The Philippine Journal of Neurology Volume 15 No.1 May 2011 ISSN 0117-3391 Consensus Gutpetines: THe MEDICAL TREATMENT OF Non-THYMoMaTous AUTOIMMUNE GENERALIZED MYASTHENIA GRAVIS ‘NEUROMUSCULAR COUNCIL OF THE PLIPPINE NEUROLOGICAL ASSOCARTON ABSTRACT hana lai is a wie spectra of seas hat thors ae varied options of reatren cresved by te Neuromuscular Counc of te Phifpne Nourlogia! kaso m= Poss opfons of weatment in generalized autommuune nyostionegiaes, Methods: Arles’ were roles om 1956 2012 trom the Intern, appraised, summarized, ar) suldele fo come ui wih recommendations inthis teament gustne The Arosa Arson ee Neurology cesses of genca (Gus iL 1) and. eves ol econmencevos Lavel ABU) ns ee E i ee eure ‘Results: Now insiohs wor tui ths paihepclgy ot atonimune imestbonia gravis rows ana _gulcome of weatmord‘ groups as well as Uy newest hmmunosupprasean which recone taag i ea immurtosupprssan. There are oly few erak population ancora oni ras on some inmuncsuperssant drugs he cyclosporine tacoma and tecerohne nea ‘Studs are tespective oc pon iaboled sluien Thus, mos recamnendaongridelea Lae @ _ Sanction, Tc gues summa he orig: Pandotgmin ihe rte eatwnt rh mi "899 of Beginning of inyashenia symptoms. For rapid progresee liness, the opton of tymecory ie Inveduind toned preaison lone aathopie Fores wapcndan me eee eed ‘ “options: eyclosphosphamido, cyclosporine, mycophenolate, tacrolimus, methotrexate and rituximab. eee gM se ors arts ana i wn nie ns azatlontina. IV cyclophosphamide may be give for fosstan sv ‘ofMG patents. [PRINeutol TE ie ane Pe ert oot ae aise oes INTRODUCTION Myasthenia gravis is a rare neurologic disorder among Filipinos. There are no present data on the epidemiology of ‘MG in the Philippines. Among developed countries, the wihenia gravis (MG) is a novel autoimmune prevalence of MG is about 5-15 per 100,000, sa snap Tee eeisrenige The chcummamee ia He eitaon or oo munity acetylcholine receptors ething in intermicene_! MG ae sill unknown as well ain other autoimmune of transmission resulting in fluctuating moror _‘iseases. The thymus glands implicated inthe pathogenesis Myasthenia gravis is the mose common disease (MIG due to sensitization of T-cells from myeid-lts ells aon in the thymus leading co B cell production of antibodies a against muscle proteins and acetylcholine receptors plus the involvement of complement and cytokines. Fifteen percent of MG patients have thymoma and 30% of thymoma patients have MG. Sixty percent of MG patients have thymic hyperplasia. As the disease progress, other muscle Counc Philippine Nrrdogia Avciation Tower Se Lk Medical Center Quen Cy2 ‘Tese Priiprive JOURNAL oF NEUROLOGY proteins may be involved as termed “epitope spreading” by Richman and Agus in 2003. ‘Thus for progressive MG, treatment should be immune directed to modulate and alter T and B cell population and activation, Recently, a new hypothesis by Michael Pender(2012, Australia) postulated the initiation of autoimmunity described in the following steps: CD8+T cell deficiency which is genetically determined, primary EBV infection; impaired CD84T cell control of EBV infection; increased. EBV load; EBV in target organs; clonal expansion of EBV- infective autoreactive B cels; infleeation of autoreactive B cells into the target organs and formation of lymphoid population or germinal centers which causes autoreactiviry. Lack of Vitamin D likewise aggravates CD*+ T' cell deficiency. In MG, the thymus is the target organ where germinal centers are established because of the clonal ‘expansion of autoreactive B cells, Thus, MG autoimmuniey is born duc to the myoid cells in the thymus. Thus, better furure treatments to target chronic EBV infection and decreaseautoreactiveB cell populations may be tied. This consensus guideline on the treatment of MG is being conceived to establish a common ground of management amidst the many options of treatment for MG. The choice of treatment for each MG patient