Far Eastern University Nicanor Reyes Medical Foundation
Pathology B Peripheral Nervous System
Mirian Viterbo M.D.
Diseases of Peripheral Nerves
Two main components of the peripheral nerves are:
Axons
Myelin Sheaths made by Schwann cells
Injuries in either of the two result in peripheral neuropathy.
Somatic motor function is carried out by the motor unit
composed of:
1. Lower motor neuron located in anterior horn of the spinal
cord or the brainstem.
2. Axon that ravels to a target muscle
3. Neuromuscular junctions
4. Multiple innervated myofibers
Somatic sensory function depends on:
1. Distal nerve endings, may contain specialized structures.
2. Axon that travels to the dorsal root ganglia
3. Proximal axon segment that synapses on neurons of the
spinal cord or the brain stem.
Autonomic nerve fibers outnumber somatic fibers in the PNS,
but s/sx related to their involvement are not prominent features.
Thin unmyelinated fibers mediate autonomic functions, pain, and
temperature sensation, have the slowest conduction speed.
Large diameter axons with thick sheaths transmit light touch and
motor signals and have fast conduction speed.
Schwann cells make only one myelin sheath that wraps around a
single axon to make a myelinated segment called internode
Internodes are separated by unmyelinated gaps referred to as
nodes of Ranvier, which are uniformly spread.
Most peripheral nerves carry out both motor and sensory
functions, thus contain axons of varying diameter.
Axons are bundled together by 3 connective tissues:
Epineurium encloses the entire nerve
Perineurium multilayer concentric tissue sheath that groups
subsets of axons into fascicles
Endoneurium surround individual nerve fibers.
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General Types of Peripheral Nerve Neuropathy
Axonal Neuropathy
Axons are the primary target of damage.
Morphologic hallmark is described as Wallerian degeneration.
Portions of axons distal to point of transection are disconnected
from the central neuron and degenerate.
Distal axons begin to fragment within days of injury and
disintegrate into spherical structures (myelin ovoids).
Regeneration starts at site of transection with formation of
growth cone and the outgrowth of new branches from the
stump of the proximal axon.
Axons grow about 1mm per day, guided by BM of Schwann cells
New myelin tends to be thinner and shorter than original.
Repair process is only successful only if the two transected ends
remain closely approximated.
Failure of outgrowing axons to find their distal target can
produce a pseudotumor termed traumatic neuroma a non-
neoplastic haphazard whorled proliferation of axonal processes
that results in a painful nodule.
Electrophysiologic hallmark is a reduction in signal strength
owing to the dropout of axons from affected peripheral nerves.
Demyelinating Nerves
Schwann cells and myelin sheath are the primary targets.
Axons are relatively preserved.
Individual sheaths degenerate in a random pattern, resulting in
discontinuous damage of myelin segments.
Electrophysiologic hallmark is slowed nerve conduction velocity,
reflective of the loss of myelin.
Neuronopathies
Destruction of neurons leading to secondary degeneration of
axonal processes.
Infections like herpes zoster and toxins like platinum compounds
may lead to neuropathies.
Since the damage is at the level of cell body, dysfunction is
equally likely to affect proximal and distal parts of the body.
Anatomic Patterns of Peripheral Neuropathy
Mononeuropathies
Affects a single nerve and result in deficits in a restricted
distribution dictated by normal anatomy.
Trauma, entrapment, infections are common causes.
Polyneuropathies
Involvement of multiple nerves, usually in symmetric fashion.
Axons are affected in a length dependent fashion, leading to
deficits that start in the feet and ascend on progression.
Hands show involvement by the time the knee is involved,
resulting to a stocking and glove distribution of sensory
deficits.
 Mononeuritis multiplex
Damage several nerves in a haphazard fashion.
Vasculitis is a common cause.
Polyradiculoneuropathies
Affect nerve roots as well as peripheral nerves.
Diffuse symmetric symptoms in proximal and distal parts.
Specific Peripheral Neuropathies
INFLAMMATORY NEUROPATHIES
Guillain-Barr Syndrome
(Acute Inflammatory Demyelinating Polyneuropathy)
May lead to life threatening respiratory paralysis.
Weakness beginning in the distal limbs that rapidly advances to
affect proximal muscles (ascending paralysis).
Histologic features are inflammation and demyelination of spinal
nerve roots and peripheral nerves (radiculoneuropathy).
PATHOGENESIS
Acute-onset immune-mediated demyelinating neuropathy.
2/3s are preceded by influenza-like illness.
Infections with C. jejuni, CMV, EBV, M. pneumoniae or prior
vaccination have association with this disease.
No infectious agent is demonstrated in the affected nerves, and
an immunologic reaction is the favored underlying cause.
T-cell mediated immune response ensues, accompanied by
segmental demyelination induced by activated macrophages.
Circulating antibodies that cross-react with components of the
peripheral nerves may also play a role.
MORPHOLOGY
Dominant finding is inflammation of peripheral nerves
manifested as perivenular and endoneurial infiltration by
lymphocytes, macrophages, and plasma cells.
Segmental demyelination is the most prominent.
Cytoplasmic processes of macrophages penetrate the BM of
Schwann cells, particularly near the nodes of Ranvier, and extend
between the lamellae, stripping the myelin sheath from the axon
Most prominent proximally, close to the nerve roots.
