Pns and muscle

Peripheral Nerve and
Skeletal Muscle Diseases

 Motor units
– (1) a lower motor neuron in the anterior horn of the spinal
cord or cranial nerve motor nucleus in the brain stem
– (2) the axon of that neuron
– (3) the multiple muscle fibers it innervates.
 Nerve fiber (an axon with its Schwann cells and
myelin sheath) - principal structural component of
peripheral nerve.

 Nerve
– Consists of numerous fibers that are grouped into fascicles by connective
tissue sheaths
– Myelinated and unmyelinated
– nodes of Ranvier – separates PNS axons
– A single Schwann cell supplies the myelin sheath for each internode.
– Unmyelinated axons > myelinated axons
– Cytoplasm of one Schwann cell envelops a variable number of
unmyelinated fibers (5 to 20 axons in humans)

– 3 major connective tissue components of
peripheral nerve
 epineurium, which encloses the entire nerve
 perineurium, a multilayered concentric connective tissue
sheath that encloses each fascicle
 endoneurium, which surrounds individual nerve fibers.

Segmental demyelination:
Random internodes of myelin are
injured and are remyelinated by
multiple Schwann cells, while the
axon and myocytes remain intact.
Axonal degeneration:
The axon and its myelin sheath
undergo anterograde degeneration
(shown for the green neuron), with
resulting denervation atrophy of the
myocytes within its motor unit
(pale-pink myocytes).
Reinnervation of muscle:
Sprouting of adjacent (red)
uninjured motor axons leads to
fiber type grouping of myocytes,
while the injured axon attempts
axonal sprouting.
Myopathy: Scattered myocytes of
adjacent motor units are small
(degenerated or regenerated),
whereas the neurons and nerve
fibers are normal.

REACTIONS OF THE MUSCLE FIBER
 Segmental necrosis
– destruction of a portion of the length of a myocyte,
may be followed by myophagocytosis as
macrophages infiltrate the region.
– loss of muscle fibers in time leads to extensive
deposition of collagen and fatty infiltration.
 Vacuolation
– alterations in structural proteins or organelles, and
accumulation of intracytoplasmic deposits may be
seen in many diseases.

 Regeneration
– when satellite precursor cells proliferate and reconstitute
the destroyed portion of the fiber.
– Regenerating portion of the muscle fiber has large
internalized nuclei and prominent nucleoli, and the
cytoplasm, laden with RNA, is basophilic.
 Fiber hypertrophy
– occurs in response to increased load, either in the setting of
exercise or in pathologic conditions in which muscle fibers
are injured.

Diseases of Peripheral Nerve
Inflammatory
Genetic
Traumatic
Metabolic and Toxic
Neoplastic

INFLAMMATORY NEUROPATHIES
 inflammatory cell infiltrates in peripheral nerves,
roots, and sensory and autonomic ganglia
– due to infectious agent
 Leprosy (Hansen Disease)
 Diphtheria
 Varicella-Zoster Virus
– due to immune mechanisms
 Guillain-Barré Syndrome/Acute Inflammatory
Demyelinating Polyradiculoneuropathy
 Chronic Inflammatory Demyelinating
Polyradiculoneuropathy

Leprosy (Hansen Disease)
 Lepromatous leprosy
– Schwann cells are invaded by Mycobacterium leprae
– Segmental demyelination and remyelination and loss of
both myelinated and unmyelinated axons
– Endoneurial fibrosis and multilayered thickening of the
perineurial sheaths occur
– (+) symmetric polyneuropathy affecting the cool extremities
– (+) involvement of pain fibers resulting to loss of sensation
contributing to injury
– (+) large traumatic ulcers may develop in the extremities

 Tuberculoid leprosy
– (+) active cell-mediated immune response to M.
leprae, with nodules of granulomatous
inflammation situated in the dermis
– (+) injury to the cutaneous nerves in the vicinity
– (+) loss of axons, Schwann cells, and myelin
– (+) fibrosis of the perineurium and endoneurium.
– (+) localized nerve involvement.

Diphtheria
 Peripheral nerve involvement results from the effects
of the diphtheria exotoxin
 Usually begins with paresthesias and weakness,
 (+) early loss of proprioception and vibratory
sensation
 Due to the incomplete blood-nerve barrier of the
sensory ganglia which allows the entry of the toxin
 (+) selective demyelination of axons, extending into
adjacent anterior and posterior roots as well as into
mixed sensorimotor nerves.

Varicella-Zoster Virus
 Latent infection persisting within neurons in the sensory ganglia of the
spinal cord and brain stem
 Reactivation leads to a painful, vesicular skin eruption in the distribution
of sensory dermatomes (shingles), most frequently thoracic or
trigeminal.
 May be transported along the sensory nerves to the skin, where it
establishes an active infection of epidermal cells.
 Affected ganglia
– (+) neuronal destruction and loss,
– (+) abundant mononuclear inflammatory infiltrates
– (+) regional necrosis with hemorrhage.
 Peripheral nerve shows axonal degeneration after the death of the
sensory neurons.
 Focal destruction of the large motor neurons of the anterior horns or
cranial nerve motor nuclei may be seen at the corresponding levels.
 (-) Intranuclear inclusions in the peripheral nervous system.

