Myasthenia Gravis Guillain-Barre Syndrome

1. Myasthenia GravisGuillain-Barre Syndrome ICU teaching April 27th

3. incidence 1 in 20 000 No racial or geographical prediliction Any age although rare in <2yrs Peaks incidence in young females Females x2 males Gender preference diminishes with increasing age Smaller second peak in elderly males

4. Pathophysiology IgG AB interact with the postsynaptic AChR at the nicotinic neuromuscular junction(NMJ). This reduces the number of functional receptors by blocking Ach attachment, by increasing the degradation of receptors and by complement induced damage to the NMJ MG pts have a reduced AChR density and have 30% the normal number of AChR This reduces the safety margin at the NMJ

5. The reduced AChR density leads to decreased amplitude in AP in the post synaptic region leading to failure in initiation in muscle fibre contraction. When it occurs at many NMJs manifests as weakness of voluntary muscle-cardinal feature

6. Aetiolgy Antibody mediated, origin uncertain Thymus gland possible generator Gland abnormal in 75% of patients with MG( hyperplasia and thymoma) B and T lymphocytes become sensitised to AChR found in myoid cells in the gland Reason for breakdown in normal immune tolerance uncertain

7. Clinical features Voluntary muscle weakness cardinal feature, with fatigability, relieved with rest 15% pts have disease confined to the eyes 85% generalised ocular, facial, bulbar, limb Respiratory muscles affected mildly however in myasthenic crisis resp failure requiring support may be required Symptoms of diplopia, ptosis, dysarthria, regurgitation,dysphagia are all common.

8. Diagnosis and Ix History and examination EMG Recording of compound muscle action potentials(CMAP) Following repetitive stimulation of motor nerve In MG this leads to reduction in CMAP (>10%)

9. All EMG abnormalities are not specific for MG Detection of anti-AChR antibodies In 80-85% cases and are pathognomonic The Tensilon test- up to 10mg edrophonium is administered IV is standard test. Mg pts show marked improvement after 30sec and lasts 5min

10. Management Anticholinesterase drugs potentiate the Ach at receptor sites, Pyridostigmine most common up to 60mg QID. Effects diminish over months Thymectomy best results and advocated early in all patients regardless of severity or presence of thymoma. Earlier remission, lower mortality, greater delay in recurrences.

11. Management continued Immunosuppression - corticosteroids mainstay effective in 70% best results when used high dose and reduced average of 4months with some indefinitely Azothiprine and methotrexate effective adjuncts, 80% helped, few remission

12. Mx continued Plasma exchange effective in achieving short term remission, for preoperative thymectomy, in myasthenic crisis or respiratory failure. Reduction in level of antibodies correlates with the improvement in muscle power. Improvement seen within days and is short lived.five exchanges 3-4litres each over 2 weeks Iv IG similar effects as plasma exchange , 400mg/kg/day for 5days. Some pts get long term benefit. No effect on ab numbers and mechanism of action unknown.

13. Complications of all treatments Sepsis and infections related to IV catheters and immunosuppression Renal failure from IgG and Cyclosporin All the complications of long term steroid use

14. Myasthenic and cholinergic crisis Known MG pts may have life threatening acute deteriorations Following infections, pregnancy and administration of some drugs Most resolve over several weeks some last months Incidence of M.crisis increases with age

15. Management of the crisis Risk of pulmonary aspiration due to bulbar muscle involvement, bacterial pneumonia due to stasis, acute resp failure and cardiorespiratory arrest. Resusitation as for any patient Followed by edrophonium, this will indicate whether patient will respond to increasing dose of anticholinergic drug.

16. If edrophonium worsens condition patient suffering cholinergic crisis which is due to over admin of anticholinesterase drugs( cramps, brady,salivation,diarrhoea) Improvement seen if anticholinesterase drugs reduced, withdrawn and restarted

17. ICU management Frequent estimations of VC and inspiratory force Consideration of mechanical ventilation given to those with severe bulbar and respiratory muscle involvement Deterioration of ABGs often late sign Good ICU care, maintaining K, Ca Mg levels normal. Physio and NG feeding. If adjustment of medications not sufficient to see improvement need to consider high dose steroid and plasma exchange therapy.

18. Drugs to avoid Polymyxin group of antibiotics Aminoglycosides B blockers Procainamide, lignocaine Suxamethonium

19. Associated disorders Thyroid abnormality Rheumatoid disease Scleroderma Psoriasis Polymyositis SLE Pernicious anaemia

20. anaesthesia Pre op optimisation Airway assessment if RA Avoid premedication Avoid depolarising mr Reduce dose of non-depolarisers if any used at all, monitoring at all times Continue steroid and give additional on day of surgery Post op hdu-up to 33% require ventilation predicted by long pre-op hx MG, high anticholinesterase requirements, VC <2.9l.