CLINICAL FEATURES
Ascending paralysis and areflexia.
DTRs disappear early in the process.
Sensory involvement including loss of pain is often present.
Nerve conduction velocity is slowed.
CSF: proteins elevated due to inflammation, little/no pleocytosis
Plasmapheresis and IV Ig appear to be beneficial.
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Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Most common chronic acquired inflammatory peripheral
neuropathy, characterized by symmetrical mixed sensorimotor
polyneuropathy that persists for 2 months or more.
Disease evolves over years, usually with relapses and remissions.
Remissions can be achieved with immunosuppressive therapy,
plasmapheresis, steroids, and agents against T-/B-cells.
Time course and response to steroids differentiate them from
Guillain-Barre Syndrome.
PATHOGENESIS
T cells and humoral factors are implicated in inflammation.
Molecules expressed by Schwann cell-axon junction appear to be
the target of the immune response.
Complement-fixing IgG and IgM are present on the myelin
sheath, deposition of these opsonins lead to recruitment of
macrophages that strip the myelin sheath off.
Recurrent myelination and demyelination leads to formation of
onion-blubs structures with multiple layers of Schwann cells.
Neuropathy Associated with Systemic Autoimmune Disease
SLE, Sjogren, RA often take form of distal sensory or
sensorimotor polyneuropathies.
Neuropathy Associated with Vasculitis
Vasculitis is a non-infectious inflammation of blood vessels.
1/3 of patients with vasculitis have peripheral nerve involvement
Often presents as mononeuritis multiplex; mononeuropathies
and polyneuropathies are also encountered.
Patchy axonal degeneration and loss.
INFECTIOUS NEUROPATHIES
Leprosy (Hansen Disease)
Peripheral nerve is involved in both lepromatous & tuberculoid.
Lepromatous Leprosy:
Schwann cells are invaded by M. leprae
Segmental demyelination, remyelination, and loss of both
myelinated and unmyelinated axons.
Endoneural fibrosis and multilayered thickening occurs
Symmetric polyneuropathy most severe in the cool distant
extremities and in the face due to lower temperature that
favors the bacterial growth.
Prominently involves the pain fibers leads to loss of sensation
Large traumatic ulcers may develop since the patient is
unaware of the painful stimuli.
Tuberculoid Leprosy
Active-cell mediated immune response to M. leprae.
Usually manifests as dermal nodules containing
granulomatous inflammation.
Injures cutaneous nerves, fibrosis of endo- and perineurium.
More localized nerve involvement.
Lyme Disease
nd rd
Cause neurologic manifestations in 2 and 3 stage of disease.
Polyradiculoneuropathy
Unilateral/bilateral facial nerve palsies.
HIV/AIDS
Several patterns of peripheral neuropathies that are poorly
understood, but appear to be related to immune dysregulation.
Early stage mononeuritis multiplex, demyelinating disorders
Later stage distal sensory neuropathy, often painful
Diphtheria
Most commonly in developing world.
Peripheral nerve results from effect of diphtheria endotoxin.
Produces an acute peripheral neuropathy associated with
prominent bulbar and respiratory muscle dysfunction.
Varicella-Zoster Virus
Following chickenpox, a latent infection persists with neurons of
sensory ganglia.
When reactivated, may be transported along sensory nerves.
It infects keratinocytes, leading to painful vesicular skin eruption
(shingles) in a distribution that follows sensory dermatomes.
Most commonly involved: thoracic and trigeminal dermatomes
Affected ganglia usually show neuronal death, accompanied by
abundant mononuclear inflammatory infiltrates, focal necrosis,
and hemorrhage.
METABOLIC, HORMONAL, AND NUTRITIONAL NEUROPATHIES
Diabetes
Most common cause of peripheral nerve neuropathy.
50% with diabetes overall, and up to 80% of those who had it
more than 15 years have clinical evidence of neuropathy.
Both types (1 and 2) are affected.
Most common pattern is ascending distal symmetric
sensorimotor polyneuropathy.
PATHOGENESIS
Both metabolic and secondary vascular changes are believed to
contribute to the damage of neurons and Schwann cells.
Hyperglycemia causes non-enzymatic glycosylation of proteins,
lipids, and nucleic acids, resulting to advanced glycosylation end
products (AGEs) that may interfere with normal protein function
and active inflammatory signaling.
Excess glucose is reduced to sorbitol, which depletes NADPH and
increases intracellular osmolality.
Vascular injuries due to hyperlipidemia causes ischemic damage
MORPHOLOGY
Distal Symmetric Sensorimotor Neuropathy, predominant finding
is an axonal neuropathy.
Reduced number of axons, axonal damaged marked by
degenerating myelin sheaths.
Endoneurial arterioles show thickening, hyalinization and intense
PAS(+) of their walls, and reduplication of basement membrane.
CLINICAL FEATURES
Distal Symmetric Sensorimotor Neuropathy presents with
sensory symptoms (numbness, loss of pain sensation, balance
difficulties, and parasthesias/dysesthesias).
Positive Symptoms Paresthesia/dysesthesias, painful sensation
that result from abnormal discharges from the damaged nerves.
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Dysfunction of the autonomic nervous system affects 20-40% of
individuals, has protean manifestations (postural hypertension,
incomplete emptying of the bladder, sexual dysfunction).
