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 Electrodiagnosis:
Chapter
Nerve Conduction and
261 Electromyography
Douglas Chang

• Introduction • Patient Preparation for a Test Leprosy

• Terminology • Special Considerations Diabetic Neuropathy
• Electromyography Overview • Pathological Conditions Disorders of Muscle
Electromyography Procedure Radiculopathies Disorders of Neuromuscular
Stages of the EMG Examination Entrapment Syndromes Junction
and Typical Findings Carpal Tunnel Syndrome Myasthenia Gravis
Summary of EMG Findings Traumatic Injuries
• Nerve Conduction Studies (NCS) Peripheral Polyneuropathies

INTRODUCTION nation findings such as focal neurological deficits in deep

Electrodiagnostic studies provide quantitative informa-
tion on the physiologic health and functioning of nerve
and muscle. They help localize injuries, quantify the extent
of injury, suggest the age of the injury and give valuable
prognostic information that can change treatment proto-
cols as well as monitor progression over time. This com-
plements the static, anatomic structural information pro-
vided by radiological imaging studies and the anatomic
cause of the deficit such as infection, tumor, or disk her-
niation. Together, electrodiagnostic and radiologic studies
are extensions of the history and physical exam, and help
refine the differential diagnosis. Consider electrodiagnos-
tic studies when a diagnosis is uncertain, either during the
initial patient presentation or as the result of non-response
to treatment. The studies can evaluate the possibility of
additional lesions (e.g. concomitant nerve entrapment
syndromes, peripheral neuropathies, and so-called “dou-
ble crush syndromes”), follow the interval progression of
both operative and non-operative treatments, and provide
preoperative baselines.
Common indications for ordering electrodiagnostic
studies include complaints such as weakness, pain, numb-
ness and/or tingling in an extremity and physical exami-
tendon reflexes, strength or sensory loss. The typical con-
ditions studied include radiculopathies, entrapment syn-
dromes, trauma, and metabolic pathology such as diabetes
and alcoholism. Other conditions include rheumatologic
disease, the universe of neuromuscular diseases, and vari-
ous infectious and neoplastic neuropathies. Details about
all of these conditions can be found in several electrodiag-
nostic textbooks.1-6
The objectives of this chapter are to introduce the basic
principles of electrodiagnosis, clarify when an electrodiag-
nostic test is ordered, and help interpret an electrodiag-
nostic report.
TERMINOLOGY
Electrodiagnostic studies have two separate components:
nerve conduction studies (NCS) and needle electromyo-
graphy (EMG). The term EMG strictly refers to the direct
needle examination of muscle, but “EMG” is often used
generically to refer to electrodiagnostic studies in general.
A typical setup is shown in Figure 261-1.
Nerve conduction studies use electrical stimulation
to evaluate peripheral nerve function. Conduction abnor-
malities can suggest injury to myelin indicated by slowed
 2 Physical Medicine and Rehabilitation
Section 12
Fig. 261-1: A typical configuration for an electrodiagnostic study.
In this figure, a monopolar electrode (in orange) is inserted into
the right vastus medialis of a subject. On the computer monitor (to
the left) appear the motor unit potentials from voluntary muscular
contractions. The equipment for a nerve conduction study would
vary slightly from this picture; instead of a needle electrode, there
would be recording electrodes.
conduction velocity or a delayed response; injury to axons
indicated by diminished amplitude response or tempo-
rally dispersed waveforms, or problems with the neuro-
muscular junction demonstrated by diminished ampli-
tude response with repetitive stimulation. The distribution
of abnormalities seen in a particular patient distinguishes
focal from diffuse global processes.
The “late responses” are specialized nerve conduc-
tion studies. Two common late response studies are the
“H-reflex” and “F-wave.” The H-reflex is an electrically
measurable analog of the ankle deep tendon reflex. The
H-reflex and ankle deep tendon reflex are specific for the
S1 monosynaptic spinal reflex arc. In the H-reflex, an elec-
trical stimulus is applied to the tibial nerve behind the
knee directed toward the spinal cord. The stimulus elicits a
wave of depolarization that travels proximally on Ia affer-
ents. The wave traverses the spinal reflex arc, synapses on
the anterior horn cell and elicits an efferent volley, caus-
ing depolarization and contraction of the gastrocnemius
muscle of the calf. The H-wave may be delayed or lost bila­
terally in large nerve fiber pathology, and unilaterally with
unilateral S1 nerve root lesions that may have occurred
in the indeterminate past. Therefore it does not distin-
guish acute from chronic injury. It will be abnormal with
advanced age, tibial or sciatic nerve injuries, and periph-
eral neuropathies.7
The F-wave may be obtained from practically any mus-
cle, but usually is used to evaluate cervical spinal nerve
root function via the median nerve. The clinical utility is
not agreed upon,1 but it may be helpful with evaluating
diabetic neuropathy, Guillain-Barre syndrome, and mul-
tifocal motor neuropathy with conduction block. F-waves
are usually abnormal in radiculopathies only when sig-
nificant disease is present. Many practitioners do not use
routine F-wave studies in the workup of focal entrapment
neuropathies such as carpal tunnel syndrome.1
Somatosensory evoked potentials (SSEP) measure
conduction between a large peripheral nerve and the
cerebral cortex or spinal cord. SSEP is sensitive to certain
lesions in the central nerve system pathways, such as may
occur in multiple sclerosis, spinal cord injury, tumor and
compressive myelopathies. Its ability to evaluate radicu-
lopathies and CNS motor pathways is poor.7
ELECTROMYOGRAPHY OVERVIEW
Electromyography Procedure
Electromyography (EMG) involves insertion of a 23–25-
gauge needle electrode into muscle and recording the
resultant electrical activity as seen on the computer moni-
tor in Figure 261-1. The muscle is examined while at rest
and during voluntary contraction. The physics are similar
to the use of surface electrodes on the chest wall to record
cardiac muscle contractions. In both cases, the EMG
provides information about muscle motor unit health
and function. With needle EMG, specific muscles can be
examined, and the pattern of pathology seen in the mus-
cles sampled gives information about the overall disease
process.8 Each muscle is examined in four stages: during
initial needle insertion, at rest, during minimal contrac-
tion and maximal contraction. In the first stage, there is
insertional activity, in the second stage the clinician looks
for abnormal spontaneous activity. The third stage evalu-
ates the motor unit potentials for amplitude, configuration
and recruitment. In the fourth stage, the interference pat-
tern is examined.
Stages of the EMG Examination and
Typical Findings
Insertional activity is a volley of electrical potentials pro-
voked by the initial mechanical irritation of needle inser-
tion and movement. It lasts a few milliseconds. If muscle
 Electrodiagnosis: Nerve Conduction and Electromyography 3

Chapter 261
A B
Figs. 261-2A and B: Abnormal spontaneous needle EMG action potentials at rest (negative values are above the baseline). (A) Inser-
tion potentials are seen in the first 250 ms of this record. They were produced as the needle moved through muscle fibers. The insertion
potentials are followed by a train of positive sharp waves; (B) Fibrillation potentials. The sharp spikes are seen against a background of
positive sharp waves. A single fibrillation potential is also illustrated.