21. Guillain Barre Syndrome Acute demyelinating polyneuropathy Commonest cause of rapid-onset flaccid paralysis since polio decline Occurs as an autoimmune response following a GI or respiratory infection Potentially severely debilitating disorder affecting 1-3 per 100,000 10% die from associated complications A further 10% suffer from long term neurological sequelae and physical dependence

22. Guillain, Barre and Strohl first described a disease affecting French soldiers ( motor weakness, areflexia and CSF abnormalities) in 1916 Descriptions date back to 1859 when Laundry described ascending paralysis

23. Despite well recognized syndrome and potentially fatal Often misdiagnosed and subtle signs of decompensation missed

24. Aetiology All ages affected with bimodal distribution towards young adults and the elderly Slight male preponderance Children less severely affected Most commonly occurs within a month of GI or resp upset. Commonest organism is campylobacter Others inc EBV, CMV, complication of HIV

25. Have been reports of association with vaccines, surgery, epidurals, bone marrow and organ transplantation, SLE, lymphoma, sarcoidosis Pregnancy and OCP confer some protection

26. Pathogenesis Immunologically mediated nerve injury Inflammatory cell infiltrates are seen in association with the demyelination, which is regarded as the primary pathological process Precise mechanism of sensitisation not known Peripheral nerves show infiltration of the endoneurium by mononuclear cells in a perivenular distribution

27. Distributed throughout the nerve length but focused at nerve roots, spinal nerves and major plexuses Macrophages actively strip myelin from bodies of schwann cells and axons Underlying immune response is complex Effectiveness of plasma exchange and IgG is thought to be blocking of demyelinating antibodies

28. Clinical presentation Several distinct clinical pictures described Acute inflammatory demyelinating polyradiculopathy (AIDP) Acute motor axonal neuropathy (AMAN) Acute motor sensory axonal neuropathy (AMSAN) Miller-Fisher syndrome ( ataxia, areflexia and opthalmoplegia which may be accompanied by limb weakness, ptosis and facial and bulbar palsy

29. Classical picture is that of ascending limb weakness with areflexia, although a purely sensory variant has been well documented Features of GBS include Progressive motor weakness, usually ascending from the legs Areflexia Facial palsy and bulbar weakness Opthalmoplegia Sensory symptoms

30. Severe pain esp girdle Resp muscle weakness Autonomic dysfunction( over or underactivity of the SNS or PSNS)

31. Features required for diagnosisdefined by national institute of neurological and communicative diseases and strokes Progressive muscle weakness of more than one limb Areflexia or marked hyporeflexia CSF cell counts of no more than 50 monocytes or 2 polymorphonuclear leucocytes Features highly suggestive Features required to rule out other diagnosis

32. Differential diagnosis Rapidly progressive space occupying lesion eg epidural abscess Critical illness polyneuropathy, associated with recovery from multiorgan failure, steroids and muscle relaxants EMG shows pure axonal degeneration patterns compared to demyelination seen in GBS CSF protein level normal in CIP

33. Monitoring Cardiac Blood pressure Vital capacity measured three times a day Bulbar function monitored to prevent aspiration

34. Investigations In over 90% patients CSF protein is raised ( >0.4g/l) within a week of onset of symptoms Level does not correlate with clinical findings Nerve conduction studies demonstrate reduced conduction velocity Liver and renal function may be impaired Antiganglioside antibody should be searched for

35. SIADH may occur in association with GBS Stool cultures for campylobacter Ecg�s for QT, T and ST abnormalities Head CT to exclude raised ICP and other pathology prior to LP

36. Treatment Major challenge Outcome excellent if complications treated or avoided Prevented by meticulous attention to detail

37. Specific treatment-disease modifying modalities Plasma exchange Immunoglobin Both should be used when patient non-ambulatory or resp decompensation occurs Both have been examined in RCT and no difference in efficacy demonstrated between them

38. Plasma exchange 2 RCT showed reduction in ventilation and reduced time to motor recovery Mortality was not altered Most effective within 7 days of onset 3-5 exchanges of 1-2 plasma volumes each over 1-2 weeks Ffp more complications than albumin CI include CVS instability, sepsis and haemostatic problems Side effects are hypotension, hypocalcaemia,coagulation abnormalities and sepsis

39. IV Immunoglobin 0.4mg/kg daily for 5-6 days Easier administration Fewer side effects Commence tx within 2 weeks of onset of symptoms CI include IgA deficiency(anaphylaxis) Renal function may deteriorate Severe congestive cardiac failure major contraindication RCT has suggested as effective as plasma exchange

40. Steroids No place in the treatment of GBS RCT have shown no advantage

41. CSF filtration Few case reports When plasmapheresis and IgG have failed Logistics difficult!

42. Supportive care Respiratory, 25% require ventilated Physio and VC monitoring in the spont breathing. If less than 15ml/kg or rising pCO2 ventilation likely Monitoring of bulbar function for prevention of aspiration Non-invasive ventilation often not useful as does not eliminate the problem of not being able to clear secretions due to poor cough Early tracheostomy should be considered

43. Supportive care Cardiovascular Full invasive monitoring Care with induction of anaesthesia as leads to hypotension and arrhythmias Care with suxamethonium may lead to arrhythmias Instability may be worsened by other drugs Autonomic instability common

44. Supportive care Nutrition, fluid and electrolytes Paralytic ileus common Tpn may be required Energy and fluid requirements are reduced in these patients Physiotherapy DVT prophylaxis Sepsis survellience Psychological care analgesia

45. Prognosis Death in up to 25% of those who require ICU has been reported often from autonomic abnormalities Approx 16% patients suffer permanent disability Those who require ventilation, improve after more than 3 weeks, not improved within 1 month have greater risk of poorer outcome Gradual improvement may occur over 18months -2years Recurrence n 2-5% cases