Older adults with long history develop asymmetric neuropathies
including mononeuropathy, cranial neuropathy, and radiculo-
plexus neuropathy (devastating painful acute disorder, presents
in the brachial or lumbosacral nerve plexus),
Often monophasic may be caused by microvascular disease.
Uremic Neuropathy
Most individuals with renal failure have peripheral neuropathy.
Typically distal, symmetric neuropathy.
May be asymptomatic or have muscle cramps, distal dysesthenia
and diminished DTR.
Axonal degeneration is the primary event, recovery are common
after dialysis.
Thyroid Dysfunction
Hypothyroidism can lead to compression mononeuropathies
such as carpal tunnel syndrome.
Distal symmetric predominantly sensory polyneuropathy.
Hypethyroidism is associated with a neuropathy resembling
Guillain-Barre Syndrome
Vitamin B12 Deficiency
Results in subacute combined degeneration with damage to long
tracts in the spinal cord and also peripheral nerves.
Other vitamin deficiencies have all been associated with
peripheral neuropathies such as: B1, B6, Folate, Vit. E, Cu, and Zn
TOXIC NEUROPATHIES
Alcohol, heavy metals, and organic solvents.
Medications can cause toxic nerve damage most notorious are
chemotherapeutic agents (vinca alkaloids, taxanes, microtubule
inhibitors that interfere with axonal transport and cisplatin
which may cause neuronopathy)
NEUROPATHIES ASSOCIATED WITH MALIGNANCY
Direct Infiltration or Compression of peripheral nerves
Common cause of mononeuropathy.
Brachial plexopathy neoplasms at apex of the lungs
Obturator palsy from pelvic malignant neoplasms
Cranial nerve palsy from intracranial tumors or tumors at the
base of the skull.
Meningeal carcinomatosis involving the cauda equine can cause
polyradiculopathy involving the lower extremities.
Paraneoplastic Neuropathies
Can occur anytime, often precede diagnosis of the tumor.
Sensorimotor neuronopathy is the most common form.
Commonly associated with lung cancer.
Antibodies that recognize proteins expressed by cancer cells and
normal neurons (e.g. anti-Hu antibodies) are often present.
Damage appears to be mediated by a CD8+ T cell attack.
Patients with anti-CV2 autoantibodies tend to present with a
mixed axonal and demyelinating sensorimotor neuropathy.
Neuropathies associated with Monoclonal Gammopathies
Neoplastic B cells may secrete monoclonal Ig or Ig fragments so-
called paraproteins that damages nerves.
IgM may be associated with demyelinating peripheral
neuropathy, the pathogenic IgM paraprotein binds to myelin-
associated antigens such as myelin associated glycoprotein.
IgG or IgA paraproteins may also be associated.
POEMS Syndrome (Polyneuropathy, Organomegaly, Endocrinopathy,
Monoclonal Gammopathy, Skin Changes) patients often develop
demyelinating neuropathy associated with deposition of
paraproteins between non-compacted myelin lamella.
Excess light chain Ig may deposit as amyloid.
NEUROPATHIES CAUSED BY PHYSICAL FORCES
Peripheral nerves are commonly injured by trauma/entrapment
Laceration results from cutting injuries and from sharp
fragments of a fractured bone.
Avulsion may occur when tension is applied, often the limb
Compression Neuropathy - (Entrapment neuropathy) occurs
when a peripheral nerve is chronically subjected to increased
pressure, often within an anatomic compartment.
Carpal Tunnel Syndrome
Most common entrapment neuropathy, due to compression of
the median nerve at the level of the wrist within the
compartment delimited by the transverse carpal ligament.
Women are more commonly affected, frequently bilateral.
Associated with edema, pregnancy, inflammatory arthritis,
hypothyroidism, amyloidosis, acromegaly, DM, and excessive
repetitive motion of the wrist.
Symptoms are limited to dysfunction of the median nerve,
includes numbness and paresthesias of the tips of thumb and
first 2 digits.
Other nerves prone to compression include:
Ulnar nerve at the level of the elbow.
Peroneal nerve at the level of the knee
Radial nerve at the level of the upper arm, occurs from
sleeping with arm in awkward position (Saturday night palsy)
Interdigital nerves found in the foot at the intermetatarsal
site, common in men, manifests as foot pain, marked by
perineural fibrosis (Moron Neuroma).
INHERITED PERIPHERAL NEUROPATHIES
Often present in adults, delayed onset.
Genes clustered into the following functionally-related groups:
Encoding myelin-associated protein
Encoding growth factors and GF receptors
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Encoding proteins that regulate mitochondrial function.
Encoding proteins involved in vesicle and axonal transport
Encoding heat-shock proteins
Encoding proteins involved in membrane structure/function
Major classifications of inherited peripheral neuropathies:
1. Hereditary motor and sensory neuropathies (CMT)
2. Hereditary motor neuropathies
3. Hereditary sensory w/ or w/o autonomic neuropathy
4. Other inherited conditions
Hereditary motor and sensory neuropathies or Charcot-Marie-
Tooth Disease (CMT)
By far the most common inherited neuropathies.
Distal muscle atrophy, sensory loss, and foot deformities.
Demyelinating forms of CMT are associated with morphology of
demyelination and remyelination (Schwann cell hyperplasia and
onion bulb formation)
More common variants:
CMT1
Autosomal dominant, most common subtype.
