45
Diseases of Muscle
Skeletal, or voluntary, muscle constitutes the principal
organ of motion, as well as a vast metabolic reservoir.
Disposed in more than 600 separate muscles, this tissue
makes up as much as 40 percent of the weight of adult
human beings. An intricacy of structure and function
undoubtedly accounts for its diverse susceptibility to dis-
ease, for which reason the main anatomic and clinical facts
are provided as an introduction to the muscle diseases.
A single muscle is composed of thousands of muscle
fibers that extend for variable distances along its longitudi-
nal axis. Each fiber is a relatively large and complex multi-
nucleated cell varying in length from a few millimeters to
several centimeters (34 cm in the human sartorius muscle)
and in diameter from 10 to 100 µm. Some fibers span the
entire length of the muscle; others are joined end to end
by connective tissue. Each muscle fiber is enveloped by an
inner plasma membrane (the sarcolemma) and an outer
basement membrane. The multiple nuclei of each fiber,
which are oriented parallel to its longitudinal axis and may
number in the thousands, lie beneath the plasma membrane
(sarcolemma); hence they are termed subsarcolemmal, or
sarcolemmal nuclei.
The cytoplasm (sarcoplasm) of the cell is abundant,
and it contains myofibrils and various organelles such
as mitochondria and ribosomes. Each myofibril is envel-
oped in a membranous net, the sarcoplasmic reticulum
(SR; Fig. 45-1). Extensions of the plasma membrane into
the fiber form the transverse tubular system (T tubules),
which are extracellular channels of communication with
the intracellular sarcoplasmic reticulum. The SR and
T tubules are anatomically independent but functionally
related membrane systems. The junctional gap between
the T tubules and SR is occupied by protein formations
that are attached to the SR and are referred to as junctional
feet; the latter have been identified as ryanodine recep-
tors and are responsible for the release of calcium from
the SR, which is a critical step in exciting the muscle (see
Franzini-Armstrong).
The myofibrils themselves are composed of longitudi-
nally oriented interdigitating filaments (myofilaments) of
contractile proteins (actin and myosin), additional struc-
tural proteins (titin and nebulin), and regulatory proteins
(tropomyosin and troponin). The series of biochemical
events by which these proteins, under the influence of
calcium ions, accomplish the contraction and relaxation of
Ropper_Ch45_p1405-p1468.indd 1405
muscle is described in Chap. 2. Droplets of stored fat, gly-
cogen, various proteins, many enzymes, and myoglobin,
the latter imparting the red color to muscle, are contained
within the sarcoplasm or its organelles.
The individual muscle fibers are surrounded by deli-
cate strands of connective tissue (endomysium), which
provide their support and permit unity of action. Capil-
laries, of which there may be several for each fiber, and
nerve fibers lie within the endomysium. Muscle fibers
are bound into groups or fascicles by sheets of collagen
(perimysium), which also bind together groups of fascicles
and surround the entire muscle (epimysium). The latter
connective tissue tunics are richly vascularized, different
types of muscle having different arrangements of arteries
and veins. The muscle fibers are attached at their ends to
tendon fibers, which, in turn, connect with the skeleton.
By this means, muscle contraction maintains posture and
imparts movement.
Other notable characteristics of muscle are its natural
mode of contraction, that is, through neural innervation—
and the necessity of intact innervation for the mainte-
nance of its normal tone and trophic state. Each muscle
fiber receives a nerve twig from a motor nerve cell in the
anterior horn of the spinal cord or nucleus of a cranial
nerve; the nerve twig joins the muscle fiber at the neuro-
muscular junction or motor endplate. As was pointed out
in Chaps. 2 and 3, groups of muscle fibers with a common
innervation from one anterior horn cell constitute the
motor unit, which is the basic physiologic unit in all reflex,
postural, and voluntary activities.
Embedded in the surface membrane are several types
of ion channels that are responsible for maintaining the
electrical potential and propagating depolarizing currents
across the muscle membrane. Diseases of these channels
are discussed in Chap. 46. Also constituting a large part of
the membrane is a series of anchoring structural proteins,
the nature of which have been thoroughly elucidated in the
past few decades. These are described in detail in relation
to the muscular dystrophies.
In addition to motor nerve endings, muscle contains
several types of sensory endings, all of them mechano-
receptors: Free nerve endings subserve the sensation
of deep pressure-pain; Ruffini and pacinian corpuscles
are pressure sensors; and the Golgi tendon organs and
muscle spindles are tension receptors and participate in
1405
2/22/19 11:59 AM
 1406 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
Triad
Terminal
cisternae
T system
Sarcoplasmic
reticulum
T system
M verse (T) system, which is an invagination
H Actin
A rounds the myofibril midway between the
Myosin
the maintenance of muscle tone and reflex activity. The
Golgi receptors are located mainly at the myotendon junc-
tions; pacinian corpuscles are localized in the tendon but
are also found sparsely in muscle itself. Muscle spindles
are specialized groups of small muscle fibers that regu-
late muscle contraction and relaxation, as described in
Chap. 2. All of these receptors are present in the highest
density in muscles that are involved in fine movements.
Muscles are not equally susceptible to disease, despite
the apparent similarity of their structure. In fact, practi-
cally no disease affects all muscles in the body and each
pathologic entity has a characteristic topography within
the musculature. The topographic differences between
diseases provide incontrovertible evidence of structural
or physiologic differences between muscles that are not
presently disclosed by the light or electron microscope.
The factors responsible for the selective vulnerability of
certain muscles are not known but several hypothetical
explanations come to mind. One may relate simply to
fiber size; consider, for example, the large diameter and
length of the fibers of the glutei and paravertebral muscles
in comparison with the smallness of the ocular muscle
fibers. The number of fibers composing a motor unit may
also be of significance; in the ocular muscles, a motor unit
contains only 6 to 10 muscle fibers (some even fewer),
but a motor unit of the gastrocnemius contains as many
as 1,800 fibers. Also, the eye muscles have a much higher
metabolic rate and a richer content of mitochondria than
Ropper_Ch45_p1405-p1468.indd 1406
A
Z
I
Figure 45-1. Schematic of the major subcel-
lular components of a myofibril. The trans-
of the plasma membrane of the cell, sur-
Z lines and the center of the A bands; the T
system is approximated to, but apparently
not continuous with, dilated elements (ter-
minal cisternae) of the sarcoplasmic reticu-
lum on either side. Thus, each sarcomere
(the repeating Z-line-to-Z-line unit) contains
two “triads,” each composed of a pair of ter-
minal cisternae on each side of the T tubule.
(From Peter, by permission.)
the large trunk muscles. Differences in patterns of vascular
supply may permit some muscles to withstand the effects
of vascular occlusion better than others. Histochemical
studies of skeletal muscles have disclosed that within any
1 muscle, there are subtle metabolic differences between
fibers, certain ones (type 1 fibers) being richer in oxida-
tive and poorer in glycolytic enzymes and others (type 2
fibers) having the opposite distribution. The distribution
of certain structural proteins may alter the topography of
disease expression; for example, the eye muscles do not
contain dystrophin, a submembrane protein that is defi-
cient in Duchenne muscular dystrophy, which explains
the muscles’ lack of involvement in this disease. The endo-
mysial fibroblasts of eye muscles contain an abundance of
glycosaminoglycans, which renders them susceptible to
thyroid diseases. Diseases of the neuromuscular junction
show a distribution of weakness in relation to the density
of these junctions in different muscles. Doubtless other
differences will be discovered.
Normal muscle is endowed with a population of
embryonic muscle precursor cells, known as satellite cells,
and, as a result, it possesses a remarkable capacity to
regenerate, a point often forgotten. It has been estimated
that enough new muscle can be generated from a piece
of normal muscle the size of a pencil eraser to provide
normal musculature for a 70-kg adult. However, with
complete destruction of the muscle fiber, this regenerative
capacity is greatly impaired. Inflammatory and metabolic
2/22/19 11:59 AM

destructive processes are usually followed by fairly com-
plete restoration of the muscle cells, provided that some
part of each fiber has survived and the endomysial sheaths
of connective tissue have not been severely disrupted.
Unfortunately, many pathologic processes of muscle are
chronic and unrelenting. Under such conditions, any
regenerative activity fails to keep pace with the disease
and the loss of muscle fibers becomes permanent. The
bulk of the muscle is then replaced by fat and collagenous
connective tissue, typical, for example, of the muscular
dystrophies.
THE DEVELOPMENT AND AGING OF MUSCLE
(SEE ALSO CHAP. 28)
The accepted view of the embryogenesis of muscle is that
muscle fibers form by fusion of myoblasts soon after the
latter differentiate from somatic mesodermal cells. Muscle
connective tissue derives from the somatopleural meso-
derm. After fusion of the myoblasts, a series of cellular
events including the sequential activation of myogenic
transcription factors leads to myofibril formation. The
newly formed fibers are thin, centrally nucleated tubes
(appropriately called myotubes) in which myofilaments
begin to be produced from polyribosomes. As myofila-
ments become organized into myofibrils, the nuclei of
the muscle fiber are displaced peripherally to a subsar-
colemmal position. Once the nuclei assume a periph-
eral position, the myofiber is fully formed. The detailed
mechanisms whereby myoblasts seek one another, the
manner in which each of a series of fused nuclei contrib-
utes to the myotube, the formation of actin and myosin
fibrils, Z-discs, and the differentiation of a small residue of
satellite cells on the surface of the fibers are reviewed by
Rubenstein and Kelly.
The mechanisms that determine the number and
arrangement of fibers in each muscle are not as well
understood. Presumably, the myoblasts themselves pos-
sess the genetic information that controls the program of
development, but within any given species there are wide
individual variations that account for obvious differences
in the size of muscles and their power of contraction.
The number of fibers assigned to each muscle is prob-
ably attained by birth, and growth of muscle thereafter
depends mainly on the enlargement of fibers. Although the
nervous system and musculature develop independently,
muscle fibers continue to grow after birth only when they
are active and under the influence of nerve. Measurements
of muscle fiber diameters from birth to old age show the
growth curve ascending rapidly in the early postnatal years
and less rapidly in adolescence, reaching a peak during
the third decade. After puberty, growth of muscle is less
in females than in males, and such differences are greater
in the arm, shoulder, and pelvic muscles than in the leg;
growth in ocular muscles is about equal in the 2 sexes. At
all ages, disuse of muscle decreases fiber size by as much
as 30 percent, and overuse increases the size by about
the same amount (work hypertrophy). Normally, type 1
Ropper_Ch45_p1405-p1468.indd 1407
Chapter 45 Diseases of Muscle 1407
(oxidative enzyme-rich) fibers are slightly smaller than type 2
(phosphorylative enzyme-rich) fibers; the numerical pro-
portions of the 2 fiber types vary in different muscles in
accordance with the natural functions of that muscle. The
exercising of young animal muscle causes a hypertrophy of
high-oxidative type 1 fibers and an increase in the propor-
tion of low-oxidative type 2 fibers; aging muscle lacks this
capacity; exercise produces only an increase in the propor-
tion of type 2 fibers (Silbermann et al). No such data are
available in humans, but clinical observation suggests that
with aging, the capacity of muscle to respond to intense,
sustained exercise is diminished.
During late adult life, the number of muscle fibers
diminishes and variation in fiber size increases as men-
tioned in Chap. 28 on aging. The variations are of 2 types:
group atrophy, in which clusters of 20 to 30 fibers are all
reduced in diameter to about the same extent, and random
single-fiber atrophy. Also, muscle cells, like other cells of
postmitotic type, are subject to aging changes (lipofuscin
accumulation, autophagic vacuolization, enzyme loss) and
to death. Group atrophy, present to a slight degree in the
gastrocnemii of almost all individuals older than 60 years,
represents denervation effect from an aging-related loss of
lumbar motor neurons and peripheral nerve fibers. Fur-
ther comments regarding muscle and aging can be found
in the work of Tomlinson and colleagues and in Chap. 28.
Denervation from spinal motor neuron or nerve dis-
ease at every age has roughly the same effect; namely, atro-
phy of muscle fibers (first in random distribution, then in
groups) and later, degeneration. Muscle necrosis at all ages
excites a regenerative response from sarcolemmal and
satellite cells in any intact parts of the fibers. If this occurs
repeatedly, the regenerative potential wanes, with ultimate
death of the fiber leading to permanent depopulation of
fibers with the expected muscle weakness.
APPROACH TO THE PATIENT WITH MUSCLE
DISEASE
The number and diversity of diseases of striated muscle
greatly exceed the number of symptoms and signs by
which they express themselves clinically; thus, differ-
ent diseases share certain common symptoms and syn-
dromes. To avoid excessive repetition in the description
of individual diseases, we discuss here, in one place, the
broad clinical manifestations of muscle disease.
The physician is initially put on the track of a myo-
pathic disease by eliciting complaints of muscle weak-
ness or fatigue, pain, limpness or stiffness, spasm, cramp,
twitching, or a muscle mass or change in muscle volume.
Of these, the symptom of weakness is by far the most fre-
quent and at the same time the most elusive. As remarked
in Chap. 23, when speaking of weakness, the patient often
means excessive fatigability and poor endurance. Although
fatigability in the strict sense of gradually reduced power
with ongoing use of a muscle may be a feature of muscle
diseases, particularly those affecting the neuromuscular
junction such as myasthenia gravis, it is far more frequently
2/22/19 11:59 AM
 1408 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
a complaint of patients with chronic systemic disease or
with anxiety or depression. As stated in Chap. 23, fatigue
is an abstruse symptom, always requiring analysis and
interpretation. When not attended by manifest reduc-
tion in muscle power, it is usually nonmuscular in origin.
It may, on medical investigation, prove to be a systemic
manifestation of infection, metabolic or endocrine disor-
der, severe anemia, reduced cardiopulmonary function,
or neoplasia. More often, when expressed as a feeling of
poor endurance, weariness, and disinclination to under-
take or sustain mental and physical activity, it is indicative
of neurasthenia, a psychiatric manifestation common to
states of chronic anxiety and depression. On the other hand,
a rare example of a physiologic muscle disorder that simu-
lates lassitude is lifelong exercise intolerance, often accom-
panied by muscle cramps during exercise, which has been
traced to mutations in the cytochrome b gene of the mito-
chondrial DNA (Andreu et al). The subject of fatigue as a
physiologic phenomenon and as a clinical feature of many
psychiatric and medical diseases, including those that are
predominantly myopathic, is considered fully in Chap. 23.
Evaluation of Muscle Weakness and Paralysis
Rather than relying on the patient’s report to distinguish
between fatigability and weakness, it is more informative
to observe the patient during the performance of certain
common activities such as walking, climbing stairs, and
arising from a sitting, kneeling, squatting, or reclining
position or using the arms over the head. Difficulty in per-
forming these tasks signifies weakness rather than fatigue.
Sometimes, the weakness of a group of muscles becomes
manifest only after a period of activity; for example, the
feet and legs may “drag” only after the patient has walked
a long distance. The physician, upon being told this by the
patient, should attempt to conduct the examination under
circumstances that duplicate the complaints. Of course,
these impairments of muscle function may be caused by a
neuropathic or central nervous system (CNS) disturbance
rather than of a myopathic one, but usually these condi-
tions can be separated by the basic methods indicated
further on in this chapter and in Chaps. 3 and 23.
Reduced strength of muscle contraction—manifest by
diminished power of single contractions against resistance
(peak power) and during the sustained performance of
prolonged or repetitive movements (i.e., endurance)—are
the indubitable signs of muscle or neuromuscular disease.
In such testing, the physician may encounter difficulty in
enlisting the patient’s cooperation. The tentative, hesitant
performance of the asthenic or suggestible individual,
or the hysteric or malingerer, poses difficulties that can
be surmounted by experience and by the techniques
described in Chap. 3. In infants and small children, who
cannot follow commands, one assesses muscle power
by the resistance to passive manipulation or by observ-
ing performance while the child is engaged in natural
activities. The patient may be reluctant to fully contract
the muscles in a painful limb; indeed, pain itself causes
a reflex diminution in the power of contraction (algesic
paresis). Estimating the strength of isometric contractions
Ropper_Ch45_p1405-p1468.indd 1408
that do not require the painful part to be moved is a way
around this difficulty.
Ascertaining the extent and severity of muscle weak-
ness requires a systematic examination of the main groups
of muscles. The patient is asked to contract each group with
as much force as possible, while the examiner opposes the
movement and offers a graded resistance in accordance
with the degree of residual power (isokinetic contraction).
Alternatively, the patient is asked to produce a maximal
contraction and the examiner estimates power by the
force needed to overcome or “break” it (isometric contrac-
tion or maximum voluntary isometric contraction). If the
weakness is unilateral, one has the advantage of being
able to compare it with the strength on the normal side.