In the third stage, the subject is asked to contract

Fig. 261-3: The components of a single motor unit. The muscle
fibers of the unit (shaded) are interspersed among fibers of other
units. The myoneural junctions are located approximately midway
between the ends of the muscle fibers.
fibers have degenerated, there are fewer electrically excit-
able cells available. As a result, there is reduced insertional
activity.
Secondly, the electrical activity of the muscle at rest
is examined. With stable muscle membranes, normally
there is electrical silence when needle movement ceases.
Abnormal spontaneous activity arises from persistent
electrical potentials that occur despite the lack of needle
movement. It is a sign of unstable muscle membranes.
The abnormal spontaneous activity can take the form of
fibrillation potentials, positive sharp waves, and complex
repetitive discharges (Figs. 261-2A and B). Spontaneous
and benign endplate spikes and endplate noise can also
be observed occasionally.
the muscle minimally to study the motor unit potentials
(MUP). A muscle motor unit is defined as all the muscle
fibers innervated by a single motor neuron (Fig. 261-3).
The motor unit potential is the electrical discharge of the
contracting motor unit. MUP amplitude, duration, shape
and discharge frequency is recorded (Figs. 261-4A to C).
These parameters are commented upon in an elec-
trodiagnostic report. The findings can be described as
“normal,” “myopathic,” or “neuropathic.” MUP amplitude
can be decreased in conditions involving a loss of muscle
fibers (e.g. myopathy), axonal neuropathy or motor neu-
ron disease. It can be increased because of re-innervation
with spatially larger motor units (e.g. recovery from neu-
ropathy). MUP duration can be decreased when there is
atrophy of muscle fibers (seen in myopathy), or increased
with reinnervation with spatially dispersed muscle fibers
as seen in recovery from neuropathy or myopathy.
In the fourth stage, the subject is asked to increase
gradually the force of muscular contraction up to a maxi-
mal effort. The number and firing rates during recruitment
are evaluated. With progressively forceful contraction in
normal muscle, the recruitment of muscle fibers follows a
pattern: an individual muscle fiber will fire and reach a fre-
quency of 15–20 Hz, at which point a second fiber will be
recruited. The second fiber will reach a frequency of 15–20
Hz and then a third fiber is recruited, and so on. Maximal
contraction in normal muscle reveals the discharge of
many MUPs, which flood the screen. The interference pat-
tern at maximal contraction is evaluated subjectively from
 4 Physical Medicine and Rehabilitation

Table 261-1 Typical EMG findings seen in normal,

neurogenic and myogenlc lesions.
Section 12

Neurogenic Myogenic
EMG stage Normal lesion - UMN lesions
1. Insertional Normal Normal— Normal—
activity (brief) increased increased,
Myotonic
discharges
A 2. Spontane- Normal Normal (silent), Normal
ous activity (silent) Fibrillation (silent),
potentials, Fibrillation
Positive sharp potentials,
waves Positive
sharp waves
3. Motor unit 0.5–1.0 mV Normal to large Small ampli-
potentials amplitude amplitude, tude,
B 5–10 msec Normal to Early
duration increased recruitment,
Normal duration, Normal Myotonic
recruitment to limited discharges
recruitment
4. Interference Full Reduced Full,
pattern Low ampli-
tude
Source: Adapted from Kimura J. Electrodiagnosis in Diseases
of Nerve and Muscle: Principles and Practice. 3rd edition. New
York: Oxford University Press; 2001.