CMT1A - duplication of a region on chromosome 17 that
includes the peripheral myelin protein 22 (PMP22) gene.
Usually presents in the second decade of life.
Slowly progressive distal demyelinating motor and sensory
neuropathy
CMT1B mutations in myelin protein zero gene, 9% of cases.
CMTX
X-linked forms of CMT, CMT1X is the most common (15%)
Linked to mutations in the GJB1 gene, encodes for
connexin32, a gap junction component of Schwann cells.
CMT2
Autosomal dominant associated with axonal rather than
demyelinating injury.
CMT2A is the most common subtype (4%), associated with
mutations in MFN2 gene required for mitochondrial fusion.
Severe, disease onset is early childhood.
Hereditary Neuropathy w/ or w/o autonomic neuropathy
Marked by loss of sensation and variable autonomic disturbance
Loss of pain and temperature sensation is the most common.
Typically axonal neuropathies.
Hereditary Neuropathy with Pressure palsy
Caused by deletion of gene encoding for PMP22.
Transient motor and sensory mononeuropathies triggered by
compression of individual nerves at sites prone to entrapment.
Usually resolves within weeks or days.
Swollen, bulbous myelin sheaths at end of internodes called
tomaculi are characteristic morphologic features.
Familial Amyloid Neuropathies
Characterized by amyloid deposition within peripheral nerves.
Most are due to germline mutations of tranthretin gene.
Clinical presentation is similar to hereditary sensory/autonomic.
Peripheral neuropathy accompanying inherited metabolic disorders
Leukodystrophies, Porphyria, Refsum disease.
Diseases of Neuromuscular Junction 50% have underlying malignancy, most often neuroendocrine
carcinoma of the lungs.
Patients without cancer have autoimmune diseases such as
vitiligo or thyroid disease.

CONGENITAL MYASTHENIC SYNDROMES

Rare, most have autosomal recessive mode of inheritance.
Marked by varying degrees of muscle weakness.
Most common is loss-of-function mutation in the gene encoding
for the -subunit of AchR.
Most present in the perinatal period with poor muscle tone,
external eye muscle weakness, and breathing difficulties.

DISORDERS CAUSED BY TOXINS

Botulism

Disorders that impair the function of NMJ tend to present with

painless weakness.

ANTIBODY-MEDIATED DISEASES OF NMJ

Myasthenia Gravis
An autoimmune disease that is usually associated with
autoantibodies against the acetylcholine receptors (AChR).
Bimodal age distribution, more common in females in young
adults, but more common in males in older adults.

PATHOGENESIS
85% have autoantibodies against postsynaptic AchR.
Most of the remaining has antibodies against sarcolemmal
protein muscle-specific receptor tyrosine kinase.
These autoantibodies are pathogenic, as they can be passively
transferred to animals with serum from affected individuals.
Postsynaptic membranes show alteration in morphologic and are
depleted of AchR, this limits the ability of the myofibers to
respond to Ach.
Autoantibodies against muscle-specific RTK interfere with
trafficking and clustering of AchR within the sarcolemma.
10% have thymoma, 30% have thymic hyperplasia.
Marked by appearance of B-cell follicles in the thymus.
Both disrupt normal thymic function; it promotes
autoimmunity against AchR expressed in thymic myoid cells.
Caused by exposure to neurotoxin called Botox produced by the
anaerobic positive organism Clostridium botulinum.
Acts by blocking the release of Ach from presynaptic neurons.
Curare is a common name for muscle relaxants that block AchR
resulting in flaccid paralysis.
Diseases of Skeletal Muscles
During embryogenesis, skeletal muscles develop through the
fusion of mononucleated precursor cells (myoblasts) into
multinucleated myotubes that mature into myofibers.

CLINICAL FEATURES
Present with fluctuating weakness that worsens with exertion.
Diplopia and ptosis due to involvement of extraocular muscles.
Cases with Ab against muscle-specific RTK have more focal
muscle involvement.
Electrophysiologic studies reveal decrement in muscle response
with repeated stimulation, a characteristic of this disorder.
Acetylcholinesterase inhibitor that increase half-life of Ach are
the first line of treatment.

Lambert-Eaton Myasthenic Syndrome

Autoimmune disorder caused by antibodies that block Ach
release by inhibiting presynaptic calcium channels.
Rapid repetitive stimulation increases muscle response.
Present with weakness of their extremities.

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SKELETAL MUSCLE ATROPHY
Common feature of any disorder.
Loss of innervation, disuse, cachexia, old age, and primary
myopathies can all produce muscle atrophy.
Certain patterns suggest underlying etiologies:
Group of atrophic fibers are seen in neurogenic diseases
Perifascicular atrophy is seen in dermatomyositis
Type II fiber atrophy with sparing of Type I is seen with
prolonged corticosteroid therapy or disuse.
NEUROGENIC ANG MYOPATHIC CHANGES IN SKELETAL MUSCLE
Damaging myofibers directly (myopathic injury) or by disrupting
muscle innervation (neurogenic injury).
Neurogenic injuries lead to fiber type grouping and grouped
atrophy, both stem from disruption of innervation.
Following denervation, myofibers undergo atrophy, often have
flattened, angulated shape.
Reinnervation restores fiber size and shape but may make a
denervated myofiber part of a different motor unit, may lead to
switch in fiber type.