If it is bilateral, the physician must refer to his concept of
what constitutes normalcy based on experience in muscle
testing. As mentioned, one can distinguish true weakness
from unwillingness to cooperate, feigned or neurasthenic
weakness, and inhibition of movement by pain.
To quantitate the degree of weakness, a rating scale
may be required. Widely used is the one proposed by the
Medical Research Council (MRC) of Great Britain, which
recognizes 6 grades of muscle strength as follows:
0—Complete paralysis
1—Minimal contraction
2—Active movement only with gravity eliminated
3—Full movement against gravity but cannot offer resis-
tance to manual muscle opposition
4—Active movement against gravity and resistance but can
be overcome by manual muscle opposition
5—Normal strength
Further gradations may be added, specified as 4+
for barely detectable weakness and 4- for easily detected
weakness, 3+ and 3-, and so on.
The ocular, facial, lingual, pharyngeal, laryngeal, cer-
vical, shoulder, upper arm, lower arm and hand, trun-
cal, pelvic, thigh, and lower leg and foot muscles are
examined sequentially. It is most convenient to compare
power generated by the same muscle from each side. To
fully and properly use tools such as the MRC scale and to
detect mild weakness, muscles such as the neck flexors
and extensors must be tested with the patient in the prone
and supine positions. The anatomic significance of each of
the actions tested, that is, what roots, nerves, and muscles
are involved, can be determined by referring to Table 45-1.
A practiced examiner can survey the strength of these
muscle groups in 2 to 3 min.
A word of caution is in order: In manually resisting the
patient’s attempts to contract the large and powerful trunk
and girdle muscles, the examiner may fail to detect slight
degrees of weakness, particularly in well-muscled indi-
viduals. These muscle groups are best examined by having
the patient use the muscle groups for their intended pur-
poses: squat and kneel and then assume the erect posture,
arise from and, walk on toes and heels, and lift a heavy
object (e.g., this textbook) over his head. The strength of
muscles of the hand can be quantified with a dynamom-
eter; for research purposes, similar but more sophisticated
devices exist for other muscle groups (see Fenichel et al).
2/22/19 11:59 AM
 Chapter 45 Diseases of Muscle 1409

Table 45-1  
DUCHENNE/BECKER, EMERY-DREIFUSS, LIMB-GIRDLE, AND RELATED MAJOR MUSCULAR DYSTROPHIES
INHERITANCE TYPE GENE/PROTEIN ONSET DECADE CK ELEVATION REGIONS AFFECTED
X-linked recessive
Duchenne/Becker DMD/Dystrophin 1st 10–50 × Proximal, then distal muscles
Cardiac muscle
Emery-Dreifuss EMD and others/Emerin 2nd–3rd 5× Proximal muscles, joint contractures;
cardiac arrhythmias
Scapuloperoneal FHL1 and others Scapular-peroneal
Autosomal dominant
LGMD 1A Myotilin 3rd–4th 2× Distal greater than proximal weakness, vocal
cords, pharynx; allelic with myofibrillar
myopathy
LGMD 1B LMNA/Lamin A/C 1st–2nd 3–5 × Resembles Emery-Dreifuss disease
Proximal muscles and heart, joint
contractures
LGMD 1C CAV3/Caveolin-3 1st 4–25 × Proximal muscles
LGMD 1D 6p 3rd–5th 2–4 × Proximal muscles; cardiomyopathy
LGMD 1E Desmin 1st Nl Proximal muscles
Autosomal recessive
LGMD 2A CPN3/Calpain-3 1st–2nd 3–15 × Proximal and distal muscles
LGMD 2B DYSF/Dysferlin 2nd–3rd 10–50 × Proximal and distal muscles
Allelic to Miyoshi myopathy
LGMD 2C–F a, b, g, d-sarcoglycans 1st–3rd 5–40 × Phenotype of Becker dystrophy
LGMD 2G Telethonin 2nd 3–17 × Proximal greater than distal muscles
LGMD 2H TRIM32 1st–3rd 2–25 × Proximal greater than distal muscles
LGMD 2I FKRP/Fukutin 1st–3rd 10–30 × Proximal greater than distal muscles
FKRP defects also cause CMD
LGMD 2J TTN/Titin 1st–3rd 2× Proximal and sometimes distal muscles
LGMD 2M POMGNT1 Birth Mutations also associated with muscle-eye-
brain diseases
CK, creatine kinase; CMD, childhood muscular dystrophy; FKRP, fukutin-related protein; LGMD, limb-girdle muscular dystrophy; Nl, normal.

Nonetheless, the examiner should not dismiss the patient’s
complaint of weakness simply if it cannot be substantiated
by the examination.
Changes in the Contractile Process
These processes relate to qualitative changes in muscle
contraction. In the myasthenic states there is a rapid failure
of contraction in the affected muscles during sustained
or repetitive activity. For instance, after the patient looks
upward at the ceiling for a few minutes, the eyelids pro-
gressively droop; closing the eyes and resting the levator
palpebrae muscles cause the ptosis to lessen or disappear.
Similarly, holding the eyes in a far lateral position will
induce diplopia and strabismus. These effects, in com-
bination with restoration of power by the administration
of neostigmine or edrophonium, are the most valuable
clinical criteria for the diagnosis of myasthenia gravis, as
described in Chap. 46.
The opposite of the myasthenic phenomenon, an
increment in power with a series of several voluntary
contractions is a feature of the Lambert-Eaton myasthenic
syndrome, which is associated in approximately 50 percent
of cases with small cell carcinoma of the lung. The same
increment occurs in botulism. In both instances there is
an increase in the amplitude of compound muscle action
potentials on the nerve conduction studies obtained fol-
lowing brief exercise (10 to 15 s), or at high rates of repetitive
nerve stimulation (20 to 50 Hz), as described in Chap. 46.
Other abnormalities may be discovered by observing
the speed and efficiency of contraction and relaxation
during one or a series of maximal actions of a group of
muscles. In myxedema, for example, stiffness and slow-
ness of contraction in a muscle such as the quadriceps may
be seen on change in posture (contraction myoedema) and
by direct percussion of a muscle, and there is an associated
prolonged duration of the tendon reflexes. Slowness in
relaxation of muscles is another feature of hypothyroidism,
accounting for the complaint of uncomfortable tightness
of proximal limb muscles. A curious rippling phenomenon
in muscles may be the result of several processes and
occurs as an inherited autosomal dominant trait. After a
period of relaxation, stiffening and rippling occur in the
contracting or stretched muscles.
A prolonged failure of relaxation following contrac-
tion of a muscle is characteristic of myotonia, which
typifies certain diseases: myotonia congenita, myotonic
dystrophy, and paramyotonia congenita (attached to
Eulenburg’s name). True myotonia, with its prolonged
discharge of membrane action potentials, requires strong
contraction to elicit, is more evident after a period of relax-
ation, and tends to disappear with repeated contractions

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 1410 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
as discussed further in relation to the ion channel disor-
ders of muscle in Chap. 46. This persistence of contrac-
tion is demonstrable also by tapping a muscle (percussion
myotonia), a phenomenon easily distinguished from the
electrically silent local bulge (myoedema) induced by tap-
ping the muscle of a myxedematous or cachetic patient
and from the brief fascicular contraction that is induced by
tapping a normal or partially denervated muscle; the latter
is referred to as idiomuscular contraction. In paramyoto-
nia congenita one observes paradoxical myotonia, which
refers to an increase in the degree of myotonia during a
series of contractions (the reverse of what happens in the
usual type of myotonia).
The effect of cold on muscle contraction may also
prove informative; either paresis or myotonia, lasting for
a few minutes, may be evoked or enhanced by cold. This
is most prominent in paramyotonia, but it may occur to
some degree in all the other myotonic disorders. Also,
a cold pack applied to a ptotic eyelid of myasthenia will
often reduce the weakness.
Myotonia and myoedema must also be distinguished
from the recruitment and spread of involuntary spasm
induced by strong and repeated contractions of limb
muscles in patients with mild or localized tetanus, with the
“stiff man” syndrome and with dystonias of various types.
These are not primary muscle phenomena but are neural
in origin, a result of an abolition of inhibitory mechanisms
and also taken up in Chap. 46.
In practice, the term contracture is applied (somewhat
indiscriminately as discussed previously) to all states of
fixed muscle shortening. Several distinct types can be rec-
ognized. In true physiologic contracture a group of muscles,
after a series of strong contractions, remain shortened for
many minutes because of failure of the metabolic mecha-
nism necessary for relaxation. In this shortened state, the
electromyogram (EMG) remains relatively silent, in con-
trast to the high-voltage, rapid discharges observed with
cramp, tetanus, and tetany. True physiologic contracture
occurs in McArdle disease (phosphorylase deficiency),
phosphofructokinase deficiency, and possibly in other
conditions, where phosphorylase seems to be present but
nonfunctional. Yet another type of exercise-induced con-
tracture, described originally by Brody, has been attrib-
uted by Karpati and coworkers to an autosomal recessive
deficiency of calcium adenosine triphosphatase in the sar-
coplasmic reticulum in type 2 muscle fibers. True contrac-
ture needs to be distinguished from paradoxical myotonia
(see earlier) and from cramp, which in certain conditions
(dehydration, tetany, pathologic cramp syndrome, amyo-
trophic lateral sclerosis [ALS]) can also be initiated by one
or a series of strong voluntary muscle contractions.
It is appropriate here to comment on pseudocontrac-
ture (myostatic or fibrous contracture), for which the term
contracture is used in general medicine. This is the com-
mon form of muscle and tendon shortening that follows
prolonged fixation and inactivity of the normally inner-
vated muscle (as occurs in a broken limb immobilized by a
cast or weakness of a limb that is allowed to remain immo-
bile). Here the shortened state of the muscle and tendons
has no clearly established anatomic, physiologic, or chem-
ical basis. Fibrosis of muscle, a state following chronic fiber
Ropper_Ch45_p1405-p1468.indd 1410
loss and immobility of muscle, is another cause of muscle
shortening. Depending on the predominant position, cer-
tain muscles are both weakened and shortened. Flexor
fibrous contracture of the arms is a prominent feature of
the Emery-Dreifuss form of muscular dystrophy. It also
accounts for the rigidity and kyphoscoliosis of the spine,
which are so frequently a part of myopathic diseases. The
latter state is distinguished from ankylosis by the springy
nature of the resistance, coincident with increased taut-
ness of muscle and tendon during passive motion, and
from Volkmann contracture, in which there is fibrosis of
muscle and surrounding tissues as a result of ischemic
injury, usually after a fracture of the elbow.
Arthrogryposis is another form of fibrous contracture
that is found in newborns, involving multiple muscle
groups; it occurs in association with several diseases that
have two features in common: an onset during intrauterine
life and an alteration of the neural or muscular apparatus
that results in muscular weakness. In other words, contrac-
tures and fixity of the limbs in arthrogryposis are the result
of reduced mobility of the developing joints, consequent
upon muscle weakness during fetal development. Most
often the cause is a loss or failure of development of ante-
rior horn cells, as in Werdnig-Hoffman disease, but the
abnormality may be in the nerve roots, peripheral nerves,
or motor endplates, or in the muscle itself. The rigid spine
syndrome (RSS) in children is yet another form of fibrous
contracture, presumably the result of an unusual axial
muscular dystrophy.
Notably, most primary muscle diseases are painless.
When pain is prominent and continuous during rest and
activity, there will usually be evidence of disease of the
peripheral nerves, as in alcoholic–nutritional neuropathy,
or of adjacent joints and ligaments (rheumatoid arthritis,
polymyalgia rheumatica). Pain localized to a group of mus-
cles is more a feature of torticollis and dystonias. Pain tends
not to be prominent in polymyositis and dermatomyositis,
but there are exceptions, as commented below. Pain tends
to be more definite in polyneuritis, poliomyelitis, and poly-
arteritis nodosa than it is in polymyositis, various forms
of dystrophy, and other myopathies. If pain is present in
polymyositis, it usually indicates coincident involvement
of connective tissues and joint structures. Hypothyroidism,
hypophosphatemia, and hyperparathyroidism are other
sources of a myalgic myopathy. Certain drugs produce
muscle aches in susceptible individuals. They include the
“statin” lipid-lowering drugs, clofibrate, captopril, lithium,
colchicine, beta-adrenergic blocking drugs, penicillamine,
cimetidine, suxamethonium, and numerous others (see
the table contained in the review by Mastaglia and Laing).
There are probably a limited number of mechanisms
of muscle pain. Prolonged and sustained contraction
gives rise to a deep aching sensation. Contraction under
ischemic conditions—as when the circulation is occluded
by a tourniquet or from atherosclerotic vascular disease—
induces pain; the pain of intermittent claudication is pre-
sumably of this type and is not accompanied by cramp. It
was postulated that lactic acid or some other metabolite
accumulates in muscles and activates pain receptors,
but there is also evidence to the contrary. The delayed
pain, swelling, and tenderness that occur after sustained
2/22/19 11:59 AM

exercise of unconditioned muscles are evidently a result of
fiber necrosis (Armstrong).
Muscle biopsy infrequently reveals the cause of these
painful syndromes, but it may be undertaken in cases of
suspected metabolic or dystrophic muscle disease. In their
retrospective series, Filosto and colleagues determined
that the biopsy was most likely to be helpful if there was
exercise-induced muscle pain and the creatine kinase (CK)
concentration was greatly elevated; even then two-thirds
of the entire group had either normal or nonspecific find-
ings on the biopsy.
Having listed all these causes of proximal pains, all
physicians are aware that arthritic and mundane mus-
culoskeletal complaints are more common causes of
discomfort.
Benign fasciculations, a common finding in otherwise
normal individuals, can be identified by the lack of mus-
cular weakness and atrophy and by the small-size muscle
fascicles involved and repetitive appearance in only one or
a few regions. The recurrent twitches of the eyelid or mus-
cles of the thumb experienced by most normal persons are
often referred to inaccurately as “live flesh” or myokymia
but are benign fasciculations of this type. Individuals with
truly benign fasciculations have normal EMGs (i.e., they
have no fibrillations) as demonstrated in a large series
of such patients studied and followed for many years by
Blexrud and colleagues. Myokymia is a less common con-
dition, in which there are repeated twitchings and rippling
of a muscle at rest.
Muscle cramps, despite their common occurrence, are
a poorly understood phenomenon. They occur at rest or
with movement (action cramps), and they are frequently
reported in motor system disease, tetany, dehydration
after excessive sweating and salt loss, metabolic disorders
(uremia and hemodialysis, hypocalcemia, hypothyroid-
ism, and hypomagnesemia), and certain muscle diseases
(e.g., rare cases of Becker muscular dystrophy and con-
genital myopathies). Gospe and colleagues reported a
familial (X-linked recessive) type of myalgia and cramps
associated with deletion of the first third of the dystrophin
gene, which is the one implicated in Duchenne dystrophy;
strangely, there was no weakness or evidence of dystrophy.
Lifelong, severe cramping of undetermined type has also
been seen in a few families. The dramatic Satoyoshi syn-
drome, is characterized by continuous, painful leg cramps,
alopecia universalis, and diarrhea, is described further on.
Far more frequent than all these types of cramping,
and experienced at one time or another by most normal
persons, is the benign form (idiopathic cramp syndrome)
in which no other neuromuscular disturbance can be
found. Most often benign cramps occur at night and affect
the muscles of the calf and foot, but they may occur at any
time and involve any muscle group. Some patients state
that cramps are more frequent when the legs are cold and
daytime activity has been excessive. In others, the cramps
are provoked by the abrupt stretching of muscles, are very
painful, and tend to wax and wane before they disap-
pear. The EMG counterpart is a high-frequency discharge.
Although of no pathologic significance, the cramps in
extreme cases are so persistent and readily provoked by
innocuous movements as to be disabling. Cramps of all
Ropper_Ch45_p1405-p1468.indd 1411
Chapter 45 Diseases of Muscle 1411
types need to be distinguished from sensations of cramp
without muscle spasm. The latter is a dysesthetic phe-
nomenon in certain polyneuropathies. The disorders that
simulate cramps, such as stiff-man syndrome and other
forms of continuous muscle fiber activity that have various
bases, are discussed in Chap. 46.
Contrasted to cramp is the already described physio-
logic contracture, observed in McArdle disease and related
metabolic myopathies, in which increasing muscle short-
ening and pain gradually develop during muscular activity.
Unlike cramping, it does not occur at rest, the pain is less
intense, and the EMG of the contracted muscle at the time
is relatively silent. Continuous spasm intensified by the
action of muscles and with no demonstrable disorder at a
neuromuscular level is a common manifestation of local-
ized tetanus and also follows the bite of the black widow
spider. There may also be difficulty distinguishing cramps
and spasms from the early stages of a dystonic illness.