should beindividualized that requires judgment, experience and the time course ofthe disease. The purpose of treatment in MG is to improve neuromuscular transmission and reduce the production and presence of antibodies against the nicotinic acetylcholine receptors (AchR). ‘The Neuromuscular Council of the Philippine Neurological Association (PNA) aims to write a consensus guideline on the treatment of MG that is adaptable and costeffcctive for Filipinos who have autoimmune MG. Thus, this guideline is written for Filipinos with MG and for Filipino neurologists managing patients with MG. To identify our patients with MG, we should clucidate the critetia for diagnosis so that we may not falter in identifying the disease. Other diseases that mimic autoimmune MG are as follows: congenital MG, mitochondrial myopathy, motor neuron disease, progressive muscle atrophy, hypokalemic periodic paralysis, Lambert-Eaton myasthenic syndrome, botulism, Miller-Fisher syndrome, polymyositis, polyneuropathies, chronic progressive ophthalmoplegia, benign essential blepharospasm and midbrain tumors. John Keesey in 2004 ‘noted that 58% of MG were diagnosed correctly inthe first year and 80% of MG in the second year of disease. Thus, careful history and physical exam plus the needed ancillary tests would make diagnosis of MG close to 100% accurate. Volume 15 No. 1 May 2011 Four critetia characterize MG as follows: 1, Clinical History and Physical Exam: a. History: symptoms of fluctuating voluntary motor weakness of the muscles involved usually in the afternoon as follows: (1) Ocular symptoms- prosis, diplopia (2) Bulbar symptoms ~ facial weakness, masticatory ‘muscle weakness, dysarthria, naslized speech and dysphagia (3) Truncal muscle sympcoms ~ weak neck muscles and lusibosacral muscles (A) Proximal muscles of 4 extremities- weakness specially on repeated use, easy fatignbilicy b. Physical Exam: ) Ocular sigass (@) Lid ewitch sign- Ask patient co gaze fully downward and slowly bring the eyes upward Up to a mid position and observe twitching of eyelids (©) Herring's sign — Prosis is accentuated by passively opening the contralateral eye (©) Prolonged upgaze for 1 minute ~ measute lid appertureat start of looking upwards and after 1 minute of continuous upgaze (@) Cogan’s sign — seesaw ptosis ~ répetitive ‘manual elevation of protic lid causes drooping ‘of opposite lid (©) Lid peck sign ~ On voluntary lid closure, the lids separate after momentary apposition resulting in widening of palpebral fissures | (6) EOM test note for asymmetry and diplopia 2) Bulbar signs: (2) Ask patient to say “ka-ka-ka? for one minute and note nasalized speech (©) Note for pharyngeal muscle weakness (IX and 20) with dysphagia, weak palaral elevation, and ‘regurgitation of fluids through the nasal caviey (©) Test for muscle strength V, VII, XT and XII ~ weak muscles of mastication (temporalis and masseter); weak facial muscles- usually symmetrical - weak orbicularis oculi, orbicularis otis, buccinators; weak sternocleidomastoid‘muscles and weak tongue muscles, Some have drooping of lower jaw and have difficulty keeping the mouth closed (@) Characteristic myasthenic “snarl” when the patient smiles or laughs due to orbicularis oris : weakness. The characteristic “snatl” develops ‘with contraction of the middle portion of the upper lip while the upper mouth corners fail to contract. (3) Truncal muscles: (@) Test cervical mustle flexion and extension with tesistance- drooped head syndrome is due to cervical extensors weakness (b) Bending tests for thoracolumbar muscles (4) Proximal muscles of extremiti (2) Prolonged arm raise for 1 minute and note time of fatigue (6) Ask patient to make 10 squats in 1 minuteand note how many were made, (5) Respiratory muscles: (@), With a tape measute around the chest, measure chest circumference at maximum inspiration and at maximum wieh expiration- normal difference is 2.5em and more () Afr one full inspiration, ask the patient to count from 1 to 20. 