Motor axons may innervate larger numbers of myofibers leading
to enlargement of motor units, each comprised of a single type
of muscle fiber, also susceptible to grouped atrophy.
Most primary myopathic processes are associated with a distinct
set of morphologic changes:
Segmental myofiber degeneration and regeneration
Seen only when part of a myofiber undergoes necrosis
Sarcomeres are removed by myophagocytosis
Fusion of activated satellite cells to damaged myofibers.
Regenerating fibers are rich in RNA, therefore basophilic
with enlarged nuclei with prominent nucleoli.
In chronic diseases, muscles show endomysial fibrosis,
dropout of myofibers and fatty replacement.
Myofiber hypertrophy
Physiologic adaptation to exercise
Can also be seen in chronic myopathic conditions.
Cytoplasmic Inclusions
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INFLAMMATORY MYOPATHIES
Polymyositis and dermatomyositis show typical features of
autoimmune inflammatory disease, associated with HLA-DR.
Dermatomyositis
Systemic autoimmune disease that present with proximal muscle
weakness and skin changes.
Most common inflammatory myopathy in children.
PATHOGENESIS
Immunologic disease in which damage to small blood vessels
contribute to muscle injury.
Can be seen as telangiectasia (dilated capillary loops) in the nail
folds, eyelids, gums, and drop out of vessels in skeletal muscles.
Shows deposition of complement MAC (C5b-C9) within capillary.
Inflammatory signature enriched for genes that are upregulated
by Type I interferons is seen In muscle and leukocytes.
Autoantibodies associated:
Anti-Mi2 against a helicase implicated in nucleosome
remodeling, linked to Gottron papules and heliotrope rash
Anti-Jo1 against histidyl t-RNA synthetase linked to
interstitial lung disease, non-erosive arthritis, skin-rash
described as mechanics hands
Anti-P155/P140 against transcription regulators linked to
paraneoplastic and juvenile cases of dermatomyositis.
MORPHOLOGY
Biopsies show infiltrates of mononuclear inflammatory cells.
Most pronounced in the perimysial connective tissue.
Distinctive perifascicular atrophy.
IHC may identify infiltrate rich CD4+ T-helper cells and deposition
of C5b-9 in capillary vessels.
EM shows tubuloreticular endothelial inclusions.
CLINICAL FEATURES
Muscle weakness is slow in onset, symmetric, and often
accompanied by myalgias, typically affects proximal muscles first
Fine movements controlled by distal muscles are only affected
late in the disease.
Elevation of serum creatine kinase.
Various rashes, most characteristic are lilac colored discoloration
of the upper eyelids (heliotrope rash) associated with periorbital
edema and a scaling erythematous eruption or dusky red
patches over the knuckles, elbows, and knees (Gottron papules)
Dysphagia may occur in 1/3 of affected individuals.
Interstitial lung disease may occur in 10% of patients.
Cardiac involvement is common, but rarely leads to failure.
Juvenile dermatomyositis average age of onset is 7 y/o
th th
Adult dermatomyositis onset from 4 to 6 decade of life
Childhood disease is more likely to be associated with calcinosis
and lipodystrophy, overall prognosis is better in children.
Polymyositis
Adult-onset inflammatory myopathy that shares myalgia and
weakness with dermatomyositis, but lacks its cutaneous features
A diagnosis of exclusion.
Similar autoantibodies.
PATHOGENESIS
Uncertain, believed to have an immunologic basis.
CD-8+ cytotoxic T cells are prominent part.
Vascular injury does not have a major role
MORPHOLOGY
Mononuclear inflammatory infiltrates are present, usually
endomysial in location.
Degenerating necrotic, regenerating, and atrophic myofibers are
typically found in a random or patchy distribution.
Perifascicular atrophy is absent.
Inclusion Body Myositis
Disease of late adulthood, affects patients older than 50.
Most common myopathy in patients older than 65 years.
Slow progressive muscle weakness, most severe in quadriceps
and distal upper extremity muscles.
Dysphagia is common, elevated creatine kinase, autoantibodies
are absent, but antibody to cN1A has recently been described.
MORPHOLOGY
Features similar to polymyositis:
Patchy, endomysial mononuclear cells (CD8)
Increased sarcolemmal expression of MHC I
Focal invasion of myofibers by inflammatory cells.
Admixed degenerating and regenerating myocytes.
More typical changes or specific for inclusion body myositis:
Abnormal cytoplasmic inclusions rimmed vacuoles
Tubulofilamentous inclusions in myofibers.
Cytoplasmic inclusions associated with neurodegenerative
disorders such as beta-amyloid, TDP-43, and ubiquitin.
Endomysial fibrosis and fatty replacement
Inclusion body myopathy familial inclusion myopathies linked
to chronic myopathic changes and rimmed vacuoles, lacking the
inflammation.
Corticosteroids are first-line for polymyositis & dermatomyositis
Immunosuppressive drugs are used for steroid-resistant diseases
or as steroid-sparing agents.
Intravenous immunoglobulins, cyclophosphamide, cyclosporine,
and rituximab are third-line agents.
Inclusion body myositis poorly responds to steroids or
immunosuppressive therapies.
TOXIC MYOPATHIES
Statins are the leading culprits; myopathy is the most common
complication of statins.
Chloroquine and Hydroxychloroquine interfere with lysosomal
function and cause drug-induced lysosomal storage myopathy.
