Neuromuscular Junction and Infectious Disorders

1. Neuromuscular Junction and Infectious Disorders Dayna Ryan, PT, DPT Winter 2012

2. Neuromuscular Junction Diseases Botulism Myasthenia Gravis Lambert-Eaton Syndrome

3. Latin: “botulus,” meaning sausage • Etiology • Neurotoxin produced by Clostridium Botulinum • Anaerobic, Gram-positive rods • Found in improperly preserved or canned foods & contaminated wounds • Classification (mode of acquisition) • Food-borne (ingested) • Wound • Unclassified Botulism

4. Lesion • Pre-synatic terminals • Mechanism • Botulinum toxin enters presynaptic terminals • Blocks the fusion of ACh vesicles with presynaptic membrane • Inhibit ACh release into neuromuscular junction • Nerve impulse fails to transmit across the neuromuscular junction • Muscle paralysis • Progression • - Typically get full recovery in both adult & infant

5. Mechanism of Action of Botulinum Toxin

6. 10 adult & 100 infant cases in US each year Infant botulism Age 3 wk - 9 month Signs and symptoms Develop within 12-36 hours following ingestion of contaminated food Mortality rate from 1990 – 1996 in US Type A (6.7%), type E (6.5%), type B (0%) Gradual recovery over weeks - 12 months Incidence

7. Signs & Symptoms • Develops within 12-36 hours following ingestion of contaminated food • Flaccid symmetrical paralysis • Blurred & double vision, photophobia • Dry mouth,nausea, & vomiting • Difficulty in swallowing & speech • Respiratory failure can occur in 6-8 hours

8. Treatment • ABE serumantitoxin (antibodies of type A, B, E toxin) • Debridement & antibiotics for wound • Removal of toxin from GI (gastric lavage) • Supportive measures, e.g. IV, mechanical vent

9. Myasthenia Gravis Fluctuating weakness & fatigability Autoimmune disorder Abnormal Thymus function in 75% of cases Classifications of MG Ocular myasthenia (~10-15%) Generalized weakness (~85%) Myasthenic crisis: respiratory failure

10. Mechanism of MG Antibodies block & damage ACh receptors • ACh receptors # reduced; Decreased efficiency of neuromuscular transmission • Nerve impulse fails to pass across the neuromuscular junction to cause muscle contraction

11. Myasthenia Gravis • Prevalence: 14/100,000 • Ratio of women-to-men= 3:2 • Factors that exacerbate MG: hyper- or hypothyroidism, menstrual cycle • Disease Progression: • Slowly, progressive weakness (maximal weakness occurs in first year in 2/3 of all cases) • After 15-20 years, weakness becomes fixed • Remissions occur in about 25% of cases

12. Signs & Symptoms • Generalized weakness: proximal muscles more affected • Fatigability of skeletal muscles • progressive muscular weakness on exertion, followed by recovery of strength after rest • Respiratory impairments

13. Signs & Symptoms • Muscle weakness varies day to day and over long periods of time • Cranial muscles are the first to show weakness • Patients compensate for weak muscles (e.g. use of thumb to close jaw)

14. Eyelids fatigue with sustained upward gaze

15. Diagnosis • Test anti-Ach receptor antibodies • if +, then MG • Tensilon test • Repetitive movements or holding a position • Compare performance following giving Tensilon (anticholinesterase) vs. Placebo (saline) • If strength/endurance is improved, then MG • EMG • Reduced amplitudes over repetitive stimulation

16. Treatment • Anticholinesterase drugs • Thymectomy • Immunosuppressants • Plasmaphoresis • Blood is routed to a machine that separates the plasma & cells • Plasma, which contains antibodies, dissolved proteins, glucose, clotting factors, etc., is discarded while cells are returned to the body • Temporarily (4-6 weeks) reducing anti-ACh receptors antibodies • Used to get a patient more stable for surgery or to get them out of crisis • Intravenous immunoglobulin (IVIG)

17. Lambert-Eaton Syndrome • Rare but still the most frequent presynaptic neuromuscular transmission disorders in adults • Etiology • ~50% of cases associated with cancer, especially small cell carcinoma of the lung • Others primarily from autoimmune disorders • e.g. RA, thyroid disease, MS

18. Mechanism • Antibodies destroy voltage-gated Ca++ channel • Block of Ca++ into presynaptic terminal • Reduced release of presynaptic ACh vesicles • Reduced probability of reaching depolarization threshold of a muscle fiber

19. Signs & Symptoms • Muscle weakness and fatigue • At proximal limbs & torso (LE > UE) • Difficulties climbing stairs, lifting objects • Early symptoms: aching of thighs and difficulty walking • Decreased or absent DTRs • Cranial nerves usually spared

20. Lambert-Eaton Syndrome

21. Diagnosis • EMG • Will see a low amplitude response to a single stimulation • Voltage-gated calcium channel antibody • If +, then LEMS • MRI or CT scan for lung cancer

22. Infectious Disorders of the NS Meningitis Encephalitis Lyme Disease West Nile Virus

23. Meningitis = meninges of the brain and SC become inflamed • All 3 layers can be involved, but usually pia and arachnoid • Etiology: bacterial or viral infection • Viral (Aseptic) – most common • Tuberculous – enter by inhalation • Bacterial – EMERGENCY!! • Incidence: 2-6/1,000,000 adults

