MG investigations for mg disease to diagnose the disease

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1. INVESTIGATIONS By Raihanah Che Ghani Neuromedical Posting

2. INTRODUCTION MG: most common disorder of neuromuscular transmission hallmark a fluctuating degree and variable combination of weakness in ocular, bulbar. Limb and respiratory muscles Weakness is the result of antibody-medicated, T cell-dependent immunologic attack directed at proteins in the postsynaptic membrane of neuromuscular junction (acetylcholine receptors or receptor-associated proteins) Diagnosis: clinical and serologic testings

3. Diagnostic approach Focused on confirming the clinical diagnosis Bedside tests (ice pack test and edrophonium test): sensitive but have major limitation due to concerns about excess false-positive results  not confirmatory tests * The diagnostic sensitivity varies depending on whether the patient has ocular or generalized disease Most reliable lab methods are: Serologic tests for autoantibodies Electrophysiologic studies : repetitive nerve stimulation (RNS) studies and single-fiber electromyography (SFEMG)

4. BEDSIDE TESTS Ice pack test - as part of neurological exam in pt with ptosis Based on physiologic principle that neuromuscular transmission improves at lower temperature In MG: ptosis can be overcome by direct cooling of the eyelid muscles. A bag (or surgical glove) is filled with ice and placed on the closed lid for 2 minutes. The ice then removed and the extent of ptosis is assessed Improvement in ptosis: positive test result The sensitivity (80%) in those with prominent ptosis due to myasthenia Predictive value has not been established Extension of physical examination rather than a diagnostic test

5. Edrophonium test ( Tensilon test) No longer available Only in those with obvious ptosis or ophtalmoparesis (improvement after infusion of the drug can be observed) The difficulty in quantifying strength independent of volition in other muscle group makes the interpretation of the response to edrophonium too unreliable

6. Edrophonium chloride: An acetylcholinesterase inhibitor with rapid onset (30 to 45 seconds) and short duration of action (5 to 10 minutes) Prolongs the presence of acethylcholine in the NMJ Results in an intermediate increase in muscle strength in many of affected muscles Potentiates the muscarinic effects of AcH especially in elderly, cardiac disease or bronchial asthma (contraindication) Develop increased salivation and mild gastrointestinal cramping. More seriously: symptomatic bradycardia or bronchospasm Antidote: atropine Sensitivity: 80-90%, a/w many false-negative and false positive result Positive results not specific for myasthenia, also can occur in other conditions (MND, brainstem tumors and compressive cranial neuropathies )

7. SEROLOGIC TESTING Pts with positive AChR -Ab, Musk-Ab or LRP4 assays have seropositive MG (SPMG) Possible in 90% of pt with generalized disease Purely ocular MG: sensitivity of AChR -Ab is lower, detectable in half of pt Although the sensitivity of the antibodies varies by disease (ocular vs generalized), their specificity in MG is very high(99% for the AChR binding antibodies).

8. Acethylcholine receptor antibodies 1 st step in the laboratory confirmation of myasthenia These antibodies are polyclonal and are present in 85% of pt with generalized disease Serologic testing for AChR -Ab should be performed prior to initiating immune modulating , as such therapy can sometimes lead to apparent seronegativity . Repeat serologic testing 6 to 12 months after initial testing has been reported to detect positive seroconversion in 15% of pt with MG who were initially seronegative

9. MuSK antibodies Present in 38 to 50% generalized MG who are AChR -Ab negative MuSK : receptor tyrosine kinase that mediates agrin dependant Achr clustering and neuromuscular junction formation during development MuSK - Ab positive MG may have different cause and pathologic mechanism than AChR -ab positive disease Generally not present in well established ocular MG, but detected in a few cases Nearly half of pt with Ach-R Ab negative MG will have MuSK antibodies, those with ACHR-Ab positive MG do not have antibodies to MuSK in most studies to date.

