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					          Peripheral Nervous System

            James A. Weyhenmeyer
515 Medical Sciences Bldg/346 Henry Admin Bldg
                   265-5440
             weyhen@uillinois.edu
Injury
• Slight injury affects myelin; more severe
  affects myelin and axon; most severe disrupts
  connective tissue
•   3 classes of injury
     ▫ Class 1 – conduction block (by e.g. transient ischemia (rapidly
        reversible) or paranodal demyelination), recovery occurs in wks
        (mild structural damage with loss of small areas of myelin around
        nodes of Ranvier)
▫ Class 2 - severe crush injuries with axonal interruption but endoneurium
  undamaged; prognosis good (regeneration through original Schwann
  cell tubes); may be muscle atrophy (denervation) and recovery may
  take mos


                   100
                     80

                     60
                                                 East
                     40                          West
                     20                          North

                      0
                          1st      3rd
                          Qtr      Qtr
▫ Class 3 – severe injury to axons, Schwann cells and endoneurium, with
  denervation atrophy of skeletal muscle; formation of neuromas, aberrant
  regeneration common
Degeneration
• Segmental demyelination
    ▫ Analogous to demyelination in brain
    ▫ Selective loss of individual myelin internodes, no primary abnormality of
      axon
    ▫ Schwann cells proliferate
    ▫ Bare axon stimulus for remyelination – new myelin sheaths thinner and
      internodal lengths shorter
    ▫ Successive episodes of demyelination and remyelination– tiers of
      alternating Schwann cell processes and collagen =“onion bulbs”
Axonal
• Follows damage to or underlying abnormality of cell body and/or axon.
• Degeneration extends back to cell body; chromatolysis (Wallerian
   degeneration); Schwann cells proliferate
    ▫ Wallerian degeneration
        • Follows peripheral transection of axon
        • Proximal – degeneration to nearest node of Ranvier;
          chromatolysis if close enough to cell body
        • Distal - – degeneration of axon and myelin, both digested by
          Schwann cells (forming small oval compartments – myelin
          ovoids)
Regeneration
• Outgrowth of multiple sprouts from
  distal end of axon (regenerating
  cluster)
   ▫ Slow process (2 mm/day) –
       limited by rate of slow
       component of axonal transport
       (tubulin, actin and intermediate
       filaments)
•   With Wallerian degeneration secondary to traumatic injury, a hematoma or
    scar may form – obstructs distal stump of nerve, producing tangled, often
    painful, mass of nerve fibers (amputation or traumatic neuroma)
Peripheral Neuropathy
• Neuropathy – functional disturbances and/or pathological changes in PNS;
  may be mild or severe; acute, subacute, or chronic; may have relapses and
  remissions
• Most common neuropathies: diabetic and alcoholic (predominantly axonal)
• Major categories:
    ▫ Inflammatory, infectious (e.g., varicellar-Zoster)
    ▫ Hereditary
    ▫ Acquired metabolic
    ▫ Toxic (industrial or environmental chemicals)
    ▫ malignancy (invasion or paraneoplastic)
    ▫ Traumatic (lacerations, avulsions, compressions (carpal tunnel
      syndrome and `Saturday night palsy´-ulnar nerve compression)
•   Polyneuropathy – caused by diffuse demyelination and axonal degeneration.
     ▫ Longest axons affected first, typically symmetric

     ▫ Clinical
        • Distal limbs – paresis and loss of deep tendon reflexes, “glove and
            stocking” sensory loss
        • ANS – may be postural hypotension, constipation, impotence
•   Classification of peripheral neuropathies based on clinical syndrome

     ▫ Axonal degeneration – paresis w/ fasciculations muscle wasting
     ▫ Demyelination – conduction failure (no denervation, fasciculations or
       wasting)
     ▫ Different etiological agents preferentially affect axons with different
       diameters or function
         • Alcohol – small myelinated and unmyelinated fibers – slowly
            progressive distal sensorimotor neuropathy
         • Acrylamide – large myelinated fibers – numbness and sweating of
            hands and feet
         • Hexane (glue sniffing) – large myelinated fibers (distal symmetric
            sensorimotor polyneuropathy)

