Peripheral Nervous System

1

• Peripheral Nervous System
• James A. Weyhenmeyer
• 515 Medical Sciences Bldg/346 Henry Admin Bldg
• 265-5440
• weyhen_at_uillinois.edu

2

• Injury
• Slight injury affects myelin more severe
• affects myelin and axon most severe
  disrupts
• connective tissue

3

• 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)

4

• 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

5

• Class 3 severe injury to axons, Schwann cells
  and endoneurium, with denervation atrophy of
  skeletal muscle formation of neuromas, aberrant
  regeneration common

6

• 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

7

• 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)

8

• 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)

9

• 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)

10

• 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)

11

• 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

12

• 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 gt 1 nerve involved
  usually symmetric

13

• 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)

14

• Inflammatory neuropathy
• AIDP (Landrys-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

15

• 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 lt50), eye movements, swallowing, and
  ANS functions affected

16

• 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

17

• Pathology
• Histology focal inflammation of peripheral
  nerve with demyelination, accumulation of
  lymphocytes and macrophages
• Inflammatory lesions throughout the PNS
  predilection for proximal nerve trunks

18

• Diagnosis difficult due to variable initial
  presentation and extensive differential
• In order of importance cord compression/transver
  se 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, Hodgkins,
  sarcoidosis, or AIDS)
• Can occur with pregnancy (3rd trimester) or
  postpartum (does not affect fetus)

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• 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 ?-globulin)
• Rehab and prognosis
• Recovery wks to mos weakness stops advancing
  after 13 wks, with plateau for several wks and
  slow improvement
• 15 no residual deficit 38 die from
  complications (e.g., ARDS, sepsis, pulmonary
  embolism) 65 left with persistent problems
  (foot-drop, distal numbness) 510 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

20

• 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

21

• 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)

22

• 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

23

• 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)

24

• 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

25

• 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)

26

• 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

27

• Neurofibromatosis-1 (gt90 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

28

• Schwannomas may occur
• Café au lait spots - develop in childhood
• 6 or more gt5 mm dia in a child or gt1.5 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)

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• 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

30

• 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
  Recklinghausens neurofibromatosis
• Schwannomas and neurofibromas occur late (5th and
  6th decade)

31

• 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)

32

• 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

33

• 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

34

• 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

35

• 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

36

• 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 Grottons
  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

37

• 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

38

• 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

39

• 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 gt50.
• 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

40

• 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

41

• 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

42

• 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

43

• Muscular Dystrophy
• Family of genetically determined myopathies
• Range from mild motor weakness (Becker type) to
  severe with early death (Duchennes dystrophy)
• Becker 1/10th as common as Duchennes
• Subgroup of inherited metabolic diseases cardiac
  muscle also affected
• Both types due to mutations in same gene

44

• Duchennes 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 dont
  live long enough to be fathers!) (some acquire
  the mutation de novo)
• Normal gene produces dystrophin (considerable
  homology with a cytoskeletal a-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

45

• 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

46

• 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

47

• 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

48

• 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

49

• 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

50

• Inherited Metabolic and Congenital Myopathies
• Include myophosphorylase deficiency (McCardles
  syndrome (Type V glycogenosis, compatible with
  normal life span)), acid maltase deficiency (Type
  II glycogenosis, Pompes 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

51

• McCardles 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)

52

• 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

53

• 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,
  Sjörgens syndrome rheumatoid arthritis, and
  hyperthyroidism)

54

• 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

55

• Histology - complement and IgG at NMJs marked
  reduction in AChRs 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

56

• 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 gt 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).

57

• 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

58

• 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