Guillain-Barré Syndrome /
Acute Inflammatory Demyelinating
 life-threatening disease of the peripheral nervous
system
 1-3 cases per 100,000 persons worldwide
 characterized by
– Clinically: weakness beginning in the distal limbs but rapidly
advancing to affect proximal muscle function (“ascending
paralysis”)
– Histologically: inflammation and demyelination of spinal
nerve roots and peripheral nerves (radiculoneuropathy).

 Pathogenesis
– an acute-onset immune-mediated demyelinating neuropathy
– 2/3 are preceded by an acute, influenza-like illness from which the affected
individual has recovered by the time the neuropathy becomes
symptomatic.
– (+) association with infections due Campylobacter jejuni,
cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae,
or prior vaccination
– No consistent demonstration of an infectious agent in peripheral nerves
– An immunological reaction is generally favored as the underlying cause.
– Immunization with a peripheral nerve myelin protein ensues a T cell–
mediated immune response, accompanied by segmental demyelination
caused by activated macrophages.
– Lymphocytes from GBS patients have been shown to produce
demyelination in tissue cultures of myelinated nerve fibers.
– Plasmapheresis can be an effective treatment

 Morphology.
– The dominant histopathologic finding is inflammation of peripheral nerve,
manifested as perivenular and endoneurial infiltration by lymphocytes,
macrophages, and a few plasma cells.
– Often localized in spinal and cranial motor roots and the adjacent parts of the
spinal and cranial nerves.
– Primary Lesion - segmental demyelination affecting peripheral nerve
– (+) damage to axons is also characteristic, particularly in severe cases
– Electron microscopy:
 The cytoplasmic processes of macrophages penetrate the basement membrane of
Schwann cells, particularly in the vicinity of the nodes of Ranvier, and extend between
the myelin lamellae, stripping away the myelin sheath from the axon.
 Remnants of the myelin sheath are engulfed by the macrophages.
 Remyelination follows the demyelination.

 Clinical Course.
– Ascending paralysis.
– Disappearance of deep tendon reflexes disappear early in the
process;
– Slowing of nerve conduction velocity because of the multifocal
destruction of myelin segments involving many axons within a
nerve
– Elevation of the CSF protein due to inflammation
– Little to no CSF pleocytosis.
– Mortality rate: 25%
– 2% to 5% die due to respiratory paralysis, autonomic instability,
cardiac arrest, or the complications of treatment
– 20% of hospitalized patients have long-term disability.

Chronic Inflammatory Demyelinating
 Inflammatory demyelinating polyradiculoneuropathy
follows a subacute or chronic course, usually with
relapses and remissions over a period of several
years
 (+) symmetric, mixed sensorimotor polyneuropathy,
 Clinical remissions may occur with steroid treatment
and plasmapheresis.
 Biopsies of sural nerves show evidence of recurrent
demyelination and remyelination associated with
well-developed onion bulb structures

HEREDITARY NEUROPATHIES
 Heterogeneous, typically progressive, and often disabling syndromes
 Hereditary motor and sensory neuropathies (HMSNs):
– most common form
– affect both strength and sensation (sensorimotor neuropathies).
 Hereditary sensory and autonomic neuropathies (HSANs)
– (+) numbness
– (+) pain
– (+) autonomic dysfunction such as orthostatic hypotension, but without weakness.
 Familial amyloid polyneuropathies:
– Deposition of amyloid within the peripheral nervous system.
– Mutation of transthyretin (a protein involved in serum binding and transport of thyroid
hormone. )gene, located on chromosome 18q11.2–q12.1.
 Peripheral neuropathy accompanying inherited metabolic disorders:

 Hereditary Motor and Sensory Neuropathy Type
I/Charcot-Marie-Tooth (CMT) disease, demyelinating
type,
– childhood or early adulthood
– progressive muscular atrophy of the leg below the knee
– may be asymptomatic, but when (+) there is distal muscle
weakness, atrophy of the leg below the knee, or secondary
orthopedic problems of the foot (such as pes cavus).
– Heterogeneous
– HMSN IA or CMT1A – most common subtype has a duplication of
a large region of chromosome 17p11.2, resulting in “segmental
trisomy” of this region.

– Histology:
 Repetitive demyelination and remyelination, with multiple onion
bulbs, more pronounced in distal nerves than in proximal
nerves
 The axon is often present in the center of the onion bulb, and
the myelin sheath is usually thin or absent.
 The redundant layers of Schwann cell hyperplasia surrounding
individual axons are associated with enlargement of involved
peripheral nerves that may become palpable, which has led to
the term hypertrophic neuropathy.
 In the longitudinal plane, the axon may show evidence of
segmental demyelination.
 Degeneration of the posterior columns of the spinal cord.