C
Figs. 261-4A to C: Samples of voluntary motor unit potentials,
recorded by monopolar needle electrodes. (A) Normal triphasic
wave. (B) polyphasic (eight phases) wave of longer duration and
of similar amplitude. (C) Large amplitude potential with a triphasic
base component and a small late component, a satellite potential
(*). Note amplitude calibration in C compared with that in A and B.
the observed density of electrical spikes, along with their
amplitude, frequency and sound.
The analysis of recruitment patterns is subjective and
can be difficult. Modern computerized analysis of the
waveforms is helpful, but the whole process depends also
on the patient’s effort. Because of pain, language problems,
poor comprehension by the patient or poor motivation the
patient may not be able to comply with the instructions
to provide a slow and progressively forceful contraction
while a needle electrode is inserted and moved around in
the muscle belly.
In disease states, there are characteristic patterns of
firing, recruitment and interference, which suggest either
muscle denervation (neuropathies), or muscle fiber
destruction (myopathies). Neuropathic disease processes
denervate the motor unit acutely. This is followed by rein-
nervation from collateral sprouting of nearby surviving
motor units. As a result, the motor units become big-
ger because the fewer surviving neurons assume control
over more and more of the muscle fibers. When the bigger
motor units fire, there is an observable pattern of muscle
fiber recruitment which is termed a “neurogenic” recruit-
ment pattern. This is also called “decreased recruitment,”
or “reduced recruitment.” There are decreased numbers of
MUPs, firing later at increased rates, in order to meet the
force demanded of the muscle.
On the other hand, the so-called myopathic recruit-
ment pattern (also called “early” or “increased” recruit-
ment) comes from the fact that insufficient force is gener-
ated by any given motor unit, and additional motor units
are recruited earlier or more rapidly than expected. The
observation is that there are too many motor units fir-
ing for the amount of contraction requested. There is an
increased number of MUPs, firing faster and earlier in the
myopathic disease state.
Summary of EMG Findings
The EMG findings in upper and lower motor neuron disor-
ders and myogenic lesions are summarized in Table 261-1,
which was adapted from Kimura.2 The exact findings seen
in a given subject depend on the disease process itself, as
well as the timing of the electrodiagnostic exam in rela-
tion to the disease process. In normal muscle, there is brief
 Electrodiagnosis: Nerve Conduction and Electromyography
Fig. 261-5: Typical mammalian nerve, involving the movement
of axons from one fascicle to another during their course. Here
lesions at A and B may be easily distinguished electromyographi-
cally by the fact that lesion A produces changes in the distribution
of branch C, whereas the lesion at B does not.
Source: Redrawn from Pease et al.6
insertional activity, no spontaneous activity, motor unit
potentials (MUPs) of 0.5–1.0 mV and 5–10 msec duration,
and a full interference pattern.
In neuropathic lesions, the EMG findings show normal
to increased insertional activity, normal (silent) to abnormal
spontaneous activity (with positive sharp waves and/
or fibrillation potentials), MUPs that are normal to large
amplitude with increased duration, complex configura-
tion and limited recruitment. During maximal contraction
(stage 4) there is a reduced interference pattern.
In myopathic lesions, the EMG findings show normal
to increased insertional activity and occasionally there
are myotonic discharges. There can be normal (silent) to
abnormal spontaneous activity (with positive sharp waves
and/or fibrillation potentials). The MUPs have small
amplitudes with early recruitment, and possibly seen are
myotonic discharges. The interference pattern is full but of
low amplitude.
NERVE CONDUCTION STUDIES (NCS)
The intraneural anatomy of the nerve fiber gives the body
a functional reserve, which protects it against catastrophic
loss with partial nerve injuries. The peripheral nerves are
similar to insulated cables, and are composed of individ-
ual nerve fibers traveling together in bundles, called fasci-
cles. However, the internal organization of the peripheral
nervous system is different from a typical electric cable,
and does not have the somato-topic organization seen in
the brain and spinal cord of the central nervous system.
In the peripheral nervous system, the fascicles exchange
5
Chapter 261
Fig. 261-6: Different types of surface recording electrodes.
nerve fibers in an interwoven course along the nerve6
(Fig. 261-5). Therefore, a partial nerve injury in the periph-
eral nervous system does not result in a Brown-Sequard
like lesion that might result from a partial injury in to the
spinal cord. In the peripheral nervous system, a partial
nerve injury will often result in partial function of most
muscles, because of spared fascicles. Furthermore, each
of the nerves distal to the injury will have at least some
abnormality that will be detectable. This intraneural anat-
omy permits partial function after a nerve injury, and per-
mits electrodiagnostic studies to pinpoint a lesion.
Nerve conduction studies test the integrity of the
peripheral nervous system, both sensory and motor. The
techniques are standardized, and there are banks of refer-
ence data.8 Reference data are established in age-matched
normal individuals who have no neurological problems.
However, subjects at the extremes of age or limb size may
not fall within these norms. In these cases, the sensitivity
of NCS can be increased if a contralateral asymptomatic
limb is used for comparison.6
In motor nerve testing, the peripheral nerve is stimu-
lated by passing electrical currents through the skin to
produce synchronized muscle contraction “downstream,”
distally. The motor response is recorded with surface
recording electrodes (Fig. 261-6) placed over the muscle
being studied. The recording is referred to as a compound
motor action potential (CMAP), with the key parameters
being onset latency and amplitude. Latency is the time
between the stimulus and the observed response. It meas-
ures conduction in the fastest nerve fibers. Amplitude is
a result both of the total number of fibers conducting the
electrical signal and their degree of synchrony (Fig. 261-7).
 6 Physical Medicine and Rehabilitation

Nerve conduction velocity is determined by measuring the velocities less than 20 m/s.6 On the other hand, with axonal
Section 12

distance between two stimulation sites along the course of
a nerve, and comparing the latency.
Sensory nerve testing involves techniques and analy-
sis similar in concept to motor testing, although there are
a few differences. The electrodes come in different shapes
and forms (Fig. 261-8). Sensory nerves may be tested in an
antidromic fashion, stimulating the nerve proximally and
recording a response distally (Figs. 261-9A and B). They
may also be tested in an orthodromic fashion, stimulating
the nerve distally and recording the response proximally.
The response from either technique is referred to as a sen-
sory nerve action potential (SNAP).
Neural pathology may be identified by examining
the CMAP and SNAP parameters (Figs. 261-10A to C). In
general, demyelinating diseases will lead to prolonged
latency measurements and slowed conduction velocity.
A long demyelinated nerve segment will have conduction
pathology there is no slowing of conduction in individual
fibers. Instead, there is loss of axons, which result in
reduced CMAP amplitude. Many disease states, such as
a compression neuropathy, cause combined demyeli-
nation and loss of, axons in varying proportions. Also, if
the pathology is severe, absent responses can occur with
either process.
Pathology of the myelinated neuron comes in three
patterns: conduction slowing, segmental conduction
block, and full-length conduction loss. Conduction slow-
ing can be seen in demyelination, remyelination and rein-
nervation. Conduction block occurs at a specific location

Fig. 261-7: CMAP parameters. (CMAP: Compound motor action

potential). Fig. 261-8: Different types of stimulators.

A B
Figs. 261-9A and B: (A) Antidromic sensory conduction studies of the median nerve. (B) Sensory nerve action potential parameters
from antidromic median nerve conduction studies.
 Electrodiagnosis: Nerve Conduction and Electromyography 7

