Pathology Ch27 -- Peripheral Nerves and Skeletal Muscle -- PARTIAL pp1227-1235 (Peripheral Nerves)
Disease of Peripheral Nerves
 Somatic Motor Function
1. Lower motor neuron located in anterior horn of the spinal cord or in the brainstem
2. Axon that travels to target muscel as aprt of a nerve
3. Neuromuscular junctions
4. Multiple innervated myofiber (muscle fibers)
 Somatic Sensory Function
1. Distal nerve endings, may contain specialized structures that register specific sensory modalities
2. Axon that travels as part of a peripheral nerve to the dorsal root ganglia
3. Proximal axon segment that synapses on neurons in the spinal cord or brain stem
 Sensations and Motor Signals
o Axons can be distinguished based on their diameter (correlated to myelin sheath thickness and conduction speeds)
 Thin unmyelinated fibers > autonomic functions + pain and temperature sensation
 Larger diameter axons w/ thick sheaths > light touch and motor signals
o Schwann cells > make one myelin sheath > create "internode" segment, separated by "nodes of Ranvier"
o Axons bundled by 3 CT components:
 Epineurium: encloses entire nerve
 Perineurium: multilayered concentric sheath that groups subsets of axons into fascicles
 Endoneurium: surrounds individual nerve fibers
 General Types of Peripheral Nerve Injury
o Axonal Neuropathies (axons are primary targets of damage)
 Morphological hallmark: Wallerian degeneration, produced experimentally via transsection
 Distal to transsection > disconnected from CNS and degenerate within days
o Macrophages remove axonal and myelin debris
o Distal myofibrils atrophy
 Regeneration starts at proximal site of transecretion w/ formation of growth cone
o Schwann cells and baement membranes guide the sprouting axons > grow 1mm/day
o Continuous pruning removes misguided axon branches
o Schwann cells create new myelin sheath, but internodes tend to be thinner/shorter
 Successful only if transsected ends remain in close proximetry
o If axons can't find distal target > produce psuedotumor aka traumatic neuroma
o >> whorled proliferation of axonal processes and Schwann cells > painful nodule
 In vivo: degenerating and regenerating axons coexist > damage outpaces repair > progressive axon loss
 Electrophysiologic: reduction in signal strength
o Demyelinating Neuropathies (Schwann cells are the primary targets of damage)
 Individual myelin sheaths degenerate in random pattern > discontinuous damage
 Schwann cells proliferate and initiate repair > again, shorter and thinner than before
 Electrophysiologic: slowed nerve conduction velocity
o Neuronopathies (destruction of neurons > secondary degeneration of axonal processes)
 Infections (herpes zoster) and toxins (platinum compounds) are examples of insults
 Damage at neuronal cell body > peripheral nerve dysfxn equal in proximal & distal parts of the body
 Anatomic Patterns of Peripheral Neuropathies
o Mononeuropathies: affect a single nerve > deficits in restricted distribution
o Polyneuropathies: affect multiple nerves (usually symmetrically) > deficits start in feet and ascend w/ progression
 Hands begin by the time disease progressed to knees > "stocking and glove" distribution of sensory deficit
o Mononeuritis multiplex: affects several nerves haphazardly > ex. L wrist drop and R foot drop
o Polyradiculoneuropathies: affect nerve roots + peripheral nerves > diffuse symmetric symptoms (proximal + distal)
 Specific Peripheral Neuropathies
o Inflammatory Neuropathies
 Guillain-Barre Syndrome (Acute Inflammatory Demyelinating Polyneuropathy)
 Pathogenesis: acute-onset immune-mediated demyelinating neurpathy
o 2/3 cases preceded by acute flu-like illness
o T-cell-mediated immune response > segmental demyelination via active macrophages
 Morphology: inflammation and demyelination of spinal nerve roots and peripheral nerves
 Clinical features: ascending paralysis (distal muscles > proximal muscles) and areflexia
o Complication leads to death: respiratory paralysis, autonomic instability, cardiac arrest
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Chronic Inflammatory Demyelinating Poly(radiculo)neuropathy
 Most common chronic acquired inflammatory peripheral neuropathy
 Pathogenesis: T cells and humoral factors implicated in inflammatory process
o Molecules at Schwann cell-axon juction targetted by immune response
o Complement-fixing IgG and IgM found on myelin sheath > recruit macrophages
 Morphology: repeat demyelination and remyelination > "onion-bulb" structures
 Clinical features: symmetrical mixed sensorimotor polyneuropathy, persists for 2+ months
 Neuropathy Associated w/ Systemic Autoimmune Disease
 Associated w/ rheumatoid arthritis, Sjogren syndrome, systemic lupus erythematosus (SLE)
 Can manifest as distal sensory or sensorimotor polyneuropathies
 Neuropathy Associated w/ Vasculitis (noninfectious inflammation of blood vessels)
 1/3 of pt w/ vasculitis have peripheral nerve involvement and neuropathy
 Often presents as mononeuritis multiplex (can be mononeuritis or polyneuropathy)
 Peripheral nerves show patchy axonal degeneration and loss
 Perivascular inflammatory infiltrates often present
Infectious Neuropathies
 Leprosy (Hansen Disease)
 Lepromatous leprosy
o Schwann cells invaded by mycobacterium leprae
o Demyelination and remyelination and loss of axons
o Progresses to endoneurial fibrosis and multilayered thickening of perineurial sheath
o Develop symmetric polyneuropathy (most severe in cool distal extremities and in face)