 HMSN II
– signs and symptoms similar to those of HMSN I
– No nerve enlargement
– Predominant finding of loss of myelinated axons
– Infrequent segmental demyelination of internodes.

 Dejerine-Sottas Neuropathy (HMSN III)
– slowly progressive, autosomal recessive disorder in early childhood
– delay in developmental milestones, such as the acquisition of motor
skills.
– muscular atrophy in both trunk and limb muscles
– PE:
 (+) enlarged peripheral nerves by inspection and palpation.
 DTR are depressed or absent, and nerve conduction velocity is slowed
– Morphologically:
 the size of individual peripheral nerve fascicles is increased, often
markedly, with abundant onion bulb formation as well as segmental
demyelination
 (+) axonal loss, and the axons that remain are often of diminished caliber
 Distal portions of peripheral nerves are most severely affected
 (+) involvement of the spinal roots

Hereditary Sensory and Autonomic
Neuropathies (HSANs)

Hereditary Neuropathies Accompanying
Inherited Metabolic Disease

TRAUMATIC NEUROPATHIES
 Lacerations - cutting injuries and can complicate fractures when a sharp
fragment of bone lacerates the nerve.
 Avulsions - tension is applied to a peripheral nerve, often as the result of a
force applied to one of the limbs.
 Regeneration of peripheral nerve axons following these types of injuries does
occur, albeit slowly.
 Regrowth may be complicated by discontinuity between the proximal and distal
portions of the nerve sheath as well as by the misalignment of individual
fascicles.
 Axons, even in the absence of correctly positioned distal segments, may
continue to grow, resulting in a mass of tangled axonal processes known as a
traumatic neuroma (pseudoneuroma or amputation neuroma).
 Within this mass, small bundles of axons appear randomly oriented; each,
however, is surrounded by organized layers containing Schwann cells,
fibroblasts, and perineurial cell

Normal appearance of peripheral
nerve
Axons aligned in a single plane
with sheaths of connective tissue
Traumatic neuroma - showing
disordered orientation of axons
(pale purple) intermixed with
connective tissue (blue).

 Compression neuropathy (Entrapment neuropathy)
– Compression of the peripheral often within an anatomic compartment.
– Carpal tunnel syndrome,
 most common entrapment neuropathy
 compression of the median nerve at the level of the wrist within the
compartment delimited by the transverse carpal ligament
 Women
 Bilateral.
 Associated with many conditions:tissue edema, pregnancy, inflammatory
arthritis, hypothyroidism, amyloidosis (especially that related to β2-
microglobulin deposition in individuals on renal dialysis), acromegaly,
diabetes mellitus, and excessive repetitive motions of the wrist.
 Symptoms: dysfunction of the median nerve ( numbness and
paresthesias of the tips of the thumb and first two digits)

– Other nerves prone to compression neuropathies:
 ulnar nerve at the level of the elbow
 peroneal nerve at the level of the knee,
 radial nerve in the upper arm (“Saturday night palsy”).
 Foot - affecting the interdigital nerve at intermetatarsal
sites (women - leading to foot pain (metatarsalgia).
– Histologic findings of the lesion (Morton
neuroma) include evidence of chronic
compression injury.

ACQUIRED METABOLIC AND
TOXIC NEUROPATHIES
 Peripheral Neuropathy in Adult-Onset Diabetes
Mellitus
– 50% of diabetics overall have peripheral neuropathy
clinically (80% (+) for disease for> 15 years)
– Widence for involvement of both the polyol pathway
and the nonenzymatic glycation of proteins

– distal symmetric sensory or sensorimotor neuropathy
 Most common
 Decreased sensation in the distal extremities with less evident motor
abnormalities
 Loss of pain sensation leading to development of poorly healing ulcer
– autonomic neuropathy
 20% to 40% of individuals
 Always in association with a distal sensorimotor neuropathy
 Protean manifestations,(postural hypotension, incomplete emptying of the
bladder thus recurrent infections, and sexual dysfuction)
– focal or multifocal asymmetric neuropathy
 Elderly
 Oculomotor nerve
 Involve vascular insufficiency, and ischemia of the affected peripheral
nerve

 Morphology
– Distal symmetric sensorimotor
neuropathy the predominant
pathologic finding is an
axonal neuropathy
– (+) segmental demyelination
– Endoneurial arterioles show
thickening, hyalinization, and
intense periodic acid–Schiff
positivity in their walls and
extensive reduplication of the
basement membrane marked loss of myelinated fibers, a thinly
myelinated fiber (arrowheads)
thickening of endoneurial vessel wall (arrow)

 Patients with renal failure have a peripheral
neuropathy (uremic neuropathy)
– distal, symmetric neuropathy
– Asymptomatic
– Associated with muscle cramps, distal dysesthesias, and
diminished deep tendon reflexes
– (+) axonal degeneration then secondary demyelination
– Regeneration and recovery are common after dialysis.
 Peripheral neuropathy can also develop: CLD,
chronic respiratory insufficiency, and thyroid
dysfunction.