•   Focal neuropathy – affect individual nerves (e.g., vasculitis); usually
    asymmetrical; may spread and present as polyneuropathy
•   Multifocal neuropathy – > 1 nerve involved; usually symmetric
Clinical syndromes
• Acute inflammatory demyelinating polyradiculoneuropathy (e.g., spinal roots
   involved) (AIDP)
     ▫ Etiology: nutritional deficiencies, toxins, drugs (e.g., vincristine, isoniazid),
       systemic diseases (arteritis, diabetes, amyloidosis), inflammation or
       demyelination (e.g., Guillain-Barré), hereditary
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) –
   common, all ages (peak 5th and 6th decades), starts with an illness similar to
   AIDP and becomes either chronic relapsing or progressive
• Demyelinating neuropathy (myelinopathy) – initial pathology in Schwann cell
   or myelin
• Neuronopathy – initial pathology in cell body (e.g., Herpes zoster, polio)
• Large fiber neuropathy – loss of position, vibration and fine touch sensation,
   decreased tendon reflexes, and LMN involvement
• Small fiber neuropathy – decreased pain/temperature sensation, spontaneous
   pain, ANS involvement (preservation of joint position, vibration and touch and
   pressure sensations)
Inflammatory neuropathy
• AIDP – (Landry’s-Guillain-Barré Syndrome)
     ▫ Acute demyelinating neuropathy – antecedent events -- 40% “viral prodrome”
       (days to wks after URI or GI infection); 5% mycoplasma; 10% allergy; 25% other
       (including surgery); 20% unknown
     ▫ Most common cause of acute paralytic illness in developed countries, occurs
       mostly in young adults
• Clinical (acute):
     – Fine paresthesia in toes and/or finger tips followed by leg
       weakness (days), minimal loss of sensation (glove/stocking)
     – Pain – common complaint, presents as bilateral sciatica, or
       aching in large muscles of thighs, flanks, or back (e.g., “Charley
       horse”)
     – Difficulty walking (common early complaint) with bilateral foot-
       drop and a waddling wide-based unsteady gait
     – Symmetrical weakness – ~50% start in lower limbs and spreads
       upward (days), helps to differentiate from other neuropathies);
       tendon reflexes absent or greatly reduced
     – Severe cases – respiratory distress (vital capacity <50%), eye
       movements, swallowing, and ANS functions affected
• Lab:
    – Abnormal nerve conduction (e.g., conduction block due to
       demyelination)
    – CSF – increased protein after 1st wk, normal or minimally increased
       cell count
    – Serum – activated protein synthesizing lymphocytes and C
       dependent anti-myelin Abs
•   Pathology
     ▫ Histology – focal inflammation of peripheral nerve with
        demyelination, accumulation of lymphocytes and
        macrophages
          • Inflammatory lesions throughout the PNS; predilection for
            proximal nerve trunks
• Diagnosis – difficult due to variable initial presentation and extensive
  differential
      – In order of importance – cord compression/transverse section;
        myasthenia gravis; basilar artery occlusion; neoplastic meningitis;
        vasculitic neuropathy; polymyositis; metabolic myopathies; paraneoplastic
        neuropathy; hypophosphatemia; heavy-metal intoxication; neurotoxic fish
        poisoning; botulism; poliomyelitis; tick paralysis
      – ~2/3 of cases preceded by acute, influenza-like illness infection, usually
        viral, includes HIV, CMV, EBV with hepatitis or mononucleosis,
        asymptomatic hepatitis
           » Campylobacter jejuni enteritis important early disease, often
                associated with severe or variant forms of the neuropathy
           » No consistent demonstration of infectious agent; immunologically
                mediated disorder of obscure origin generally favored
      – Small group of cases occur in presence of underlying disease (e.g.,
        lupus, Hodgkin’s, sarcoidosis, or AIDS)
      – Can occur with pregnancy (3rd trimester) or postpartum (does not affect
        fetus)
• Etiology – T cell mechanism resulting in inflammation
     – Acute phase – circulating activated T cells and increased IL-2 in
       serum
     – Circulating anti-myelin Abs
     – May be multiple triggering events
• Treatment: plasma exchange (may be replaced by daily infusions of
  γ-globulin)
• Rehab and prognosis:
     – Recovery – wks to mos; weakness stops advancing after 1–3
       wks, with plateau for several wks and slow improvement
     – ~15% no residual deficit; 3–8% die from complications (e.g.,
       ARDS, sepsis, pulmonary embolism); 65% left with persistent
       problems (foot-drop, distal numbness); 5–10% permanent
       weakness, imbalance, decreased sensation
     – Recurrence – may occur at 10-15 yr intervals
     – Mild symptoms – with early improvement, best prognosis
     – Illness may be less severe in children than adults
Acquired Metabolic Neuropathy
• Diabetic neuropathy
   ▫ 2 types: symmetric polyneuropathies (foot pain, paraesthesias, weakness
      of toe and foot extensors; static or progressive), mononeuropathies
      (acute, affecting lumbosacral plexus, sciatic femoral, median, ulnar, 3rd
      and 7th cranial nerves; often clears w/o Rx)
   ▫ Often the most troublesome complication of diabetes mellitus
   ▫ Clinical – earliest sign distal, symmetric, and predominantly sensory,
      unilateral ocular nerve palsy (with sparing of reflexes)
   ▫ Pathology – axonal neuropathy with some segmental demyelination;
      mostly loss of small myelinated and unmyelinated fibers
   ▫ Etiology – unclear; metabolic dysfunction is prominent in rapidly reversible
      neuropathies of newly diagnosed diabetics
Hereditary
• Most affect strength and sensation; some affect sensation and ANS
• Peroneal Muscular Atrophy (Charcot-Marie-Tooth Disease HMSN I and II)
   ▫ Relatively common, dominantly inherited, slowly progressive sensorimotor
      disease
   ▫ Weakness/wasting in lower leg and foot producing “stork leg” deformity
      (foot drop and steppage gait)
▫ Histology – “onion bulbs” with axon in the center of the bulb