10. Pts with AChR -Ab negative MG and MuSK ab have a much lower frequency of thymic pathology than patients with AChR - Ab positive MG. Thymic hyperplasia is frequent in AChR -Ab positive MG but less frequent in the MuSK -Ab positive group Pt with typical clinical features of MG who is AChR -Ab negative, MuSK ab testing can clarify the diagnosis and direct treatment

11. Clinical Features of AChR - Ab negative, Musk- Ab positive MG Onset at any age Female preponderance An oculobulbar form with diplopia, ptosis, and dysarthria; not purely ocular myasthenia gravis A restricted myopathic form with prominent respiratory and/or proximal weakness, especially neck extension’ No thymic pathology (thymoma) and uncertain role of thymectomy

12. Ocular features ( eg , ptosis and diplopia) are common in MuSK -Ab positive myasthenia gravis and may be the presenting feature they are typically more symmetric, less severe, and less likely to fluctuate compared with ocular involvement in "typical" AChR -Ab positive myasthenia gravis

13. LRP4 ANTIBODIES Antibodies against LRP4, an agrin receptor required for agrin -induced activation of MuSK and AChR clustering and NMJ formation, have been found in 13% of patients who are seronegative for both AChR and MuSK antibodies Ocular onset and mild symptoms predominated However, at maximal disease severity, pts with LRP4/ agrin antibodies had more severe sx than those without positive antibodies Most patients improved with standard immunosuppressive therapy No association with thymic pathology (in particular thymoma)

14. Other Antibodies Anti- agrin antibodies Anti cortactin antibody Anti titin antibody

15. Seronegative myasthenia Seronegative/ antibody-negative MG: 6 to 10% of pts who have negative standard assays for both AChR antibodies and MuSK ab and rarely LRP4 ab Pt with seronegative MG: more likely to have purely ocular disease than those who are seropositive. Generalised MG have a better outcome after treatment Same features as SPMG Electrophysiologic findings are identical Respond in similar fashion to pyridostigmine, plasma exchange, glucocorticoids and immunosuppressive therapies as well as thymectomy

16. Other antibodies Anti-striated muscle antibodies: target heterogenous striated muscle protein Present in 36% of pt with MG but in 80% of those with thymoma Useful marker for thymoma in pt btw 20 and 50 years of age ( ie : early onset MG)

17. ELECTROPHYSIOLOGIC CONFIRMATION Provide confirmation of the diagnosis of MG In generalized MG: the diagnostic sensitivity of RNS studies is 75 to 80% while single-fiber electromyography (SFEMG) is 95%

18. Repetitive nerve stimulation Most frequently used electrodiagnostic test for MG normal muscles : no change in CMAP amplitude with RNS. In myasthenia: a progressive decline in the CMAP amplitude with the first four to five stimuli (a decremental response) considered positive (abnormal): if the decrement is greater than 10 percent positive in 75 to 80 percent of patients with generalized myasthenia if recordings are made from proximal (usually trapezius and orbicularis oculi), as well as distal muscles. Sensitivity improves with more severe weakness and may be greater than 90 percent in patients with myasthenic crisis the sensitivity of RNS is much lower (15 to 45 percent) in patients with ocular myasthenia. 

19. A decremental response is not specific for myasthenia gravis. Decrements may be seen in other disorders of neuromuscular transmission (Lambert-Eaton myasthenic syndrome or botulism) and motor neuron disease

20. Single-fiber electromyography most sensitive diagnostic test This technique allows simultaneous recording of the action potentials of two muscle fibers innervated by the same motor axon. The variability in time of the second action potential relative to the first is called "jitter“ Any disorder, such as myasthenia gravis, that reduces the safety factor of transmission at the neuromuscular junction will produce increased jitter. To maximize the sensitivity, a limb and facial muscle may be studied. Variation in the latency of various muscle fiber responses (abnormal jitter)