 Thiamine deficiency
– (+) axonal neuropathy
– “neuropathic beriberi”
– Axonal neuropathies also occur with deficiencies of
vitamins B12 (cobalamin), B6 (pyridoxine), and E (α-
tocopherol).
 Excessive chronic consumption of ethyl alcohol
– (+) axonal neuropathy
– (+) dietary deficiency
– (+) thiamine deficiency.

 Neuropathies Associated with Malignancy
– Direct infiltration or compression of peripheral nerves by tumor is
a common cause of mononeuropathy and may be the presenting
symptom of cancer.
– brachial plexopathy from neoplasms of the apex of the lung
– obturator palsy from pelvic malignant neoplasms
– cranial nerve palsies from intracranial tumors and tumors of the
base of the sk
– polyradiculopathy involving the lower extremity may develop
when the cauda equina is involved by meningeal carcinomatosis.

– In contrast, a diffuse, symmetric peripheral neuropathy may
occur in individuals with a distant carcinoma as a
paraneoplastic effect
 sensorimotor neuropathy (most common) characterized by
weakness and sensory deficits that are often more pronounced in
the lower extremities and that progress during months to years.[
 most frequently associated with small-cell carcinoma of the lung
(2% to 5%)
 pure sensory neuropathy – (+) numbness and paresthesias that
may precede the diagnosis of the malignancy by 6 to 15
 (+) immunological mechanism for the neuropathy has been
suggested
– presence of inflammatory infiltrates within the dorsal root ganglia
– identification of IgG antibodies that bind a 35- to 38-kD RNA-binding
protein expressed by neurons and the tumor
– severity of clinical symptoms correlates with antibody tite

– Paraneoplastic neuropathy
 individuals with plasma cell neoplasms
 through the deposition of light-chain (AL type)
amyloid in peripheral nerves
 the production of monoclonal immunoglobulin
that recognizes a major protein of myelin,
myelin-associated glycoprotein

 Toxic Neuropathies
– (+) exposure to industrial or environmental
chemicals, biologic toxins, or therapeutic drugs
– Prominent are heavy metals: lead and arsenic
– Organic compounds are known to be toxic to the
peripheral nervous system

TUMORS
 Malignant Peripheral Nerve Sheath Tumor
– highly malignant tumors
– locally invasive
– frequently with multiple recurrences
– metastatic spread
– associated with medium to large nerves,
– close to 50% of cases arise in the setting of NF1—either from
transformation of a plexiform neurofibroma or following radiation
therapy
– disruption of p53- and RB-dependent pathways for regulation of
cell proliferation.
– Morphology: The lesions are poorly defined tumor masses that
frequently infiltrate along the axis of the parent nerve and invade
adjacent soft tissues.

– Micscopic examination:.
 Patterns reminiscent of fibrosarcoma or pleomorphic sarcoma may be
found.
 Rresemble Schwann cells, with elongated nuclei and prominent bipolar
processes
 (+) Fascicle formation
 (+) Mitoses, necrosis, and extreme nuclear anaplasia are common.
 Some but not all are immunoreactive for S-100 protein
 Epithelial structures, rhabdomyoblastic differentiation (termed Triton
tumors), cartilage, and even bone
 Epithelioid malignant schwannomas
– aggressive variants with tumor cells that have visible cell borders and
grow in nests.
– immunoreactive for S-100 but not for keratin

Diseases of Skeletal Muscle
DENERVATION ATROPHY
MUSCULAR DYSTROPHIES
CONGENITAL MYOPATHIES
MYOPATHIES ASSOCIATED WITH
INBORN ERRORS OF
METABOLISM
INFLAMMATORY MYOPATHIES
TOXIC MYOPATHIES
DISEASES OF THE
NEUROMUSCULAR JUNCTION
TUMORS

DENERVATION ATROPHY
 Caused by disorders that affect motor neurons
 Spinal Muscular Atrophy (Infantile Motor Neuron Disease)
– progressive neurologic illnesses
– destroy the anterior horn cells in the spinal cord and cranial nerve motor
neurons.
– Spinal muscular atrophy (SMA)
 autosomal recessive motor neuron diseases
 childhood or adolescence
 mutations affecting survival motor neuron 1 (SMN1), a gene on chromosome
5 that is required for motor neuron survival
 Homozygous deletions of SMN1 (or less commonly, intragenic mutations)
 # of copies of the homologous SMN2 modifies the clinical phenotype( inc in
copies =milder neurologic phenotype)
 SMN protein is critical for normal axonal transport and integrity of
neuromuscular junctions, and thus promotes survival of motor neurons.

