction velocity of, in children, 1434, 1435 "Trapezius hump," 1233, 1285
Thalamus, as somatosensory evoked potential as extensor digiti brevis innervation," 561-562 Tremors, 1467
recording site, 365 F-wave reference values of, 243 amiodarone-related, 1001
Thalidomide H-reflex of, 244, 245, 854 needle electromyography examination of, 281
as leprosy trearment, 973 injuries to nondystonic, botulinum toxin therapy for,
as neuropathy cause, 1002 in ankle and foot, 1101-1105 500-501
Thallium in knee, 1101 surface electromyography examination of, 338
as neuropathy cause, 1009-1010 tibial tarsal syndrome of, 1101-1105 Trendelenburg sign, positive, during ambulation,
screening for exposure to, 887 intussusception of, 135 1233
Thenar eminence, compound motor action lower-limb innervation by, 841 Triad, of muscle fiber, 24
potentials of, 80 lower-limb muscle innervation by, 722 Triad neuropathy, 1074
Thenar muscles maturation of, 1433 Triceps muscle, innervation of, 721
compound motor action potentials of, 178 nerve conduction studies of, 212-213, 528 Trichinosis, 1392
congenital absence of, 1065 proximal, tumors of, 1105 Tricyclic antidepressants
Thermal stimuli response. See also Body somatosensory evoked potential studies of, 362, as diabetic distal symmetric sensory and
temperature 364, 365, 366, 367 sensorimotor polyneuropathy treatment,
quantitative sensory testing of, 429, 430 central conduction time in, 383 980
Thermography, 1466 recording electrode placement in, 369-370 as diabetic neuropathy treatment, 980-981
Thermoregulatory sweat test, 1466 reference data for, 383 as painful sensory neuropathy treatment, 976
Thiamine deficiency, neuropathies associated with, Tic, 1467 Trigeminal nerve
1011-1012 Tick paralysis, 1189, 1193-1195 involvement in systemic sclerosis, 969
Thigh Ticks, detection and removal of, 1195 myelination of, 1436
diabetic infarction of, 1399 Tilt table test, 1467 somatosensory evoked potential studies of,
innervation of, 841 Time domain measurements, 318-320 400-402
Thiopentine, effect on intraoperative Tinel's sign stimulation studies of, 232-234
neurophysiologic monitoring, 451 in carpal tunnel syndrome, 1059 Trigger points, in myofascial pain syndrome,
Thomsen's disease, 1297, 1301 in dorsal ulnar cutaneous nerve injury, 1085 1417
Thoracic nerves, 781 in idiopathic perineuritis, 970 Trilaminar myopathy, 1319, 1325
Thoracic outlet syndrome, 817-820, 823, in median nerve compression, 1055, 1056 Triphasic action potential, 1467
1466-1467 in peroneal nerve injuries, 1099, 1100 Triple discharge, 1467
with congenital absence of thenar muscles, 1065 in third-degree nerve injury, 126 Tropheryma whippeli, 987
differentiated from ulnar neuropathy, 1086 Titin, 1269 Tropomyosin, 22, 23, 1269
neurogenic, 818-820 Toluene abuse, as myopathy cause, 1405, 1415 a-Tropomyosin gene, 1321
pain treatment in, 506-507 Tone, 1467 Troponin, 22, 23, 1269
vascular, 818 Tongue, electrodiagnostic examination of, in motor in muscle contraction, 25
Thoracic spine neuron disease, 534 Trousseau's sign, 281, 1396, 1401
anatomy of, 717 Total body irradiation, as inflammatory myopathy Trunk
as peroneal nerve stimulation site, 394-395 treatment, 1389-1390 brachial plexopathies of, 804-806
radiculopathies of, 750-751 Total intravenous anesthetic (TIVA), 450, 451, musculature of, 721
as somatosensory evoked potential recording 452^53 Trypanosomiasis, 1392-1393
site, 366, 367 Total lymphoid radiation, as chronic inflammatory suramin treatment for, 999
