Neuromuscular Disorders

1. Neuromuscular Disorders Rebecca Burton-MacLeod R4, Emergency Med April 26th, 2007

2. Objectives • Discuss pathophys • Classification schemes • Specific disorders • Cases • A few fun pics…

3. Main concerns • Respiratory compromise!!!! • Altered vision • Difficulty swallowing • Difficulty speaking • Motor failure Bulbar symptoms

4. Brainstem and above: Unilateral weakness usually If bilateral weakness then associated CN involvement or altered mental status CNS o/e: Spasticity Hyperreflexia Positive Babinski No fasciculations PNS: Dec muscle tone Hyporreflexia Atrophy Fasciculations Negative Babinski Determining level

5. Definitions • Myelopathies—involve spinal cord • Radiculopathies—involve nerve roots as they leave spinal cord • Neuropathies—involve peripheral nerves • Myopathies—involve muscles

6. Neuromuscular junction • Link between CNS and MSK • Depolarization of neuron causes release of neurotransmitters at nerve terminal (Ach), which binds to muscle fiber receptor and initiates another wave of depolarization causing muscle contraction • Must have: sufficient quantity of neurotransmitters AND adequate number of receptors on postsynaptic membrane

7. Nicotinic synapse: Muscle weakness Disorders of postsynaptic membrane Muscarinic synapse: Anticholinergic symptoms Presynaptic and synaptic disorders NMJ

8. Etiologies • Congenital—congenital MG, Achesterase deficiency • Infectious—botulinum • Autoimmune—MG, Lambert-Eaton s/o • Toxins—snake/scorpions, organophosphates • Drugs—Mg, aminoglycosides, fluoroquinolones

9. NMJ disorders

10. General: Cranial muscle weakness Proximity muscle weakness Resp muscle involvement Presynaptic: Improvement after initiation of activity Autonomic involvement Postsynaptic: Improvement in strength after rest History—specific features

11. Clinical characteristics

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17. Case • 65M who has been noticing difficulty swallowing. 2x visits to ED in last 3months for esophageal obstructions due to food boluses. Also notices double vision after reading for a while, generalized fatigue. • O/e: ptosis of L eye. Normal PERL. Rapid neuro screen otherwise normal. • Any thoughts?

18. Myasthenia gravis • Causes fluctuating, fatigable weakness of voluntary muscles • Incidence 14/100,000 • Bimodal distribution—2nd/3rd decades (F), and then 6th/7th decades (M) • Association with thymic hyperplasia (70% pts), thymoma (15% pts)

19. MG pathophys • Ach-R loss due to: • Accelerated endocytosis and degradation of receptors • Complement-mediated damage • Functional blockade of Ach-R (minor contributor)

20. Clinical course • 85% pts generalized weakness within 1yr • 85% pts have max severity of illness within 5yrs of onset of symptoms • <50% pts have remissions • Extremely variable course of illness

21. Severity classification • Bella and Chad’s classification: • Class 1—any ocular muscle weakness, but other strength is normal • Class 2—mild weakness other than ocular muscles • Class 3—moderate weakness other than ocular • Class 4—severe weakness other than ocular • Class 5—intubation

22. S/S MG

23. Diagnosis • Physical exam: • Normal reflexes, sensation, coordination • Asymmetrical ptosis • Symmetrical, fluctuating EOM weakness • Normal PERL • Fatigability • Tests: • Tensilon test • Ice test • Immune testing • EP studies

24. Tensilon test • IV edrophonium 1-5mg IV (tensilon) provides rapid (within 30sec) and short acting (~5min) improvement of ocular symptoms in pts with MG • Edrophonium is Ach-esterase inhibitor • **always have atropine at bedside as may cause bradycardia!!

25. Ice test • Cooling improves MG symptoms, heat exacerbates • Measure distance b/w upper and lower eyelids • Apply icepack x2min then measure again (should improve >2mm for positive MG) • Positive in 80% of pts with MG

26. Other tests • Ach-R Ab levels (present in 90-95% pts) • EP studies—repetitive nerve stimulation shows decremental response in MG

27. Mgmt • Anticholinesterase agents (pyridostigmine first-line; lose efficacy over time) • Immunosuppression (steroids reduce levels of Ach-R Ab; transient exacerbation after initiation so should be hospitalized) • Thymectomy (59% pts show sustained improvement post-op) • Plasmapheresis • IVIG

28. Disposition • Any suspected MG case requires neuro consult / close f/u

29. Case • 43F brought in by EMS after sudden resp failure at work. Hx from colleagues of “muscle disorder” and taking steroids, which were recently d/c. Also doubled the dose of her other med “?” 1wk ago. • Pt unable to speak, only nods head slightly. Obviously shallow resps. ++salivation, incontinent, bradycardic. • Any thoughts?

30. Myasthenic crisis • True emergency! • Often underlying precipitating event (infection, changes in meds) • Weakness due to MG progression or else complication of anticholinesterase therapy (cholinergic crisis) • Thus d/c all anticholinesterase meds if suspect myasthenic crisis • Support ventilation, ICU admission, plasmapheresis/IVIG, high-dose steroids (only if airway secured)

31. Case • 62M with known SCC lung Ca. c/o generalized leg weakness. Difficulty climbing stairs. Also c/o dry mouth and erectile dysfxn. • O/e: testing grip strength—initially weak, then strengthens, then weakens again; hyporeflexia in LE • Any thoughts?