 Werdnig-Hoffmann disease (SMA type 1) – most
common
– onset at birth or within the first 4 months of life with
severe hypotonia (lack of muscle tone and “floppiness”)
– usually leads to death within the first 3 years of life.
 SMA 2
– between 3 and 15 months of age in SMA 2
– usually die in childhood after age 4
 SMA 3
– after 2 years of age
– survive into adulthood.

(+) groups of round atrophic
muscle fibers, or panfascicular
atrophy,
Morphology:
(+) large numbers of atrophic fibers,
often only a few micrometers in
diamete
.Panfascicular atrophy – atrophy of
the entire fascicle
(+) scattered large fibers that are two
to four times normal size.

MUSCULAR DYSTROPHIES
 heterogeneous group of inherited disorders
of muscle
 often in childhood
 (+) progressive weakness and muscle
wasting.
 Histologically:
– (+) muscle fibers degeneration
– (+) fibrofatty tissue and collagen.

 X-Linked Muscular Dystrophy
– Duchenne Muscular Dystrophy (DMD)
– Becker Muscular Dystrophy (BMD)
 DMD
– most severe and common
– 1 per 3500 live male births
– manifest by the age of 5 years; wheelchair
dependence by 10 to 12 years of age, and r
progresses relentlessly.

 DMD and BMD are caused by abnormalities in
DMD( gene that is located in the Xp21 region)
 .DMD is one of the largest human genes which
encodes a 427-kD protein named dystrophin.
 2/3 of cases are familial with female
asymptomatic carriers with elevated serum
creatine kinase
 Female carriers and affected males - at risk for
developing dilated cardiomyopathy

DMD showing variation in muscle fiber size, increased endomysial
connective tissue, and regenerating fibers (blue hue).

 Morphology common to DMD and BMD
– (1) variation in fiber size (diameter) due to the presence of both small
and enlarged fibers, sometimes with fiber splitting
– (2) increased numbers of internalized nuclei (beyond the normal range
of 3% to 5%)
– (3) degeneration, necrosis, and phagocytosis of muscle fibers
– (4) regeneration of muscle fibers
– (5) proliferation of endomysial connective tissue
– DMD cases - show enlarged, rounded, hyaline fibers that have lost
their normal cross-striations; such fibers, believed to be
hypercontracted, are rare in BMD.
– Later stages the muscles eventually become almost totally replaced
by fat and connective tissue.
– Cardiac involvement, when present, consists of interstitial fibrosis, more
prominent in the subendocardium.

 Clinical Course of DMD
– Normal at birth
– Walking is often delayed,
– 1st indications of muscle weakness: clumsiness and
inability to keep up with peers.
– Weakness begins in the pelvic girdle muscles and then
extends to the shoulder girdle.
– (+) pseudohypertrophy – enlargement of lower leg muscle
with weakness
– (+) pathologic changes in the heart leading to heart failure
or arrhythmias
– (+) cognitive impairment
– Death results from respiratory insufficiency, pulmonary
infection, and cardiac decompensation

Boys with BMD
– develop symptoms at a later age (later childhood
or in adolescence)
– followed by a slower and more variable rate of
progression
– Many patients have a nearly normal life span
– (+) Cardiac disease is frequently seen

 Limb Girdle Muscular dystrophies
– affect the proximal musculature of the trunk and limbs
– inherited in either an autosomal dominant (type 1) or
autosomal recessive (type 2) pattern
– 6 subtypes of the dominant LGMDs
– 11 subtypes of the recessive LGMDs
– Mutations of the sarcoglycan complex of proteins have been
identified in 4 of the limb girdle muscular dystrophies (2C,
2D, 2E, and 2F)

Limb-Girdle Muscular Dystrophies
(LGMDs)

Other Selected Muscular Dystrophies

 Myotonic Dystrophy
– Myotonia - cardinal symptom.
– Patients often complain of “stiffness” and have
difficulty in releasing their grip, for instance, after
a handshake.
– (+) myotonia by percussion of the thenar
eminence.

 Pathogenesis
– autosomal dominant trait
– associated with a CTG trinucleotide repeat expansion on chromosome 19q13.2–
q13.3.
– The mutation is not stable within a pedigree; with each generation more repeats
accumulate, and the disease becomes more severe, a phenomenon called
anticipation
 Morphology
– Skeletal muscle may show variation in fiber size
– Increase in the number of internal nuclei, which on longitudinal section may form
conspicuous chains.
– (+) ring fiber, with a subsarcolemmal band of cytoplasm that appears distinct from
the center of the fiber. The ring fiber may be associated with an irregular mass of
sarcoplasm (sarcoplasmic mass) extending outward from the ring.
– Of all the dystrophies, only myotonic dystrophy shows pathologic changes in the
intrafusal fibers of muscle spindles, with fiber splitting, necrosis, and regeneration.