2 Positive Pharmacologic response: Positive improved strength observed after IV Edrophonium 10 mg for adults and 5 mg for children less than 34 kg body ‘weight and strength seen immediately, Positive improved strength observed with 15 mg Neostigmine TV and seea after 15 minutes, Positive improvement of strength observed with oral pyridostigmine 60 mg tablet for adults and Img/kg for children after 60-90 minutes of observation. Atropine sulfate should be at hand if IV medications are given. Positive neurophysiology tests: Positive decrement (at least 10% at the 2nd to Sth response) on a low frequency repetitive nerve _ stimulation at?-Shz. esseisus Guipetines: THe Meicat,Trearoevr oF NON-THYMOMATOUS AUTOIMMUNE GENERALIZED MYASTHENIA Gravis 3, ZG Bagabaldo ctal(1989 Philippines) showed a minimum decrement of 11.8% which was significane at 95% level using a 4-minute test. She reported 6 types. of repetitive nerve stimulation (RNS) figures: carly decrement (up to 11th response); late decrement (12th response and beyond); eatly decrement followed by increment; continuous increments progressive decrement and straight. Sixty-two percent of MG patients showed early decrement type. Among normal subjects, the common RINS figures were increment and straight. b, Increased jitter on single fiber EMG Jitter means the variation of time interval between ‘two action potentials of the same motor unit. Abnormal jet means the value exceeded the upper limit of the normal value for that muscle and more than 10% of the pairs have increased jitcer. Extensor digitorumcommunis is the rauscle frequently tested. VA Selvan (2011 India) stated that single fiber EMG is highly sensitive (85-95%) in MG but not specific. 4, Positive Antibody to AchR (>0.5ng/dl): ‘Types: Binding antibodies; Modulating Antibodies; and Blocking Antibodies “Ten to fifteen percent of patients are seronegative for AchR antibodies. It has been pointed out that some patients may have antibodies that do not react to the usual mode of assay; or they may possess another type of muscle antibodies like anti-MUSK, anti-ryonidine or antistriational ancibodies. Diagnosis of Autoimmune MG is ascertained if all 4 criteria arc satisfied. However, in the absence of antibody assays, criteria 1,2, and 3 may be enough to support the diagnosis of MG as itis in the Philippines where assays are not available ‘TYPES OF AUTOIMMUNE MG: 1. According to muscles involved: a. Purely ocular MG b, Bulbar MG © Generalized MG 2. According to Age of Onset: a. Neonatal MG ~ newborn (passive transfer of ‘maternal antibodies)4 ‘Tue Purvis JouRNAL oF NevRoLocy Juvenile MG ~age 2 to 18 c. Early Adult MG ~ age 19-55 4. Lateadult MG ~ age 56 and above 3. According to positivity of antibodies: a. Seropositive MG bb. Seronegative MG 4, According to Presence or Absence of Thymoma: a. Non-Thymomatous MG b. MG with Thymoma or Thymomatous MG 5. According to severity called types: a. Osserman’ classification (see appendix) — Types wlV b. Myasthenia Gravis Foundation of America (MGFA) Classification (see appendix) ~"Types I to V ‘THE NATURAL CLINICAL HISTORY OF MG: Untreated MG as written in the early 1900 showed that 1/3 of patients progressively worsened to crisis and died; 1/3 showed a chronic, relapsing, and remitting type with a history of crisis and1/3 improved and led active lives with MG. Eleven percent achieved remission even without treatment. Myasthenie crisis occurs in 15 t0 20% of cases usually in the first 3 years of illness. The most important advancementin MG therapeuticsis the advent of positive pressure ventilator machines in 1953 and improved respiratory care management that reduced mortality in MG crisis. In 1900, mortality for MG was at 80%, and was reduced to 696 in 1970's and 4% since 1994. A retrospective study by Oosterhuis from 73 MG patients in Amsterdam hospital from 1926 to 1965 showed amortality of 29%. Ocular symptoms initiated the disease