Chapter 261
A B C
Figs. 261-10A to C: Schematic representation of the determination of median nerve motor conduction velocity (NCV) from the elbow to
wrist, illustrating three different types of responses: tE and tW are the latencies from time of stimulation to time of onset of response of the
muscle, from elbow and wrist stimulation, respectively. D is the distance between the two points of stimulation. (A) A normal response.
Note that the amplitude of the response from the elbow and wrist stimulations are essentially equal, as are the wave shapes. (B) Tem-
poral dispersion associated with segmental demyelination. Note the smaller amplitude of the response on elbow stimulation compared
with stimulation at the wrist, as well as distortion of the wave when the elbow response is compared with the wrist response. (C) Partial
neurapraxic block between the two points of stimulation. Note the much smaller response from elbow stimulation without distortion of
wave form when compared with the response on wrist stimulation.1

along the nerve. It is frequently caused by local trauma,
ischemia, autoimmune, metabolic or vascular disease.
Axons are spared, and the segments above and below the
lesion will conduct signals normally.
Axon loss, total or partial, occurs in various disease
states and injuries. Some examples include diabetic neu-
ropathy, vitamin E deficiency, alcoholic neuropathy,
chronic renal failure with uremia and hereditary neu-
ropathies such as Charcot-Marie-Tooth disease. Complete
axon loss, following a stab wound for instance, results in a
characteristic picture. For 3 to 7 days after complete axonal
injury, the distal nerve will continue to conduct because
there are enough stored materials and energy sources for
independent function.6 After this period, the conduction
of the distal nerve will fail completely because of neural
dissolution, a process known as Wallerian degeneration.
Regeneration of the injured distal nerve segments can
occur as long as the nerve cell body is intact. Addition-
ally, there must be some connective tissue integrity about
the nerve fiber to provide a permissive environment and
conduit for regeneration. In a completely severed nerve,
surgical approximation is required to permit regenera-
tion. After interruption of the axons, the cell body requires
about a month before regeneration begins. Thereafter, the
regrowth occurs at a rate of approximately a millimeter per
day or an inch per month. Motor nerves may then require
yet another month after the regenerating nerve estab-
lishes connection to the muscle in order to establish new
myoneural junctions.
PATIENT PREPARATION FOR A TEST
Inform patients prior to the examination not to use heavy
lotions or creams on their skin. Place the patient in the
most comfortable position possible on an exam table or
chair, with pillows and blankets. To reduce anxiety and fear
of pain counsel, educate and reassure the patient about
the procedure. Expose and cleanse the area to be studied
with an alcohol pad. An important environmental factor is
temperature and every EMG report should report the skin
temperature. Keep the patient warm because cool limbs
result in slowed nerve conduction and latency measure-
ments, and increased amplitudes. A wrist temperature of
32°C and ankle temperature of 29°C is considered stand-
ard. Many clinics have warmer requirements. Regulate
the patient’s temperature with a combination of heating
pads, blankets, and heat lamps. Sometimes a patient can
be asked to exercise or drink hot beverages. Lastly, tem-
perature correction formulae exist to normalize the elec-
trophysiologic data obtained from suboptimal studies.1,8
 8 Physical Medicine and Rehabilitation
SPECIAL CONSIDERATIONS
Section 12
An EMG study is a mildly unpleasant experience for patients.
Perception of pain is affected by various psychological
factors such as advice from friends, fear of needles, sound
emanating from the medical instrumentation speaker and
unfamiliarity with the test. Certainly, the puncture of skin
by the electrode and movement through the tissue fascia
causes most of the pain. Some areas are more painful than
others. The most painful are the cervical and lumbosacral
paraspinal muscles, and the hand intrinsics. Concentric
needles are more painful than mono-polar Teflon® coated
needles. Rarely, a short-acting benzodiazepine may be
required for anxious patients.
There are no absolute contraindications to a focused
EMG exam, but the risk-benefit ratio should be weighed.
Bleeding after EMG is rare, and there is risk in stopping
anticoagulation in certain patients. Relative contraindi-
cations to an EMG include bleeding risk in patients with
mild thrombocytopenia, whose platelet counts are below
50,000/mm3. In patients on anticoagulation there are spe-
cial considerations.9,10 Expert opinion suggests there is no
reason to exclude patients on aspirin, antiplatelet agents,
non-steroidal antiinflammatory medications, herbal sup-
plements, prophylactic heparin, or patients with an INR
< 3.0. For patients with INR > 3.0, discretion is necessary.
Some practitioners suggest stopping Coumadin three days
prior to an EMG examination. Subcutaneous adminis-
tered low-molecular-weight-heparin may be stopped 12
hours prior to the study. Other strategies include gentle
use of a small EMG needle (e.g. 30 gauge) and being selec-
tive about which muscles to test, avoiding deep muscles
that are difficult to manually compress, or muscles that are
near vital blood vessels or nerves.
Pneumothorax is a rare but potentially catastrophic
complication of EMG studies. Use caution when study-
ing the muscles of the shoulder girdle such as the serratus
anterior, trapezius, pectoralis, rhomboids and paraspinous
muscles near the cervicothoracic junction.
With regard to NCS examinations, precautions are
advised in patients with implanted pacemaker-defibril-
lators.11 There are no reported complications of nerve
conduction studies in patients with regular, implanted
pacemakers.9 However, general guidelines suggest that
NCS studies be performed more than 6 inches away from
the pacemaker, using a stimulus duration of 0.2 ms or less,
and a stimulus rate of less than 1 Hz. For patients with an
implantable automatic cardioverter-defibrillator, there is
a greater theoretical risk and consultation with a cardio­
logist is recommended. One option is to deactivate the
device and provide cardiac monitoring during the study.9
The only other medication consideration is stopping
the use of pyridostigmine in patients being tested for
a neuromuscular junction disease such as myasthenia
gravis or Lambert-Eaton syndrome.
Lastly, after the needle EMG examination, a patient’s
serum creatine phosphokinase (CPK) may be mildly
elevated for up to 3 days. This may affect a workup for
myopathy.
PATHOLOGICAL CONDITIONS
The EMG-NCS examination can provide diagnostic infor-
mation to help clarify the diagnosis. It is useful in several
situations, such as radiculopathy, focal nerve entrapment
syndromes, trauma, and peripheral neuropathies due
to such conditions as diabetes, hypothyroidism or alco-
hol abuse. It is vital for the diagnosis of other conditions
such as neuromuscular junction disease (e.g. myasthenia
gravis, Lambert-Eaton syndrome, botulism), neuropathies
(e.g. Guillain-Barre syndrome, amyotrophic lateral scle-
rosis), and myopathies (e.g. the inheritable dystrophies
and inflammatory myositis conditions). Although clini-
cians need to be mindful of these important conditions,
these diseases are not regularly encountered in a typical
orthopedic practice. For the sake of brevity, the ensuing
text will not focus on these conditions apart from the brief
summary at the end of the section. Further details may be
found in common Neurology and Electrodiagnostic medi-
cine texts.1-6
Radiculopathies
For many patients suspected of having a radiculopathy,
there is little practical value from electrodiagnostic testing.
This is the case for a younger patient with a consistent his-
tory of radicular pain, a neurological exam with focal defi-
cits, and radiological images showing spinal stenosis at the
appropriate neurological level. However, many patients do
not have such a tidy presentation. With a more complex
presentation, electrodiagnostic testing can be very helpful.
A common presentation is an older patient with a com-
plex past medical history including diabetes and surgical
release for CTS, scattered neurological exam findings, and
spine imaging showing various stages of degeneration at
multiple levels.
To understand the electrodiagnostic nerve conduction
findings in a radiculopathy a good knowledge of anatomy
is essential (Figs. 261-11A and B).12 Spinal radiculopathies
usually involve stenosis of the spinal nerve roots at a loca-
tion that lies proximal to the dorsal root ganglion (DRG).
 Electrodiagnosis: Nerve Conduction and Electromyography 9