▫ Prognosis – life span normal
▫ Etiology – in most pedigrees (HMSN I), altered gene on chromosome 17
  encoding for myelin-specific protein (PMP-22), gene on chromosome 1
  encoding for myelin protein Po, or gene on X chromosome encoding for gap
  junction protein “connexin”
Peripheral nerve sheath tumors
• Schwannomas - arise from Schwann cells; typically on sensory nerves
  (e.g., vestibular branch of VIII).
    ▫ Tumor is white/grey, firm, solitary, circumscribed, encapsulated, and in
       eccentric position on proximal nerve or spinal nerve root (left/right)




         • Areas of high cellularity (Antoni A) (possibly with palisaded nuclei
           and fibers called Verocay bodies)
         • Areas of low cellularity (Antoni B)
▫ Tumors on cranial and spinal nerve roots responsible for most serious
  symptoms
    • Acoustic Schwannomas often present with tinnitus and hearing
      loss; large tumors - pressure on V and VII producing palsies, or
      brain stem compression and hydrocephalus
    • Spinal root tumors may present with slowly progressive cord
      compression or cauda equina syndrome; more distal tumors
      produce local complaints
    • Benign Schwannomas may transform to malignant
•   Neurofibromas - arise from Schwann cells, perineural cells or
    fibroblasts.
      ▫ Common forms are cutaneous neurofibromas (may be large,
         rarely malignant) and peripheral nerve neurofibromas (solitary
         neurofibromas); both occur sporadically as well as in association
         with neurofibromatosis Type I (NFI)
      ▫ Histology - bands of delicate spindle cells w/ elongated, slender,
         wavy nuclei; loose myxoid stroma (left/right)
▫ Both Schwannomas and neurofibromas contain S100 protein - useful
  marker for fibrous tissue tumors
▫ Neurofibromatoses - at least two autosomal dominant disorders
   • Neurofibromatosis-1 (NF1, von Recklinghausen, peripheral NF) and
      neurofibromatosis-2 (NF2, bilateral acoustic neurofibromatosis,
      central NF) - clinically and genetically distinct
• Neurofibromatosis-1 (>90% of cases) - one of the most common autosomal
  dominant diseases (~1/3,000 births) worldwide
    – Single altered gene located on chromosome 17 encoding for
      neurofibromin (contains region homologous to GTPase-activating
      protein – acts as a negative regulator of a growth stimulating pathway
      (tumor suppressor gene))
    – Multiple neurofibromas appear during puberty to adult
         » Associated with nerve trunks anywhere in skin or any internal site
            (especially acoustic nerve)
         » Often subcutaneous or fusiform enlargement of distal nerves
• Schwannomas may occur
• Café au lait spots - develop in childhood
    – 6 or more >5 mm dia in a child or >1.5 cm dia in an adult – most
      likely NF1
    – Giant melanosomes found in epidermal cells
    – Spots often overlie neurofibromas




