myasthenia gravis management guidelines

Dr. Rahi kiran. B
SR Neurology
GMC Kota

1. Myasthenia Gravis Management Guidelines Dr. Rahi kiran . B SR Neurology GMC Kota International Consensus Guidance For Management Of Myasthenia Gravis- Executive Summary; Donald B. Sanders, MD Et. Al. ; Neurology® 2016;87:419–425 UPTODATE. Com

2. Severity of attacks

3. Question 1- Symptomatic Pyridostigmine -initial therapy for mild to moderate MG, Dose S/B adjusted based on symptoms not met Rx goals after an adequate trial of pyridostigmine - Corticosteroids or IS therapy

4. Impending crisis - Rapid clinical worsening , in the opinion of the treating physician, could lead to crisis in the short term (days to weeks). Manifest crisis - a serious life-threatening, rapid worsening of MG and potential airway compromise from ventilatory or bulbar dysfunction Although cholinergic crisis is rare , it cannot be completely excluded as a cause of clinical worsening Question 2- Myasthenic crisis

5. hospital admission- to an ICU if it progresses to manifest crisis . PLEX and IVIg - mainstay of management Corticosteroids or other IS agents-started at the same time to achieve a sustained response Clinical trials - IVIg = PLEX Expert consensus –PLEX> IVIg Question 2- Myasthenic crisis

6. Respiratory assistance MIP < 20 cm H2O, tidal volume < 4 to 5 cc/kg MBC less than three times the tidal volume forced vital capacity is <15 cc/kg body weight.

7. Significant steroid side effects, deemed by the pt. or the treating physician Inadequate response to an adequate trial of corticosteroids Corticosteroid dose cannot be reduced d/t symptom relapse . Question 3- Prophylactic - Nonsteroidal IS agent

8. Azathioprine - first-line IS agent in MG. Mycophenolate mofetil – not proven by RCT, but used widely Cyclosporine – RCT favour , but more s/e – less used M ethotrexate - not proven by RCT T acrolimus Question 3- Prophylactic - Nonsteroidal IS agent

9. Question 4- Treatment goals Minimal Manifestation Status ( MMS ) or better no more than grade 1 Common Terminology Criteria for Adverse Events ( CTCAE ) MMS : no symptoms or functional limitations from MG but has some weakness on examination of some muscles. CTCAE grade 1 medication side effects: asymptomatic or only mild symptoms; intervention not indicated.

10. Question 5- Remission has no symptoms or signs of MG. Weakness of eyelid closure is accepted, but there is no weakness of any other muscle.

11. Question 7 - Non responders Refractory MG unchanged or worse after CS and at least 2 other IS agents, used in adequate doses for an adequate duration, with persistent symptoms or side effects that limit functioning, as defined by patient and physician. Agents used - Chronic IVIg >> chronic PLEX (d/t s/e) Cyp Rituximab , for which evidence of efficacy is building

12. short-term treatment – with life-threatening signs such as respiratory insufficiency or dysphagia In preparation for surgery in patients with significant bulbar dysfunction one or two weeks before When a rapid response to treatment is needed; when other treatments are insufficiently effective Prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations maintenance therapy- refractory MG or for IS are c/I Question 8- Indications for IVIG and PLEX

13. choice depends on individual patient factors and the availability of each. equally effective in the treatment of severe generalized MG. The efficacy of IVIg is less certain in milder or ocular MG. PLEX may be more effective than IVIg in MuSK -MG Question 8- IVIG vs PLEX

14. Question 9 - When to stop treatment? corticosteroid - gradually tapered once treatment goals achieved. Nonsteroidal IS - once goals achieved, maintain for 6 months to 2 years and taper slowly Dosage adjustments should be made no more frequently than every 3–6 months If relapse – increase the dose In some, long term IS needed - individualised

15. Question 10- Treatment of relapse Risk - higher in symptomatic or after rapid taper In some, maintainance is needed for many years, sometimes for life - individualised Make upward adjustments in dose.

16. Question 11 - If complications occur? Changing to an alternative IS agent - if adverse effects and complications are medically significant or create undue hardship for the patient.  

17. Question 12 - Dosages Pyridostigmine – start 30 mg three times for 2-3 days if cholinergic s/e occur- glycopyrrolate 1 mg with each dose, maximum dose is usually 120 mg every four hours while awake. children and younger adolescents, the initial dose is 0.5 to 1 mg/kg every four to six hours, max 7mg/kg

18. Question 13 – Drugs Contraindicated Neuromuscular blocking agents and Anesthetic agents Aminoglycosides Clindamycin Fluoroquinolones Vancomycin Beta blockers Botulinum toxin Chloroquine Penicillamine Tetracyclines Macrolides Metronidazole Carbamazepine Ethosuximide Gabapentin Haloperidol, CPZ, Li Riluzole CS

19. Question 14 - Special situations – Ocular myasthenia Pyridostigmine – symptomatic CS – effective, delay or reduce the frequency of progression to generalized disease Start prednisone at an initial dose of 10–20 mg/day with gradual increases every 3–5 days until achieving a clinical response Thymectomy – c/I

20. respond poorly to ChEIs , Respond well to CS and steroid-sparing agents. tend to remain CS dependent despite concomitant treatment with steroid-sparing agents PLEX >> IVIg - less effective Rituximab - early therapeutic option in patients with MuSK -MG who have an unsatisfactory response to initial immunotherapy Question 15 - Special situations – MuSK antibodies