The peripheral nerve cell bodies of the sensory neurons For example, a severe L5 radiculopathy could result in

reside in the DRG and send their nerve fibers distally.
Usually in the case of a radiculopathy, there are normal
sensory nerve conduction studies because the site of ste-
nosis is proximal to the entirety of the sensory nerve cell
bodies and tracts. In contrast, motor nerve function can
be compromised in cases of severe radiculopathy. The
site of stenosis may impact the spinal cord anterior horn,
which affects the motor nerve cell bodies and results in
axon loss in the motor nerve fiber tracts. This loss shows
loss of amplitude in the motor nerve conduction studies.
Chapter 261
decreased CMAP amplitude in the deep peroneal nerve
conduction studies to the extensor digitorum brevis. In
general however, radiculopathies do not result in observ-
able abnormalities in the nerve conduction studies.
Needle EMG exam provides specificity but has poor
sensitivity in the diagnosis of a radiculopathy. The EMG
diagnosis of an acute or subacute radiculopathy depends
on the observation of abnormal spontaneous activity,
with positive sharp waves and fibrillation potentials. Such
spontaneous activity should be seen in two peripheral

B
Figs. 261-11A and B: Relationship between the intervertebral disc, spinal cord, spinal nerve roots, and the ventral and dorsal rami.
(A) Cervical spine axial depiction. (B) Lumbar spine MRI (left slice is a T2 sagittal, right is a T2 axial slice) images. Notice that the dorsal
root ganglion is at the intervertebral foramen.
Source: Redrawn from Pease WS, Lew HL, Johnson EW. Johnson’s Practical Electromyography. Philadelphia: Lippincott Williams &
Wilkins; 2007.
 10 Physical Medicine and Rehabilitation

muscles that share the same nerve root origin, but are Table 261-2 Representative muscle nerve root and
Section 12

innervated by different peripheral nerves. An example peripheral nerve innervation.

