Peripheral Nerves and

Skeletal Muscles

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Diseases of Peripheral Nerves
• The two main components of PNS…

• Functions of PNS:
• Somatic motor function
• Somatic sensory function
• Autonomic nerve fibers

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• General Types of Peripheral Nerve Injury:
Axonal Neuropathies
Demyelinating Neuropathies

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• Peripheral neuropathies can be separated into several groups
according to the anatomic distribution of involvement:
• Mononeuropathies
• Polyneuropathies
• Mononeuritis multiplex
• Polyradiculoneuropathies

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Specific Peripheral Neuropathies
• Inflammatory Neuropathies
• Infectious Neuropathies
• Metabolic, Hormonal, and Nutritional Neuropathies
• Neuropathies Associated with Malignancy
• Neuropathies Caused by Physical Forces
• Inherited Peripheral Neuropathies
• Toxic Neuropathies

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Inflammatory Neuropathies
Guillain-Barré Syndrome
• A demyelinating peripheral neuropathy that may lead to life-
threatening respiratory paralysis.

• “Ascending paralysis”

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Pathogenesis
• In most cases thought to be an acute-onset immune-mediated
demyelinating neuropathy.

• Approximately two thirds of cases are preceded by an acute,

influenza-like illness.

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MORPHOLOGY
• The dominant histopathologic finding is inflammation of peripheral
nerves.

• Segmental demyelination affecting peripheral nerves is the most

prominent lesion.

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Clinical Features
• The clinical picture is dominated by ascending paralysis and areflexia.

• CSF protein levels are elevated and there is little or no CSF

pleocytosis.

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• Many patients spend weeks in hospital intensive-care units before
recovering normal function.

• Plasmapheresis and intravenous immunoglobulin appear to be

beneficial.

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Chronic Inflammatory Demyelinating
Poly(radiculo)neuropathy
• This is the most common chronic acquired inflammatory peripheral
neuropathy.

• Characterized by symmetrical mixed sensorimotor polyneuropathy

that persists for 2 months or more.

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• T cells as well as humoral factors are implicated in the inflammatory
process.

• Complement-fixing IgG and IgM can be found on the myelin sheath.

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• Sural nerve biopsies show evidence of recurrent demyelination and
remyelination associated with proliferation of Schwann cells.

• Immunosuppressive therapies
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Infectious Neuropathies
Leprosy (Hansen Disease)
• Lepromatous leprosy:
• Schwann cells are invaded by Mycobacterium leprae, which proliferate and
eventually infect other cells.

• Segmental demyelination and remyelination

• Affected individuals develop a symmetric polyneuropathy

• Large traumatic ulcers may develop

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• Tuberculoid leprosy:
• Inflammation injures cutaneous nerves

• Localized nerve involvement.

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Metabolic, Hormonal, and Nutritional
Neuropathies
Diabetic Neuropathy
• The most common cause of peripheral neuropathy.

• Ascending distal symmetric sensorimotor polyneuropathy is the most

common.

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Pathogenesis
• Both metabolic and secondary vascular changes are believed to
contribute to the damage of neurons and Schwann cells.

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MORPHOLOGY
• Nerve biopsies show reduced numbers of axons.

• Variable degrees of ongoing axonal damage, marked by degenerating

myelin sheaths and regenerative axonal clusters, may be present.

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Clinical Features
• Numbness, loss of pain sensation, difficulty with balance, and
paresthesias or dysesthesias.

• Neuropathy leads to considerable morbidity.

• ANS manifestations

• Peripheral neuropathy that manifests with asymmetric presentations

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Neuropathies Associated with Malignancy
• Direct infiltration or compression of peripheral nerves; dependent on
the sites

• Complications of chemotherapy, radiation, poor nutrition and

infection.

• Paraneoplastic neuropathies

• Neuropathies associated with monoclonal gammopathies.

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Neuropathies Caused by Physical Forces

Inherited Peripheral Neuropathies

Toxic Neuropathies

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Diseases of the Neuromuscular Junction
• Regardless of cause, present with painless weakness.

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Antibody-Mediated Diseases of the
Neuromuscular Junction
Myasthenia Gravis
• Autoimmune disease.

• The female-to-male ratio is 2 : 1 in the young adults, but in older

adults there is a male predominance

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Pathogenesis
• About 85% of patients have autoantibodies against postsynaptic
acetylcholine receptors.

• Strong association with thymic abnormalities

• Antibodies against muscle-specific receptor tyrosine kinase

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Clinical Features
• Fluctuating weakness that worsens with exertion and often over the
course of the day.

• Diplopia and ptosis

• Dx

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• Acetylcholinesterase inhibitors

• Plasmapheresis and immunosuppressive drugs

• Thymectomy

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Lambert-Eaton Myasthenic Syndrome
• Autoimmune disorder.