as tibial nerve stimulation site, 392 demyelinating polyneuropathy treatment, 954 L-Tryptophan
Thoracodorsal nerve, 781 Touch sense of, paraneoplastic neuropathy-related contaminated, as eosinophilia myalgia
anatomic course of, 783 loss of, 989 syndrome cause, 1005
in brachial plexus injury, 808 Tourniquet, as radial or ulnar neuropathy cause, as inflammatory myopathy cause, 1411
function of, 808 1089 as myopathy cause, 1405
upper-limb muscle innervation by, 721 Toxic oil syndrome, 1411-1412 T (transverse) tubules, 21-22, 24
Thoracolumbar spine, recording electrode Toxins in muscle contraction, 25
placement in, 365-366, 367, 370 exposure to, patient history of, 1232 terminal cisternae association of, 1269
Threshold stimulus, 173 injection of, as peripheral nerve injury cause, triad junctions of, 1269, 1270
Thrombosis 825 Tuberculosis, pharmacologic treatment of, as
effort, 818 as myopathy cause. See Myopathies, acquired, neuropathy cause, 1004
focal segmental, microscopic polyangiitis- toxic Tuberculous leprosy, 971, 972
related, 966 as neuropathy cause, 886 D-Tubocurare testing, in neuromuscular junction
Throwing, as ulnar neuropathy cause, 1079 Toxoplasmosis, 1392-1393 disorders, 1160-1162
Thymectomy Tramadol Tubular aggregate myopathy, 1319, 1325^-1326
as inflammatory myopathy treatment, 1390 as diabetic distal symmetric sensory and Tumor infiltration, neuropathies associated with,
as myasthenia gravis treatment, 1175-1176 sensorimotor polyneuropathy treatment, 991-992
Thymoma, 1164 981 Tumor necrosis factor, 980
INDEX — 1523
Tumors, of spinal canal, as radiculopathy cause, Unacceptable electrodiagnostic medicine Vincristine, as myopathy cause, 1405, 1408-1409
768-769 consultations, 522-524 Vinyl benzene, neuropathies associated with, 1008
T wave, 1466, 14~,5 Unit membranes, 3 Viral infections
Twitch time, 268-269 Upper limb Guillain-Barre syndrome-associated, 938
anomalous innervation of, 191-193 vasculitis-associated, 966
Tyrosine, kinase /.-nerve growth factor, 914 nerve conduction studies of, 194-209 "Virtual cathode" effect, 50
of median antebrachial cutaneous nerve, Visual evoked potentials, 1471
U 206-208 intraoperative, 445, 1467
Ulcerative colitis, 987 mixed nerve studies, 208-209 effect of elevated intracranial pressure on, 454
Ulna, fractures of 1053. 1090-1091 motor nerve conduction studies, 194-200 effect of hematocrit on, 454
Ulnar claw hand, 1074-1075, 1083, 1086 sensory nerve conduction studies, 200-206 techniques in, 471
Ulnar nerve painful, electrodiagnostic medicine evaluation Vitamin Bj, neuropathies associated with,
anatomic course of, 186, 196, 783, 812, of, 524-528 1011-1012
1070-1071, 1073 somatosensory evoked potential examination of, Vitamin B 6
abnormalities of, 1079 385 isoniazid-related deficiency of, 1004
anatomy of, 1070-1074 Upper motor unit syndrome, 1467 toxicity of, 1003-1004
axillary stimuktion of, 227 Urea molecules, plasma membrane lipid bilayer Vitamin B 12
coactivation wi:h median nerve. 50, 183-184 permeability of, 4, 5 human immunodeficiency virus infection-
compound mobr action potentials of, 175, 176, Uremic neuropathy, 984—986 related, 976
812 Urethral sphincter, as botulinum toxin injection malabsorption of, 986
connection with median nerve, 192 site, 505 Vitamin B ! 2 deficiency, 1012
deep, anatomic course of, 783 Urticaria, needle electromyography-related, 287 quantitative sensory testing in, 433
in diabetic mononeuropathy, 983 Uterine cancer, 990 secondary to nitrous oxide inhalation, 1013