involves the abducens pollicis brevis (APB) and first dor- Muscle Spinal nerve root Peripheral nerve
sal interosseus (1st DI) muscles of the hand. Both of these Upper Limb
muscles originate from the C8 and T1 nerve roots. However Supraspinatus C5, C6 Suprascapular
the APB is innervated by the median nerve, while the 1st Deltoid C5, C6 Axillary
DI is innervated by the ulnar nerve. The diagnosis of suba- Biceps brachii C5, C6 Musculocutaneous
cute radiculopathy can also be made with the observation
Brachioradialis C5, C6 Radial
of abnormal spontaneous activity in one peripheral mus-
Pronator teres C6, C7 Median
cle and one proximal trunk muscle, such as the paraspi-
Triceps brachii C6, C7, C8 Radial
nal muscles. An example would be the APB and the lower
Extensor indicis C7, C8 Radial
cervical spine multifidus muscles. Nerve root innervation proprius
of the muscles has some degree of individual anatomi-
Abductor pollicis C8, T1 Median
cal variation. Nevertheless, there are commonly acepted brevis
tables to guide the electromyographer (Table 261-2). Dorsal interossei C8, T1 Ulnar
A screen for radiculopathy should involve no less than Abductor digiti minimi C8, T1 Ulnar
5 muscles in an affected limb and include the proximal
Lower Limb
trunk musculature.13
Adductor longus L2, L3, L4 Obturator
As mentioned the needle EMG examination does not
Vastus medialis L2, L3, L4 Femoral
have good sensitivity. An exam that does not uncover
Anterior tibialis L4, L5 Deep peroneal
abnormal spontaneous activity does not rule out a radicu-
Gluteus medius L4, L5, S1 Superior gluteal
lopathy. There are several reasons why a needle EMG exam
might not show muscle abnormalities in the presence of a Peroneus longus L5, S1 Superficial
peroneal
true radiculopathy. A false negative result can arise from
Flexor digitorum L5, S1 Tibial
sampling errors. For example, there are several L5 inner- longus
vated muscles to examine with a needle electrode. The
Biceps femoris short L5, S1 Sciatic (peroneal)
electromyographer may choose to examine the peroneus head
longus (L5) and anterior tibialis (L4, L5) muscles, but the Gastrocnemius S1 Tibial
muscle abnormalities could be limited to the flexor digito-
rum longus and medial head of the gastrocnemius (L5, S1).
There may not be representative muscle groups to sample, False-positive examinations are rare. The false posi-
for instance in a C3 radiculopathy. Furthermore, a given tive problem arises from the diagnosis of a radiculopathy,
muscle should be sampled with a needle placed in four or when there is actually a systemic problem such as a poly-
five different locations within the muscle. The ability of the radiculopathy, plexopathy, or motor neuron disease. The
patient to cooperate (by keeping relaxed during an uncom- false-positive problem comes either from a deficient study
fortable needle exam) can introduce muscle noise artifacts (not sampling enough muscles during EMG or performing
that make it difficult to see or hear subtle spontaneous an inadequate NCS), or from testing too early in the dis-
muscle activity. The timing of the EMG needle exam can ease process before widespread findings are apparent.
also affect the results. Abnormal spontaneous activity dis-
appears with time even though clinical symptoms persist. Entrapment Syndromes
The likelihood of false negative exams increases with cer-
vical spine radiculopathies lasting longer than 6 months, Carpal Tunnel Syndrome
and with lumbosacral radiculopathies lasting longer than Carpal tunnel syndrome (CTS) is the most common
12–18 months.13,14 Proximal muscles heal faster than distal entrapment neuropathy. It is caused by compression of
muscles, and false negative results are more likely in a high the median nerve under the transverse carpal ligament
cervical or high lumbar radiculopathy, than with a radicu- that provides the “roof” of the carpal tunnel in the palmar
lopathy affecting a lower nerve root. wrist. (see Chapters 80 and 84).1
 Electrodiagnosis: Nerve Conduction and Electromyography
There is some increased association between cervical
spine degenerative disease, ulnar nerve pathology at the
cubital tunnel and median nerve pathology at the carpal
tunnel.5 The best objective diagnostic test is an electrodi-
agnostic evaluation with nerve conduction studies and
needle electromyography to determine which factors may
be contributing most to a patient’s symptomatology. An
electrodiagnostic study can be useful also to document
presurgical and postsurgical function. Ultrasound is an
alternative test, and can confirm the diagnosis of CTS with
equal sensitivity to electrodiagnostic testing in certain indi-
viduals, although with inferior ability to grade carpal tun-
nel severity and limited ability to evaluate other possible
comorbid conditions (such as a cervical radiculopathy,
ulnar neuropathy or peripheral polyneuropathy).15
Recently, the condition of carpal tunnel has also been
studied using automated, “handheld” nerve conduction
study systems.16-18 Such systems have also been used to
study the ulnar and peroneal nerves.19 The systems use
pre-packaged surface electrode configuration panels,
and proprietary computational algorithms. They attempt
to automate the technical aspects of NCS testing. Needle
EMG is not performed. The goal is to expand the number
and types of practitioners, beyond neurologists and phy-
siatrists, who utilize NCS in their clinical practice.
There is a growing consensus that the newer automated
systems may have a role in evaluating CTS18 however many
of the studies have been funded by commercial interests,
contain methodological flaws, and have other limita-
tions.20 There is a tendency to “overdiagnose” CTS20 or to
have a high false-negative rate.17 Other limitations are the
lack of an EMG examination and well-established refer-
ence values. Thus, after a decade of research, such hand-
held systems have yet to stand independent scrutiny and
gain widespread acceptance.21
Carpal tunnel syndrome is fundamentally a clinical
diagnosis. In the syndrome, electrodiagnostic studies will
demonstrate conduction abnormalities of the sensory
and/or motor nerve branches of the median nerve only.
In mild cases, abnormalities of the sensory nerve SNAPs
will precede abnormalities of the motor nerve CMAPs,
although the reverse may occur. If the SNAPs are recorded
between the wrist and digits, an abnormality may not be
localized to the wrist. The abnormal SNAPs could also be
the result of proximal compression (e.g. pronator teres
syndrome) or a diffuse neuropathy. Any of these condi-
tions would produce distal abnormalities. A better local-
izing feature would be slowing of the CMAP distal latency,
11
and normal forearm conduction velocity. In severe cases,
Chapter 261
slowing of the median motor nerve conduction velocity is
seen in the forearm. This slowing, occurring proximal to
the wrist, may be due to retrograde changes in the nerve.
Severe cases of CTS may demonstrate axonal loss in the
distal median nerve innervated muscles, i.e. APB.
For these reasons, CTS evaluation should include
sensory and motor nerve conduction studies of both the
ulnar and median nerves. The sensory exam of choice is
“antidromic,” meaning the electrical stimulus is applied
proximally on the median nerve and the recording is made
distally. If this exam is “normal”, a short segment “ortho-
dromic” sensory exam is indicated because the orthodro-
mic studies have less likelihood of false negative results
with higher sensitivity.22 With regard to the ulnar nerve,
electrodiagnostic studies show that 15%-40% of patients
with CTS also have objective evidence of ulnar nerve
dysfunction.1 The likely explanation is that many CTS
patients may have a predisposition to multiple entrap-
ment neuropathies, or a more generalized peripheral
neuropathy.
Lastly, the CTS evaluation should also include needle
exam of the APB to determine the presence of axon loss.
The needle EMG exam is less sensitive than NCS in the
evaluation of CTS, because the pathology is mainly demy-
elination. Demyelinating diseases affect the sensory nerve
responses with slowing and prolongation of the SNAP
latency. The needle exam is usually not too revealing in
most CTS cases until late in the disease. If there is evidence
of membrane instability in the APB, then it is important to
sample another C8-T1 innervated muscle to evaluate for
cervical radiculopathy. The first dorsal interosseus mus-
cle is a good muscle to sample because it is a C8-T1 mus-
cle innervated by the ulnar nerve. Also, needle sampling
of C6, C6 innervated muscles such as the pronator teres
or flexor carpi radialis can be helpful, because C6 and C7
radiculopathies commonly present with thumb and hand
pain. Lastly, 11% of patients with CTS have a concomitant
cervical radiculopathy,1 a phenomenon termed “double
crush syndrome.”
The diagnosis and treatment of CTS is discussed in
Chapters 80 and 84. The usefulness of electrodiagnostic
studies is illustrated in this case:
A 56-year-old female with mild central canal stenosis
at C3/4 and C5/6, with moderately severe right C5/C5 neu-
roforaminal stenosis (Fig. 261-12) was treated with three
cervical epidural steroid injections during the course of
a year. The shots were mildly helpful in treating her bilat-
 12 Physical Medicine and Rehabilitation

Table 261-3 Anatomic sites susceptible to traumatic

Section 12

nerve injury.
Traumatic event Vulnerable nerve
Upper Limb
Penetrating neck wound, trac- Brachial plexus
tion injury at birth
Shoulder dislocation, intra- Axillary
muscular injection
Humerus (spiral groove) frac- Radial
ture, pressure
Elbow subluxation, fracture, Ulnar
dislocation
Humerus, elbow, radioulnar Median
joint fractures
Lower Limb
Fig. 261-12: Sagittal T2 image of the cervical spine, showing mul-
tilevel degenerative disc disease with mild central canal stenosis Regional anesthesia (femoral Femoral
at C5-6 and C3-4. Axial images (not shown) demonstrate moder- block)
ate to severe right neuroforaminal stenosis at C5-6. Hip, pelvic fracture Sciatic (peroneal > tibial)
Knee injuries Peroneal
Ankle fractures Tibial, peronea