• Lisch nodules - pigmented iris hamartomas (small yellow/brown
  elevations), aide in diagnosis (only occur in NF1)
▫ NF1 (or with a family history) – more susceptible to oncogenic effect of
  radiation (develop malignant peripheral nerve sheath tumors and
  sarcomas)
▫ Condition disfiguring (elephant man)
    • May be serious due to greater risk of developing tumors (e.g., optic
       gliomas, meningiomas, pheochromocytomas), location of nodules,
       malignancies in 3% of cases (especially those attached to large nerve
       trunks of neck and extremities); scoliosis or erosive bone defects may
       develop
• Neurofibromatosis-2
    More rare than NF1, most have peripheral neurofibromas and café au
     lait spots, bilateral acoustic Schwannomas, no Lisch nodules
    Altered gene on chromosome 22 encoding for protein interacting w/
     membrane and cytoskeleton
    Genes for NF-1/2 act as tumor suppressor genes
    Both Schwannomas and neurofibromas may develop marked nuclear
     pleomorphism, giant cells, and myxoid or xanthomatous degeneration
    Malignant transformation may occur in both types (less so in
     Schwannomas); tumors resemble fibrosarcoma, occur mostly in von
     Recklinghausen’s neurofibromatosis
    Schwannomas and neurofibromas occur late (5th and 6th decade)
Skeletal Muscle

•   Muscle pathology often secondary (e.g., UMN and/or LMN disease and certain
    systemic diseases (e.g., sarcoidosis, arteritis, toxins, alcohol, drugs, infection
    (viral, bacterial (e.g., Trichinella spiralis))
•   Categories of specific muscle diseases: myopathic and neurogenic
•   Structural changes (e.g., myasthenia)
•   Pathology
     ▫ Atrophy – occurs w/ lack of use, general malnutrition, ischemia and
        denervation
          • Fibers smaller on cross-section (especially w/ denervation or when
            denervated fibers are compressed by adjacent innervated fibers)
          • Myofibrils and other organelles lost, but marginal nuclei persist and
            increase in number as fiber shrinks




          • Eventual interstitial fibrosis, decreased muscle mass
▫ Degeneration – occurs in number of diseases
    • Usually only part of fiber affected, fiber can reconstitute from
       remaining undamaged segments
    • Fibers or part of fiber becomes necrotic, removed by macrophages
▫ Regeneration – accomplished by activation and proliferation of myoblasts
▫ Increased variation in fiber diameter – both neurogenic and myopathic
  diseases
▫ Increased number of central nuclei – nonspecific
▫ Ring fibers – produced when peripheral myofibrils are reoriented to run
  circumferentially; characteristic of myotonic dystrophy
▫ Fiber splitting – appears as clefts in myofiber; probably due to defective
  regeneration
▫ LMN lesions (e.g., poliomyelitis) - both Type I (“slow twitch”) and II (“fast
  twitch”) myofibers affected
▫ UMN lesions (e.g., stroke) - Type II fibers mainly affected
▫ Type I/II fibers are in random array; motor units contain muscle fibers dispersed
  among other motor units
▫ Fiber type determined by innervation; if a muscle is denervated and then reinnervated
  by another nerve, the muscle fiber will change its biochemical characteristics to match
  fibers innervated by that nerve
▫ Fast twitch fibers (Type II) richer in glycolytic enzymes; stain dark with ATPase at pH
  9.4; responsible for rapid phase contractions