in 50% followeid by bulbar symptoms. After 22 years of follow-up, 2296 were in remission, 34% have improved, 1696 were unchanged and 3% deteriorated. These patients ‘were managed by Pyridostigmine alone. A follow-up among ocular MG, 1/3 remained ocular, while 2/3 became generalized within 2 years of illness. ‘Twenty-two percent had spontaneous remission in the first ‘year, but relapsed in the second year of illness. Ifocular MG. has noc progressed after 2 years, ic is unlikely chac it will progress. The clinical course of MG is very variable from patient Volume 15 No. 1 May 2011 incerfere with activities to the worst kind presenting with crisis or eespiratory insufficiency. MG patients should be monitored closely within the first 2 years of illness where progression usually occurs Regarding MG in paediatrics called juvenile MG (IMG), prepubertal cases are different from that of adulls Prepubertal JMG are often ocular specially among Chinese, equal males and females population and has a higher rate ‘of spontaneous remission than pubertal and post-pubertal JMG. Also JMG has a lower rate of generalization than adults. Thymmomas are also rare in JMG. Regarding autoimmune myasthenia gravis with anti- MuSK (muscle specific tyrosine kinase) antibodies, ic is about 50% of seronegative for AchR antibody MG patients (15% of all MG). The other half has antibodies to other proteins in the neuromuscular junction. Kawakami ex al, 2011 reported that. MuSK mediates the agrin signalling pathway and also anchors the collagenic tail subunit (ColQ) of acetyicholinesterase. MuSK- IgG blocks binding of ColQ to the neuromuscalar junction. Ant ‘MusSK positive patients usually presents atypically with facial, bulbar, paraspinal and esophageal weakness without ocular symptoms. Respiratory crisis are more common among anti-MuSK positive MG than anti-Achl+ patients. Enhanced sensitivity, non-responsiveness or even clinical ‘worsening happens with pyridostigmine treatment. Thymus histology is usually normal. Pasnoor et al, 2010 reported that most patients respond favourably to immunotherapy with the best response t0 steroids and plasma exchange. ‘The poorest response was to IVIg. The long term outcome ‘was favourable in 60% of 53 anti-MuSK+ MG patients observed. Regarding MG in pregnancy, 3 retrospective studies combined with182 pregnancies showed normal pregnancy and delivery but with 41/182 (22.5%) MG deterioration during preganancy, 15/182 during puerperium and 28 babies (15,496) with neonatal MG. AIMS OF THIS GUIDELINE: 1, To write recommendations as a consensus among neurologists about the most effective and most economic plan of treatment for Filipinos with non- ‘thymomatous autoimmune MG. 2. Tosearch the literature to provide evidence for the most efficacious therapy for autoimmune MG. 3. To disseminate the recommendations made based onners, pediatricians, and family physicians. This guidelin¢ is limited co literature evidence published as found in the internet currentas of March, 2012 plus other related literature available, This guideline is limited co stakeholders belonging to Filipinos with non-thymomatous, autoimmune generalized MG, and to neurologists and other interested physicians in the Philippines CLINICAL QUESTIONS ON THE MANAGEMENT (OF AUTOIMMUNE MG: _ £ HOW WOULD YOU USE PYRIDOSYIGMINE IN THE TREATMENT OF GENERALIZED AUTOIMMUNE MG? IMMUNOSUPPRESSION STRATEGIES IN THE LONG TERM TREATMENT OF GENERALIZED AUTOIMMUNE MG? © BL HOW WOULD YOU MANAGE A CASE OF ". MYASTHENIC CRISIS? "YL: Search the literature in the internet using Cochraneand Pubmed limiting the year ofpublication to 1966-2012. plus othe related literature on hand. Critical appraisal of articles gathered... The American ‘Academy of Neurology criteria for evidence grade was used. (Appendix IV) Bd. Condensing articles rlevane vo clinical questions ‘Consensus meeting of the Neuromuscular Council ‘members on May 17, 2011 and to write frst draft of guideline