Altered structure and function of muscle are not accu-
rately revealed by palpation. Of course, the difference
between the firm, hypertrophied muscle of a well-condi-
tioned athlete and the slack muscle of a sedentary person is
as apparent to the palpating fingers as to the eye, as is also
the persistent contraction in tetanus, cramp, contracture,
fibrosis, and extrapyramidal rigidity. The muscles in dys-
trophy are said to have a “doughy” or “elastic” feel, but we
find this difficult to judge. In the Pompe type of glycogen
storage disease, attention may be attracted to the muscu-
lature by an unnatural firmness and increase in bulk. The
swollen, edematous, weak muscles in acute rhabdomyoly-
sis with myoglobinuria or severe polymyositis may feel taut
and firm but are usually not tender. Areas of tenderness in
muscles that otherwise function normally, a state called
myogelosis, have been attributed to fibrositis or fibromyosi-
tis, but their nature has not been divulged by biopsy.
Topographic Patterns of Myopathic Weakness
In almost all the diseases under consideration, some
muscles are affected and others spared, each disease dis-
playing its own pattern. Restated, the topography or dis-
tribution of weakness tends to be alike in all patients with
the same disease. The pattern of weakness is as important
a diagnostic attribute of muscular disease as for the vari-
ous diseases of the peripheral nervous system discussed in
Chap. 43, but the configurations differ in important ways.
As a general rule, muscle diseases are identified by a pre-
dominantly proximal weakness that is symmetric.
The following patterns of muscle involvement consti-
tute a core of essential clinical knowledge in this field. Sub-
acute and chronic evolution of weakness is distinguished
in each category from more acute causes.
Ocular palsies presenting as ptosis, diplopia, and
strabismus Primary diseases of muscle do not involve
the pupil, and in most instances their effects are bilateral.
In lesions of the third, fourth, or sixth cranial nerves, a
neural origin is disclosed by the pattern of ocular muscle
palsies, abnormalities of the pupil, or both. When weak-
ness of the orbicularis oculi (muscles of eye closure) is
added to weakness of eye opening (levator palpebrae;
ptosis), it nearly always signifies myasthenia gravis. The
2/22/19 11:59 AM
 1412 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
rare primary disease of ocular muscle (progressive exter-
nal ophthalmoplegia) is usually symmetric and does not
produce diplopia. Other causes of subacute and chronic
development of relatively pure weakness of the muscles
of eye movement are oculopharyngeal dystrophy, and
exophthalmic (hyperthyroid) ophthalmopathy. In PEO,
the muscles, including the levators of the eyelids, become
paralyzed almost symmetrically over a period of years.
In most cases, this disorder is a form of mitochondrial
myopathy. Oculopharyngeal dystrophy involves primar-
ily the levators of the eyelids and, to a lesser extent, other
eye muscles and pharyngeal-upper esophageal striated
muscles. It begins in middle or late adult life and later,
and—like PEO—tends only decades later to involve girdle
and proximal limb muscles.
There are several other less common chronic myopa-
thies in which external ophthalmoplegia is associated with
involvement of other muscles or organs, namely, the con-
genital ophthalmoplegia of the Goldenhar-Gorlin syndrome
(see Aleksic et al); the Kearns-Sayre syndrome (retinitis pig-
mentosa, heart block, short stature, generalized weakness,
and ovarian hypoplasia); other congenital myotubular and
mitochondrial myopathies; and nuclear ophthalmoplegia
with bifacial weakness (Möbius syndrome). Rarely, eye
muscle weakness may occur at a late stage in a few other
dystrophies. Ptosis has a wider diagnostic range than oph-
thalmoplegia that includes myotonic dystrophy. Although
not a regular feature of the disease, ophthalmoparesis can
occur in the Lambert-Eaton myasthenic syndrome.
Ptosis is variable in all of these conditions. When pres-
ent in infantile myopathic disease, it is frequently a marker
of the congenital myasthenic syndromes. The periorbital
edema of Trichinosis is a rare cause, associated also with
periorbital edema.
Bifacial palsy presenting as an inability to smile, to
expose the teeth, and to close the eyes Varying degrees
of bifacial weakness are observed in myasthenia gravis,
usually conjoined with ptosis and ocular palsies. On occa-
sion, weakness of facial muscles may be combined with
myasthenic weakness of the masseters and other bulbar
muscles without involvement of ocular muscles. Facial
weakness and ptosis are features of myotonic dystrophy.
More severe or complete facial palsy occurs in facioscapu-
lohumeral dystrophy, sometimes presenting several years
before weakness of the shoulder girdle muscles. Bifacial
weakness is also a feature of certain congenital myopathies
(centronuclear, nemaline), Kennedy type of degenerative
bulbospinal motor neuron disease, and the Möbius syn-
drome of the absence of the facial nuclei (in combination
with abducens palsies).
Advanced scleroderma, Parkinson disease, or a pseu-
dobulbar state can immobilize the face to the point of
simulating myopathic or neuropathic paralysis, but always
in a context that makes the cause obvious.
Bulbar (oropharyngeal) palsy presenting as dyspho-
nia, dysarthria, and dysphagia with or without weakness
of jaw or facial muscles Myasthenia gravis is the most fre-
quent cause of this syndrome and must also be considered
whenever a patient presents with the solitary finding of a
hanging jaw or fatigue of the jaw while eating or talking;
Ropper_Ch45_p1405-p1468.indd 1412
usually, however, ptosis and ocular palsies are conjoined.
Dysphagia and dysphonia may be early and prominent
signs of polymyositis, as well as inclusion body myositis
(IBM), and may appear in patients with myotonic dystro-
phy, because of upper esophageal atonia.
Combinations of these palsies are not typically of mus-
cular or neuromuscular origin but instead are observed as
an acute syndrome in botulism, in brainstem stroke, and at
the outset of Guillain-Barré syndrome. Diphtheria and bul-
bar poliomyelitis are now rare diseases that may present in
this way. Progressive bulbar palsy (motor neuron disease)
may be the basis of this syndrome (see Chap. 38); the last
of these diagnoses is most obvious when the tongue is
withered and twitching. Syringobulbia, basilar invagina-
tion of the skull, and certain types of Chiari malformation
may reproduce some of the findings of bulbar palsy by
involving the lower cranial nerves. Rare cases of progres-
sive aphonia include the X-linked Kennedy syndrome of
bulbospinal atrophy.
Cervical palsy presenting with inability to hold the
head erect or to lift the head from the pillow (“hanging,
or dropped, head” syndrome, “camptocormia”) This is
caused by weakness of the posterior neck muscles and of
the sternocleidomastoids and other anterior neck muscles.
In advanced forms of this syndrome, the head may hang
with chin on chest unless the patient holds it up with the
hands. There may be difficulty differentiating the condi-
tion from a dystonic anterocollis; in the latter there is pal-
pable tonic spasm of the sternomastoid and posterior neck
muscles. A pattern of neck and spine extensor weakness
also occurs in advanced Parkinson disease. A common
error in all these cases is to attribute the problem to struc-
tural disease of the cervical spine.
This topographic pattern occurs most often in idio-
pathic polymyositis and IBM, in which cases it is often
combined with mild dysphagia, dysphonia, and weakness
of girdle muscles. The same symptom may be a feature of
motor neuron disease and is infrequently the presenting
feature of that process. Myasthenic patients commonly
complain of an inability to hold up their heads late in the
day; both flexors and extensors of the neck are found to be
weak. Occasionally, this pattern of weakness is observed
in patients with nemaline rod myopathy. Cases of hanging
head have appeared many years after local radiation of
the neck and thorax for Hodgkin disease as described by
Rowin and colleagues and with syringomyelia (Nalini and
Ravishankar).
There is, in addition, a poorly characterized local
myopathic process isolated to the cervical paraspinal mus-
cles, which has no distinguishing histopathologic or histo-
chemical features but has accounted for many of the cases
of neck extensor weakness that we have encountered. The
condition is observed in elderly persons, in some series
mainly men, but our experience has included as many
women. There is severe but relatively nonprogressive
weakness of the neck extensors and only mild weakness
of shoulder girdle and proximal arm muscles. Katz and
colleagues have suggested the designation “isolated neck
extensor myopathy” in preference to dropped head syn-
drome. What has been referred to as a bent spine syndrome
2/22/19 11:59 AM

(for which the term camptocormia is also used) is probably
the same entity and may follow after years of the condition
affecting the neck, or it may surface independently. These
conditions of cervical weakness are reviewed by Umapathi
and colleagues and by Azher and Jankovic. Several recent
series have suggested that mutations in RYR1 that encode
for ryanodine receptor may be a common cause of late
onset axial myopathy and neck extensor weakness-bent
spine syndrome (Løseth et al). Mutations in RYR1 are more
commonly associated with the central core congenital
myopathy or malignant hyperthermia as noted in a later
section, “Central Core Myopathy (RYR1 Mutation).”
The major types of progressive muscular dystrophies,
when advanced, usually affect the anterior neck muscles
severely. Syringomyelia, spinal accessory neuropathy,
some form of meningoradiculitis, and loss of anterior
horn cells in conjunction with systemic lymphoma or
carcinoma may differentially paralyze the various neck
muscles.
Weakness of respiratory and trunk Muscles Usually
the diaphragm, chest, and trunk muscles are affected in
association with shoulder and proximal limb muscles,
but occasionally, isolated weakness of the respiratory
muscles is the initial or the dominant manifestation of a
muscle disease. Dyspnea and diminished vital capacity
first bring the patient to the pulmonary clinic. The main
causes are motor neuron disease, myasthenia gravis and
less often because of their rarity, glycogen storage disease
(acid maltase deficiency—Pompe disease), mitochondrial
myopathies, and nemaline myopathy. Polymyositis may
cause respiratory weakness, but pulmonary difficulty is
more often the result of interstitial lung disease. Unilateral
paralysis of the diaphragm may result from compres-
sion of the phrenic nerve in the thorax by tumor or aortic
aneurysm; an idiopathic or postinfectious variety may be
related to brachial plexitis (see Chap. 43). The diaphragm
and accessory muscles may be severely affected in some
types of muscular dystrophies, but usually in association
with pelvocrural and shoulder muscle weakness. Noc-
turnal dyspnea, sleep apnea, and respiratory arrest may
occur, particularly in myasthenics and in patients with
glycogen storage myopathies, and respiratory failure may
threaten life in severe myasthenia gravis, Guillain-Barré
syndrome, and poliomyelitis.
As a general observation, in the acute neuromuscular
paralyses, the cervical and shoulder muscles and the dia-
phragm, all of which share a common innervation, show
a similar degree of weakness. Asking the patient to count
aloud on 1 maximal breath can help detect diaphragmatic
weakness (counting to 20 equates with a vital capacity of
approximately 2 L). Paradoxical inward movement of the
abdomen with inspiration is another sign of diaphragm
weakness. Disorders of breathing and ventilation are dis-
cussed in Chap. 25 that discusses respiratory control and
Chap. 43 in relation to its most dramatic presentation in
the Guillain-Barré syndrome.
Bibrachial palsy and the dangling-arm (flail-arm)
syndrome Weakness, atrophy, and fasciculations of the
hands, arms, and shoulders characterize the common
form of motor neuron disease, ALS. Primary diseases of
muscle hardly ever weaken these parts disproportionately.
Ropper_Ch45_p1405-p1468.indd 1413
Chapter 45 Diseases of Muscle 1413
A diffuse weakness of both arms and the shoulder muscles
may occur in the early stages of Guillain-Barré syndrome,
paraneoplastic neuropathy, and amyloid polyneuropathy,
in special forms of immunoglobulin (Ig) M-related parapro-
teinemic, or in inflammatory polyneuropathy (e.g., brachial
neuritis) and porphyric polyneuropathy. A lesion affecting
the central portion of the spinal cord in the cervical region
produces this same pattern, but in that case there is an
associated loss of pain and thermal sensation in the upper
limbs and shoulders, signs that exclude disease of muscle.
Proximal limb-girdle palsies presenting as inability
to raise the arms or to arise from a squatting, kneeling, or
sitting position This is the common pattern of a number
of myopathies. Polymyositis, IBM, dermatomyositis, and
the muscular dystrophies most often manifest themselves
in this fashion. The endocrine and the acquired metabolic
myopathies (e.g., Cushing disease, hyperthyroidism, and
steroid or statin administration) are other typical causes.
Proximal limb weakness is a feature of myasthenia but
almost always after the development of ocular or pha-
ryngeal involvement. The childhood Duchenne, Becker,
and limb-girdle types of dystrophies tend first to affect the
muscles of the pelvic girdle, gluteal region, and thighs,
resulting in a lumbar lordosis and protuberant abdomen,
a waddling gait, and difficulty in arising from the floor and
climbing stairs without the assistance of the arms. Climb-
ing up by placing the hands on the thighs (Gower sign) is
particularly characteristic of the dystrophies. Facioscapu-
lohumeral dystrophy affects the muscles of the face and
shoulder girdles foremost, and it is manifest by incomplete
eye closure, inability to whistle and to raise the arms above
the head, winging of the scapulae, and thinness of the
upper arms with preserved forearm bulk (“Popeye” effect).
Certain early or mild forms of dystrophy may selectively
involve only the peroneal and scapular muscles. In milder
forms of polymyositis, weakness may be limited to the
neck muscles or to the shoulder or pelvic girdles.
A number of other diseases of muscle may express
themselves by a disproportionate weakness of girdle and
proximal limb musculature. An intrinsic metabolic myop-
athy, such as the adult form of acid maltase deficiency and
the familial types of periodic paralysis, may affect only this
region. The congenital myopathies (central core, nemaline,
myotubular) cause a relatively nonprogressive weakness of
girdle muscles more than distal ones. Proximal muscles
are occasionally implicated in spinal muscular atrophy or
late onset type and in Kennedy bulbospinal atrophy.
Bicrural palsy presenting as lower leg weakness with
inability to walk on the heels and toes, or as paralysis of
all leg muscles With the exception of certain distinctive
distal types of muscular dystrophies, this pattern, usually
due to weakness of peroneal, anterior tibial, and thigh
muscles, is usually not a result of myopathy. Symmetrical
weakness of the lower legs is more often caused by poly-
neuropathy. In cases of total leg and thigh weakness, one
first considers a spinal cord disease. Motor neuron disease
may begin in the legs, asymmetrically and distally as a rule,
and affect them disproportionately to other parts of the
body. Thus the differential diagnosis of distal or general-
ized leg weakness involves more diseases than are involved
in the restricted paralyses of other parts of the body.
2/22/19 11:59 AM
 1414 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
Isolated quadriceps femoris weakness Isolated quad-
riceps femoris weakness may be the expression of several
diseases. In adults, the most common cause is IBM (where
it may be unilateral or asymmetrical) or, a restricted form
of Becker muscular dystrophy. In thyrotoxic and ste-
roid myopathies, the major effects are on the quadriceps
muscles. If unilateral or bilateral with loss of patellar reflex
and sensation over the inner leg, this condition is most
often the result of a femoral neuropathy, as occurs from
diabetes, or of an upper lumbosacral plexus lesion. Inju-
ries to the hip and knee cause rapid disuse atrophy of the
quadriceps muscles. A painful condition of infarction of
the muscle on 1 side is seen in diabetic patients.
Distal bilateral limb palsies presenting as foot-drop
with steppage gait (with or without pes cavus), weak-
ness of all lower leg muscles, and later wrist-drop and
weakness of hands The principal cause of this syndrome
is a familial polyneuropathy, mainly of the Charcot-Marie-
Tooth type (see Chap. 43); the course is over decades. Also
presenting in this way are paraproteinemic and inflamma-
tory polyneuropathies, with or without motor conduction
block and exceptionally, some forms of familial progressive
muscular atrophy and distal types of progressive muscular
dystrophy, and sarcoid myopathy. In myotonic dystrophy,
there may be weakness of the leg muscles as well as the
forearms, sternocleidomastoids, face, and eyes. With these
exceptions, the generalization that girdle weakness with-
out sensory changes is indicative of myopathy and that dis-
tal weakness is indicative of neuropathy is clinically useful.
Generalized or universal paralysis: Limb (but usu-
ally not cranial) muscles, involved either in attacks or as
a chronic persistent, progressive deterioration (see also
Chap. 46) When acute in onset and episodic, this syn-
drome is usually a manifestation of familial or acquired
hypokalemic or hyperkalemic periodic paralysis. One
variety of the hypokalemic type is associated with hyper-
thyroidism, another with hyperaldosteronism. Attacks of
porphyric neuropathy and of Refsum disease with general-
ized weakness have an episodic nature. Widespread pare-
sis (rather than paralysis) that has an acute onset and lasts
many weeks is at times a feature of a severe form of idio-
pathic or parasitic (trichinosis) polymyositis and, rarely, of
the toxic effects of certain pharmaceutical agents, particu-
larly those used to treat hypercholesterolemia. Idiopathic
polymyositis and, rarely, IBM may involve all limb and
trunk muscles, but usually spare the facial and ocular
muscles, whereas the weakness in trichinosis is mainly
in the ocular and lingual muscles. In infants and young
children, a chronic and persistent generalized weakness
of all muscles, except those of the eyes, always raises the
question of Werdnig-Hoffman spinal muscular atrophy or,
if milder in degree and relatively nonprogressive, of one of
the congenital myopathies or polyneuropathies. In these
diseases of infancy, paucity of movement, hypotonia, and
retardation of motor development may be more obvious
than weakness, and there is arthrogryposis at birth.