21. SFEMG is positive in greater than 90 percent of those with generalized myasthenia. In ocular myasthenia gravis , the diagnostic sensitivity of SFEMG ranges from 80 to 95 percent if a facial muscle is studied Abnormal jitter is not specific for myasthenia. It may be abnormal in motor neuron disease, polymyositis, peripheral neuropathy, Lambert-Eaton myasthenic syndrome, and other neuromuscular disorders. However, it is specific for a disorder of neuromuscular transmission when no other abnormalities are seen on standard needle EMG examination

22. Further Investigation To exclude other disease Ocular or bulbar symptoms: MRI brain (helpful to evaluate for mass lesions compressing the cranial nerves or a brainstem lesion that may masquerade as ocular MG) CT/ USG Orbits: helpful in the differential diagnosis of ocular myasthenia and thyroid ophthalmopathy LP: to exclude lymphomatous or carcinomatous meningitis Blood tests: TFT, autoimmune screening (ANA,RF) Once the diagnosis of MG has been established  chest CT or MRI to look for a possible associated thymoma

23. Managements

24. MANAGEMENTS Goals: to render pt minimally symptomatic or better while minimizing side effects of medication Response is judged by improvement in the clinical symptoms and neurological deficit

25. 4 primary therapies

26. General Care for all patients Avoid drugs that may exacerbate MG Can reduce the effectiveness of neuromuscular transmission and cause increased clinical weakness Routine vaccination      

27. Immunizations Annual influenza vaccination for all receiving immunosuppressive therapy Pneumococcal vaccine for all with generalised and ocular MG Most live-attenuated vaccines should be avoided in patient with MG taking immunosuppressive medications such as prednisolone, azathioprine and MMF Zoster vaccine is not recommended in highly immunocompromised

28. Initial Symptomatic Therapy Pyridostigmine (Acetylcholinesterase inhibitors) Action : Retard the degradation of Ach that occur by enzymatic hydrolysis in the NMJ  effect of Ach is prolonged  variable improvement in strength The response to pyridostigmine is not uniform Most pt with MuSK positive disease have a poor response to anti cholinesterase agents Often the symptoms improvement may be mixed Eg : resolution of neck weakness and ptosis with persistence of diplopia Limb and bulbar symptoms (dysphagia, fatigable chewing and dysarthria) respond better to anticholinesterase drugs than ocular manifestation (ptosis and diplopia) Provide only symptomatic therapy and usually not sufficient in generalized MG

29. Dose: Pyridostigminine 30 mg tds with meal for 2 to 3 days to assess the cholinergic SE Excessive cholinergic SE: add oral glycopyrrolate 1mg with each pyridostigmine dose to block the bothersome sx If tolerate pyridostigmine well with or without anticholinergic effect  increase the dose by 30 mg increments until good therapeutic effect or limited side effects Maximum dose: 120 mg every 4 hours while awake

30. SE: cholinergic side effects Most bothersome muscarinic SE: abdominal cramping, diarrhea. Others are increased salivation and bronchial secretions, nausea, sweating and bradycardia Nicotinic side effect: fasciculation and muscle cramping Cholinergic crisis: - rare, if dose >960 mg/day major SE of excessive anticholinesterase : weakness

31. Plasma Exchange and IVIG as rescue or bridge therapies Plasmapharesis and IVIG: immunomodulating “rapid” therapies for MG -> start to work quickly (over days) but the benefit are only short term (weeks) Similar efficacy Primarily based on factors related to clinical preference and convenience Used in: Acute exacerbations including myasthenia crisis Preoperatively , before thymectomy or other surgery As a “bridge” to slower- acting immunosuppressive therapies for pts in whom it is especially desirable to avoid or minimize glucocorticoid use

32. ACUTE EXACERBATIONS Myasthenia crisis Transient worsening of myasthenic symptoms can be precipitated by: Concurrent infection Surgery Pregnancy Childbirth Certain medications Tapering of immunosuppressive medication Spontaneously as part of natural history of the disease Worsening weakness (ptosis, ophthalmoplegia, generalized weakness), severe bulbar weakness, dysphonia, weak cough with difficulty clearing secretions and difficulty in breathing