Slowly progressive muscle weakness.
Muscle show myopathic changes including vacuolization that
predominantly affects type I fibers.
Aggregates of whorled, lamellar membranous structures.
ICU myopathy or myosin deficient myopathy
Seen in patients in ICU especially with steroid therapy.
Relatively selective degradation of sarcomeric myosin
filaments producing profound weakness.
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Thyrotoxic myopathy
Presents most common as acute/chronic proximal weakness
May also present with exophthalmic ophthalmoplegia
swelling of the eyelids, edema of conjunctiva, and diplopia.
Hypothyroidism can cause cramping or aching of muscles.
Reflexes may be slowed.
Fiber atrophy, increase number of abnormally localized
nuclei, glycogen aggregates, and mucopolysaccharide deposit
Alcohol
Binge drinking may produce acute toxic syndrome of
rhabdomyolysis, myoglobinuria, and renal failure.
Acute myalgias which may be confined or generalized.
INHERITED DISEASES OF SKELETAL MUSCLES
Heart is of importance since its common and life-limiting.
See Table 27-2, Robbins 9th Ed., Page 1241 for summary
Congenital myopathies present in infancy with muscle defects
that tend to be static or to even improve over time, often
associated with distinct structural abnormalities of the muscle.
Muscular dystrophies progressive muscle damage that comes
to attention after infancy, except congenital muscular dystrophy,
includes two important groups:
Conditions with defects in ECM surrounding myofibers
Exemplified by Ullrich Congenital Dystrophy (UCMD) and
merosin deficiency.
In UCMD, causative mutation involve one of three collagen
VI alpha genes. In merosin, the gene encoding for it is
disrupted.
UCMD proximal contractures, distal hyperextensibility,
and hypotonia, morphologic hallmark is mismatched
expression of normally co-localized matrix proteins
perlecan and collagen VI.
Conditions with abnormalities in receptors for ECM
Disrupt the post-translational modification of alpha-
dystroglycan by O-linked glycosylation.
Alpha-dystroglycan is important for CNS and eye devt.
Muscular Dystrophies
Common progressive muscle damage that typically manifests
itself between childhood and adulthood.
X-linked Muscular Dystrophy with Dystropin Mutation
Duchenne and Becker Muscular Dystrophy
Most common muscular dystrophies are X-linked and stem from
mutations that disrupt the function of a large structural protein
called dystrophin.
Duchenne muscular dystrophy most common early onset form
Becker muscular dystrophy second common dystrophinopathy
characterized by later onset and milder phenotype.
Present with isolated cardiomyopathy, asymptomatic elevation
in creatine kinase, myalgias and cramps.
PATHOGENESIS
Both are caused by loss-of-function mutations in the dystrophin
gene on the X-chromosome, it is a key component of the
dystrophin glycoprotein complex (DCG).

Serves as a link of the cytoskeletons inside to the outside.
Amino terminus of dytrophin binds actin filaments, while the
carboxy terminus binds beta-dystroglycan.
Provides mechanical stability to the myofiber and its cell
membrane during muscle contraction.
Defects in the complex may lead to small membrane tears that
permit calcium influx triggering myofiber degeneration.
Carboxy terminus also interacts with nitric oxide synthase.
Duchenne muscular dystrophy associated with deletions or
frame shift mutations that result in total absence of dystrophin.
Becker muscular dystrophy permit the synthesis of a truncated
version of dystrophin, which retains some function
MORPHOLOGY
Changes in the two are similar but differ in degree.
Marked by chronic muscle damage that outplaces repair.
Ongoing damage in form of segmental myofiber degeneration
and regeneration with an atrophic myofibers.
Fascicular architecture is preserved at this stage of disease.
Usually no inflammation, but with myophagocytosis.
Muscle tissue is replaced by collagen and fat cells (fatty
replacement or fatty infiltration).
IHC for dystrophin show absence of normal sarcolemmal staining
pattern in Duchenne muscular dystrophy and reduced staining in
Becker muscular dystrophy.
CLINICAL FEATURES
Boys with Duchenne muscular dystrophy are normal at birth.
Walking is often delayed.
First indications are clumsiness & inability to keep up with peers
Begins in the pelvic girdle then extends to the shoulder girdle.
Enlargement of muscle of lower leg associated with weakness
termed pseudohypertrophy, is often present.
Mean age for wheel-chair dependence is 9.5 years old.
Develops joint contractures, scoliosis, worsening respiratory
reserve and sleep hypoventilation.
Dystrophin deficiency in cardiac muscle leads to development of
cardiomyopathy and arrhythmias, particularly in older patients.
May produce mental retardation.
Mean age of death is 25-30 years of age, due to respiratory
insufficiency, pulmonary infection, or heart failure.
In Becker muscular dystrophy presents in later childhood,
adolescence or adult life, more slowly progressive.
Diagnosis based on history, PE, and laboratory studies.
st
Serum creatine kinase markedly elevated during 1 decade.
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Creatine kinase falls as dse progress & muscle mass is lost.
Current treatment consists of primary supportive care.
Definitive therapy requires restoration of dystrophin levels.
Myotonic Dystrophy
Autosomal dominant multisystem disorder associated with
skeletal muscle weakness, cataracts, endocrinopathy, and
cardiomyopathy.