 Clinical Course.
– (+) in late childhood
– (+) abnormalities in gait secondary to weakness of foot
dorsiflexors and subsequently progresses to weakness of
the hand intrinsic muscles and wrist extensors
– (+) atrophy of muscles of the face and ptosis ensue, leading
to the typical facial appearance
– (+) cataracts
– (+) frontal balding, gonadal atrophy, cardiomyopathy,
smooth muscle involvement, decreased plasma IgG, and
abnormal glucose tolerance
– (+) Dementia

ION CHANNEL MYOPATHIES
(CHANNELOPATHIES)
 a group of familial diseases featuring myotonia, relapsing episodes of
hypotonic paralysis (induced by vigorous exercise, cold, or a high-
carbohydrate meal), or both
 Hypotonia variants
– Hyperkalemic periodic paralysis
– Hypokalemic periodic paralysis
– Normokalemic periodic paralysis
 Pathogenesis.
– caused by mutations in genes that encode ion channels
– Hyperkalemic periodic paralysis
 mutations in the gene that encodes a skeletal muscle sodium channel protein (SCN4A),
which regulates the entry of sodium into muscle during contraction.
– Hypokalemic periodic paralysis
 encodes a voltage-gated L-type calcium channel.

 Malignant hyperpyrexia (malignant hyperthermia)
 marked hypermetabolic state (tachycardia, tachypnea, muscle
spasms, and later hyperpyrexia)
 triggered by anesthetics (halogenated inhalational agents and
succinylcholine)
 may occur in predisposed individuals with hereditary muscle
diseases, including congenital myopathies,
dystrophinopathies, and metabolic myopathies
 Mutations in genes encoding L-type voltage-dependent
calcium channel, notably the rynodine receptor (RyR1).
– Upon exposure to anesthetic, the mutant receptor allows
uncontrolled efflux of calcium from the sarcoplasm
– Leading to tetany, increased muscle metabolism, and excessive
heat production.

CONGENITAL MYOPATHIES
 group of disorders defined largely on the basis of the
pathologic findings within muscle
 onset in early life
 nonprogressive or slowly progressive course
 proximal or generalized muscle weakness, and
hypotonia
 At birth or in early infancy
– “floppy infants” because of hypotonia
– severe joint contractures (arthrogryposis)

Nemaline myopathy with
numerous rod-shaped,
intracytoplasmic inclusions
(dark purple structures).

MYOPATHIES ASSOCIATED WITH
INBORN ERRORS OF METABOLISM
 Lipid Myopathies
– Abnormalities of carnitine transport or deficiencies
of the mitochondrial dehydrogenase enzyme
systems - blocks in fatty acid oxidation and
accumulation of lipid droplets within muscle
– (+) muscle pain, tightness, and myoglobinuria
following prolonged exercise or exercise during
fasting states.
– Concomitant cardiomyopathies and fatty liver may
also occur.

 Mitochondrial Myopathies (Oxidative Phosphorylation
Diseases)
– 1/5 proteins involved in oxidative phosphorylation are
encoded by the mitochondrial genome (mtDNA
– Mutations in both nuclear and mitochondrial genes cause the
so-called mitochondrial myopathies.
– High mutation rate for mtDNA compared with nuclear DNA
– (+) in young adulthood and manifest with proximal muscle
weakness, sometimes with severe involvement of the
extraocular muscles involved in eye movements (external
ophthalmoplegia).
– (+) other neurologic symptoms, lactic acidosis, and
cardiomyopathy - mitochondrial encephalomyopathies

 (+) aggregates of abnormal mitochondria that are
demonstrable only by special techniques
 (+) ragged red fibers - distortion of the myofibrils,
the muscle fiber contour becomes irregular on cross-
section
 ON EM – inc # of mitochondria with irregular shapes.
Some contain paracrystalline parking lot inclusions
or alterations in the structure of cristae

A. Irregular fiber with subsarcolemmal collections of mitochondria that stain red with
the modified Gomori trichrome stain (ragged red fiber). B, Electron micrograph of
mitochondria from biopsy specimen in A showing “parking lot” inclusions.

Three general types of mutations:
 Point mutations in mtDNA.
– Maternal pattern of inheritance
– Myoclonic epilepsy with ragged red fibers, Leber hereditary optic
neuropathy, and mitochondrial encephalomyopathy with lactic
acidosis and strokelike episodes.
 Mutations involving genes encoded by nuclear DNA and shows
autosomal dominant or autosomal recessive inheritance.
– Some cases of subacute necrotizing encephalopathy (Leigh
syndrome), exertional myoglobinuria, and infantile X-linked
cardioskeletal myopathy (Barth syndrome)
 Deletions or duplications of mtDNA.
– Chronic progressive external ophthalmoplegia - myopathy with
prominent weakness of external ocular movements.
– Kearns-Sayre syndrome, - ophthalmoplegia but, in addition,
includes pigmentary degeneration of the retina and complete heart
block.