32. Lambert-Eaton s/o • Rare autoimmune condition • Primary cause, also paraneoplastic d/o (3% of pts with SCC of lung…may precede diagnosis)

33. LES pathophys • Insufficient release of neurotransmitter at presynaptic terminal • Ab-blockade of voltage-gated Ca channels results in dec Ca influx and deficient neurotransmitter release

34. LES diagnosis • Classic triad—muscle weakness (legs, prox), hyporeflexia, autonomic symptoms • EP studies—resting action potential is low, decrement with slow repetitive stimulation; with rapid stimulation causes doubling from baseline amplitude

35. Mgmt • R/o underlying Ca • Anticholinesterase agents (pyridostigmine) • Neurotransmitter enhancers (aminopyridines): • K-channel blockers prolongs AP and keeps Ca channels open longer resulting in inc Ca influx and neurotransmitter release • Immunosuppression

36. Case • 6mo M presented to ED with parents • 3day hx of URTI symptoms • Small cough, Congestion,Tactile fever, Symptoms worsening today, Friend with similar URTI symptoms week prior • Normally BF, pt has been refusing any fluids for 2days • No BM x 2days • PMHx: healthy

37. Case cont’d • O/E: • 37.9C 142 52 87% r/a • Child appears lethargic • Lungs—wheezing L>R • Pt mildly dehydrated • Any thoughts?

38. Case cont’d • During ICU stay: • Hx of poor sucking prior to admission • Pt being given “bactrex”—homeopathic supplement containing a wealth of ingredients to ‘boost the immune system’ • Noted to have profound generalized muscle weakness on exam • No BM x2weeks despite aggressive bowel routine • Pulmonary, ID, Neurology involved in care

39. Botulism • 5 types of botulism: • Food-bourne (ingestion of pre-formed heat labile toxin) • Infant (ingestion of spores with in vivo toxin produced) • Wound (IVDU) • Unclassified • Inadvertent (botox injections)

40. Pathophys • Most cases caused by strains A, B, E (7 strains exist) of clostridium botulinum • Most potent biologic toxins known • Doses of 0.05-0.1mcg can cause death in adults • Toxin transported from GI tract/wound to neuron, toxin irreversibly binds to presynaptic nerve membrane and internalized, blocks release of Ach resulting in neuromuscular blockade • Primarily occurs at cholinergic synapses of CN, autonomic nerves, NMJ

41. MoA Horowitz BZ. Botulinum toxin. Crit Care Clinic. 2005.

42. Diagnosis • CN findings in presence of GI symptoms and associated anticholinergic symptoms • Onset usually within 12-36hrs after ingestion • Symmetrical, descending, rapidly progressive weakness (may occur within 24hrs) • Suspect wound botulism in IVDU with bulbar findings

43. Diagnosis • C. botulinum toxin positive in stool (60% of pts) • Normal nerve conduction studies • EMG may show findings consistent with acute denervation; rapid repetitive nerve stimulation shows incremental response Fox CK et al. Recent advances in infant botulism. Pediatr Neurol. 2005.

44. Mgmt • Supportive measures • Although sepsis on differential, avoid use of aminoglycosides • Have neuromuscular blocking activity which may exacerbate botulinum blockade • Study of 99 infantile botulism pts, 61% required mechanical ventilation if received aminoglycoside vs. 26% if no aminoglycoside given Wilson R et al. Clinical characteristics of infant botulism in the US. Ped Infect Dis. 1982.

45. Antitoxin ? • BabyBIG • Approved in 2003 by FDA for cases of proven infantile botulism • Ig prepared from plasma of donors immunized with botulinum toxoid • Cost is $45,000 US per infant, shipped from the US • Significantly decreases LOS hospital/ICU, length of mechanical ventilation

46. Case • 28F G1P0 develops eclampsia in Cranbrook. Call to STARS. Pt retrieved, treated en route with Mg 5gm IV. Undergoes stat C-section on arrival at FMC. Post-op, unable to extubate pt. • Any thoughts?

47. Medications causing NM d/o • D-penicillamine causes iatrogenic MG • Aminoglycosides, chloroquine, and fluoroquinolones all may have pre- and post-synaptic effects • Mg…

48. HyperMg • Mg regulates Ca in presynaptic membrane thru voltage-gated Ca channels by blocking Ca influx • Prevents exocytosis of neurotransmitter • Also causes anticholinergic symptoms • Also potentiates action of NMB agents to produce prolonged respiratory weakness

49. Case • 22F comes to ED with difficulty raising arms—noticed while fixing hair over last couple of weeks. Also c/o pain in shoulders bilaterally. • O/e: periorbital heliotrope rash!! • Any thoughts?

50. Dermatomyositis • Weakness, pain, tenderness of involved muscles • Inflammatory myopathy (also polymyositis) • PM does not have classic skin findings • Associated inc risk of ca—breast, ovary, lung, GI, lymphoproliferative