recommendations. Writing recommendations according to | recommendations A, B, C. and D. Those grade A evidence were labelled as good practice p recommended by experts on the topic. The American “Academy of Neurology grades of recommendation was | used. (Appendix V) J & Presentation of finished guideline to a PNA meeting on {7 Jane 3, 2011 and gathering feedback through a survey. /Trenty-four respondents approved the guideline. OUD TUELINES) AE NEURAL LNEALMSAL UF INUNIBIMUMAIUUS AUIUIBIMUNE GENERALE MYASTHENIA GRAMS > 7. Rewriting guidelines for publication second draft on ‘Aug.17, 2011 and final draft on March 3, 2012, SUMMARY OF SURVEY DONE AMONG PNA FELLOWS ON THE MANAGEMENT. OF GENERALIZED AUTOIMMUNE MG IN 2010 Fifty-four neurologists participated in the survey, Eighty-five percent(85%) were PNA fellows while 15% were residents, One hundred percent (10096) of neurologists would give Pyridostigmine bromide (PB) in all stages of MG. Twenty-eight percent(28%) start PB at 30 mg 3 times a days 26% would start PB at 60 mg 3 times a day and 16% would start PB at 30 mg 2 times a day. Maximum dose of PB that was given was 200 mg per day by 43% neurologists and 300 mg of PB per day by 26%; 180 mg of PB per day by 209%; and greater than 300 mg per day by 79 of neurologists. Oral steroids (Prednisone) was given if BB was not sufficient to improve muscle strength, ‘Thirty-five percent(35%) would give oral steroids at Stage 1, 43% at stage Ia, 40% ae stage II-b and 100% give steroids at stage Il and IV. Management of MG crisis were as follows: 29% used oral steroids; 13% used IV steroids, 23% used plasmapheresis; 16% used IV Ig and 1 96 used 1V cyclophosphamide GUIDELINE RECOMMENDATIONS BASED ON EVIDENCE, CLINICAL QUESTION I. A HOW WOULD YOU USE PYRIDOSTIGMINE BROMIDE (PB)IN THE MANAGEMENT OF GENERALIZED AUTOIMMUNE MG? Acetylcholinesterase inhibitors represented by Pysidoscimine bromide (PB) brand name Mestinon which ‘was commonly used for MG since 1954 is the fist line drug for MG. PB remains the premier drug ofthis class of ‘compounds in cerms of effectiveness, smoothness of action and predictability as stated by Genkins et al, 1992. All MG patients are started on PB. The drug blocks the enzyme acetylcholinesterase at the neuromuscular junction allowing acetylcholine to linger and have more chances of bindiag to the reduced number of AchR that will be activated. Ie provides improvement of muscle srengeh temporarily thae the patient can be fictional on a daily basis butt does not cure MG, Iedoes not affect the natural course of MG.6 ‘Tae Paine JouRNAaL oF NEvROLOGY There are no double blind clinical tials for PB in MG. According to the Cochrane data in 2011, response oacetylcholinesterase inhibitors (ACHEI) in observational studies i so clear that a randomized controlled trial would bbe depriving participants in the placebo arm treatment and this is difficule co justify ethically. ‘Neostigmine discovered in the 1930's and PB discovered in the 1950s have withstood the test of time. It is most effective in the mildest form of MG.Magei and Mantegaza (2011) stated that Pyridostigmine has been used for treatment in MG for over 50 years in safety and is suitable for long term solo treatment in patients with generalized non-progressive milder disease and as an adjunctive tharpy in patients wit immunotherapy. moderate to severe disease receiving Pharmacokinetics of pyridostigmine showed a peak. plasma concentration afier ewo hours of oral administration and bioavailability is only 10% and a half-life of 20-30 minutes according to Aquilonius and Hartvig (1986). Impaired renal function prolong the half life and ‘methylcellulose impair the absorption ofthe drug from the gastrointestinal tract. When pyridostigmine was taken with food, the time to reach the peak plasma concentration was prolonged from 1.7 to 3.2 hours. Bioavailability was not influenced by concomitant food intake. (Aquilonius et al, 1980) PB is well