Paralysis of single muscles or a group of muscles This
is usually neuropathic, less often spinal or myopathic.
Muscle disease does not need to be considered except in
certain instances of pressure-ischemic necrosis of muscle
as a result of local pressure or infarction, as in monoplegic
Ropper_Ch45_p1405-p1468.indd 1414
alcoholic myopathy or in diabetic muscle infarction. The
weakness of IBM has a preference for certain sites, spe-
cifically parts of the quadriceps, or of the forearm muscles,
particularly the long finger flexors (flexor digitorum pro-
fundus), and also therefore enters into consideration.
From this exposition of the topographic aspects of
weakness, one can appreciate that each neuromuscular
disease exhibits a predilection for particular groups of mus-
cles. Apart from these patterns that suggest certain possi-
bilities of disease and exclude others, diagnosis depends on
the age of the patient at the time of onset and tempo of pro-
gression, the coexistence of medical disorders, certain labo-
ratory findings (serum concentrations of muscle enzymes,
EMG, and biopsy findings), and genetic determinants.
The symptoms and signs of muscle disease are con-
sidered in this chapter mainly in connection with the age
of the patient at the time of onset, their mode of evolu-
tion, and the presence or absence of familial occurrence.
Because many muscle diseases are hereditary, a careful
family history is important. The pattern of inheritance
has diagnostic significance and, if genetic counseling or
prenatal diagnosis is a consideration, a detailed genea-
logic tree becomes essential. When historical data are
insufficient, it is often necessary to examine siblings and
parents of the proband. The molecular genetics and other
genetic aspects of the heritable muscle diseases, subjects
of intense interest in recent years, are discussed at appro-
priate points in the chapter.
In summary, the clinical recognition of myopathic
diseases is facilitated by a prior knowledge of a few topo-
graphic syndromes, the age of the patient at the onset of
the illness, a familial occurrence of the same or similar
illnesses, and of the medical setting in which weakness
evolves. Diagnostic accuracy is aided by the intelligent use
of the laboratory examinations discussed in Chap. 2, par-
ticularly the muscle enzymes, EMG, and muscle biopsy.
THE INFECTIOUS MYOPATHIES
The discovery that striated skeletal muscle and that cardiac
muscle could be the sole targets of a number of infectious
agents came about during the era of the development of
microbiology and occupied the attention of many promi-
nent clinicians, including Osler. As these diseases were
being characterized, however, a number of other inflam-
matory states affecting muscle were found for which
there was no infectious cause. Later, an autoimmune
mechanism was postulated, but even today this is not
securely established. This group of idiopathic inflamma-
tory myopathies figures so prominently in clinical myology
that we devote a separate section to the subject. First, the
infections of muscle are described.
Parasitic Myositis
Included here are trichinosis, toxoplasmosis, parasitic and
fungal infections, and a number of viral infections. The related
but unclassifiable entity of sarcoid myopathy is addressed in
a latter section of this chapter under “Sarcoid Myopathy,
Granulomatous Myositis, and Localized Nodular Myositis.”
2/22/19 11:59 AM

Trichinosis
This parasitic disease is caused by the nematode
Trichinella spiralis. Its general features are discussed in
Chap. 31. Regarding the myopathic aspect of the illness, the
authors have been most impressed with the ocular muscle
weakness, which results in strabismus and diplopia; with
weakness of the tongue, resulting in dysarthria; and with
weakness of the masseter and pharyngeal muscles, which
interferes with chewing and swallowing. Any weakness of
limb muscles is usually mild and more severe proximally
than distally. However, the diaphragm may be involved, as
well as the myocardium. The affected muscles are slightly
swollen and tender in the acute stage of the disease. Often,
there is conjunctival, orbital, and facial edema, sometimes
accompanied by subconjunctival and subungual splinter
hemorrhages. As the trichinae become encysted over a
period of a few weeks, the symptoms subside and recov-
ery is complete. Many, perhaps the majority, of infected
patients are asymptomatic throughout the invasive period,
and as much as 1 to 3 percent of the population in certain
regions of the country will be found at autopsy to have
calcified trichinella cysts in their muscles with no history
of parasitic illness. Heavy infestations have been known
to end fatally, usually from cardiac and diaphragmatic
involvement. In these more massive infections, the brain
also may be involved, probably by emboli that arise in the
heart from an associated myocarditis.
Diagnosis Clinically, one should suspect the disease
in a patient who presents with a puffy face and tender
muscles. Eosinophilia is practically always present in the
peripheral blood (>700 cells/mm3), although the sedimen-
tation rate is often normal. The CK level is moderately ele-
vated. A skin test using Trichinella antigen is available, but
it is unreliable. The enzyme-linked immunosorbent assay
(ELISA) blood test is more accurate, but it becomes posi-
tive only after 1 or 2 weeks of illness. Biopsy of almost any
muscle (usually the deltoid or gastrocnemius), regardless
of whether it is painful or tender, is probably the most reli-
able confirmatory test. More than 500 mg of muscle may
be required to demonstrate larvae, but smaller specimens
will almost invariably show an inflammatory myopathy.
Muscle fibers undergo segmental necrosis, and the inter-
stitial inflammatory infiltrates contain a predominance
of eosinophils. This accounts for the edema, pain, and
tenderness of heavily infested muscles. The capsules of the
larvae gradually thicken in the first month of the infection
and then calcify. The EMG may exhibit profuse fibrilla-
tion potentials, a phenomenon attributed on theoretical
grounds to the disconnection of segments of muscle fibers
from their motor endplates (Gross and Ochoa).
Treatment No treatment is required in most cases.
In patients with severe weakness and pain, a combination
of thiabendazole, 25 to 50 mg/kg daily in divided doses
for 5 to 10 days, and prednisone, 40 to 60 mg/d, is rec-
ommended. Albendazole, in a single oral dose of 400 mg
daily, or mebendazole are equally effective but are quite
expensive in the United States. Recovery, as mentioned,
is complete as a rule, except in rare patients with cerebral
infarcts. Other aspects of this parasitic infestation are dis-
cussed in Chap. 31.
Ropper_Ch45_p1405-p1468.indd 1415
Chapter 45 Diseases of Muscle 1415
Toxoplasmosis
This is an acute or subacute systemic infection caused by the
encephalitozoon Toxoplasma gondii. Most Toxoplasma infec-
tions in immunocompetent patients, which occur in up to 10
to 30 percent of the population, are asymptomatic, but there
may be fever and varying degrees of involvement of the skin,
lymph nodes, retina, myocardium, liver, brain, and muscle. In
one such case studied by our colleagues, Toxoplasma organ-
isms and pseudocysts were detected in skeletal muscle (Kass
et al); wherever a parasitic pseudocyst had ruptured, there was
focal inflammation. Some muscle fibers had undergone seg-
mental necrosis, but this was not prominent (one contained
the organism), accounting for the relative paucity of muscle
symptoms. With the emergence of HIV, many more toxoplas-
mic infections of the brain, but also including those of skeletal
muscle, were seen (Gherardi et al). However, physicians who
see many cases of HIV have indicated to us that a primary HIV
myopathy and treatment-related muscle diseases are more
common (see later under “HIV and Human T-Lymphotropic
Virus Type I Myositis”). Again, in this population, brain infes-
tation with Toxoplasma is many times more common than
is myositis. The subject of HIV is discussed in Chap. 31 and
toxoplasmic infection is discussed in greater detail in Chap. 32.
The myopathy, which occurs with variable fever, lym-
phopenia, and failure of other organs, consists of weakness,
wasting, myalgia, and elevated CK levels. Presumably, the
immunocompromised patient is unable to respond to
protozoan infections, allowing latent infections to be reac-
tivated. Sulfadiazine in combination with pyrimethamine
or trisulfapyrimidine, which acts synergistically against the
toxoplasmic trophozoites, improves the muscle symptoms
and reduces serum CK. Folic acid is given in addition.
Other Parasitic and Fungal Infections of Muscle
Echinococcosis, cysticercosis, trypanosomiasis (Chagas
disease), sparganosis, toxocariasis, and actinomycosis
have all been known to affect skeletal muscle on occa-
sion, but the major symptoms relate more to involvement
of other organs. Only cysticercosis may first claim the
attention of the clinical myologist because of a dramatic
pseudohypertrophy of thigh and calf muscles. Hydatids
infest the paravertebral and lumbar girdle muscles in
5 percent of cases and may lead to their enlargement.
Coenurosis and sparganosis are causes of movable lumps
in the rectus abdominis, thigh, calf, and pectoralis mus-
cles. Protozoan infections of muscle—microsporidiosis,
African and American trypanosomiasis—which occurred
only rarely until a few decades ago, are now being observed
in immunodeficient (HIV-infected) individuals in endemic
areas. The reader who seeks more details may refer to the
chapter on parasitic myositis by Banker (2004).
Viral Infections of Muscle
HIV and Human T-Lymphotropic Virus Type I Myositis
HIV and human T-lymphotropic (or leukemia) virus type I
(HTLV-I) are increasingly common causes of viral myositis
(Engel and Emslie-Smith). Moreover, as discussed further
on, zidovudine (ZVD), a drug included in many regimens
2/22/19 11:59 AM
 1416 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
to treat HIV infections, may itself induce a myopathy with
myalgia and weakness that is, at times, indistinguishable
from HIV myopathy (Dalakas et al).
An inflammatory, and presumed infectious, myopa-
thy may develop early in the course of HIV infection but
is rarely the initial manifestation. The pattern is like that
of idiopathic polymyositis with painless weakness of the
girdle and proximal limb muscles. Reflexes are diminished
in most cases, but this is difficult to interpret in view of the
high incidence of concomitant polyneuropathy. Serum CK
is elevated, and the EMG shows an active myopathy with
fibrillations, brief polyphasic motor units, and complex
repetitive discharges.
The myopathologic changes in AIDS are also like
those of idiopathic polymyositis described further on.
Additionally, in some cases electron microscopy discloses
the presence of nemaline (rod) bodies within type 1 fibers,
similar to those observed in the congenital form of nema-
line myopathy discussed further on. As implied earlier,
the pathogenesis of the HIV myopathy has not been firmly
established as there is scant evidence of a direct viral
infection of the muscle fibers. An immune basis has been
suggested in view of a response to corticosteroids, plasma
exchange, and gamma globulin, comparable to the benefi-
cial effects in the idiopathic variety of polymyositis. Corti-
costeroids in doses similar to those used in the treatment
of idiopathic polymyositis are effective in ameliorating the
weakness, but they entail special risks in immunocompro-
mised patients.
The clinical features of putative ZVD-induced myopa-
thy are much the same as those of HIV myopathy except
that moderate pain is said to be characteristic of the drug-
induced variety. The myopathy has been attributed to the
mitochondrial toxicity of the drug, which may account for
the presence of “ragged red” fibers in biopsy specimens.
The onset of symptoms appears to be related to the sus-
tained administration of high doses of the drug (1,200 mg
daily for a year or longer). Cessation or reduction in dos-
age of the drug diminishes the muscular discomfort within
weeks, but strength recovers more slowly.
Distinguished from the HIV- and ZVD-related inflam-
matory myopathies is the severe generalized muscle wast-
ing that characterizes advanced, cachectic AIDS. Muscle
enzymes are normal and strength is affected little, espe-
cially considering the loss of muscle bulk. Histologically,
there is atrophy of type 2 fibers. The pathogenesis of this
cachectic syndrome is uncertain; it has been attributed
to a multiplicity of systemic factors, including circulating
catabolic cytokines, just as in other wasting syndromes
such as cancer.
A myopathy caused by HTLV-I infection also simulates
polymyositis in its clinical and histologic features. The ill-
ness occurs most often in endemic areas but is less com-
mon than the myelopathy that is associated with the virus.
Other Viral Myopathies
In most patients with pleurodynia (epidemic myalgia,
Bornholm disease), muscle biopsies disclose no abnor-
malities and there is no clear explanation of the pain.
However, group B Coxsackie virus has been isolated from
Ropper_Ch45_p1405-p1468.indd 1416
striated muscle of a few patients with this disorder. A
necrotizing myositis has been suspected in a number of
patients with influenza; under the electron microscope,
some muscle fibers contain structures with the features of
influenza virions. Malaise, myalgia, and slight weakness
and stiffness were the clinical manifestations. Because
of the myalgia, it is difficult to know how much of the
weakness is only apparent. Recovery has been complete
within a few weeks. In 1 patient with generalized myalgia
and myoglobinuria, the influenza virus was isolated from
muscle (Gamboa et al). These observations suggest that
the intense muscle pain in certain viral illnesses might be
the result of a direct viral infection of muscle. However,
there are many cases of influenzal myalgia, mainly of the
calves and thighs, such as those reported by Lundberg and
by Antony and coworkers, in which it was not possible to
establish that there was a muscular disorder at all. In the
condition described as epidemic neuromyasthenia (benign
myalgic encephalomyelitis, Icelandic disease), in which
influenza-like symptoms were combined with severe pain
and weakness of muscles, a viral cause was postulated,
but an organism was never isolated. The illness has been
absorbed into the large and indistinct category of chronic
fatigue syndrome (discussed in Chap. 23).
Despite these ambiguities, viral myositis is an estab-
lished entity in myopathology. Echo 9, adenovirus 21,
herpes simplex, Epstein-Barr virus, coxsackievirus, and
Mycoplasma pneumoniae have all been cited by Mastaglia
and Ojeda and by others as causes of sporadic myositis
with rhabdomyolysis. In these infections the nonmyo-
pathic aspects of the disease usually predominate; in
some of them, the evidence of invasion of muscle has not
been fully substantiated, as in many instances a nonspe-
cific (Zenker-type) degeneration could have explained the
muscle findings. The existence of a postinfectious type of
polymyositis is also unsettled.
IMMUNE-INFLAMMATORY MYOPATHIES
These are common diseases that affect primarily the stri-
ated muscle and skin and sometimes connective tissues.
The term used to describe the disease reflects the tis-
sues involved. If the inflammatory changes are restricted
clinically to the striated muscles, the disease is called
polymyositis (PM); if, in addition, the skin is involved, it is
called dermatomyositis (DM), although the two diseases
are now understood to be immunopathologically distinct
and some authorities question the existence, or at least
the frequency, of an independent idiopathic polymyositis.
Either may be associated with a rheumatologic disorder, in
which case the designation is PM or DM with rheumatoid
arthritis, rheumatic fever, lupus erythematosus, sclero-
derma, Sjögren syndrome, or mixed connective tissue
disease, as the case may be. There is also an important but
inconsistent relationship of these myositides and systemic
carcinoma, as discussed further on. Dalakas (2015) has
provided a comprehensive review of the subject.
Both diseases have been known since the nineteenth
century. Polymyositis was first described by Wagner in
2/22/19 11:59 AM

1863 and 1887, and DM was established as an entity by
Unverricht in a series of articles written from 1887 to 1891.
A modern classification introduced in the monograph of
Walton and Adams included categories associated with
neoplasia and with connective tissue diseases. References
to the original articles and a survey of the literature since
that time can be found in the monograph of Kakulas and
Adams and in the chapters on the PM and DM syndromes
by Engel and colleagues.
It is mentioned above and emphasized further on that
there is disagreement regarding the frequency of PM as an
independent entity. Amato and Griggs have expressed the
opinion that many cases so classified are a result of DM, an
immune necrotizing myopathy commented on below, or
IBM, or are related to an underlying connective tissue dis-
ease. Even other cases are examples of muscular dystrophy
with secondary inflammatory changes. The main point of
controversy has been the proposal they favor, that isolated
PM is rare and overdiagnosed (see van der Muelen et al).
Inflammatory myopathy coexists with numerous sys-
temic diseases as discussed, and some authors consider
it to be a syndrome rather than a disease. The current
authors continue to see a few well-studied and convinc-
ingly documented cases of “classic” PM that are unassoci-
ated with other disease.
Recently added to the traditional group of inflamma-
tory myopathies is an increasingly recognized immune-
mediated necrotizing myopathy (IMNM); these are
instances of myopathy that were previously classified as
either dermato- or polymyositis but are now recognized
as being the result of antibodies to anti-signal recognition
particle (SRP), and some cases of necrotizing myopathy
that are due to statins are similarly caused by antibodies
directed at HMGCoA reductase, and not a direct toxic
effect of the medication. This emphasizes that clinicians
should conduct a careful evaluation before concluding
that a patient has idiopathic polymyositis.