INFLAMMATORY MYOPATHIES
 Noninfectious inflammatory
– heterogeneous group of disorders that are most
likely immune mediated
– characterized by injury and inflammation of
skeletal muscle.
– dermatomyositis, polymyositis, and inclusion
body myositis,
– may occur as an isolated myopathy or as one
component of an immune-mediated systemic
disease, particularly systemic sclerosis

– Dermatomyositis.
 inflammatory disorder of the skin as well as skeletal muscle
 (+) distinctive skin (lilac or heliotrope discoloration of the
upper eyelids associated with periorbital edema) rash
that may accompany or precede the onset of muscle
disease.
 (+) scaling erythematous eruption or dusky red patches
over the knuckles, elbows, and knees (Grotton lesions)
 Muscle weakness - slow onset, bilaterally symmetric, and
with myalgias,(affecting the proximal muscles first)
 (+) Dysphagia in 1/3 of affected individuals
 Extramuscular manifestations: interstitial lung disease,
vasculitis, and myocarditis
 Risk of developing visceral cancers about 20% to 25%.

– Capillaries are the principal targets in
dermatomyositis.
– Deposits of antibodies and complement are
present in small blood vessels, and are
associated with foci of myocyte necrosis
– B cells and CD4+ T cells are present within the
muscle, with paucity of lymphocytes within the
areas of myofiber injury.
– Perifascicular distribution of myocyte injury
suggests a vascular pathogenesis

– Morphology
 Inflammatory infiltrates are located predominantly around small
blood vessels and in the perimysial connective tissue
 perifascicular atrophy - groups of atrophic fibers are
particularly prominent at the periphery of fascicles
 Related to a relative state of hypoperfusion of the periphery of
muscle fascicles.
 (+) reduction in the intramuscular capillaries due to vascular
endothelial injury and fibrosis
 (+) necrotic muscle fibers and regeneration throughout the
fascicle

A. Heliotrope rash
affecting the eyelids.
B. The histologic
appearance of
muscle shows
perifascicular atrophy
of muscle fibers and
inflammation

– Juvenile dermatomyositis
 (+) similar onset of rash and muscle weakness
 (+) abdominal pain and involvement of the
gastrointestinal tract
 Mucosal ulceration, hemorrhage, and perforation may
occur as the result of the dermatomyositis-associated
vasculopathy.
 (+) Calcinosis, which is uncommon in adult
dermatomyositis in 1/3 of those with juvenile
dermatomyositis.

 Polymyositis.
– symmetric proximal muscle involvement, similar
to that seen in dermatomyositis but lacks of
cutaneous involvement
– mainly in adults
– (+) inflammatory involvement of heart, lungs, and
blood vessels.

 Polymyositis caused by cell mediated injury
of myocytes.
– CD8+ cytotoxic T cells and macrophages are
seen near damaged muscle fibers
– Expression of HLA class I and class II molecules
is increased on the sarcolemma of normal fibers.
– ANA/ antinuclear antibodies are present in a
variable number of cases,

– Morphology:
 Inflammatory cells are found in the endomysium
 CD8+ lymphocytes and other lymphoid cells surround
and invade healthy muscle fibers.
 Both necrotic and regenerating muscle fibers are
scattered throughout the fascicle
 NO perifascicular atrophy
 No evidence of vascular injury

 Inclusion Body Myositis.
– involvement of distal
muscles, especially
extensors of the knee
(quadriceps) and flexors of
the wrists and fingers
– Asymmetric weakness
– Affects individuals over the
age of 50 years.
– Most cases are sporadic,
Inclusion body myositis
showing a vacuole within a
myocyte

 Pathogenesis of inclusion body myositis is less clear.
– Immunosuppressive therapy is not beneficial
– (+) Intracellular deposits of β-amyloid protein, amyloid β–
pleated sheet fibrils, and hyperphosphorylated tau protein,
features shared with Alzheimer disease,
– Protein deposition may result from abnormal protein folding.
– Two hereditary forms of inclusion body myopathy have a
similar morphology:
 Autosomal recessive form - mutations in the GNE gene
(encoding UDP-N-acetylglucosamine 2-epimerase/N-
acetylmannosamine kinase)
 Autosomal dominant form - mutations in the gene encoding
myosin heavy chain IIa

 Inclusion Body Myositis
– (+) rimmed vacuoles - vacuoles are present
within myocytes, and they are highlighted by
basophilic granules at their periphery
– (+) amyloid deposits that reveal typical staining
with Congo red
– Under EM:
 tubular and filamentous inclusions (+) in the cytoplasm
 nucleus are composed of β-amyloid or
hyperphosphorylated tau.