24. Meningitis

25. Signs & Symptoms • Fever & chills • Severe headache • Stiff & painful neck! (cardinal sign) • Mental status changes • Sensitivity to light (photophobia) • Confusion • Vomiting • Pain in lumbar area and posterior thigh • Positive Kernig sign

26. Signs & Symptoms - Progression • Positive Brudzinski sign as it progresses • when neck is flexed, patient flexes leg to decreased stretch on meninges • Seizures or coma if untreated • Focal neurologic signs, e.g. CN palsies or deafness • Edema, which causes increased ICP and can lead to lethargy and confusion

27. Bacterial Meningitis in a Baby • Fever • Poor feeding • Vomiting • Bulging Fontanels • Soft spots • Seizures • High-pitched cry

28. Diagnosis • Lumbar puncture: CSF analysis & culture • Blood culture • CT, MRI: brain abscess or infarction • Bacterial type • Isolation for 3 days • Bed rest • Antibiotics ASAP • Meds for seizure • Corticosteroids for cerebral edema or vasculitis • Viral type • Meds to control headache and nausea • Treatment

29. Encephalitis • Lesion Site: gray matter of the CNS • Etiology: viral or bacterial infection • Most often from viral infection • In US, Herpes simplex encephalitis most common; 1/250,000 – 1/500,000

30. Encephalitis • Most cases: only mild symptoms or asymptomatic • Serious cases cause: • Fever & chills • Headache • Nausea & vomiting • Mental status changes; irritability • Lethargy, fatigue • Seizures • Stiff neck (if meninges are involved) • Bulging fontanels (soft spot in skull) in infants • Focal neurological signs, e.g. ataxia, hemiparesis, aphasia

31. Encephalitis • Prognosis depends on type • Mortality rate varies from <1% to 50-70% • Permanent neural damage is more likely in infants • Diagnose with spinal tap, EEG, CT scan, or MRI

32. Lyme Disease Lyme disease was first reported in the US in the town of Old Lyme, Connecticut, in 1975. Most cases (90%) in mid-Atlantic, northeast, & north central regions. Lesion Sites: CNSand PNS Incidence on the rise 23,763 cases in 2002

33. Etiology • Bitten by an infected tick carrying the bacterium Borrelia burgdorferi • Risk Factors • Having a pet • Outdoor activities • Walking in high grasses

34. Signs & Symptoms – Early Stage • The initial sign is rash • Bull's-eye appearances (i.e. erythema migrans) at the site of tick bite • Present in ~80% of patients • Gradually expands to ~ 12” across • Flu-like symptoms: chills, fever, headache, lethargy, muscle pain • Chronic RA is the most commonly recognized symptom • Some neurologic and psychiatric symptoms

35. Lyme Disease

36. Progression of Lyme Disease • Stage 1 • Flu-like symptoms and rash (7-14 days after tick bite) • Stage 2 • Generalized fatigue, loss of appetite, vomiting • Neurologic or cardiac abnormalities develop weeks to months later • Stage 3 (weeks to year later) • RA develops in >50% of people who did not receive earlier treatment • Affects knees mostly • Often unilateral presentation of joint involved

37. Signs & Symptoms – Later Stages Swollen knee from chronic rheumatoid arthritis is most commonly recognized symptom

38. Treatment of Lyme Disease • Oral antibiotics • Removal of tick • Joint surgeries **15% of those who received early treatments still get complications involving heart, joints, and nervous system MOST people have complete recovery within weeks or months of antibiotic treatment

39. Prevention is Key • Wear long pants • Walk on cleared paths • Wear high socks and appropriate shoes • Wear light-colored clothing to make ticks easier to see

40. West Nile Virus It was first discovered in the United States in the summer of 1999 in New York. Since then, the virus has spread throughout the United States Lesion: CNS, PNS, Multi-systems (depends on where bitten)

41. West Nile Virus 2009 West Nile Virus Activity in US (Reported to CDC as of December 2009)

42. West Nile Virus • Etiology: • Single-stranded RNA virus from mosquitos primarily • Flavivirus • No treatment available – only supportive care • Risk factors: age, hypertension, diabetes, CAD, immunosuppression

43. Signs & Symptoms • ~80% of individuals are asymptomatic • ~20% of individuals affected by the virus develop systemic symptoms • < 1% develop neurological manifestations • Those that do develop nervous system involvement usually evolve a severe illness • Mortality rates 12%-14%

44. Presenting Signs and Symptoms • Fever • Headache • Muscle Ache • Joint Pain • Fatigue • Rash (with swollen lymph nodes) • Nausea/vomiting • Periocular pain • Muscle weakness • Altered mental status • Backache • Photophobia • GI/Respiratory Symptoms

45. Neurologic Signs & Symptoms • Encephalitis • Meningitis • Meningoencephalitis • Anterior myelitis • Acute flaccid paralysis • Proximal muscles affected more than distal • From damage to anterior horn cells • Painless, asymmetric weakness • No sensory abnormalities

46. Serious Signs & Symptoms • High fever • Severe headache • Stiff neck • Disorientation • Coma • Tremors • Convulsions • Muscle weakness • Ataxia and extrapyramidal signs • CN abnormalities • Optic neuritis/vision loss • Polyradiculitis • Seizures • Myelitis • Photophobia • Numbness • Paralysis