• In contrast to myasthenia gravis, rapid repetitive stimulation increases

muscle response.

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Diseases of Skeletal Muscle
Skeletal Muscle Atrophy

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Inflammatory Myopathies
• Dermatomyositis

• Polymyositis

• Inclusion body myositis

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Dermatomyositis
• A systemic autoimmune disease that typically presents with proximal
muscle weakness and skin changes.

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Pathogenesis
• An immunologic disease in which damage to small blood vessels
contributes to muscle injury.

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MORPHOLOGY
• Muscle biopsies of affected patients show infiltrates of mononuclear
inflammatory cells that tend to be most pronounced in the perimysial
connective tissue and around blood vessels.

• Perifascicular atrophy.

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Clinical Features
• Muscle weakness is slow in onset, symmetric, and often
accompanied by myalgias; typically involving the proximal muscles
first.

• Elevation in serum creatine kinase levels

• Juvenile and adult forms are recognized.

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• Heliotrope rash and Gottron papules

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Polymyositis
• An adult-onset inflammatory myopathy that shares myalgia and
weakness with dermatomyositis but lacks its distinctive cutaneous
features.

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MORPHOLOGY
• Mononuclear inflammatory cell infiltrates are present, but in contrast
to dermatomyositis, these are usually endomysial in location.

• Degenerating necrotic, regenerating, and atrophic myofibers are

typically found in a random or patchy distribution.

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Inclusion Body Myositis
• The most common inflammatory myopathy in patients older than age
65 years.

• Most affected individuals present with slowly progressive muscle

weakness that tends to be most severe in the quadriceps and the
distal upper extremity muscles.

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MORPHOLOGY
• Abnormal cytoplasmic inclusions described as “rimmed vacuoles”

• Tubolofilamentous inclusions in myofibers, seen by electron microscopiy

• Cytoplasmic inclusions containing proteins typically associated with

neurodegenerative diseases.

• Endomysial fibrosis and fatty replacement

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Inherited Diseases of Skeletal Muscle
Muscular Dystrophies
• Include several inherited disorders of skeletal muscle that have in
common progressive muscle damage that typically manifests itself
between childhood and adulthood.

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Duchenne and Becker Muscular Dystrophy
• The most common muscular dystrophies are X-linked and stem from
mutations of dystrophin.

• Duchenne muscular dystrophy

• Becker muscular dystrophy

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Pathogenesis
• Duchenne and Becker muscular dystrophy are caused by loss-of-
function mutations in the dystrophin gene on the X chromosome.

• Dystrophin, is a key component of the dystrophin glycoprotein

complex (DGC)

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MORPHOLOGY
• The changes in Duchenne and Becker muscular dystrophy are similar,
but differ in degree.

• Muscle biopsies in young boys show ongoing damage in the form of

segmental myofiber degeneration and regeneration associated with an
admixture of atrophic myofibers.

• As the disease progresses, muscle tissue is replaced by collagen and fat

cells
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Clinical Features
• Boys with Duchenne muscular dystrophy are normal at birth.
• The first indications of muscle weakness are clumsiness and inability to keep
up with peers.

• Pseudohypertrophy.

• The mean age of wheel chair dependence is around 9.5 years.

• Dystrophin is also expressed in the heart and the central nervous system,
hence both are affected.
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• Becker muscular dystrophy:
• presents in later childhood, adolescence or adult life.

• Its course is more slowly progressive often with a near normal life expectancy.

• Dx and Rx

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Peripheral Nerve Sheath Tumors
Schwannomas
• These are benign tumors that exhibit Schwann cell differentiation and
often arise directly from peripheral nerves.

• Loss of expression of the NF2 gene product, merlin, is a consistent

finding in all schwannomas.

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MORPHOLOGY
• Grossly, firm, gray masses.

• Microscopically, they are comprised of an admixture of dense and

loose areas referred to as Antoni A and Antoni B areas.

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Clinical Features
• Most Schwannomas cause symptoms by local compression of the
involved nerve or adjacent structures

• Within the cranial vault, most schwannomas occur at the

cerebellopontine angle, where they are attached to the vestibular
branch of the eighth nerve.

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Neurofibromas
• Neurofibromas are benign nerve sheath tumors that are more
heterogeneous in composition than schwannomas.

• Neurofibromas may be either sporadic or NF1-associated.

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Pathogenesis
• Only the Schwann cells in neurofibromas show complete loss of the
NF1 gene product, neurofibromin, indicating that these are the
neoplastic cells.

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MORPHOLOGY
• Schwann cells admixed with stromal cells such as mast cells,
perineurial cells, CD34+ spindle cells, and fibroblasts.

• Different types depending on their growth pattern:

• Localized cutaneous neurofibroma
• Diffuse neurofibroma
• Plexiform neurofibroma

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THANKS…
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