33. Therapeutic plasma exchange Directly removes acetylcholine receptor antibodies from the circulation Clinical improvement with plasmapheresis roughly correlates with the reduction in antibody levels. Beneficial clinical effect of plasmapheresis is usually seen within days, but the benefit typically lasts only 3 to 6 weeks The AChR antibody levels rebound within weeks if no concurrent immunotherapy ( eg : glucocorticoids) is used Established tx for seriously ill patient in the midst of myasthenia crisis Less severe exacerbations: IVIG and plasma exchange had similar efficacy in 81 adults with MG and worsening weakness

34. Course of treatment: Consist of 5 exchanges (3 to 5 L of plasma each) over 7 to 10 days Complications: Repeated plasmapheresis leads to inadequate peripheral venous access and requires placement of large bore, double lumen central catheter Significant chronic catheter complication: infection and thrombosis Others: bleeding, hypotension, cardiac arrhythmias, muscle cramp and toxic reaction to the citrate used in procedure

35. Despite these concerns, plasmapheresis can be used safely for patients with MG. In an analysis of 42 patients with moderate to severe MG who were treated with plasmapheresis in a prospective trial, there were no complications in 55 percent and mild to moderate complications that did not require stopping treatment in 45 percent [ 44 ]. The adverse events in this study were mainly citrate reactions and peripheral vascular access problems that were easily managed. In most cases, plasmapheresis was performed in the outpatient setting (90 percent) using peripheral venous access (83 percent).

36. Intravenous immunoglobulin (IVIG) Effect of IVIG is seen typically in less than a week , and the benefit can last for 3 to 6 weeks To quickly reverse a severe and life threatening exacerbation of myasthenia IVIG also offers an alternative to plasmapheresis or multiple immunosuppressive agents in select patients with refractory MG, as a preoperative treatment before thymectomy or as a "bridge" to slower-acting immunotherapies.

37. IVIG Immunoglobulins isolated from pooled human plasma by ethanol cryoprecipitation Dose: Total dose of IVIG is 2g/kg, usually over 2 to 5 days (IVIG 0.4g/kg/day x5/7) Side effects: headache, chills, dizziness and fluid retention Uncommon complications: aseptic meningitis, acute renal failure, thrombotic events and anaphylaxis

38. Pulsed glucocorticoids Some used pulsed IV methylprednisolone ( eg : 2 g daily for 1-2 days) for moderate exacerbation of MG, followed by 30 mg of oral prednisolone IV methylprednisolone is avoided in patients with myasthenic crisis, who are receiving IVIG or plasmapheresis  because of a potential to increase the risk of critical illness myopathy

39. Addition of immunosuppressive therapy

40. Addition of immunosuppressive therapy Indicated for: Pt who remain significantly symptomatic on pyridostigmine OR Who become symptomatic again after temporary response to pyridostigmine

41. Glucocorticoids Due to rapid onset of effect , glucocorticoids are the most commonly used initial immunosuppressive therapy Prednisolone : started at 20 mg daily, with gradual dose escalation to a usual target dose of 60 mg per day (or 1 mg/kg per day, maximum 80 mg daily). Gradual dose escalation  to avoid the early transient worsening associated with high-dose glucocorticoids. Once an effective clinical response is obtained, glucocorticoids should be gradually tapered to the lowest dose necessary to maintain disease stability Reduce prednisolone by 5 to 10 mg per month until a daily dose of 30 mg is reached, then even more slowly ( eg : no more than 5 mg per month)

42. monitored regularly for side effects and toxicities of glucocorticoids. Calcium and vitamin D supplementation: to reduce bone mineral loss Pneumocystis  pneumonia prophylaxis should be considered in patients on prolonged courses of steroids, particularly at doses of prednisolone ≥20 mg daily and other risk factors for immunosuppression.