▫ Slow twitch fibers (Type I) contain abundant myoglobin, oxidative enzymes and
  mitochondria; stain dark with ATPase at pH 4.6; responsible for tonic contraction and
  maintenance of posture
Myopathic Disease
• Myositis – (inflammatory myopathies)
   ▫ Most important forms seen in collagen vascular diseases (polymyositis
     and polyarteritis nodosa); direct invasion by blood-borne microbes rare,
     but when present, bacterial toxins may proteolyze large areas of muscle
   ▫ Dermatomyositis – chronic inflammatory myopathy (symmetric) with skin
     rash, particularly around the eyes (classic presentation – rash is a lilac or
     heliotrope discoloration of upper eyelids), face, and extensor surfaces of
     the limbs (red patches over knuckles, elbows, knees – Grotton’s lesions)
        • Juvenile – widespread vasculitis of skin and GI tract, myositis, bowel
           infarction with perforation and skin ulcerations prominent features
        • Muscle weakness usually begins in shoulders and pelvic girdle,
           spreads to neck and distal extremities; pharyngeal muscle weakness
           common
▫ Polymyositis – chronic inflammatory myopathy (symmetric), muscle
  weakness
    • Condition occurs at any age with bimodal peaks at 5-15 and 50-60 yr.
▫ Histology – necrosis of groups or single muscle cells, phagocytosis of
  muscle cell fragments (more characteristic of myositis than dystrophies),
  and prominent perivascular, endomysial, and perimysial inflammatory
  infiltrates
• Central vacuolization of muscle fibers virtually pathognomonic for
  polymyositis