Dermatomyositis
This is the representative example of inflammatopry
myopathy. The onset is usually insidious and the course
progressive over a period of several weeks or months. It
may develop at almost any age and in either sex; however,
the majority of patients are 30 to 60 years of age, and a
smaller group shows a peak incidence at 15 years of age;
women predominate in all age groups. A febrile illness or
benign infection may precede the weakness, but in most
patients the first symptoms develop in the absence of these
or other apparent initiating events.
The usual mode of onset is with mainly painless weak-
ness of the proximal limb muscles, especially of the hips
and thighs and to a lesser extent the shoulder girdle and
neck muscles. Often, the patient cannot easily determine
the time of onset of weakness. Certain actions—such as
arising from a deep or low chair or from a squatting or
kneeling position, climbing or descending stairs, walking,
putting an object on a high shelf, or combing the hair—
become increasingly difficult. Pain of an aching variety
in the buttocks, calves, or shoulders is experienced by
approximately 15 percent of patients, and it may indicate a
Ropper_Ch45_p1405-p1468.indd 1417
Chapter 45 Diseases of Muscle 1417
combination of myositis and rheumatoid arthritis, tendon-
itis, or other rhuematologic disorder.
When the patient is first seen, many of the muscles of
the trunk, shoulders, hips, upper arms, and thighs are usu-
ally involved. The posterior and anterior neck muscles (the
head may loll) and the pharyngeal, striated esophageal,
and laryngeal muscles (dysphagia and dysphonia) may be
involved as well. In restricted forms of the disease, only the
neck or paraspinal muscles (camptocormia) may be impli-
cated. Ocular muscles are not affected but there are rare
instances of combined myositis and myasthenia gravis.
The facial, tongue, and jaw muscles are only occasionally
affected, and the distal muscles, namely the forearm, hand,
leg, and foot are spared in 75 percent of cases. The respira-
tory muscles are weakened to a minor degree and in only
an exceptional case is there dyspnea, the cause of which is
revealed only by an intercostal muscle biopsy (Thomas and
Lancaster). Occasionally, the early symptoms predominate
in one proximal limb before becoming generalized. As
emphasized further on, onset after age 50 years, normal
CK, or aberrant patterns of weakness, such as early wrist or
finger flexor, quadriceps, or ankle dorsiflexor involvement,
are indicative of IBM (see further on).
The muscles are usually not tender, and atrophy and
reduction in tendon reflexes, although sometimes pres-
ent, are far less pronounced than they are in patients
with chronic denervation atrophy, IBM, or Lambert-Eaton
myasthenic syndrome (the last of these is discussed in
Chap. 46). As the weeks and months pass, the weakness
and muscle atrophy progress unless treatment is initiated.
Without physical therapy, fibrous contracture of muscles
eventually develops. Some elderly individuals with a par-
ticularly chronic form of the disease may present with
severe atrophy and fibrosis of muscles; the response to
treatment in such cases is poor.
The presentation of muscle weakness is similar to
that of polymyositis, but the denominative feature is the
skin changes. Most often, the skin changes precede the
muscle syndrome and take the form of a localized or diffuse
erythema, maculopapular eruption, scaling eczematoid
dermatitis, or exfoliative dermatitis. Sometimes, skin and
muscle changes evolve together over a period of 3 weeks
or less. A characteristic form of the skin lesions are patches
of a scaly roughness over the extensor surfaces of joints
(elbows, knuckles, and knees) with varying degrees of pink-
purple coloration. Red, raised papules may be present over
exposed surfaces such as the elbows, knuckles, and distal
and proximal interphalangeal joints (Gottron papules—
applied in some writings to all the skin changes over the
knuckles and extensor prominences); these are particularly
prominent in DM of childhood. Also typical is a lilac-
colored (heliotrope) change in the skin over the eyelids, on
the bridge of the nose, on the cheeks, and over the forehead;
it may have a scaly component. Itching may be a trouble-
some symptom in regions of the other skin eruptions. A
predominance of rash over the neck and upper shoulders
has been termed the V sign, while rash over the shoulders
and upper arms, the shawl sign. This distribution suggests
that the skin changes reflect heightened photosensitivity
(a feature shared with pellagra). Periorbital and perioral
edema are additional findings but mainly in fulminant
2/22/19 11:59 AM
 1418 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
cases. Skin changes may be transient and in some instances
are restricted to 1 or more patches of dermatitis; they are
difficult to appreciate in dark-skinned individuals. Eva-
nescent and restricted skin manifestations are emphasized
because they are frequently overlooked and provide clues to
diagnosis. In the healing stage, the skin lesions leave whit-
ened atrophic scars with a flat, scaly base. Dilated capillary
loops at the cuticular nail beds may be seen but are more
characteristic of the childhood type discussed further on.
In contrast to PM, DM affects children and adults
about equally. Among adults, DM is more frequent in
women, whereas in childhood males and females are
affected equally.
Other physical signs include periarticular and sub-
cutaneous calcifications that are common in the child-
hood form. Signs of associated connective tissue disease
are more frequent than in pure PM (see further on). The
Raynaud phenomenon has been reported in nearly one-
third of the patients and a similar number have dilated or
thrombosed nail fold capillaries. Whether this signifies the
presence of a systemic autoimmune tissue disease has not
been clarified. Others subsequently develop a mild form
of scleroderma, and an associated esophageal weakness
is demonstrated by fluoroscopy in up to 30 percent of all
patients. The superior constrictors of the pharynx may be
involved, but cinefluoroscopy may be necessary to demon-
strate the abnormality.
Polymyositis
In the strictest sense, this is an idiopathic subacute or
chronic and symmetrical weakness of proximal limb and
trunk muscles without dermatitis. The pattern of weak-
ness is similar and most comments pertaining to DM given
above also apply to PM. The difference is the rash and
associated skin changes, which by definition are absent in
this disorder. In question is the frequency of this disorder
as an independent entity, with some authorities question-
ing its existence.
In both PM and DM, there may be involvement of
organs other than muscle. In a surprising number of our
cases of PM (and DM), cardiac abnormalities have been
observed and in a small proportion of these, sudden
death has occurred. The cardiac manifestations have taken
the form of relatively minor electrocardiographic (ECG)
changes, but several patients have had arrhythmias with
clinical consequences. Among the fatal cases, about half
have shown necrosis of myocardial fibers at autopsy, usu-
ally with only modest inflammatory changes. Interstitial
lung disease is another known association in a few cases;
its frequency ranges from 10 to 47 percent in different
series and up to 70 percent in one subtype with anti-Jo
antibodies (see further on under “Laboratory Diagnosis
of PM and DM”), but the lower figure is probably correct.
Exceptionally, there is a low-grade fever, especially if joint
pain coexists.
Carcinoma with adult polymyositis or dermatomyositis
At one time this was a controversial subject and in some
respects it remains so because of widely varying incidences
of concurrence between systemic malignancy with PM and
Ropper_Ch45_p1405-p1468.indd 1418
DM (see Engel et al and Buchbinder and Hill). In the large
series reported by Sigurgeirsson and colleagues, 9 percent
of 396 patients with PM were found to have carcinoma,
either at the time of diagnosis of the muscle disease or
within 5 years. DeVere and Bradley reported that 29 percent
of their overall group of DM patients had an associated
carcinoma; this figure rose to 40 percent if the patient
was older than 40 years, and to 66 percent if the patient
was both male and older than 40 years. This, however, is
higher than reported in most other series. The relation-
ship between myositis and malignancy is not understood;
nonetheless, the connection appears valid, even if of
uncertain frequency.
The neoplastic processes linked most often with myosi-
tis are lung and colon cancer in men and breast and ovarian
cancer in women; however, tumors have been reported in
nearly every organ of the body. In about half the cases, myo-
sitis antedates the clinical manifestations of the malignancy,
sometimes by 1 to 2 years, an interval that has brought the
association into question by several authors. The morbidity
and mortality of patients with this combination is usually
determined by the nature of the underlying tumor and its
response to therapy. Occasionally, excision of the tumor is
attended by remission of the myositis, but information on
this point comes mostly from sporadic reports.
Dermatomyositis of Childhood
Idiopathic myositis occurs in children, but less frequently
than in adults. Some cases tend to be relatively benign
but otherwise do not differ from the syndrome in adults.
More frequently, there is a distinctive illness, described
by Banker and Victor, which differs in some respects from
the usual adult form of the disease. In these children and
adolescents, there is greater involvement of blood vessels
in the connective tissue of multiple organs, as well as in
skin and muscle. This childhood form of DM begins, as a
rule, with typical skin changes accompanied by anorexia
and fatigue. Erythematous discoloration of the upper
eyelids (the previously noted heliotrope rash), frequently
with facial edema, is another characteristic early sign. The
erythema spreads to involve the periorbital regions, nose,
malar areas, and upper lip as well as the skin over the
knuckles, elbows, and knees. Cuticular overgrowth, sub-
ungual telangiectasia, and ulceration of the fingertips may
be found. Capillary prominence in the nail beds and avas-
cular regions in the cuticle are said to be characteristic but
need to be sought with a magnifying lens or ophthalmo-
scope (these signs are also seen in the “CREST” [calcinosis
cutis, Raynaud phenomenon, esophageal motility disor-
der, sclerodactyly, telangiectasia] form of scleroderma).
Symptoms of weakness, stiffness, and pain in the
muscles usually follow but may precede the skin mani-
festations. The weakness is generalized but always more
severe in the muscles of the shoulders and hips and
proximal portions of the limbs. A tiptoe gait, the result of
fibrous contractures of flexors of the ankles, is a common
late abnormality. Tendon reflexes are depressed or abol-
ished, but only commensurate with the degree of muscle
weakness. Intermittent low-grade fever, substernal and
2/22/19 11:59 AM

abdominal pain (like that of peptic ulcer), melena, and
hematemesis from bowel infarction may occur, the result
of an accompanying systemic vasculitis.
The mode of progression of DM of childhood, like that
of the adult form, is variable. In fulminant cases, the weak-
ness appears rapidly, involving all the muscles including
those of chewing, swallowing, talking, and breathing and
leading to total incapacitation. Perforation of the gastroin-
testinal tract from bowel infarction may be the immediate
cause of death, as it has been in two of our patients. In oth-
ers, there is slow progression or arrest of the disease and,
in a small number, there is a remission of weakness. Flex-
ion contractures at the elbows, hips, knees, and ankles and
subcutaneous calcification and ulceration of the overlying
skin, with extrusion of calcific debris are manifestations in
the late, untreated stages of the disease.
Systemic Autoimmune (Rheumatologic) Diseases
With Polymyositis and Dermatomyositis
In both PM and DM, the inflammatory changes are often
not confined to muscle but are associated with systemic
autoimmune diseases such as rheumatoid arthritis, sclero-
derma, lupus erythematosus, or combinations thereof
(mixed connective tissue disease); the same muscle changes
are associated less often with the Sjögren syndrome. Con-
versely, in the aforementioned immune diseases, inflam-
matory muscle changes are frequently found but in only
a limited number of muscles and often asymptomatically.
The incidence of these “crossover” or overlap cases cannot
be stated with certainty. A true necrotizing–inflammatory
myopathy has been reported in up to 8 percent of cases of
lupus erythematosus (far higher than in our experience),
and an even smaller proportion of cases of systemic scle-
rosis, rheumatoid arthritis, and Sjögren syndrome. The
treatment of rheumatoid arthritis with D-penicillamine
increases the incidence of, or perhaps independently pre-
cipitates, a myositis.
Also notable is the sporadic concurrence of myositis
with other autoimmune diseases such as myasthenia gra-
vis and Hashimoto thyroiditis and less often, with a mono-
clonal paraprotein in the blood; it is not clear whether
these are coincidental, but it is likely that they reflect an
underlying genetic propensity to autoimmune disease.
In the overlap syndromes that incorporate autoim-
mune disease and myositis, there is usually greater mus-
cular weakness and atrophy than can be accounted for
by the muscle changes alone. Inasmuch as arthritis or
periarticular inflammation may limit motion because of
pain, result in disuse atrophy, and also at times cause a
vasculitic polyneuropathy, the interpretation of dimin-
ished strength in these autoimmune diseases is not simple.
Malaise, aches, and pains are common and attributable
mostly to the systemic disease. Sometimes the diagnosis
of myositis must depend on muscle biopsy, EMG findings,
and measurements of muscle enzymes in the serum. In
these complicated cases, myositis may accompany the
connective tissue disease or occur many years later.
It is worth noting that PM may occur during preg-
nancy and that rarely the fetus is affected (most often the
Ropper_Ch45_p1405-p1468.indd 1419
Chapter 45 Diseases of Muscle 1419
fetus and neonate are normal) with elevated CK levels for
months postpartum (Messina et al).
Laboratory Diagnosis of PM and DM
In the majority of patients, serum levels of CK and other
muscle enzymes, such as aldolase, are elevated. Serum
CK levels tend to be higher in PM than in DM because
of the widespread single-fiber necrosis in the former (as
described in the following section on pathologic changes).
However, in DM, if there are infarcts in muscle, CK levels
will be moderately elevated as well. The sedimentation
rate is normal or mildly elevated in both diseases.
It has been appreciated that some cases of PM and
DM are associated with autoantibodies in the blood. Some
of these are undoubtedly nonspecific markers of an auto-
immune or inflammatory state (see Brouwer et al), but
others may be of pathogenetic significance or are mark-
ers for syndromes with multiorgan damage that extends
beyond muscle. Tests for circulating rheumatoid factor or
antinuclear antibody (ANA) are positive in fewer than half
of cases. A high titer of ANA, in conjunction with elevated
antiribonuclear antibodies, suggests the coexistence of
systemic lupus or mixed connective tissue disease. It must
be emphasized, however, that absent or low-titer ANA and
a normal sedimentation rate do not exclude the diagnosis
of PM, a fact that limits their diagnostic usefulness. Other
antibodies can be found on occasion that are directed
against constituents of a nucleolar protein complex (PM-
Scl) and ribonucleoproteins (Ro/SS-A and La/SS-B).
Of greater interest are the findings that 20 to 30 per-
cent of patients with DM have antibodies against various
cellular components of muscle, in particular, antibodies
directed against cytoplasmic transfer ribonucleic acid
(tRNA) synthetases (anti-Jo1), or against the tRNA itself.
These are found when the myositis is coupled with an
expanded illness that involves other tissues. The clinical
disorders associated with these antibodies usually com-
bine myositis with (1) interstitial lung disease but also (2)
arthritis, (3) Raynaud syndrome, and (4) thickening of the
skin of the hands (“mechanic’s hands”). Following from
the designation of the main type of antibody, these have
been termed synthetase syndromes.
A proportion of cases of severe, necrotizing inflam-
matory myositis show specific antibodies that are directed
against a cytoplasmic ribonucleoprotein complex (SRP), or
against a protein complex that is a nuclear helicase (Mi-2).
These are now classified as separate entities from DM and
in some series have carried a heightened risk of cardiac
muscle inflammatory involvement. Similarly, in the cat-
egory of necrotizing inflammatory myositis, a proportion
of patients display antibodies to HMGCR, the target of
statin drugs, but may also be present without exposure to
these drugs. Although these various autoantibodies, with
the possible exception of anti-Jo1, have not been especially
useful as primary diagnostic tools, they do have a role in
refining diagnosis. For example, a positive Jo1 antibody,
although too uncommon to use as a screening test, argues
against the diagnosis of inclusion body myopathy (which
has been associated with a different set of autoantibodies
as discussed further on) and its presence raises concern
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 1420 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
about the later development of interstitial lung disease.
The presence of these antibodies also underscores the role
for the humoral immune system in the pathogenesis of
inflammatory myositis and raises opportunities for inves-
tigation discussed as follows.
Myoglobinuria can be detected in the majority of
patients with most forms of myositis, particularly a necro-
tizing form, provided that a sensitive immunoassay proce-
dure is used, but this test is not routinely performed.
The EMG is quite helpful in diagnosis but has been
normal in a small proportion of our patients, even
when many muscles are sampled. A typical “myopathic
pattern” is disclosed, that is, many abnormally brief action
potentials of low voltage in addition to numerous fibrilla-
tion potentials, trains of positive sharp waves, occasional
polyphasic units, and myotonic activity—all but the brief
potentials possibly reflecting irritability of the muscle
membranes (see Chap. 46). These findings are most appar-
ent in weak muscles and are almost always seen when
proximal weakness is well developed but they also may
be observed in clinically unaffected areas. Indolent and
chronic cases in which fibrosis of muscle and wasting
have supervened may show polyphasic units that simulate
denervation–reinnervation changes, juxtaposed with myo-
pathic motor units. The EMG is also helpful in choosing a
muscle for biopsy sampling but care must be taken not to
obtain tissue from precisely the same site as a recent EMG
needle insertion as a spurious histopathologic appear-
ance of muscle damage may be obtained in this region
(see the following text). Our approach has been to perform
the needle EMG examination on one side of the body and
biopsies on the other side.
