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
§ 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
o 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
o 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
o 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
o Toxic Neuropathies
§ After exposure to industrial or environmental chemicals, biologic toxins, or chemotherapeutic drugs
§ Alcohol, heavy metals (lead, mercury, arsenic, thallium), and organic solvents
o 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
o 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
o 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)