eral hand and forearm pain. Because of the muted ben-

efit of epidural injections, an electrodiagnostic study was
ordered.
Evaluation of the left median nerve CMAP had normal
amplitude with decreased latency and normal conduction
velocity across the forearm. The right median nerve CMAP
had decreased latency, amplitude and conduction veloc-
ity. These results demonstrated a bilateral median nerve
sensorimotor mononeuropathy. On the left there was evi-
dence of demyelination, on the right there was evidence
of demyelination with axon loss. Both sides are consistent
with a diagnosis of moderate CTS. The EMG exam refo-
cused the treatment plan.
Traumatic Injuries
Trauma can cause a nerve injury in just about any part of
the body. Some of the more common scenarios are pre-
sented in Table 261-3, adapted from Liveson.5 Nerve tran-
section can occur with fractures or penetrating injuries.
Traction injuries are commonly seen with dislocations,
blows to the shoulder and neck and in infants during
childbirth. Compression injuries may result from blunt
trauma, hematomas, compartment syndromes, or posi-
tioning issues during surgery.
During the acute phase, within 4 weeks of injury, the
electrodiagnostic exam can identify the location of the
injury, the possibility of muscle paralysis, and whether
the nerve is in continuity. It can be important in the
acute phase to identify outright nerve injury, as opposed
to pain inhibited function or cognitive impairment (e.g.
an obtunded patient). If no volitional motor activity is
observed with the needle EMG exam, then there is no
nerve conduction to the muscle. This could be due to
complete severance of the nerve, or temporary conduc-
tion block (neuropraxia). If some motor unit potentials are
seen, then there is neural continuity to the muscle. Nerve
conduction studies give information about neural trans-
mission.
In the chronic phase, the needle EMG becomes very
useful. If nerve section or axon death exists, then there
will be observable membrane instability with abnormal
spontaneous activity. The nerve interruption is complete
if membrane instability is present and no voluntary motor
unit potentials are present. The location of the injury can
be identified by strategically examining muscles along the
course of a particular nerve. In the chronic phase, nerve
conduction studies permit the distinction between tem-
porary conduction block and complete axon interruption.
Serial examinations over time can document interval pro-
gress and healing.
Peripheral Polyneuropathies
There are many different types of acquired peripheral poly-
neuropathies, involving infectious, toxic, metabolic, phar-
macologic, hereditary, autoimmune, nutritional, systemic
 Electrodiagnosis: Nerve Conduction and Electromyography
illness-related, malignant, and endocrine disorders.23
Most polyneuropathies cause distal, symmetrical weak-
ness and/or sensory loss. The sensory deficit is frequently
most severe in the distal extremities in a “stocking-glove”
distribution. Occasionally a polyneuropathy will preferen-
tially affect the proximal limbs. The disorder may present
over a variable time course, and the predominant neuro-
logical deficit may involve motor, sensory, and autonomic
nervous system manifestations.
Leprosy
Leprosy (Hansen’s disease) is the most common cause
of polyneuropathy worldwide. Worldwide use of leprosy
drugs in the 1980s and 1990s has led to a drastic decline
in new cases, but still more than 210,000 cases are newly
reported each year, especially in India, Brazil and Indo-
nesia.24 In this disease, mycobacterium leprae invades
Schwann cells in the endoneurium and perineurium.
Three manifestations of the disease are recognized: lep-
romatous, borderline, and tuberculoid. The host’s immu-
nologic status determines which form of the disease
develops. Patients with lepromatous disease may develop
diffuse and symmetric sensorimotor polyneuropathies,
mononeuropathies and mononeuropathy multiplex.1
Patients with tuberculoid disease exhibit nerve damage
about the skin lesions, with sensory and/or motor impair-
ment when the hands and feet are affected. The disease
is slowly progressive with chronic complications such as
sensory loss, muscle atrophy, deformities and non-healing
wounds. Multidrug therapy over the course of 6–12 months
is the treatment, but resistant strains of the bacteria are
emerging.
Diabetic Neuropathy
The most common cause of neuropathy in the United
States is diabetes.6 The common etiology involves chronic
hyperglycemia, however there appear to be diverse causes.
The precise mechanism is not known, but direct axonal
injury due to hyperglycemia, autoimmune injury with
anti-neural antibodies, and increased intraneural pressure
and ischemia seem to be contributing factors.25 Addition-
ally, patients with renal failure independent of diabetes
develop a sensorimotor neuropathy due to uremia. About
half of the patients with diabetes have a distal symmetric
polyneuropathy. It is most common in patients older than
50 years. Patients experience sensory complaints with dys-
esthesias, painful parasthesias, and sensory loss in the dis-
13
tal extremities. Early signs include decreased perception of
Chapter 261
vibration and pain. In advanced disease, proprioception is
affected and also there is weakness in the distal muscles.
Painless injuries and loss of balance are common. Later,
proximal weakness can occur.
Most asymptomatic, neurologically intact diabetic
patients have nerve conduction velocities that are mildly
slow, around the lower limit of normal.6 As the severity
of the neuropathy advances, sensory amplitudes disap-
pear in the lower extremities. Motor amplitudes become
reduced. Abnormal temporal dispersion and partial
conduction block are common. Needle EMG findings
will show abnormal spontaneous activity in the distal
muscles.
A pure autonomic neuropathy is rare, but some degree
of autonomic involvement is present in most patients with
diabetes. Autonomic symptoms include pseudomotor
(dry skin), papillary (poor dark adaptation), cardiovas-
cular (orthostatic hypotension), urinary (incontinence,
impotence), or gastrointestinal (transit, constipation
problems).
There are several other presentations of diabetic neu-
ropathy. Some diabetic patients will have a polyneuropa-
thy affecting mainly the small-diameter sensory fibers
(A delta and C fibers) that manifests as painful paresthesias.