dorsal cutaneoas, 783 Utrophin, 1268 Vitamin D
anatomy of, 1073, 1085 forms of, 1395
injuries to, 1085-1086 V osteomalacia-related deficiency of, 1396
F-wave reference values of, 243 Valleix phenomenon, 1103 Vitamin D supplementation, as osteomalacia-
growth rate of. 120 Valsalva maneuver, 1467 related myopathy treatment, 1396
in Guillain-Baire syndrome, 940, 941 Valsalva ratio, 1467 Vitamin E
injuries to, 812 Vasculitic neuropathies, 962-968 deficiency of, neuropathies associated with,
carpal tunnel syndrome-associated, 1069 nonsystemic, 967 1013-1014
categories o", 1077 primary, 962, 964-966 malabsorption of, 986
lateral root of, 783 secondary, 962, 966-967 Vitiligo, needle electromyography-related, 287
maturation of, 1433 treatment of, 967-968 Vocal cords
mixed-nerve somatosensory evoked potential Vasculitis amyloid deposition in, 995
studies of. 387-388 definition of, 962 as botulinum toxin injection site, 492—493
motor conduction studies of, 195 diabetic polyradiculoneuropathy-related, 982 distal myopathy-related paralysis of, 1295
in forearm, elbow and arm, 196-198 gastrointestinal, dermatomyositis-related, 1375 Voice tremor, botulinum toxin therapy for, 493
in hand, 198 necrotizing, Sjogren's syndrome-related, 968 Volatile agents, inhalation of, 1415
nerve conduction studies of, in painful upper paraneoplastic, 990 Volleyball players, suprascapular nerve injuries in,
limb and cervical region , 526 perineuritis-related, 971 806
nerve conduction velocity in, in children, 1434, primary, 962 Voltage, 98, 100
1435 rheumatoid arthritis-related, 969 Voltage clamp technique, 9-10
in neuromuscular junction disorders, 537, 1159 secondary, 962 Voltage-gated ion channels, 10-12
neuropathies of Vaughn-Jackson syndrome, 1086 refractory periods of, 11
amyloid myopathy-related, 1401 Ventilation, intraoperative, effect on evoked Volume conduction, 896-897, 1467
anatomic sites of, 1077-1078 potentials, 454 bipolar recording montage in, 28-29
in arm, 1074-1076 Ventral posterolateral nucleus, 359-360 as diagnostic error source, 547-552
cubital tunnel syndrome, 1079 Vertebrae of far-field potentials, 28, 35-37, 39,47,48
differential diagnosis of, 1086 anatomic variations of, 718 monopolar recording montage in, 29
in distal arm and supracondylar regions, anatomy of, 713-718 montages in, 28
1076 third, as somatosensory evoked potential of near-field potentials, 28
in elbow, 1076-1082, 1467 recording site, 365 neural propagation directional changes in,
in forearm, 1082-1083 twelfth, as somatosensory evoked potential 39-40
Froment's sign of. 1075, 1077 recording site, 366
in leprosy, 971 of positive sharp waves, 48-49
Martin-Gruber anastomosis-associated, 561 Vertebral bodies, anatomy of, 714 referential recording montage in, 29
palmarus brevis sign of, 1084 Vertebral canal, 714 spatial gradient in, 28
shoulder girdle weakness associated with, Vertebral column isopotential lines of, 28, 29
1243 anatomy of, 713-718 theory of, 27-34
Wartenberg's sign of, 1077 length discrepancy with spinal cord. 722-723 Volume conductors
in wrist (Guyon's canal), 1083-1085 Vertebral end-plate, 716 local circuit currents in, 31-34
palmar cutaneous branch of, 783, 1072-1073 Vertebral notch, superior and inferior, 714-715 in large-volume conductors, 32-34
refractory periods of. 238 Vesicle-associated membrane protein in restricted-volume conductors, 31-32
residual latency of, 235 (VAMP)/synapatobrevin, 480, 481, 1187 waveform asymmetry in, 34