o Infection prominently involves pain fibers > loss of pain sensation
 Tuberculoid leprosy
o Active cell-mediated immuner esponse to M. leprae
o Manifest as dermal nodules containing granulomatous inflammation
o Injures cutaneous nerves in the vicinity
o Axons, Schwann cells, myelin are lost > fibrosis of perineurium and endoneurium
o Much more localized nerve involvement
 Lyme Disease
 Neurologic manifestations in second and third stages of disease
 Polyradiculoneuropathy and unilateral or bilateral facial nerve palsies
 HIV/AIDS
 HIV > peripheral neuropathy due to immune dysregulation
 Early stage = mononeuritis multiplex and demyelinating disorders or chronic inflammatory
demyelinating polyradiculoneuropathy
 Later stages = distal sensory neuropathy (often painful)
 Diphtheria
 Diphthernia exotoxin produces acute peripheral neuropathy
 Associated w/ prominent bulbar and respiratory muscle dysfunction > disability/death
 Varicella-Zoster Virus
 One of the most common viral infections of the PNS
 Following chickenpox, latent infection persists within neurons of sensory ganglia
 If reactivated later on > transported along sensory nerves to skin > infects keratinocytes
 Painful, vesicular skin eruption (shingles) in distribution that follows sensory dermatomes
 Decreased cell-mediated immunity though to play a role in reactivation
Metabolic, Hormonal, and Nutritional Neuropathies
 Diabetes
 Most common cause of peripheral neuropathy
 Prevalence depends on duration of disease (50% overall, 80% of those w/ 15 years)
 Pathogenesis: metabolic and vascular changes contribute to damage of neurons/Schwann cells
o Nonenzymatic glycosylation > advanced glycosylation end products (AGEs) > interfere
w/ normal protein function > activate inflammatory signaling
 Morphology: axonal neuropathy
 Clinical features: ascending distal symmetric sensorimotor polyneuropathy MOST COMMON
o Numbness, loss of pain sensation, difficulty w/ balance, paresthesias or dysesthesias
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Can also cause dysfunction of the ANS > postural hypotension, incomplete bladder
emptying, sexual dysfunction
 Other Metabolic, Hormonal, and Nutritional Neuropathies
 Uremic neuropathy: most renal failure pts have peripheral neuropathy, recover after dialysis
 Thyroid dysfunction: hypothyroidism > compression mononeuropathies or distal symmetric
sensory polyneuropathy
 Vitamin B12 (cyanocobalamin) deficiency: subacute degeneration and damage to long tracts in
spinal cord and peripheral nerves
 Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), folate, vitamin E, copper, and zinc
Toxic Neuropathies
 After exposure to industrial or environmental chemicals, biologic toxins, or chemotherapeutic drugs
 Alcohol, heavy metals (lead, mercury, arsenic, thallium), and organic solvents
Neuropathies Associated w/ Malignancy
 Direct infiltration or compression of peripheral nerves by tumor > brachial plexopathy (apex of lung),
obturator palsy (pelvic neoplasms), cranial nerve palsies (intracranial tumors), polyradiculopathy of lower
extremities (cauda equina infiltrated)
 Radiation, poor nutrition and infection, along w/ chemotherapy > damage nerves
 Paraneuropastlic neuropathies > sensorimotor neuronopathy is the most common (small cell lung cancer)
 Neuropatheis associated w/ monoclonal gammopathies > neuplastic B cells secrete monoclonal
immunoglobulins (IgM, IgG, IgA) > damage nerves
Neuropathies Caused by Physical Forces
 Lacerations > cutting injuries or sharp fragments of fractured bone
 Avulsion > results of tension being applied, often to one of the limbs
 Compression (entrapment) neuropathy > peripheral nerve chronically subjected to increased pressure
 Ex. carpal tunnel syndrome
 "Saturday night palsy" = sleeping w/ arm in awkward position
Inherited Peripheral Neuropathies
 Group of genetically diverse disorders w/ overlapping clinical phenotypes that often present in adults
 Subsets of involved genes grouped based on coding for the following:
 Myelin-associated proteins
 Growth factors and growth factor receptors
 Proteins that regulate mitochondrial function
 Proteins that are involved in vesicle and axonal transport
 Heart shock proteins, which may prevent protein aggregation
 Proteins that are involved in cell membrane structure or function
 Hereditary motor and sensory neuropathies (Charcot-Marie-Tooth disease)**
 Distal muscle atrophy, sensory loss, and foot deformities
 CMT1: duplication of region on c17 for peripheral myelin protein 22 (PMP22) gene
 CMTX: mutation in GJB1 gene (encodes connexin32, a gap junction component in Schwann cells)
 CMT2: associated w/ axonal rather than demyelinating injury > MFN2 gene mutation
 Hereditary sensory neuropathies, w/ or w/o autonomic neuropathy
 Typically axonal neuropathies
 Loss of sensation (pain and temperature most common) and variable autonomic disturbances
 Hereditary neuropathy w/ pressure palsy
 Caused by deletion of PMP22 gene
 Transient motor and sensory mononeuropathies, triggered by compression
 Symptoms usually resolve within days/weeks, but some progress to chronic disease
 Morphology: swollen, bulbous myelin sheaths at end of internodes ("tomaculi")
 Familial amyloid polyneuropathies
 Germ line mtuation of transthyretin gene
 Amyloid deposition within peripheral nerves
 Peripheral neuropathy accompanying inherited metabolic disorders
 Leukodystrophies (ex. adrenoleukodystrophy, porphyria, Refsum disease)