Myotonia a sustained involuntary contraction of muscles, is a
key feature of this disease.
PATHOGENESIS
Caused by expansion of CTG repeats in the 3-noncoding region
of the myotonic dystrophy protein kinase (DMPK) gene.
Skeletal muscle phenotype stems from a toxic gain-of-function
mutation caused by the triple repeat expansion.
CUG-repeats transcript appear to bind and sequester a protein
called muscleblind-like1 which has an important role in RNA
splicing, the protein inhibits the muscleblind-like1 function.
RNA splicing defect causes missplicing including the transcript of
CCL1 a chloride channel. Deficiency of CCL1 is believed to be the
cause of myotonia.
Emery-Dreifuss Muscular Dystrophy
EMD is caused by mutations in genes that encode nuclear lamina
proteins, marked by a triad of:
1. Slowly progressive humeroperoneal weakness
2. Cardiomyopathy associated with conduction defects
3. Early contractures of Achilles tendon, spine, and elbows
X-linked (EDM1) and autosomal form (EDM2) are caused by
mutations in the genes encoding emerin and laminin A/C,
respectively, both localize to the inner face of nuclear membrane
These proteins help maintain the shape and mechanical stability
of the nucleus during muscle contraction.
Fascioscapulohumeral Dystrophy
Characteristic pattern involvement that includes prominent
weakness of facial muscles and muscles of shoulder girdle.
PATHOGENESIS
Involves overexpression of gene called DUX4 that is located in a
region of subteleomeric repeats on long arm of chromosome 4.
The disease is confined to those who also inherit creatin SNPs at
positions immediately 3 of the DUX4 coding sequence.
Limb-Girdle Muscular Dystrophy
Heterogeneous group of at least 6 autosomal dominant and 15
autosomal recessive entities.
All forms are characterized by muscle weakness, preferentially
involves proximal muscle groups.
Implicated genes encoding for:
Structural components (sarcoglycans) of the dystrophin
glycoprotein complex
Enzymes responsible for glycosylation of -dystroglycan, a
component of the dystrophin glycoprotein complex
Proteins associated with Z-disks of sarcomere
Proteins involved in vesicle trafficking and cell signaling.
Genes that stand alone, like protein calpain3 and laminin A/C
Diseases of Lipid of Glycogen Metabolism
Tends to produce 2 general patterns of muscle dysfunction:
Some become symptomatic only when exercising or fasting,
which may produce severe muscle cramping and pain.
Some have extensive muscle necrosis (rhabdomyolysis)
Carnitine Palmitoyltransferase II deficiency
Most common disorder of lipid metabolism.
Causes episodic muscle damage with exercise or fasting.
Defect impairs the transport of FFA into the mitochondria.
Myophosphorylase deficiency (McArdle disease)
More common glycogen storage diseases affecting muscles.
Results in episodic muscle damage with exercise.
Acid Maltase deficiency
Impaired lysosomal conversion of glycogen to glucose.
Glycogen accumulation within the lysosomes.
Severe deficiency results in generalized glycogenosis of infancy,
Pompe disease.
Mitochondrial Myopathies
Complex systemic conditions that involve many organ systems.
May appear to impair the ability of mitochondria to produce ATP
Tends to affect skeletal muscle and other tissues with high ATP
requirements (cardiac and nerve muscles).
Skeletal involvement can manifest as weakness, elevation of
serum creatine kinase, or rhabdomyolysis.
Chronic progressive external ophthalmoplegia is a common
feature, may be in isolation or as part of multisystem disease.
MORPHOLOGY
Most consistent change is abnormal aggregates of mitochondria
seen in the subsarcolemmal area of affected fiber producing an
appearance referred as ragged red fibers.
On EM, morphologically abnormal mitochondria are seen.
CLINICAL FEATURES
Single point mutations in the mitochondrial leucine tRNA gene
may have isolated chronic progressive external opthalmoplegia.
Severe phenotype may have mitochondrial encephalomyopathy
with lactic acidosis and stroke-like episodes.
Deletions in mtDNA may lead to isolated ophthalmoplegia or
Kearns-Sayre syndrome ophthalmoplegia, pigmentarty
degeneration of the retina, and complete heart block.
Myoclonic epilepsy with ragged fiber and Leber hereditary optic
neuropathy are other examples.
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Spinal Muscular Atrophy and the Differential Diagnosis of a
Hypotonic Infant
Spinal muscular atrophy is a neuropathic disorder in which loss
of motor neurons lead to muscle weakness and atrophy.
Infants may present with generalized hypotonia (floppy infant)
Differential diagnosis:
Primary diseases of skeletal muscle
Abnormalities of the brain
Neuronopathies
Autosomal recessive, caused by loss-of-function mutations in
SMN1 gene, function is uncertain, but SMN1 deficiency has
dramatic effect on motor neuron survival.
Resulting denervation may lead to characteristic morphologic
change consist of large zones of severely atrophic myofibers
mixed with scattered normal sized or hypertrophied fibers.
Ion Channel Myopathies (Channelopathies)
Mutations affecting the function of ion channel proteins.
Most are autosomal dominant with variable penetrance.
May present with epilepsy, migraine, movement disorders with
cerebellar dysfunction, peripheral nerve or muscle disease.
Disorders associated with hypotonia can be sub-classified based
on whether patient have hyperkalemic, hypokalemic, or
normokalemic periodic paralysis.