segmental somatosensory evoked potential Vibration sensitivity size/tissue resistance difference of, 38-39
examination of, 389-390 colchicine-related loss of, 1001 Voluntary motor unit action potentials, in
sensory nerve conduction studies of, 203-204 Lyme disease-related loss of, 974 radiculopathies, 743-745
in dorsal ulnar cutaneous nerve, 203-205 paraneoplastic neuropathy-related loss of, 989 von Gierke's disease, 1329
in pediatric patients, 1438 suramin-related loss of, 999 von Recklinghausen disease, 821
somatosensory nerve action potentials of, 812 Vibratory stimuli response, quantitative sensory V-sign, of dermatomyositis, 1375
gender differences in, 562-563 testing of, 429,430, 431-433
stimulation site distance in, 184 Vidarabine, as polyarteritis nodosa-associated W
submaximal stimulus in, 549 hepatitis treatment, 967-968 Wake-up test, 465, 1467-1468
superficial branch of, 1072 Vinca alkaloids Waldenstrom's macroglobulinemia, peripheral
tardy ulnar palsy of, 1078-1079 as myopathy cause, 1408-1409 neuropathies associated with, 994
upper-limb muscle innervation by, 721 as neuropathy cause, 996, 997, 98 Walker-Warburg syndrome, 1282, 1284, 1442
1524 — INDEX
Wallerian degeneration, 893, 125-126, Waveform morphology (cont.) Wrist (cont.)
1468 in muscle (cont.) median nerve anatomy in, 1049
alcoholic neuropathy-related, 1015 motor unit potentials of, 42-45 as radial nerve injury site, 1094
clinical correlates of, 129-131 positive sharp waves of, 48-49 as ulnar neuropathy site, 1083-1085
electrophysiologic correlates of, 128-129 in single-muscle fiber, 41-^2 Writer's cramp, 498-^199
in intermediate neural injury, 133-134, in nerves, 34-40
137 * in restricted-volume conductors, 31-32 X
nerve conduction velocity in, 126-127 Waveforms X-linked Charcot-Marie-Tooth disease, 909-910
neurophysiologic correlates of, 126-128 circuit model of, 31 v
X-linked myopathy with excessive autophagy, 1337
of peripheral nerves, 116-120, 128-129 hard copies of, 518 X-rays
of radial nerve, 812 Wegener's granulomatosis, 965-966 in brachial plexopathies, 798
Waning discharge, 1468 Weight loss of pelvic arterial aneurysm, 855
Warm-up phenomenon, of myotonic dystrophy- asymmetric, painful diabetic
related myotonia, 1296 polyradiculoneuropathy-related, 981 Z
Wartenberg's migrant neuropathy, 911, 970 diabetic neuropathic cachexia-related, 981 Zaleitabane, neuropathies associated with, 1004
Wartenberg's sign, 1074 Weight loss, as peroneal compressive lesion cause, Z bands, 23
Water 1095 Z discs, 23
plasma membrane lipid bilayer permeability of, Welander myopathy, 1292-1293 Zebra body myopathy, 1319, 1325
4,5 Werdnig-Hoffmann disease, 1440, 1445 Zellweger's syndrome, 918
transport through cell membranes, 4 Western blot analysis, 1235 Zidovudine
Waveform morphology Wheelchair users, radial neuropathy in, as myopathy cause, 1405, 1409-1411
asymmetry of, 34 1089 myotoxicity of, 1390
circuit model of, 31 Whipple's disease, 987 Zona fasciculata, 1397
in large-volume conductors, 32-34 Whitlows, 911-912 Zona glomerulosa, 1397
in muscle, 40-49 Wire electrodes, 1468 Zona occludens, 162
compound muscle action potentials of, Work, electrical, 6-7 Zona reticularis, 1397
45^17 Wound infections, by Clostridium botulinum, Zygapophyseal joints, 714, 717-718
endplate potentials of, 40-41 1184, 1185 anatomy of, 717-718
far-field potentials of, 47 Wrist as low back pain source, 728-729
fibrillation potentials of, 47-48 fractures of, as carpal tunnel syndrome cause, 1067 in spinal stenosis, 756-757