As stated earlier, the ECG is abnormal in some cases
and this finding may suggest the need for vigilance regard-
ing cardiac symptoms and arrhythmias.
The results of magnetic resonance imaging (MRI) of
muscle have been interesting and may aid the clinician
in that abnormalities in T1, T2, and STIR signal intensity
define regions of increased water content and inflam-
mation and spectroscopic studies demonstrate regional
deficits in energy production. Although MRI cannot at this
time replace a biopsy for diagnosis, it can refine the distri-
bution of lesions and aid in targeting the muscle biopsy,
as well as provide a useful index of the efficacy of drug
therapy. In some cases, MRI can distinguish IBM from
either PM or metabolic muscle disease (see Lodi et al and
also Dion et al).
Pathologic Changes in PM and DM
Because of the scattered distribution of inflammatory
lesions and destructive changes, only part (or none) of the
complex of pathologic changes may be divulged in any
single biopsy specimen. Because of this limitation, more
than one site of biopsy or multiple samples through one
incision is advisable.
In DM, there are several distinctive histopathologic
changes. In contrast to the evident necrosis of single fibers
of PM, DM is characterized by perifascicular muscle fiber
atrophy (referring to changes at the periphery of a fascicle,
for reasons noted below). Moreover, the inflammatory
Ropper_Ch45_p1405-p1468.indd 1420
infiltrates in DM predominate in the perimysial connective
tissue, whereas in PM they are scattered throughout the
muscle and are most prominent in relation to the muscle
fiber membrane and the endomysium. The muscle lesions
in dermatomyositis of childhood are similar to those of the
adult form, only greatly accentuated. In a biopsy sample,
the diagnosis can be inferred from the perifascicular pat-
tern of degeneration and atrophy of muscle fibers.
The principal changes in idiopathic PM consist of
widespread destruction of segments of muscle fibers with
an inflammatory reaction, that is, phagocytosis of muscle
fibers by mononuclear cells and infiltration with a vary-
ing number of lymphocytes and lesser numbers of other
mononuclear and plasma cells. Evidence of regenerative
activity of muscle, mainly in the form of proliferating sar-
colemmal nuclei, basophilic (RNA-rich) sarcoplasm, and
new myofibrils, is evident in damaged regions. Many of the
residual muscle fibers are small, with increased numbers
of sarcolemmal nuclei. Some of the small fibers are found
in clusters, the result of splitting of regenerating fibers.
Either the degeneration of muscle fibers or an infiltra-
tion of inflammatory cells may predominate in any given
biopsy specimen, although both types of changes are in
evidence at autopsy.
In a single section from a biopsy sample, there may be
only necrosis and phagocytosis of individual muscle fibers
without infiltrates of inflammatory cells, or the reverse
may be observed. However, in serial sections, muscle
necrosis is shown to be adjacent to inflammatory infil-
trates. Repeated attacks of a necrotizing myositis exhaust
the regenerative potential of the muscles so that fiber loss,
fibrosis, and residual thin and large fibers in haphazard
arrangement may eventually impart a dystrophic appear-
ance. For all these reasons, the pathologic picture can be
correctly interpreted only in relation to clinical and other
laboratory data. Guidelines for the interpretation of the
muscle biopsy reflecting these comments, a critical step
in correct diagnosis of the inflammatory myopathies, are
given in the review by Dalakas and Hohlfeld.
Even more distinctive of DM are microvascular
changes in muscle. Endothelial alterations (tubular aggre-
gates in the endothelial cytoplasm) and occlusion of ves-
sels by fibrin thrombi may be appreciated, with associated
zones of infarction. The same vascular changes underlie
the lesions in the connective tissue of skin, subcutaneous
tissue, and gastrointestinal tract when they are present.
The perifascicular muscle fiber atrophy had in the past
been attributed to an ischemic process set up by capillary
occlusion, but recent evidence suggests otherwise (see
Greenberg and Amato).
Etiology and Pathogenesis
All attempts to isolate an infective agent in the inflamma-
tory myopathies have been unsuccessful. Several elec-
tron microscopists observed virus-like particles in muscle
fibers, but a causative role has not been proved. A poly-
myositic illness has not been induced in animals by
injections of affected muscle as it has in models of several
other inflammatory neurologic conditions. Nevertheless,
the notion that an autoimmune mechanism is operative
2/22/19 11:59 AM

in PM and DM is supported by the association of these
disorders with a number of the more clearly established
autoimmune diseases enumerated earlier in this chapter.
Further evidence of an autoimmune nature is given by the
presence of specific autoantibodies in nearly half of cases,
as also described earlier.
Immunopathologic studies have substantiated an
autoimmune mechanism and suggested that PM, DM,
and necritizing myositis can be distinguished from one
another on the basis of their immunopathologic character-
istics. In DM, immune complexes, IgG, IgM, complement
(C3), and membrane-attack complexes are deposited in
the walls of venules and arterioles, indicating that the
immune response is directed primarily against intramus-
cular blood vessels (Whitaker and Engel; Kissel et al). Such
a response is lacking in PM (and in IBM, discussed further
on). Engel and Arahata have demonstrated a difference
between the two disorders on the basis of the subsets and
locations of lymphocytes that make up the intramuscu-
lar inflammatory aggregates. However, the deposition of
these complexes may be a secondary event as our col-
leagues Greenberg and Amato propose. In PM, there are a
large number of activated T cells, mainly of the CD8 class,
whereas B cells are sparse. Moreover, T cells, accompanied
by macrophages, enclose and invade nonnecrotic muscle
fibers. In DM, very few fibers are affected in this manner,
and the percentage of B cells at all sites is significantly
higher than it is in PM. Engel and Arahata interpreted these
differences as indicating that the effector response in DM
is predominantly humoral, whereas in PM the response is
composed of cytotoxic T cells, clones of which have been
sensitized to a yet undefined antigen on the muscle fiber.
The current understanding of immunopathogenesis is
summarized in the review by Dalakas (2015).
Treatment
Most clinicians agree that glucocorticoids (e.g., predni-
sone, 1 mg/kg, as a single daily dose orally, or intrave-
nously) are a reasonable first therapy for both PM and
DM. The response to treatment is monitored by testing
of strength and measurement of CK (not by following
the erythrocyte sedimentation rate [ESR]). In patients
who respond clinically, the serum CK decreases before
the weakness subsides; with relapse, the serum CK rises
before weakness returns. Once the CK level normalizes
and strength improves, typically several weeks or longer,
one approach is to reduce the dosage gradually—by no
more than 5 mg every 2 weeks—toward 20 mg daily. It is
then appropriate to attempt to control the disease with
an alternate-day schedule with double this amount (i.e.,
prednisone, 40 mg every other day) so as to reduce the side
effects of the drug. After cautious reduction of prednisone
over a period of 6 months to 1 year or longer, the patient
can usually be maintained on doses of 7.5 to 20 mg daily,
with the aim of eventual discontinuation of the drug. Cor-
ticosteroids should not be discontinued prematurely, for
the relapse that may follow is often more difficult to treat
than the original illness. Some clinicians prefer to add an
immunosuppressive agent at this time rather than wait for
Ropper_Ch45_p1405-p1468.indd 1421
Chapter 45 Diseases of Muscle 1421
failure of glucocorticoids or as a means of reducing steroid
dependence, as discussed below.
In acute and particularly severe cases, treatment may
be facilitated by the use initially of high-dose meth-
ylprednisolone (1 g intravenously each day for 3 to
5 days). This form of treatment should be regarded as a
temporary measure until oral prednisone or a more fast-
acting treatment becomes effective.
Alternatively, or sometimes in tandem with this
approach in severe cases, intravenous immunoglobulin
(IVIg) or plasma exchanges may be instituted. In patients
with DM who respond poorly to corticosteroids and other
immunosuppressants or are severely affected early on, the
addition of IVIg infusions often proves helpful, although
several courses of treatment at monthly intervals may be
required to achieve sustained improvement. In several
controlled studies of small numbers of patients with DM,
practically all showed improvement in muscle strength
and in skin changes, and a reduction in CK concentra-
tion (see Dalakas 1997; Mastaglia et al). PM has also been
reported to respond favorably to treatment with IVIg, but
the evidence is less certain. Further controlled studies are
required to corroborate these reports and to establish, in
both PM and DM, the optimal doses and modes of admin-
istration. It is noteworthy from our experience that IVIg has
seldom been effective in PM or DM when used alone or as
initial therapy. These options are discussed in the review
by Dalakas (2015). The proper use of these treatments in
crossover cases with connective tissue disease has not
been established.
Some patients who cannot tolerate, or are refractory to,
prednisone may respond favorably to oral azathioprine with
care being taken to avoid severe leukopenia. Methotrexate
is currently favored by many groups over azathioprine
as an adjunct to steroids (5 to 10 mg/week in 3 divided
oral doses, increased by 2.5 mg/week, to a total dose of
20 mg weekly). Methotrexate or azathioprine should gen-
erally be given along with the lowest effective doses (15 to
25 mg) of prednisone. Although one study failed to show
efficacy (Oddis et al), in cases that have been refractory to
corticosteroids and methotrexate, we and our colleagues
have had success with rituximab intravenously, 750 mg/m2,
repeated in 2 weeks and sometimes required every 6 to
18 months. Some clinicians favor, from the beginning, a
combination of prednisone in low dosage and one of these
immunosuppressant drugs, and this approach is generally
necessary when myocarditis or interstitial pneumonitis
is coupled with DM. It has been suspected that patients
with anti-Jo or other antibodies may respond more favor-
ably. Mycophenolate mofetil has also been introduced
and has allowed a reduction in steroid dose within several
months in both PM and DM, according to a number of
anecdotal reports, but has not proven clearly effective in
a randomized trial; the reasons for this failure are being
actively discussed and we have not abandoned its use.
Cyclosporine has also been used in recalcitrant cases; it has
few advantages over other immunosuppressant drugs and
has a number of potentially serious side effects, including
nephrotoxicity. Cyclophosphamide, which is a useful drug
in the treatment of Wegener granulomatosis, polyarteritis,
2/22/19 11:59 AM
 1422 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
and other vasculitides, is said to be of lesser value in PM,
but it may be useful in refractory cases and has perhaps the
highest toxicity of the immunosuppressive medications
that are used for inflammatory myopathies; we no longer
use it with any regularity.
Prognosis
Except for patients with malignancy, the prognosis in adult
PM and DM is generally favorable. Only a small propor-
tion of patients with PM succumb to the disease and then
usually from a secondary pulmonary complication or from
myocarditis as already mentioned. Several of our patients
have had severe aspiration pneumonias as a result of their
dysphagia. The period of activity of disease varies con-
siderably but is typically 2 to 3 years in both the child and
adult. As indicated earlier, the majority improves with cor-
ticosteroid therapy, but many are left with varying degrees
of weakness of the shoulders and hips. Approximately
20 percent of our patients have recovered completely
after steroid therapy and long-term remissions have been
achieved after withdrawal of medication in about an equal
number. The extent of recovery is roughly proportional to
the acuteness and severity of the disease and the duration
of symptoms prior to institution of therapy. Patients with
acute or subacute PM in whom treatment is begun soon
after the onset of symptoms have the best prognosis. In the
series collected by DeVere and Bradley, in which patients
were treated early, there was remission in more than
50 percent of cases, whereas Riddoch and Morgan-Hughes
reported a far lower rate in patients who were treated more
than 2 years after onset of the disease. Those patients who
have come to our attention after a long period of proxi-
mal weakness and with substantial muscle atrophy have
not recovered completely, although some improvement
occurred over years.
Even in patients who have a coexistent malignancy,
muscle weakness may lessen and serum enzyme levels
decline in response to corticosteroid therapy, but weak-
ness returns after a few months and may then be resistant
to further treatment. As already stated, if the tumor is suc-
cessfully removed, muscle symptoms may remit, but this
experience has not been uniform.
The overall mortality after several years of illness
had in the past approximated 15 percent, being higher in
childhood DM, in PM with rheumatologic diseases, and,
of course, when a malignancy is found. Recent figures give
more optimistic results.
Inclusion Body Myositis (IBM)
Inclusion body myositis (IBM) is the third major form of
idiopathic myopathy and, depending on the care taken
with histologic diagnosis, is the most common one in
patients older than 50 years. It is often identifiable by cer-
tain topographic features of the weakness described below.
There is consensus that the disease is immune mediated,
even when the inflammatory component is not promi-
nent in biopsy material. A source of confusion has been
the separate entity of inclusion body myopathy, a largely
hereditary, pauci-inflammatory process, which displays
Ropper_Ch45_p1405-p1468.indd 1422
a different pattern of weakness from IBM. Its defining
pathologic features, intracytoplasmic and intranuclear
inclusions, were first described in 1965 by R.D. Adams and
colleagues, who also drew attention to a number of clinical
attributes now considered characteristic. By 1994, only 240
sporadic cases had been recorded in the medical literature
(Mikol and Engel), but the diagnosis is now made so fre-
quently that this low number almost certainly reflects the
misidentification of IBM as PM in the past. Garlepp and
Mastaglia concluded that more than one-third of cases
of inflammatory myopathy, especially in men, are IBM.
Moreover, as alluded to, the majority of myopathies in
patients over 50 years, not attributable to medication toxic-
ity, are probably due to IBM. A set of clinical and pathologic
diagnostic criteria for the disease have been proposed by
Griggs and coworkers and are useful for research purposes.
The myositis, as alluded to, predominates in men (in
a ratio of 3:1) and has its onset in middle or late adult life.
Diabetes, any one of a variety of autoimmune diseases,
and a relatively mild polyneuropathy are associated in
approximately 20 percent of sporadic cases of IBM, but
associations with malignancy or systemic autoimmune
disease have not been established.
Clinical Manifestations
The illness is more variable but generally more focal in
presentation than is PM and DM. It is characterized by a
steadily progressive, painless muscular weakness and mod-
est atrophy, which is usually distal in the arms and both
proximal and distal in the legs. In approximately 20 percent
of cases, the disease begins with focal weakness of the
quadriceps, finger or wrist flexors, or lower leg muscles on
one or both sides, and gradually spreads to other muscle
groups after many months or years. Selective weakness
of the flexor pollicis longus is a particularly characteristic
pattern of involvement, and isolated quadriceps weakness
or neck extensor weakness should also bring the diagnosis
to mind, although IBM is not the exclusive cause of these
patterns. In most patients, the deltoids are spared and the
thumb flexors are weak, the opposite pattern to PM and
DM. The tendon reflexes are normal initially but dimin-
ish in about half the patients, especially the knee jerks, as
the disease progresses. Interestingly, the knee jerks may
be depressed or lost even without much in the way of
quadriceps weakness; this is not the case in PM, in which
the reflexes are spared until the muscle is extremely weak.
These clinical features are well displayed in the series
reported by Amato and colleagues. Dysphagia is common
(Wintzen et al). Selective or asymmetric involvement of
distal muscles, when it occurs, erroneously suggests the
diagnosis of motor neuron disease (the reflexes are not,
however, enhanced as they are in ALS).
Laboratory and Muscle Biopsy Features
The CK is normal or slightly elevated, generally showing
lower levels than in cases of PM with comparable amounts
of weakness. EMG abnormalities are much like those
found in PM, as discussed earlier. In addition, a small
proportion of IBM patients display a more typically neuro-
pathic EMG pattern, mainly with long-duration polyphasic
potentials because of the chronicity of the disease, in the
2/22/19 11:59 AM

distal limb muscles. However, the EMG changes tend to
be restricted to weakened muscles, a distinction from ALS.
The diagnosis depends on the clinical features and
is supported by the muscle biopsy. There are structural
abnormalities of muscle fibers and inflammatory changes.
The latter are similar to, but usually of lesser severity than,
those observed in idiopathic PM. (The infiltrating cells are
mainly T cells of the CD8 type.) The denominative find-
ing is of intracytoplasmic, subsarcolemmal vacuoles, and
eosinophilic inclusions in both the cytoplasm and nuclei
of degenerating muscle fibers. The vacuoles contain,
and are rimmed by, basophilic granular material, called
“rimmed vacuoles.” Special stains, particularly Gomori
trichrome on frozen sections, and extensive inspection
of biopsy specimens are required to disclose the rimmed
vacuoles, for they are infrequent, widely dispersed, and
easily overlooked. The inclusions may be congophilic, and
often stain for TDP-43, p62, SM1-31, and, particularly, beta
amyloid. As noted in subsequent sections similar inclu-
sions are found in a number of other muscle diseases and
are not in and of themselves diagnostic, especially without
the destructive and mildly inflammatory changes of IBM.
Moreover, the clinical context of these other diseases usu-
ally causes little difficulty in identifying the inclusions as
ancillary and minor abnormalities on the biopsy.