43. insufficient response to glucocorticoids, inability to taper steroids below a reasonably acceptable level without return of symptoms, or intolerance of chronic steroids  the addition of steroid-sparing immunosuppressive therapy ( Grade 1B ). preferred first-line agents vary based on individual patient and disease factors

44. Pt with ( AChR ) antibody-positive or seronegative MG:  azathioprine  or mycophenolate mofetil as a first-line steroid-sparing agent ( Grade 2C ) Cyclosporine or tacrolimus : intolerant of or unresponsive to an adequate trial of azathioprine or mycophenolate mofetil.

45. most patients with muscle-specific tyrosine kinase ( MuSK )-positive MG    rituximab  first line ( Grade 2C ). Patients with MuSK -positive MG often have a poor response to anticholinesterase agents and remain dependent on glucocorticoids despite the addition of azathioprine and mycophenolate mofetil  observational studies and clinical experience suggest that rituximab is effective If cost or access to rituximab is prohibitive  azathioprine and mycophenolate mofetil remain reasonable to use as first-line steroid-sparing therapies.

46. Source: International Consensus Guidance for Management of Myasthenia Gravis 2020 Update

47. The clinical benefit azathioprine and mycophenolate mofetil is typically delayed for 6 to 12 months, with a maximal effect often not seen until one to two years of treatment Patients require regular laboratory monitoring during treatment. A slow prednisolone taper is typically started once the minimum time to onset of clinical response of the steroid-sparing agent has passed Approximately 10 percent of patients with severe MG are refractory to, or are limited by the specific toxicities of, the first-line immunosuppressive therapies ( ie , azathioprine, mycophenolate, cyclosporine or tacrolimus) Some require unacceptably high doses of glucocorticoids despite concurrent use of these agents. In these refractory patients, treatment options:  eculizumab,rituximab , and maintenance IVIG. cyclophosphamide has serious potential side effects and is usually reserved for the small percent of patients with severe MG who are refractory to the other immunomodulating therapies, including trials of  eculizumab,rituximab , or maintenance IVIG.

48. OCULAR MG Source: International Consensus Guidance for Management of Myasthenia Gravis 2020 Update

49. Role and timing of thymectomy The thymus: role in inducing acetylcholine receptor antibody production Patients with thymoma 10 to 15% of pt with MG associated with thymoma  surgery is indicated in whom a complete resection is considered feasible Mx: complete resection of the thymus. Sometimes involves chemotherapy and radiation therapy Patients without thymoma - Thymectomy in the absence of thymoma is recommended in patients with generalized MG and AChR ab positive who are ≤ 50 years

50. Source: International Consensus Guidance for Management of Myasthenia Gravis 2020 Update

51. REFRACTORY DISEASE about 10 percent of patients with severe MG are refractory to, or are limited by the specific toxicities of, the first-line glucocorticoid-sparing therapies (azathioprine, mycophenolate, cyclosporine and tacrolimus) Refractory disease is generally considered with any of the following: Disease that is unchanged or worse after glucocorticoids and at least one other immunosuppressive agent, used in adequate dose and duration, with persistent symptoms or side effects that limit function Need for ongoing rescue therapy with IVIG or plasma exchange, or frequent myasthenic crises, while on immunosuppressive therapy Intolerable adverse reactions or the presence of comorbid illnesses that preclude use of conventional immunosuppressive therapies

52. Most would require a minimum of glucocorticoids plus an adequate trial ( ie , one year or more) of either azathioprine or MMF (but not both) before considering a patient to have refractory disease. consider a trial of cyclosporine or tacrolimus before moving on to the treatment option Some require unacceptably high doses of glucocorticoids despite concurrent use of these agents. treatment options: eculizumab, rituximab and maintenance IVIG.

53. Source: International Consensus Guidance for Management of Myasthenia Gravis 2020 Update

54. Source: the NEJM, Myasthenia Gravis, 2016

55. Source: the NEJM, Myasthenia Gravis, 2016

56. References Uptodate International Consensus Guidance for Management of Myasthenia Gravis 2020 Update the NEJM, Myasthenia Gravis, 2016