Mutated genes associated with muscle dysfunction:
KCNJ2 affect K+ channel, causes Andersen-Twail syndrome,
autosomal, associated with periodic paralysis, heart
arrhythmias, and skeletal abrnomalities.
SCN4A affect Na+ channel, myotonia to periodic paralysis
CACNA1S missense mutation, a subunit of muscle calcium
channel, most common cause of hypokalemic paralysis.
CLC1 mutations in Cl channels, cause myotonia congenita
RYR1 disrupts function of ryanodine receptors, linked to
congenital myopathy and malignant hyperthermia.
Peripheral Nerve Sheath Tumors
Malignant or benign, majority are composed of cells that show
evidence of Schwann cell differentiation
Three common types: schwannoma, neurofibroma and malignant
peripheral nerve sheath tumor (MPNST)
Abrupt transition between central and peripheral myelination
that occurs as nerves extend out from the brain
Arise within the dura & distal course of the peripheral nerves
Familial Tumor Syndromes (NF1, NF2, schwannomatosis)
Schwannomas
Benign tumors that exhibit Schwann cell differentiation and arise
directly from peripheral nerves
Component of NF2 loss of expression of the NF2 gene product,
merlin, is a consistent finding in schwannomas
Morphology
Well-circumscribed, encapsulated masses that abut the
associated nerve without invading it
Firm, gray masses, comprised of an admixture of dense and loose
areas referred to as Antoni A (Hypercellular) and B
(Hypocellular), respectively
Verocay Bodies the regions of palisading nuclear material
Characterized by presence of a spindled elongated nucleus with a
wavy or buckled shape
EM: basement membrane deposits encasing single cells and
collagen fibers
Silver stains or Immunostains: axons are largely excluded from the
tumor, although trapped in the capsule
Degenerative changes: nuclear pleormorphism, xanthomatous
change, vascular hyalinization, cystic change, necrosis and mitotic
activity
Clinical Features
Local compression of involved nerve or adjacent structures
Most often in the cerebellopontine angle, attached to the
vestibular branch of the eight nerve (acoustic neuroma)
tinnitus and hearing loss
Sensory nerves like branches of trigeminal and dorsal roots may
also be involved
Surgical removal is curative
Neurofibromas
Benign nerve sheath tumors that are more heterogeneous in
composition than schwannomas
Neoplastic Schwann cells are admixed with perineural-like cells,
fibroblasts, mast cells and CD34+ spindle cells
Sporadic or NF1 associated
Different types:
Superficial cutaneous neurofibromas present as pedunculated
nodules, isolated: sporadic; multiple: NF1
Diffuse neurofibromas large plaque-like elevation of skin, NF1
Plexiform neurofibromas deep or superficial in nerve roots or
large nerves, NF1
Pathogenesis
Show complete loss of neurofibromin (NF1 gene product)
Plexiform and dermal neurofibromas arise from different neural
crest derived precursor cells
Transformation to MPNST is seen in plexiform neurofibromas
Morphology
Localized Cutaneous Neurofibroma small, well-delineated, un-
encapsulated nodular lesions arising in the dermis and SQ fat.
Low cellularity with entrapped adnexal structures at the edge
of the lesion. Stroma contains loose collagen
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Diffuse neurofibroma similar to LCN but with different growth
pattern, infiltrating the dermis and SQ connective tissue,
entrapping fat and appendage structures producing plaque-like
appearance
Large, focal collections of pseudo Meissner corpuscles or
tactile-like bodies
Plexiform neurofibroma grow within and expand nerve
fascicles, entrapping axons
Bag of worms appearance of expanded nerve fascicles
Shredded carrot appearance of collagen bundles
Malignant Peripheral Nerve Sheath Tumors (MPNST)
85% are high grade tumors
50% in NF1 patients plexiform transformation
Sporadic are de novo
Larger peripheral nerves in the chest, abdomen, pelvis, neck or
limb-girdle
Morphology
Poorly defined mass that infiltrate along the axis of the parent
nerve and invade adjacent soft tissues
Typical cases show fasciculated arrangement of spindle cells
Marble-ized due to variations in cellularity: mitoses, necrosis
and anaplasia are common.
Divergent differentiation presence of focal areas that exhibit
other lines of differentiation (glandular, cartilaginous, osseous or
rhabdomyoblastic)
Triton tumor rhabdomyoblastic morphology
Neurofibromatosis Type 1 and 2
Neurofibromatosis Type 1
AD systemic disease associated with neoplastic and non-
neoplastic manifestations
Neoplastic lesions may be: neurofibromas, MPNTS, gliomas of the
optic nerve, glial, hamartomatous lesions, pheochromocytomas
Mental retardation, seizures, skeletal defects pigmented nodules
of the iris (Lisch nodules) and cutaneous hyperpigmented macules
(cafe au lait spots)
Distribution is attributable to mosaicism
Loss of function of NF1 gene encoding for neurofibromin
Neurofibromatosis Type II
th
AD disorder resulting in a range of tumors (bilateral 8 nerve
schwannomas, multiple meningiomas, gliomas and ependymomas
of the spinal cord)
Schwannosis, meningioangiomatosis and glial hamartia are the
non-neoplastic lesions
Less common than NF1
Loss of function in NF2 encoding for merlin a cytoskeletal protein