• Chronic cases – foci of fibrosis and/or fat replacing muscle
• Skin rash (~40%) presents as edema with mononuclear cells
  around blood vessels
▫ Clinical – variable; muscle weakness and disability most important
    • 20% have connective tissue disorder (e.g., lupus), systemic sclerosis;
       malignancy in 15% of males and slightly less in females >50.
▫ Etiology – unkown but tissue damage mediated by immunologic
  mechanism; auto-Abs and antinuclear antibodies (e.g., rheumatoid factor)
    • Dermatomyositis – capillaries attacked by Abs and complement – foci
       of myocyte necrosis; supported by higher percentage than normal of
       B cells within muscle
    • Polymyositis – cell-mediated immunity implicated; CD8+ cytotoxic T
       cells and macrophages near damaged muscle
▫ Lab
    • Nonspecific except for Jo-1 antigen antibody (against histidyl tRNA
       synthetase), considered to be specific
    • Children and some adults with acute involvement – widespread
       necrotizing vasculitis involving lungs, kidneys, heart, and other
       organs; adults diffuse pulmonary fibrosis w/ anti-Jo-1 antibodies
▫ Diagnosis – biopsy; remissions and exacerbations
▫ Rx and prognosis - most cases respond to immunosuppressive therapy; 5
  yr survival rate in adults – 75%
▫ ~20% risk of malignancy of lungs, ovaries, and stomach in patients w/
  dermatomyositis
•   Polyarteritis nodosa (PAN)
     ▫ Transmural acute necrotizing inflammation in small to medium sized
        arteries; typically involves renal and visceral vessels
     ▫ Lesions are focal, random, and episodic in nature, produce irregular
        aneurysmal dilatations, nodularity and vascular obstruction/infarction
     ▫ Middle age disorder
     ▫ Etiology – unknown (immune complexes suggested)
          • Circulating anti-neutrophil cytoplasmic antibodies correlate w/ disease
          • Organs involved in descending order of frequency: kidney, heart,
             liver, GIT, pancreas, testes, skeletal muscle, NS, skin
   • Lesions involve localized segements of vessel and occur at branch
      points and bifurcations
        – Initial – acute transmural vasculitis w/ fibrinoid necrosis of inner
           wall
        – Late – fibrous thickening of the wall and a mononuclear infiltrate
           (eventually disappears)
        – All stages may coexist w/in same or different vessels
▫ Diagnosis – biopsy (kidney and skeletal muscle)
▫ Untreated – fatal
• Muscular Dystrophy
   ▫ Family of genetically determined myopathies
      • Range from mild motor weakness (Becker type) to severe with early
        death (Duchenne’s dystrophy)
           – Becker 1/10th as common as Duchenne’s
           – Subgroup of inherited metabolic diseases; cardiac muscle also
               affected
           – Both types due to mutations in same gene
▫ Duchenne’s dystrophy – most common and devastating of the dystrophies
   • Caused by a mutation of gene on short arm of X chromosome
   • Most are sons of carrier mothers (males don’t live long enough to be
     fathers!) (some acquire the mutation de novo)
   • Normal gene produces dystrophin (considerable homology with a
     cytoskeletal α-actinin and spectrin, membrane associated and
     localized to T-tubule system)
        – Mutation produces decreased dystrophin leading to abnormal
           cell contraction and progressive muscle weakness (possibly by
           interfering with Ca release or weakening myocytes); changes
           most marked in shoulder and pelvis muscles, followed by
           extremities
▫ Histology -
   • Vacuoles
   • Fragmentation and coagulation necrosis of individual myofibers,
      invasion of macrophages
   • Some damaged myofibers regenerate
   • Nuclei central, contraction bands (marked shortening of some
      sarcomeres), fiber splitting, and variation in fiber diameter
•   Damaged fibers removed and replaced by fibro-fatty tissue,
    unaffected fibers undergo hypertrophy - result is pseudohypertrophy
    (especially in calf muscles)
•   Myofibers degenerate, muscles shrink, become pale and flabby,
    replaced by fibro-fatty tissue
▫ Clinical
   • Starts in early childhood - difficulty standing, walking, and getting out
       of a chair
   • Muscle weakness progressive and most evident in legs (eventually
       arms affected)
   • Pseudohypertrophy of calf muscles (initial hypertrophy of muscle
       fibers, with muscle atrophy there is an increase in fat and connective
       tissue)
   • Involvement of trunk muscles - curved spine
   • By 12 yr most in wheelchairs; by 20 yr death (e.g., pulmonary
       infections (weak muscles and aspirated foods))
   • Cardiac failure may occur (degeneration of cardiac cells)
   • Decreased dystrophin may affect neuronal membrane skeleton -
       intellectual impairment
▫ Diagnosis - clinical features, increased serum muscle enzymes (creatine
  kinase), EMG; confirmed by biopsy
    • Use peripheral lymphocytes to detect carriers of Duchenne or Becker
      type muscular dystrophy
• Myotonic dystrophy
   ▫ Autosomal dominant disease with mutation on chromosome 19 of gene
     that codes for myotonin-protein kinase
   ▫ Clinical
       • Myotonia (sustained, involuntary contraction of a group of muscles)
       • Atrophy of facial muscles with ptosis
       • Disease appears at younger age in each succeeding generation
   ▫ Histology
       • Central nuclei, ring fibers (peripheral myofibrils form a ring around
          central ones running longitudinally)
       • Sarcoplasmic masses devoid of striations, chains of nuclei
       • Type 1 fiber atrophy
•   Inherited Metabolic and Congenital Myopathies
     ▫ Include myophosphorylase deficiency (McCardle’s syndrome (Type V
        glycogenosis, compatible with normal life span)), acid maltase deficiency
        (Type II glycogenosis, Pompe’s disease), phosphofructokinase deficiency
        (Type IV glycogen storage disease), and mitochondrial myopathies
     ▫ In congenital myopathies - most present as “floppy infant” with symmetric
        weakness, most severe proximally
     ▫ Nemaline (rod body) myopathy - autosomal dominant disease causing
        hypotonia and weakness
           • EM - nemaline rod as masses of round Z body material
• McCardle’s and phosphofructokinase deficiency - impaired energy
  production, muscle weakness and cramps after exercise and failure
  to detect increased serum lactate after exercise
• Acid maltase (lysosomal enzyme) deficiency - glycogen storage in
  many organs, early death
• Cardiomegaly - prominent
• Mitochondrial myopathies - defect in substrate transport (carnitine
  metabolism and the pyruvate dehydrogenase complex), energy
  conservation (ATPase deficiency), respiratory chain (cytochrome
  deficiency)
• Acquired Metabolic and Toxic Myopathies
   ▫ Major disorders occur in hypo- and hyperthyroidism and steroid-induced
     myopathy
   ▫ Clinical - diffuse muscle weakness, some wasting
   ▫ Histology – no pathognomonic morphology
   ▫ Diagnosis - by exclusion and history of hormonal deficiency
   ▫ Etiology
       • Toxins - alcohol (occurs after “binge” drinking and results in muscle
          breakdown and myoglobinuria), anti-fibrinolytic agent
          (epsilon-aminocaproic acid), chloroquine, steroids, D-penicillamine,
          and procainamide
Neurogenic Disease
• Myasthenia gravis (MG) - most frequent of myasthenic syndromes; muscle
  weakness and fatigability
   ▫ Autoimmune disease with Abs to AChR at muscle endplate
   ▫ Onset peaks at ~20
   ▫ 2/3s associated w/ thymic hyperplasia; 20% w/ thymomas
   ▫ Other associated autoimmune diseases (e.g., SLE, Sjörgen’s syndrome
     rheumatoid arthritis, and hyperthyroidism)
▫ Pathogenesis – 90% have circulating Abs to AChR, may be absent in mild
  cases
    • Muscular weakness due to increased loss of receptors (Ab/complement-
      mediated lysis??) and inhibition of ACh binding
    • Thymic hyperplasia associated w/ appearance of AChR on thymic
      epithelial and myoid cells; some neoplastic epithelial cells in thymomas
      express AchR; assumed that these antigens sensitize B cells to produce
      auto-Abs
▫ Histology - complement and IgG at NMJs; marked reduction in AChR’s and
  reduced or abolished junctional folds
    • Disuse changes in type II fibers (atrophy)
▫ Clinical - variation in course of disease
    • Thymoma and high titers of circulating AChR Abs - poor prognosis
    • Weakness and fatigue start in most active muscles (extraocular, facial,
        tongue, extremities), in severe cases other muscles become progressively
        involved; eventually, trunk and limb muscles and speech and swallowing
        affected