Of clinical utility has been the recent introduction of
testing for cytosolic antibodies (anti-cN1; NT5C1A) that
are found in two-thirds of patients with IBM. They appear
to be specific and assist in particular by differentiating this
disease from the other inflammatory myopathies and in
its detection when there is a pattern of weakness that is
not typical of an inflammatory myopathy. Testing other
antibodies such as anti-Jo is probably suited to confirm-
ing cases that have the elements of a larger syndrome that
includes, for example, interstitial lung disease.
Ultrastructural studies show that the protein inclusions
accumulate at or near foci of abnormal tubulofilamentous
structures in both the nuclei and cytoplasm. The nature of
these diverse changes is obscure. The tubulofilamentous
inclusions suggested to earlier investigators a viral origin,
but an agent has never been isolated and serologic studies
have failed to substantiate an infectious causation.
Treatment
IBM has not responded in any consistent fashion to treat-
ment with corticosteroids or other immunosuppressive
drugs. Indeed, the disease should be suspected in recal-
citrant cases of apparent PM or DM. The level of CK and
the degree of leukocyte infiltration of muscle often dimin-
ish with corticosteroid treatment despite a lack of clinical
improvement. On this basis, Barohn and coworkers sug-
gested that the inflammatory response is not a primary
cause of muscle destruction. In a few cases there has
been brief improvement in response to glucocorticoids
or IVIg, especially in weakened muscles involved in swal-
lowing, but the gains have been unsustained and serial
histopathologic examinations have detected no change.
Two controlled trials have failed to show a benefit of IVIg.
Plasma exchange and leukocytapheresis have also been
tried, with generally discouraging results. In a preliminary
Ropper_Ch45_p1405-p1468.indd 1423
Chapter 45 Diseases of Muscle 1423
trial of bimagrumab, an antibody directed to signaling of
TGF-β receptor, has shown some improvement of muscle
mass but a definitive clinical demonstration of effect has
not been tested (Amato et al, 2014).
The disease in most patients is relentlessly progressive
over many years, sometimes very slowly, and no method
of treatment has so far altered the long-term prognosis.
Sometimes, the process remains fairly restricted in scope
or severity for up to a decade, thereby creating less disabil-
ity than in cases that become generalized.
Problems in Diagnosis of Inflammatory Myopathy
The main issue here is differentiation of DM and PM
from inclusion body myopathy. The specific problem of
determining which patients with DM or PM should have
an extensive evaluation for a systemic malignancy and for
connective tissue disease has been partially settled. We
have adopted the practice of careful inspection of the chest
radiograph, routine blood tests and stool examination for
blood for all patients, and of undertaking a more extensive
evaluation in patients older than 55 years and in smokers
of any age. The evaluation of patients over 55 and smok-
ers includes chest and abdominal computed tomographic
(CT) scans, colonoscopy, pelvic ultrasound, cancer anti-
gen (CA)-125, carcinoembryonic antigen (CEA), as well as
other tests. In patients with recent weight loss, anorexia,
or other symptoms suggestive of malignancy, we have
included upper endoscopy and resorted to a body positron
emission tomography scanning.
In addition to these main issues of distinguishing PM
and DM from IBM, currently aided by antibody testing,
we call attention to the following problems that we have
encountered in connection with diagnosis:
1. The patient with proximal muscle weakness is incorrectly
diagnosed as having progressive muscular dystrophy
(actually, the opposite pertains more often). Points in
favor of myositis are (1) lack of family history (although
many dystrophies have recessive inheritance); (2) older
age at onset; (3) rapid evolution of weakness; (4) evi-
dence, past or present, of other connective tissue dis-
eases; (5) high serum CK values (again, can be high
in certain dystrophies); (6) marked degeneration and
regeneration in muscle biopsy; and, finally, if there is
still doubt, (7) unmistakable improvement with corti-
costeroid therapy.
2. The patient with a systemic autoimmune disease (rheu-
matoid arthritis, scleroderma, lupus erythematosus,
Sjögren syndrome) is suspected of having PM in addi-
tion. Pain in these conditions prevents strong exertion
(algesic pseudoparesis). Points against the coexistence
of myositis are (1) the inability to document weakness
out of proportion to muscle atrophy and the presence
of pain on passive movement of the limbs; (2) normal
EMG; (3) normal serum CK; and (4) normal muscle
biopsy except possibly for areas of infiltration of chronic
inflammatory cells in the endomysial and perimysial
connective tissue (interstitial myositis).
3. When muscle pain is a prominent feature, polymyalgia
rheumatica must be differentiated. This latter syndrome
is characterized by pain, stiffness, and tenderness in
2/22/19 11:59 AM
 1424 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
the muscles of the neck, shoulders, and arms, and
sometimes of the hips and thighs; even passive motion
of the limbs causes pain because of the periarticular
locus of this disease. A high sedimentation rate, usually
above 65 mm/h, is a diagnostic feature, but more typi-
cally the value is close to 100 mm/h, levels higher than
in myositis. Biopsy of the temporal artery frequently
discloses a giant cell arteritis. CK levels—and, of course,
muscle biopsy—are normal. Rapid disappearance of
pain with administration of small doses of predni-
sone is also diagnostic of polymyalgia rheumatica (see
Chap. 9).
4. The patient has restricted muscle weakness. Weakness
or paralysis of the posterior neck muscles, with inabil-
ity to hold up the head, restricted bilateral quadriceps
weakness, and other limited pelvocrural palsies are
examples. Most often, the head-hanging or head-lolling
syndrome proves to be caused by PM, and the other
syndromes are caused by restricted forms of dystrophy
or by motor neuron disease. IBM is the main alternative
consideration in cases of neck or quadriceps weakness,
particularly if the latter weakness is asymmetric; muscle
enzymes in the serum are normal or slightly elevated.
EMG and biopsy are helpful in diagnosis.
5. The patient has diffuse myalgia and fatigability. Most
such patients have proved to be depressed and only
rarely to have a myopathy. A few will be found to be
caused by a toxic myopathy, particularly from one of
the statin class of drugs. Hypothyroidism, McArdle
disease, hyperparathyroidism, steroid myopathy, adre-
nal insufficiency, and early rheumatoid arthritis must
be excluded by appropriate studies. Features that vir-
tually exclude a myositis are (1) lack of reduced peak
power of contraction and (2) normal EMG, serum
enzymes, and muscle biopsy.
6. Trichinosis, toxoplasmosis, HIV, and other infectious
causes of myositis can simulate acute immune myositis
as described in the early parts of this chapter. Occa-
sionally, the diagnosis of sarcoidosis is made from the
muscle biopsy, but the myopathic features (weakness
and pain) tend to be minor.
Other Inflammatory Myopathies
There are a large number of unrelated myositides and
rare forms of focal myositis or relatively minor changes in
muscle that occur in the course of inflammatory diseases
of blood vessels or systemic infections and, curiously, with
certain tumors such as thymoma. Most of these do not war-
rant extensive consideration and are described in detail
in monographs devoted to muscle disease (see Banker).
We are uncertain how to place the newly described and
undoubtedly rare entity of myositis with abundant mac-
rophage infiltration and aluminum hydroxide crystalline
deposits. A type of fasciitis that is characterized by pro-
nounced infiltration of macrophages has been related to
vaccinations that contain the aluminum compound, but
the myositis does not seem to be related to this aforemen-
tioned entity (see Bassez et al).
Three inflammatory myopathic diseases, however, are
distinctive and of interest to neurologists: (1) eosinophilic
Ropper_Ch45_p1405-p1468.indd 1424
myositis, fasciitis, and myalgia syndrome, (2) orbital myo-
sitis, and (3) sarcoidosis of muscle.
Eosinophilic Myositis and Fasciitis
This term has been applied to 4 overlapping clinical enti-
ties: (1) eosinophilic fasciitis, (2) eosinophilic monomyosi-
tis (sometimes multiplex), (3) eosinophilic PM, and (4) the
eosinophilia-myalgia syndrome.
Eosinophilic fasciitis This condition, mistakable for
PM, was reported by Shulman in 1974. He described
2 men with a scleroderma-like appearance of the skin and
flexion contractures at the knees and elbows associated
with hyperglobulinemia, elevated sedimentation rate, and
eosinophilia. Biopsy revealed greatly thickened fascia,
extending from the subcutaneous tissue to the muscle
and infiltrated with plasma cells, lymphocytes, and many
eosinophils; the muscle itself appeared normal and the
skin lacked the characteristic histologic changes of sclero-
derma. One of Shulman’s patients recovered in response
to prednisone.
The many reports that followed have substantiated
and amplified Shulman’s original description. The dis-
ease predominates in men in a ratio of 2:1. Symptoms
appear between the ages of 30 and 60 years and are often
precipitated by heavy exercise (Michet et al). There may
be low-grade fever and myalgia followed by the sub-
acute development of diffuse cutaneous thickening and
limitation of movement of small and large joints. In some
patients, proximal muscle weakness and eosinophilic infil-
tration of muscle can be demonstrated (Michet et al).
Repeated examinations of the blood disclose an eosino-
philia in most but not all patients. The disease usually
remits spontaneously or responds well to corticosteroids.
A small number relapse and do not respond to treatment
and some have developed aplastic anemia and lympho- or
myeloproliferative disease.
Eosinophilic monomyositis Painful swelling of a calf
muscle or, less frequently, some other muscle has been
the chief characteristic of this disorder. Biopsy discloses
inflammatory necrosis and edema of the interstitial tis-
sues; the infiltrates contain large but variable numbers of
eosinophils. The disorder was typified by 1 of our patients,
a young woman who developed such an inflammatory
mass first in 1 calf and, 3 months later, in the other. The
response to prednisone was dramatic; the swelling and
pain subsided in 2 to 3 weeks and her power of contraction
was then normal. When the connective tissue and muscle
are both damaged, a chaotic regeneration of fibroblasts
and myoblasts may result, forming a pseudotumorous
mass that may persist indefinitely.
Eosinophilic polymyositis Layzer and associates
described an eosinophilic disorder that they classified
as “subacute polymyositis.” Their patients were adults in
whom predominantly proximal weakness evolved over
several weeks. The features of the muscle disorder were
typical of PM except that the inflammatory infiltration was
predominantly eosinophilic and the muscles were swollen
and painful. Moreover, the muscle disorder was part of
a widespread systemic illness typical of the hypereosino-
philic syndrome. The systemic manifestations included a
2/22/19 11:59 AM

striking eosinophilia (20 to 55 percent of the white blood
cells), cardiac involvement (conduction disturbances and
congestive failure), vascular disorder (Raynaud phenom-
enon, subungual hemorrhages), pulmonary infiltrates,
strokes, anemia, neuropathy, and hypergammaglobu-
linemia. There was a favorable response to corticosteroids
in 2 patients, but in a third the outcome was fatal in 9
months. Layzer and coworkers noted that a lack of necro-
tizing arteritis distinguished this process from polyarteritis
nodosa and Churg-Strauss disease. No infective agent was
isolated. An allergic mechanism seems possible, and in the
present authors’ view one cannot exclude an angiitis as a
cause of the muscle lesions.
The last two of these previously mentioned syndromes
(eosinophilic monomyositis and polymyositis) have over-
lapping features as shown by Stark’s cases, in which a
monomyositis was accompanied by several of the systemic
features described by Layzer and colleagues. An uncer-
tain proportion of cases are attributable to mutations in
CAPN3, the gene for calpain-3 (Krahn et al). Moreover,
some cases of eosinophilic polymyositis without systemic
features have been found to be limb-girdle muscular dys-
trophy 2A, also due to a calpain mutation (i.e., both are
considered to be “calpainopathies”). Patients with the dys-
trophic process, who also have a peripheral eosinophilia,
probably have eosinophilic myositis.
Eosinophilia-Myalgia syndrome Beginning in 1980,
sporadic reports documented a lingering systemic illness
characterized by severe generalized myalgia and eosino-
philia of the peripheral blood following the ingestion of
contaminated l-tryptophan. In late 1989 and early 1990, an
outbreak occurred of this eosinophilia-myalgia syndrome,
as the illness came to be called. More than 1,200 cases
were reported to the Centers for Disease Control and Pre-
vention (Medsger) and we examined several of them. The
outbreak was ultimately traced to the use of nonprescrip-
tion l-tryptophan tablets used as a sleep aid supplied by a
single manufacturer and contaminated by ethylidene-bis-
tryptophan and methyltetrahydro-beta-carboline-
carboxylic acid, both close chemical relatives of l-tryptophan
(Mayeno et al, 1990, 1992).
The onset of the muscular illness was relatively
acute, with fatigue, low-grade fever, and eosinophilia
(>1,000 cells/mm3). Muscle pain and tenderness, cramps,
weakness, paresthesias of the extremities, and induration
of the skin were the main clinical features. A severe axonal
neuropathy with slow and incomplete recovery was asso-
ciated in some cases. Biopsies of the skin fascia, muscle,
and peripheral nerve disclosed a microangiopathy and
an inflammatory reaction in connective tissue structures;
changes like those observed in scleroderma, eosinophilic
fasciitis, and in the toxic oil syndrome. The latter syn-
drome, caused by the ingestion of contaminated rapeseed
oil, occurred in an outbreak in Spain in 1981 and gave rise
to a constellation of clinical and pathologic changes that
were essentially identical to those caused by contaminated
l-tryptophan (Ricoy et al; see also Chap. 41). The two tox-
ins are also closely linked chemically and there have been
other more limited outbreaks of the toxic neuropathy, usu-
ally from adulterated cooking oil.
Ropper_Ch45_p1405-p1468.indd 1425
Chapter 45 Diseases of Muscle 1425
The cutaneous lesions and eosinophilia of this syn-
drome responded to treatment with prednisone and other
immunosuppressive drugs, but other symptoms persisted.
Severe axonal neuropathy in our patients improved incom-
pletely over several years, leaving one chair-bound with
severe distal atrophic weakness after 15 years. Although
no longer a problem that is likely to be seen by physi-
cians, it serves as a model for future peculiar myopathic
syndromes from adulterated drugs that otherwise would
seem innocuous.
Acute Orbital Myositis
Among the many cases of orbital inflammatory disease
(pseudotumor of the orbit and Tolosa-Hunt syndrome,
as described in Chap. 13), there is a small group in whom
the inflammatory process appears to be localized to the
extraocular muscles. To this group, the term acute orbital
myositis has been applied. The abrupt onset of orbital pain
that is made worse by eye motion, redness of the conjunc-
tiva adjacent to the muscle insertions, diplopia caused
by restrictions of ocular movements, lid edema, and mild
proptosis are the main clinical features and, admittedly,
the distinctions from orbital pseudotumor are not clear.
It may spread from one orbit to the other. The ESR is usu-
ally elevated and the patient may feel generally unwell,
but only rarely can the ocular disorder be related to a sys-
temic autoimmune disease or any other specific systemic
disease. CT and MRI have proved to be particularly useful
in demonstrating the swollen ocular muscles or muscle,
and in separating orbital myositis from the other remit-
ting inflammatory orbital and retroorbital conditions (Dua
et al). As a rule, acute orbital myositis resolves spontane-
ously in a matter of a few weeks, although it may recur in
the same or the opposite eye. Administration of steroids
appears to hasten recovery.
Sarcoid Myopathy, Granulomatous Myositis, and
Localized Nodular Myositis
There are undoubted examples of muscle involvement in
patients with sarcoidosis, but they seem to be less frequent
and less certain than would appear from the medical lit-
erature. In some cases, sarcoid myopathy becomes evident
as a slowly progressive, occasionally fulminant, painless
proximal or distal weakness. The CK levels are elevated.
Muscle biopsy discloses numerous noncaseating granulo-
mas. However, such lesions may also be found in patients
with sarcoidosis who have no weakness. Treatment with
moderate doses of corticosteroids (prednisone, 25 to
50 mg daily) is usually effective in symptomatic cases, but
an additional immunosuppressive agent, such as cyclo-
sporine, may have to be instituted if improvement is not
evident in several weeks.
Much more puzzling have been cases of myopathy
with the clinical features of idiopathic polymyositis and
the presence of noncaseating granulomas in the muscle
biopsy but with no evidence of sarcoidosis of the nervous
system, lungs, bone, skin, or lymph nodes. Such cases
call into question the validity of a muscle granuloma as a
criterion of sarcoidosis, but the matter cannot be settled
2/22/19 11:59 AM
 1426 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
until we have a better definition and etiology for sarcoid-
osis. These cases are presently classified as granulomatous
myositis and, if limited to one or a small group of muscles,
localized nodular myositis (Cumming et al). In a syndrome
described by Namba and colleagues, this type of myositis
was combined with myasthenia gravis, myocarditis, and
thyroiditis. The muscle process has, on a few occasions,
also been associated with Crohn disease. Electron micros-
copy has disclosed muscle fiber invasion by lymphocytes,
suggesting a cell-mediated immune reaction. Very rarely,
a granulomatous myositis may complicate tuberculosis or
syphilis.