TOXIC MYOPATHIES
 Thyrotoxic Myopathy
– acute or chronic proximal muscle weakness preceding the
onset of other signs of thyroid dysfunction.
– Exophthalmic ophthalmoplegia -
 swelling of the eyelids, edema of the conjunctiva, and diplopia.
 Limited to EOMs causing edema and enlargement
– Hypothyroidism
 cramping or aching of muscles
 slowed movements and reflexes
 fiber atrophy
 ncreased number of internal nuclei, glycogen aggregates, and,
 deposition of mucopolysaccharides in the connective tissue.

 (+) myofiber necrosis, regeneration, and
interstitial lymphocytosis.
 In chronic thyrotoxic myopathy
– slight variability of muscle fiber size
– mitochondrial hypertroph
– focal myofibril degeneration
– fatty infiltration of muscle is seen in severe cases.

 Ethanol Myopathy
– Binge drinking of alcohol producing an acute toxic
syndrome of rhabdomyolysis with accompanying
myoglobinuria
– May lead to renal failure
– (+) acute pain that is either generalized or confined to a
single muscle group
– (+) proximal muscle weakness and electrophysiologic
evidence of myopathy superimposed on alcoholic
neuropathy
– Histology: swelling of myocytes, fiber necrosis,
myophagocytosis, and regeneration. There may also be
evidence of denervation.

 Drug-Induced Myopathies
– Proximal muscle weakness and atrophy due to steroids
use ( Cushing syndrome or steroid myopathy)
– (+) muscle fiber atrophy, predominantly of type 2 fibers.
– In severe cases- (+) bimodal distribution of fibers due to the
presence of type 1 fibers of nearly normal caliber and
markedly atrophic type 2 fibers
– Microscopic findings: (+) dilation of the sarcoplasmic
reticulum and thickening of the basal laminae.

 Chloroquine
– proximal myopathy in humans
– (+) also in hydrochloroquine
– Most prominent finding is the presence of vacuoles within
myocytes
– (+) Vacuolescin 50% of the myocytes, most commonly type 1
fibers which can lead to myocyte necrosis
– Two types of vacuoles:
 (1) autophagic membrane-bound vacuoles containing
membranous debris
 (2) curvilinear bodies with short curved membranous structures
with alternating light and dark zones.

 Statins
– Myopathy is the most common complication
– “Statin-induced myopathy” can occur with use of
any of the statins (e.g., atorvastatin, simvastatin,
pravastatin)
– 1.5% of users w/c is unrelated to dose,
cumulative dose, or statin subtype.

DISEASES OF THE
NEUROMUSCULAR JUNCTION
 Myasthenia Gravis
– immune-mediated loss of acetylcholine receptor
– 30 in 100,000 persons
– Women: before age 40 years
– Equal in both sexes in older patients
– (+) Thymic hyperplasia in 65%
– (+) Thymoma in 15%
– Decrease in the number of muscle acetylcholine receptors
(AChRs), and circulating antibodies to the AChR are
present in nearly all cases.

– Autoantibodies against the AChR lead to loss of
functional AChRs at the neuromuscular junction
by:
 (1) fixing complement and causing direct injury to the
postsynaptic membrane
 (2) increasing the internalization and degradation of the
receptors
 (3) inhibiting binding of acetylcholine.

– Morphology.
 Severe cases (+) type 2 fiber atrophy due to disuse
 By EM - the postsynaptic membrane is simplified, and
there is loss of AChRs from the region of the synapse.
 (+) Immune complexes and the complement membrane
attack complex (C5–C9) along the postsynaptic
membrane

 Weakness begins with the extraocular muscles; drooping eyelids
(ptosis) and double vision (diplopia)
 Initial symptoms can be generalized weakness fluctuating to
days, hours, or even minutes, and intercurrent medical
conditions can lead to exacerbations.
 (+) Improvement in strength with anticholinesterase agents
administration
 Respiratory compromise was a major cause of mortality in the
past but due to improved methods, 95% of affected individuals
have > 5 years of survival rate.
 TX: anticholinesterase drugs, prednisone, plasmapheresis, and
thymectomy when thymic lesions are present

 Lambert-Eaton Myasthenic Syndrome
– usually a paraneoplastic process, 60% with small-cell
carcinoma of the lung
– can occur in the absence of underlying malignant disease
– proximal muscle weakness and autonomic dysfunction.
– No improvement with anticholinesterase agents
– Electrophysiologic studies: enhanced neurotransmission
with repetitive stimulation.
– Normal anticholinesterase content in neuromuscular
junction synaptic vesicles,
– Postsynaptic membrane is normally responsive to
anticholinesterase, but fewer vesicles are released in
response to each presynaptic action potential.

TUMORS
 RHABDOMYOSARCOMA
LEIOMYOMA

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