     • Respiration compromised, pulmonary infections and death
     • In mild cases - may only be slight increased fatigability of extraocular and
       face muscles
▫ Diagnosis and Rx - thymectomy for hyperplasia, removal of a tumor, anticholine
  esterases, and immunosuppressive agents




   • With severe generalized disease, there is about a 10% death rate in 10 yr
   • Overall > 90% respond to treatment with long-term reduction in disability and
      improvement in quality of life.
▫ Other myasthenic syndromes (e.g., Lambert-Eaton syndrome), 2/3 associated with
  malignancy (usually small cell carcinoma of the lung).
• Denervation atrophy
   ▫ Occurs in peripheral neuropathies with axonal degeneration leading
     to denervation and muscle atrophies (e.g., ALS - motor neuron
     disease affecting both LMNs and UMNs
   ▫ Muscle may become reinnervated by collateral sprouting from an
     adjacent nerve fiber, leads to “type grouping” as the reinnervated
     fiber will be the same type as the one providing the “sprout”
        • Staining with ATPase, that distinguishes Type I from Type II
          fibers; the types are grouped rather than scattered
          (checkerboard) as seen normally
▫ With further denervation, muscle fibers atrophy in groups (“group
  atrophy”); type grouping and group atrophy hallmarks of
  denervation
▫ Clinical - muscle weakness and loss of muscle mass, fasciculations -
  manifestation of hypersensitivity resulting from increased number of
  AChRs scattered over the whole surface rather than concentrated at
  the NMJ

				
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