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Contents

1 Nerve and Muscle Anatomy and Physiology 3

10 Magnetic Stimulation of the Central and Peripheral Nervous Systems . . 415

Part IH P A T I E N T CARE-RELATED ISSUES

14 The Electrodiagnostic Medicine Consultation: Approach and Report . . 515

16 Disorders Affecting Motor Neurons 581

Focal Peripheral Neuropathies

Focal compromise of peripheral nerves secondary to entrap- ELECTROPHYSIOLOGIC CORRELATES O F

bundle. The ulnar and musculocutaneous nerves are observed to be as-

medial head of the triceps muscle. At the level of the coraco-

ing subcutaneous. The median nerve trunk, in association with

nerve is no longer closely associated with any other neural struc-

Tendon of flexor pollicis longus / Abductor pollicis

Dorsal branch Tendon of extensor carpi

Transverse Carpal Ligament

Sublimis 3 Figure 24-5. Median nerve tissue rela-

Figure 24-14. Ulnar nerve in postcondylar groove.The ulnar

and is referred to as the arcade of Struthers (Fig. 24-13). This

Figure 24-16. Ulnar nerve In canal of Guyon.The

Figure 24-/7. Deep branch of ulnar nerve.The deep branch of

of the ulnar nerve arises to course distally and supply a vari-

Site 5: Exit of ulnar nerve from flexor carpi uinaris

Site 1: Intermuscular septum

Site 2: Area of medial epicondyle Site 3: Epicondylar groove

Table 24-5. Classification of Ulnar Neuropathies at the Wrist

Figure 24-24. Radial nerve. Neural branching of the radial nerve

Fbrvneuslongus~ \ neural compromise about the fibular head is some form of

Figure 24-29. Five major patterns of electro-

Extensor digitorum Tibialis anterior

Figure 24-31. Tarsal tunnel region. The tibial nerve is

to the medial calcaneal nerve's origin, the inferior calcaneal

The electrodiagnostic medicine evaluation of neuromuscular ANATOMY O F THE NEUROMUSCULAR

Figure 25-/. A mammalian NMJ. A.The presynaptic por-

Figure 25-4. Sequential magnifications of the frog

postdocking function, which remains to be fully clarified. The

cate to the nerve terminal's cytoplasm by first combining with

Figure 25-13. Amplitudes of EPPs resulting

Amplitude of end-plate potentials (mV)

Time of spike |peak

can approach 50-60 mV or greater.93-94-521 Given these numbers

released for one depolarization of the nerve terminal. In frogs, 1 1 1

are released with nerve terminal depolarization. Mammalian

Figure 25-/5. Endplate potential (EPP) magnitude

Entry of CA** into

Near synchronous Release occasional

Dissociation ACh-R and Miniature EPC x 50-60

Table 25-4. Electrodiagnostic Medicine Evaluation of Suspected NMJ Disorders

sponse may be repaired or eliminated completely. It is also pos- 1 3 5 1 3 5

Figure 25-21. Concentric needle recording in a pa-

0.5 0.6 0.7 m V 08

Table 25-6. Comparison of Muscles Used for Repetitive Stimulation

Femoral Quadriceps Inguinal region Relatively proximal Hard to stabilize; painful

FIRST STEP SECOND STEP

Stim 3/sec - 4 min - 20 min later

Tetracycline dence of myasthenia gravis is slightly greater in women than in

Figure 25-30. Schematic representation of NMJ in normal

myasthenia gravis have evidence consistent with thymic hyper-

Figure 25-32. Antibody mediated reduc-

decrement found in the abductor digiti minimi to repetitive stim-

tervals after the high-rate train of stimuli.The percent decrement

The trigger for initiating the afferent limb of the autoimmune

Figure 25-43. Typical CMAPs produced to

OTHER DISORDERS T H A T MAY MANIFEST