THE MUSCULAR DYSTROPHIES (TABLES 45-1
THROUGH 45-3)
The muscular dystrophies are a group of progressive
hereditary degenerative diseases of skeletal muscles. The
intensity of the degenerative changes in muscle and the
cellular response and nature of the regenerative changes
distinguish the dystrophies histologically from other dis-
eases of muscle and also have implications regarding
their pathogenesis. The category of more benign and
relatively nonprogressive myopathies—each named from
its special histopathologic appearance, such as cen-
tral core, nemaline, mitochondrial, and centronuclear
diseases—present greater difficulty in classification. Like
the dystrophies, they are primarily diseases of muscle and
are often heredofamilial in nature, but they are placed in
a separate category because of a nonprogressive or slowly
progressive course and their distinctive histochemical and
ultrastructural features.
The current clinical classification of the muscular dys-
trophies is based mainly on the distribution of the dominant
muscle weakness and the responsible mutation but several
of the classical types have retained their eponymic desig-
nations: Duchenne, Becker, Emery-Dreifuss, Landouzy-
Dejerine, Miyoshi, Welander, Fazio-Londe, and Bethlem
are among the ones that still have utility in shorthand. To
these are added myotonic dystrophy and a group of so-
called congenital muscular dystrophies, usually severe in
degree.
The extraordinary depth of information regarding the
molecular nature of the dystrophies is one of the most grati-
fying developments of modern neuroscience. The major-
ity of the dystrophies are caused by changes in structural
elements of the muscle cell, mainly in its membrane, but
other important mechanisms also are being identified. In
keeping with the outlook expressed throughout the book,
we adhere to a clinical orientation in describing the muscu-
lar dystrophies but make clear that treatment in the future
could be determined based on understanding of molecular
mechanisms. Each of the muscular dystrophies is described
in accordance with this scheme.
The differentiation of dystrophic diseases of muscle
from those secondary to neuronal degeneration was an
achievement of neurologists of the second half of the
nineteenth century. Isolated cases of muscular dystrophy
Ropper_Ch45_p1405-p1468.indd 1426
had been described earlier, but no distinction was made
between neuropathic and myopathic disease. In 1855,
Duchenne described the progressive muscular atrophy of
childhood that now bears his name. However, it was not
until the second edition of his monograph in 1861 that the
“hypertrophic paraplegia of infancy” was recognized as a
distinct syndrome. By 1868, he was able to write a com-
prehensive description of 13 cases and recognized that the
disease was muscular in origin and restricted to males.
Gowers in 1879 gave a masterful account of 21 personally
observed cases and called attention to the characteristic
way in which such patients arose from the floor (Gowers
sign). Erb, in 1891, crystallized the clinical and histologic
concept of a group of diseases caused by primary degen-
eration of muscle, which he named muscular dystrophies.
The first descriptions of facioscapulohumeral dystrophy
were published by Landouzy and Dejerine in 1894; of pro-
gressive ocular myopathy by Fuchs in 1890; of myotonic
dystrophy by Steinert and by Batten and Gibb in 1909; of
distal dystrophy by Gowers in 1888, Milhorat and Wolff
in 1943, Welander in 1951, and Miyoshi and colleagues
in 1986; and of oculopharyngeal dystrophy by Victor and
associates in 1962. References to these and other writ-
ings of historical importance can be found in the works
of Kakulas and Adams, of Walton and colleagues, and
of Engel and Franzini-Armstrong, and most recently of
Amato and Russell.
In the more recent history of the dystrophies, the
most notable event was the discovery by Kunkel, in 1986,
of the dystrophin gene and its protein product. Since then
there has been an extraordinary accumulation of molecu-
lar-genetic, ultrastructural, and biochemical information
about the muscular dystrophies, which has broadened our
understanding of their mechanisms. It has also clarified a
number of uncertainties as to their clinical presentations
and has necessitated a revision of an older classification.
Duchenne Muscular Dystrophy (DMD Mutation)
This is the most frequent and prototypic early-onset mus-
cular dystrophies. It begins in early childhood and runs
a relatively rapid, progressive course. The incidence is in
the range of 13 to 33 per 100,000 yearly or about 1 in 3,300
live male births. There is a strong familial liability as the
disease is transmitted as an X-linked recessive trait, occur-
ring almost exclusively in males, and involving the DMD
gene and the protein dystrophin. Careful examination of
the mothers of affected boys shows slight muscle involve-
ment in as many as half of them, as pointed out by Roses
and coworkers (a frequency higher than in our limited
experience). Approximately 30 percent of patients have no
family history of the disease and these represent spontane-
ous mutations.
Rarely, a severe proximal Duchenne-type muscular
dystrophy occurs in young girls. This may have several
explanations. The female may have only 1 X chromo-
some, as occurs in the Turner (XO) syndrome, and that
chromosome carries the Duchenne gene, or the Lyon
principle may be operative; that is, there is inactivation of
the unaffected paternal X chromosome allowing expres-
sion of the mutated Duchenne protein from the maternal
2/22/19 11:59 AM

chromosome in a large proportion of embryonic cells
(mosaicism). It so happens that most childhood dystro-
phies in girls prove to be of an entirely different type that
is caused by an autosomal recessive mutation causing a
limb-girdle dystrophy as discussed further on.
Clinical Features
Duchenne muscular dystrophy is usually recognized
by the third year of life and almost always before the
sixth year. Nearly half of children show evidence of dis-
ease before beginning to walk. Many of them are slightly
backward in other ways (mild developmental delay) and
the muscle weakness may at first be overlooked. A greatly
elevated CK may be the clue. In another group of young
children, an indisposition to walk or run normally at the
expected time brings them to medical attention or, having
achieved these motor milestones, they appear less active
than expected and are prone to falls. Increasing difficulty
in walking, running, and climbing stairs, excessive lumbar
lordosis, and waddling gait become more obvious as time
passes. The iliopsoas, quadriceps, and gluteal muscles
are involved initially; then the pretibial muscles weaken
(foot-drop and toe walking). Muscles of the pectoral girdle
and upper limbs are affected after the pelvicrural ones; the
serrati, lower parts of pectorals, latissimus dorsi, biceps,
and brachioradialis muscles are affected, more or less in
this order.
Enlargement of the calves and certain other muscles
is progressive in the early stages of the disease but most
of the muscles, even the ones that are originally enlarged,
eventually decrease in size; only the gastrocnemii, and to a
lesser extent the lateral vasti and deltoids, are consistently
large and this peculiarity may attract attention before the
weakness becomes evident. The enlarged muscles have
a firm, resilient (“rubbery”) feel and are slightly weaker
and more hypotonic than healthy ones. Thus the muscle
enlargement is a pseudohypertrophy. Rarely, all muscles
are at first large and strong, even the facial muscles, as in
one of Duchenne’s cases (from the marble statue, Farnese
Hercules); histologically, this is a true muscle hypertrophy.
Muscles of the pelvic girdle, lumbosacral spine, and
shoulders become weak and wasted, accounting for cer-
tain clinical peculiarities. Weakness of abdominal and
paravertebral muscles accounts for a lordotic posture and
protuberant abdomen when standing and the rounded
back when sitting. Weakness of the extensors of the knees
and hips interferes with equilibrium and with activities
such as climbing stairs or rising from a chair or from a
stooped posture. In standing and walking, the patient
places his feet wide apart so as to increase his base of sup-
port. To rise from a sitting position, he first flexes his trunk
at the hips, puts his hands on his knees, and pushes the
trunk upward by working the hands up the thighs. In ris-
ing from the ground, the child first assumes a four-point
position by extending the arms and legs to the fullest pos-
sible extent and then works each hand alternately up the
corresponding thigh (the sign traditionally attached to
Gowers’ name). In getting up from a recumbent position,
the patient turns his head and trunk and pushes himself
sideways to a sitting position. S.A.K. Wilson used an allit-
erative phrase to describe the characteristic abnormalities
Ropper_Ch45_p1405-p1468.indd 1427
Chapter 45 Diseases of Muscle 1427
of stance and gait: The patient “straddles as he stands and
waddles as he walks.” The waddle is the result of bilat-
eral weakness of the gluteus medius. Many affected boys
have a tendency to walk on their toes as a consequence
of contractures in the gastrocnemii muscles. Calf pain is
frequent. Weakening of the muscles that fix the scapulae to
the thorax (serratus anterior, lower trapezius, rhomboids)
causes winging of the scapulae, and the scapular angles
can sometimes be seen above the shoulders when one is
facing the patient.
Later, weakness and atrophy spread to the muscles of
the legs and forearms. The muscles that are preferentially
affected among these are the neck flexors, wrist extensors,
brachioradialis, costal part of the pectoralis major, latissi-
mus dorsi, biceps, triceps, and anterior tibial and peroneal
muscles. The ocular, facial, bulbar, and hand muscles are
usually spared, although weakness of the facial and ster-
nocleidomastoid muscles and of the diaphragm occurs in
the late stages of the disease. As the trunk muscles atrophy,
the bones stand out like those of a skeleton. The space
between the lower ribs and iliac crests diminishes with
atrophy and weakness of the abdominal muscles.
The limbs are usually loose and slack, but as the dis-
ability progresses, fibrous contractures appear as a result
of the limbs remaining in one position and the imbalance
between agonists and antagonists. Early in the ambula-
tory phase of the disease, the feet assume an equinovarus
position as a result of shortening of the posterior calf
muscles, which act without the normal opposition of
the pretibial and peroneal muscles. Later, the hamstring
muscles become permanently shortened because of a lack
of counteraction of the weaker quadriceps muscles. Simi-
larly, contractures occur in the hip flexors because of the
relatively greater weakness of hip extensors and abdomi-
nal muscles. This leads to a pelvic tilt and compensatory
lordosis to maintain standing equilibrium. The conse-
quences of these contractures account for the habitual
posture of the patient with Duchenne dystrophy: lumbar
lordosis, hip flexion and abduction, knee flexion, and
plantar flexion. As they become severe, these contractures
contribute importantly to the eventual loss of ambulation.
Scoliosis, as a result of unequal weakening of the paraver-
tebral muscles, and flexion contractures of the forearms
appear, usually after walking is no longer possible.
The tendon reflexes are diminished and then lost as
muscle fibers disappear, the ankle reflexes being the last to
go. The bones are thin and demineralized, and the appear-
ance of ossification centers is delayed. Smooth muscles
are spared, but the heart is affected by various types of
arrhythmias. The ECG shows prominent R waves in the
right precordial leads and deep Q waves in the left pre-
cordial and limb leads, the result of cardiac fiber loss and
replacement fibrosis of the basal part of the left ventricular
wall (Perloff et al).
Death is usually the result of pulmonary infections
and respiratory failure and sometimes, of cardiac decom-
pensation. Patients with Duchenne dystrophy usually
survive until late adolescence, but not more than 20 to
25 percent live beyond the twenty-fifth year. The last years
of life are spent in a wheelchair; finally the patient becomes
bedfast.
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 1428 Part 5 DISEASES OF SPINAL CORD, PERIPHERAL NERVE, AND MUSCLE
Mild degrees of developmental delay as mentioned,
which is nonprogressive, are observed in many cases. The
average IQ is 85 and approximately one-quarter have an IQ
below 70, but the range has been 40 to 130.
As mentioned earlier, female carriers of the disease
(i.e., the mothers of affected boys) and described slight
weakness and enlargement of the calves as well as elevated
CK values and abnormalities of the electromyelogram
(EMG) and muscle biopsy, all slight in degree, in more
than half; as mentioned, this is far higher than in our
experience and that of our colleagues. A small number of
female carriers manifest a moderate myopathy that may
mimic limb-girdle dystrophy (see further on). The muscle
fibers of such patients (referred to as manifesting or symp-
tomatic carriers) show a mosaic immunostaining pattern
mentioned earlier, some fibers containing dystrophin and
others lacking it (Hoffman et al, 1988). This diagnostic
information is particularly helpful in genetic counseling.
The serum CK values are 25 to 200 times normal, which,
with the EMG and muscle biopsy findings, help exclude spi-
nal muscular atrophy. The EMG shows fibrillations, posi-
tive waves, low-amplitude and brief polyphasic motor unit
potentials, and, sometimes, high-frequency discharges. The
female carrier may occasionally display the same abnor-
malities, but to a much milder degree. The molecular and
genetic bases of the disease are discussed further on.
Becker Muscular Dystrophy
This milder dystrophy is closely related to the Duchenne
type clinically, genetically, and ultrastructurally, involv-
ing the same DMD gene as in the Duchenne type. It had
long been noted that mixed with the Duchenne group
were relatively benign cases. In 1955, Becker and Keiner
proposed that the latter be separated as a distinct entity,
now called Becker muscular dystrophy. The incidence is
difficult to ascertain, but it has been estimated as 3 to 6
per 100,000 male births. Like the Duchenne form, it is an
X-linked disorder, practically limited to males and trans-
mitted by females. It causes weakness and hypertrophy in
the same muscles as Duchenne dystrophy, but the onset
is much later (mean age: 12 years; range: 5 to 45 years).
While boys with Duchenne dystrophy are usually depen-
dent on a wheel-chair by early in the second decade, it is
not uncommon for those with Becker dystrophy to walk
well into adult life. In comparison to Duchenne dystrophy,
those with Becker and intermediate types retain their abil-
ity to raise the head fully off the bed. We have, for example,
encountered patients who served in the military with the
disease undetected. If maternal uncles are affected by the
disease and are still walking, the diagnosis is relatively
easy. Mentation is usually normal and cardiac involve-
ment is far less frequent than in Duchenne dystrophy, but
there are cases that present with a cardiomyopathy and
we have been made aware of 2 brothers who had cardiac
transplantation before the disease was detected. Kuhn
and associates have reported a genealogy in which early
myocardial disease and cramping myalgia were promi-
nent features. The molecular-genetic basis of this form is
discussed below.
Ropper_Ch45_p1405-p1468.indd 1428
Pathology of Duchenne and Becker Dystrophies
In the early stages of Duchenne dystrophy, the most dis-
tinctive features are prominent segmental degeneration
and phagocytosis of single muscle fibers or groups of
fibers and evidence of regenerative activity (basophilia
of sarcoplasm, hyperplasia and nucleation of sarcolem-
mal nuclei, and the presence of myotubes and myocytes).
The necrosis excites a regenerative or restorative process,
which explains the forking of fibers and clustering of small
fibers with prominent nuclei. The necrotic sarcoplasm
and sarcolemma are removed by mononuclear phagocytic
(macrophage) cells. There may also be a few T lympho-
cytes in the region, suggesting inflammation. There is a
hyalinization of the sarcoplasm of many degenerating and
nondegenerating fibers. In longitudinal sections these are
seen as “contraction bands,” expressive of the irritability
of dystrophic muscle. This phenomenon may be present
before there is any significant degree of degeneration and
is more extensive in Duchenne than in any of the other
dystrophies. Eventually, there are histologic changes that
are common to all types of advanced muscular dystro-
phies: loss of muscle fibers, residual fibers of larger and
smaller size than normal, all in haphazard arrangement,
and the secondary reaction of an increase in lipocytes and
fibrosis.
Hypertrophy of muscle is apparently the result of
work-induced enlargement of the remaining sound fibers
in the face of adjacent fiber injury. However, examples of
true hypertrophy of entire muscles prior to the first sign of
weakness also occur and are difficult to explain. In these
cases, large fibers may be present when at most there are
only a few degenerating fibers. The more common feature
of pseudohypertrophy is a result of lipocytic replacement
of degenerated muscle fibers, but in its earlier stages, the
presence of many enlarged fibers may contribute to the
enlargement of muscle. Thus a true hypertrophy appears
to give way to pseudohypertrophy. In the late stage of the
dystrophic process, only a few scattered muscle fibers
remain, almost lost in a sea of fat cells. It is notable that
the late, or burned-out, stage of chronic polymyositis
resembles muscular dystrophy in that the fiber population
is depleted, the residual fibers are of variable size, and fat
cells and endomysial fibrous tissue are increased; lack-
ing only are the hypertrophied fibers of dystrophy. This
resemblance confirms that many of the typical changes of
muscular dystrophy are nonspecific, reflecting mainly the
chronicity of the myopathic process.
Molecular Biology of Duchenne and Becker Dystrophies
The first important development in our understanding of
the Duchenne and Becker muscular dystrophies was the
discovery by Kunkel of the mutation on the X chromosome
in what was later named DMD and of its gene product,
dystrophin (Hoffman et al, 1987). The protein is expressed
in skeletal, cardiac, and smooth muscle, as well as in brain.
To date, the dystrophin gene is the largest one known in
humans, spanning more than 2 Mb of DNA. This is in
part the explanation for the observation that one-third of
2/22/19 11:59 AM