Another presentation is diabetic neuropathic cachexia,
which involves a precipitous and profound weight loss. It is
rather uncommon. Mononeuropathies are more common
in diabetics (refer to the previous entrapment neuropathy
section). A diabetic femoral neuropathy may present with
pain, weakness and atrophy of muscles innervated by the
femoral nerve. The presentation of a diabetic polyradicu-
lopathy resembles a radiculopathy due to spinal degener-
ation (see the previous radiculopathy section).26 The neu-
ropathy usually begins with severe, unilateral pain in the
low back, hip and thigh. However multiple spinal nerve
roots are involved and there is weakness in the expected
myotomal distributions. Coexisting symmetrical polyneu-
ropathy often is present.
The presentation of a patient with diabetes can arise
from a combination of degenerative musculoskeletal and
nervous system disorders. The electrodiagnostic exam
helps to refine the diagnosis, direct treatments, and estab-
lish treatment expectations.
Disorders of Muscle
Myopathy is disease of skeletal muscle that presents with
symmetrical, proximal muscle weakness. These are dis-
 14 Physical Medicine and Rehabilitation
cussed in detail in Chapter 277. Motor and sensory nerve
Section 12
conduction studies are usually normal. Needle EMG will
reveal a striking finding called the myotonic discharge,
which involves waxing and waning of both the amplitude
and frequency of motor units.
Disorders of Neuromuscular Junction
Myasthenia Gravis
Disorders of the neuromuscular junction are rare. In
myasthenia gravis, pathogenic autoantibodies are directed
against the acetylcholine receptor, muscle-specific kinase,
lipoprotein-related protein 4, or agrin protein at the
neuromuscular junction.27 As a result, the amplitude of
the endplate potential is reduced and may fail to reach the
necessary threshold to produce a muscle action potential.
The patient experiences easy fatigability and weakness. An
initial effort may produce strong muscular contraction, but
subsequent efforts become progressively weaker. In one
variation, the disorder is ocular, affecting all eye muscles.
The diagnosis rests on a form of nerve conduction testing
called repetitive nerve stimulation. Treatment is directed
at blocking acetylcholinesterase in order to prolong neu-
rotransmitter function. Immunosuppressive therapies,
including thymectomy, may be of benefit.
REFERENCES
1. Dumitru D, Amato A, Zwarts M (Eds). Electrodiagnostic
Medicine, 2nd edition. Philadelphia: Hanley & Belfus;
2001.
2. Kimura J. Electrodiagnosis in Diseases of Nerve and
Muscle: Principles and Practice, 3rd edition: USA: Oxford
University Press; 2001.
3. Oh S. Clinical Electromyography: Nerve Conduction
Studies, 3rd edition. Philadelphia, PA: Lippincott Williams
& Wilkins; 2002.
4. Weiss L, Silver J, Weiss J (Eds). Easy EMG, 1st edition.
Edinburgh: Butterworth-Heinemann; 2004.
5. Liveson J. Peripheral Neurology: Case Studies. New York,
NY: Oxford University Press; 2000.
6. Pease WS, Lew HL, Johnson EW (Eds). Johnson's Practical
Electromyography, 4th edition. Philadelphia, PA: Lippincott
Williams & Wilkins; 2007.
7. Carragee E. Electromyography, local blocks/injections, dis-
cograms. In: Bono C, Garfin S (Eds). Orthopaedic Surgery
Essentials Spine. Philadelphia, PA: Lippincott Williams &
Wilkins; 2004. pp. 28-34.
8. Lee H, DeLisa J. Manual of Nerve Conduction Study and
Surface Anatomy for Needle Electromyography, 4th edi-
tion. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
View publication stats
9. Al-Shekhlee A, Shapiro B, Preston D. Iatrogenic compli
cations and risks of nerve conduction studies and needle
electromyography. Muscle Nerve. 2003;27(5):517-26.
10. Gertken JT, Patel AT, Boon AJ. Electromyography and anti-
coagulation. PM R. 2013;5(5 Suppl):S3-7.
11. Pease WS, Grove SL. Electrical safety in electrodiagnostic
medicine. PM R. 2013;5(5 Suppl):S8-13.
12. Debivort. Annotated diagram of cervical vertebra:
Wikipedia; 2007 [cited 10/24/2016]. Available from: https://
en.wikipedia.org/wiki/File:Cervical_vertebra_english.png.
13. Wilbourn A, Aminoff M. AAEM minimonograph 32: the
electrodiagnostic examination in patients with radiculop-
athies. Muscle Nerve. 1998;21:1612-31.
14. Waylonis G. Electromyographic findings in chronic
cervical radicular symptoms. Arch Phys Med Rehabil.
1968;49(7):407-12.
15. Fowler JR, Munsch M, Tosti R, et al. Comparison of
ultrasound and electrodiagnostic testing for diagnosis of
carpal tunnel syndrome: study using a validated clini-
cal tool as the reference standard. J Bone Joint Surg Am.
2014;96(17):e148.
16. Tolonen U, Kallio M, Ryhanen J, et al. A handheld nerve
conduction measuring device in carpal tunnel syndrome.
Acta Neurol Scand. 2007;115(6):390-7.
17. David W, Chaudhry V, Dubin A, et al. Literature review:
nervepace digital electroneurometer in the diagnosis of
carpal tunnel syndrome. Muscle Nerve. 2003;27(3):378-85.
18. Megerian J, Kong X, Lesser E, et al. NC-stat as a screening
tool for carpal tunnel syndrome. J Occup Environ Med.
2006;48(8):755-6. author reply 7-8.
19. Jabre J, Salzseider B, Gnemi K. Criterion validity of the
NC-stat automated nerve conduction measurement instru-
ment. Physiol Meas. 2007;28(1):95-104.
20. Katz R. NC-stat as a screening tool for carpal tunnel
syndrome in industrial workers. J Occup Environ Med.
2006;48(4):414-8.
21. England JD, Franklin GM. Automated hand-held nerve
conduction devices: raw data, raw interpretations. Muscle
Nerve. 2011;43(1):6-8.
22. Lew H, Date E, Pan S, et al. Sensitivity, specificity, and vari-
ability of nerve conduction velocity measurements in carpal
tunnel syndrome. Arch Phys Med Rehabil. 2005;86:12-6.
23. Donofrio P, Albers J. Polyneuropathy: classification by
nerve conduction studies and electromyography. Muscle
Nerve. 1990;13:889-903.
24. Reibel F, Cambau E, Aubry A. Update on the epidemi-
ology, diagnosis, and treatment of leprosy. Med Mal
Infect.  2015;45(9):383-93.
25. Zochodne D. Diabetes mellitus and the peripheral nervous
system: manifestations and mechanisms. Muscle Nerve.
2007;36(2):144-66.
26. Dyck P, Windebank A. Diabetic and nondiabetic lumbosa-
cral radiculoplexus neuropathies: new insights into patho-
physiology and treatment. Muscle Nerve. 2002;25(4):477-91.
27. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup
classification and therapeutic strategies. Lancet Neurol.
2015;14(10):1023-36.