21. Question 16 - Special situations – Pregnancy If under good control before pregnancy, majority will remain stable throughout. If worsening occurs, more likely during the first trimester and first month after delivery . objective -Spontaneous vaginal delivery. Eclampsia - Magnesium sulfate is c/ i , Barbiturates or phenytoin - useful

22. first-line-Oral pyridostigmine IV ChEIs –c/I - produce uterine contractions Thymectomy - postponed , as benefit is unlikely during pregnancy. IS agent of choice - Prednisone Question 16 - Special situations – Pregnancy

23. nonsteroidal IS of choice- Azathioprine relatively safe - Azathioprine and cyclosporine MMF and MTX –c/I increased teratogenicity Rapid short term - PLEX or IVIg – risk vs benefit – individualised , no consensus Question 16 - Special situations – Pregnancy

24. babies born to myasthenic mothers- examined for evidence of transient myasthenic weakness and should have rapid access to neonatal critical care support . The maternal antibody level correlates with the frequency and severity Decreased fetal movement as a possible indication for PLEX or IVIg . Birth of a child with arthrogryposis should also prompt a search for MG in the mother. hypotonic and feed poorly, Symptoms – 2-12 weeks Treatment- pyridostigmine , exchange transfusion, MV   Question 17 - Transient Neonatal Myasthenia Gravis (TNMG)

25. young children with only ocular symptoms of MG can be treated initially with pyridostigmine - more likely than adults to go into spontaneous remission. Immunotherapy can be initiated if goals of therapy are not met . Maintenance PLEX or IVIg are alternatives to IS drugs in JMG Long term treatment with corticosteroids –if no response to above – more chance of side effects Question 18 - Juvenile MG

26. Non- thymomatous MG – option to potentially avoid or minimize the dose or duration of immunotherapy If patients fail to respond to an initial trial of immunotherapy or have intolerable side-effects from that therapy Time - when the patient is stable and deemed safe to undergo a procedure where postoperative pain and mechanical factors can limit respiratory function Question 19 - Thymectomy in MG

27. Thymomatous MG - all patients should undergo surgery to remove the tumor. Incompletely resected thymomas should be managed after surgery with an interdisciplinary treatment approach (radiotherapy, chemotherapy). may be considered in patients with generalized MG without detectable AChR antibodies if they fail to respond adequately to IS therapy, or to avoid/minimize intolerable adverse effects from IS therapy. Current evidence does not support an indication for thymectomy in patients with ocular MG, MuSK , LRP4, or agrin antibodies. Question 19 - Thymectomy in MG

28. Question 19 - Thymectomy in MG - Children In prepubertal patients – unclear Seropositive generalized MG – s hould be considered If the response to pyridostigmine and IS therapy is unsatisfactory In order to avoid potential complications of IS therapy. Seronegative generalized MG - possibility of a congenital myasthenic syndrome or other neuromuscular condition should be entertained, and evaluation is of value prior to thymectomy .

29. Question 20 - Diet and triggers

30. Question 21 - Immunizations annual seasonal influenza vaccination for all individuals receiving immunosuppressive therapy, for those with generalized MG, Ocular MG within three years of onset

31. Question 22 - Recent drugs Etanercept Eculizumab Belimumab Autologous stem-cell transplantation in refractory MG

32. Flow chart showing pharmacologic prophylaxis

33. Which meal option would be the most appropriate for a patient with myasthenia gravis ? A . Fried potatoes and burger B. kachori and samosa C. mashed potatoes and daliya D. parantha and poori sabji

34. A patient with myasthenia gravis will be eating lunch at 12pm. It is now 10am and the patient is scheduled to take Pyridostigmine . At what time should you administer this medication so the patient will have the maximum benefit of this medication ?

35. A 65 yr female symptomatic since 4 months diagnosed with ocular MG, next best step for treatment – A. Pyridostigmine B. Pyridostigmine + CS C. wait and watch D. IVIG/ PLEX

36. A 60yr male diagnosed with Gen MG, tried on max dose of pyridostigmine + CS for adequate duration, weakness improved significantly, thymoma evaluation negative, ptosis persisted…next step A . CST B. Increase the dose C. urgent IVIG/PLEX D. Shift to Stroke unit and mechanical ventilation

37. Thank you

38. Crisis - Corticosteroids or other IS agents are often started at the same time to achieve a sus tained clinical response. (Because corticosteroids may cause transient worsening of myasthenic weakness, it may be appropriate to wait several days for PLEX or IVIg to have a beneficial effect before starting corticosteroids).

39. All thymus tissue should be removed along with the tumor. Because of the long delay in onset of effect, thymectomy for MG is an elective procedure. It should be performed when the patient is stable

40. the acetylcholine receptor ( AChR ) antibody levels as a marker for treatment response in MG is not recommended. In general, limb and bulbar symptoms ( dysphagia , fatigable chewing, and dysarthria ) respond better to anticholinesterase drugs than the ocular manifestations ( ptosis and diplopia ). Diplopia is particularly resistant to these medications in many patients

41. Long-acting pyridostigmine is not a good choice for daytime use because its variable release and delayed absorption make it difficult to provide a consistent effect and to regulate the overall pyridostigmine dose.

42. . Cholinergic crisis is so rare that it should not be the presumed cause of increasing weakness unless the doses taken are known to significantly exceed total daily dose of ≤960 mg Otherwise, even in the presence of cholinergic side effects, it should be assumed that the patient's underlying MG is worsening, and appropriate treatment should be initiated