tolerated and adverse events ensue as the dose is increased. Muscatinic side effects are the following guthypermobility, increased GI and respiratory secretions, increased sweating and bradycardia, Nicotinic side effects are mainly muscle fasciculations and muscle cramps. PB is administered individually according to the severity of sympcoms and the sensitivity ofthe individual to acetylcholine. Thus no general guideline on administration may apply. Patient participation in the dosaging is important that the attending neurologist should educate the patient on the recognition of strength improvement, ‘non-improvement and the onsct of muscarinic side effects. Improvement is usually noted after 30 to 90 minutes after taking PB and muscle strength peaks at 2 to 3 hours and lasts for 4-6 hours. For adults, PB is usually started at 30 mg, every 4,5 0r6 hours as the need arises during waking hours depending on the symptoms and the need to have sufficient strength to be functionalin hishher daly activities. PB can be given 30-60 minutes before meals in patients with bulbar symptoms to give them enough strength at mealtimes. A gradual increase of 30 mg increments is advised!as the need arises up to a maximum of 90mg per dose. The optimal dose Volume 15 No, | May 2011 isa balance of strength improvement and adverse effects ‘A dose beyond 600 mg per day is not recommended. For paediatrics, PB is given ac 0.5 to Img/kg per dose. (Class IV evidence - good practice point — expert opinion from Osserman, 1955; Genkins etal, 1992, EFNS guidelines2010, Neurology Asia, 2009, Menggioli and Sanders, 2009 and John Kesey, 2004) i CLINICAL QUESTION NO.2 HOW WOULD YOU USE AVAILABLE IMMUNOSUPPRESSION STRATEGIES IN THE, LONG TERM TREATMENT OF GENERALIZED AUTOIMMUNE MG? Generalized MG is defined by MGFA and Osserman's Classifications thatstart with type or stage Ind above up to stage V or IV respectively. t means involvement of most of the voluntary muscles of the body plus or minus the ocular muscles. These symptoms would impair activities of daily living Shore verm treatmene that affects the concentration of | circulating antibodies and its action on the neuromuscular junction is indicated in the following scenario in the ‘management of generalized autoimmune MG i | | 1. Improvementof MGFA grade in preparation for thymectomy. 2. MG Crisis es SHORT TERM TREATMENT OF GENERALIZED | AUTOIMMUNE MG THAT AFFECTS THE ACTION } OF ANTIBODIES ON THE NEUROMUSCULAR |, JUNCTION TO RELIEVE THE SYMPTOMS IN A j FEW DAYS USING THE FOLLOWING OPTIONS: 1, PLASMA PHERESIS OR PLASMA EXCHANGE (PE)- decrease the load of circulating antibodies 2, INTRAVENOUS IMMUNOGLOBULIN (IVIg)- decrease the effects of circulating antibodies Long term treatment using immunosuppression is indicated in the following scenario in the management of generalized autoimmune MG: Ae Rea pidlipree con an feria ea pears] earner tet generalized in 2-3 months| Gossesus Gupaunss: Tre Mepical Tazxrwenr oF NoN-THYMOMATOUS AUTOIMMUNE GENEMLIZED MvastHieNia Gravis 7 Inadequate response to PB as to muscle strength at a dose of 300 -450 mg per day or che advent of adverse events ata lower dose “3. Moderate to severe muscle weakness that hinder daily functional activities specially bulbar muscle weakness ONG TERM TREATMENT OF GENERALIZED “AUTOIMUNE MG IS IMMUNOSUPPRESSION | THAT ELLIMINATES OR DESTROYS THE, IMMUNOGLOBULIN PRODUCTION USING THE » FOLLOWING OPTIONS: A. Thymectomy- removes the thymus ‘Oral Corticosteroids (Prednisone) — wide variety of effects on the immune system, Azathioprine- DNA synthesis inhibitor ‘Other Immunosuppressants for resistant cases a. Cyclosporine A affects activated T cells b. Cyclophosphamide — DNA inhibitor that leads to cell death of proliferating cells in the immune system c. Methotrexate- antifolate that inhibie purine and pytimidine synthesis fe ’ dd. Mycophenolate-acts on activated T and B cells ¢. Tacrolimus-inhibits T cell activation and proliferation £ Rituximab- monoclonal antibody against ‘CD 20antigen on premature and mature B cells THYMECTOMY 5 Please refer toa previous guideline on thymectomy for chymomatous MG published in the Philippine Journal __ Tn most centers in the USA and Europe, patients fail co improve with PB are given fist the option of gectomy. Thus thymectomy is suggested as the sccond fe oF treatment for generalized autoimmune MG. Ic is d that thymectomy removes the antigen source of T cells thus reducing further T cell and B cell improvement (26% in complete remission). Gregory Bulkley etal (1997, USA) reviewed 202 thymectomiesand noted 86% improvement in 5 years post thymectomy. Inclusion criteria for patients given the option of thymectomy: 1. Presence of thymoma in all ages 2. Non-thymomarous MG that is generalized at the onset with a high level of antibodies to AchR, rapid progression of disease, aged 18-55 years and within 3-5 years of MG duration. According to Trenchant, 2009, thymectomy is considered state of the art in MG treatment on the basis of circumstantial evidence and expert opinion. (level IV) Weare anticipating the results ofa randomized trial of thymectomy inMG. Exclusion Criteria for thymectomy: 1. Ocular MG 2. Seronegative MG 3. High surgical risk patient MEDICAL IMMUNOSUPRESSION Patients who do not qualify for surgery are given medical immunosuppression. Sanders and voli at Duke University Medical Center, they reported 820 MG patients, on immunosuppression using prednisone in all and azathioprine as first choice immunosuppressant followed by mycophenolate and cyclosporine, Treatment was ultimately ‘withdrawn in 20% of seropositive non-thymomatous MG and 7% in thymomatous MG. From the MG series at the University of the Philippines- Philippine General Hospital Medical Center in 1979 to 1987, a toral of 154 MG patients on immunosuppression ‘were reported by M. Perez and L. Renales, Treatment used were PB, prednisone alone, cyclophosphamide alone, prednisone-cyclophosphamide combination in majority, and thymectomy according to severity of symptoms... ‘Thirty-four (3496) achieved remission without medications and 4.5% died. AchR antibody assays were not performed. “Treatment analysis was not done. (unpublished data)fil 8 ‘Te Peatuponse Journal. oF Neuaniocy CORTICOSTEROIDS Oral corticosteroids remain to be widely used as immunosuppressantsin MG with prednisone being the most commonly used drug when symptoms are not adequately controlled by PB and quality of life is compromised. Steroids control the inflammatory effect of complement ‘which destroys receptors and reduces the B cell production, of antibodies. JY Kim et al (2011 Korea) summarized in detail the effects of corticosteroids in the following actions: (1) reduce the distribution of leukocytes; (2)inhibition of recruitment and migration of lymphocytes to inflammatory ) blockade of various T-cell functions; (4) reduce the production and secretion of cytokines and other immune ‘mediators; and (5) decrease the maturation of dendritic cells. Vijayan and Dreyfus(1975) reported the use of steroids since the late 1940's and showed cither short term benefit ‘ot exacerbations of symptoms using 100 mg dose while less deterioration was seen using 25 mg dose. He also recommended to reduce pyridostigmine if symptoms improved with steroids to avoid cholinergic side effects. In four large retrospective studies of steroid treatment for generalized MG, 73% of 422 patients achieved marked improvement or remission (Pascuzzi, Sghitlanzoni, Cosi, Evol). A prospective study of 600 patients in China (151 generalized and 449 ocular) treated with moderate doses of steroids followed by low-dose maincenance achieved 95% improvement as reported by Sathasivam, 2011. ‘Two case reports by Hiroshi Kaaoka et al (2011, Japan) achieved complete remission after 9 and 18 years of treatment with PB and prednisone alone. One case started as JMG treated with pulse methylprednisolone and recurred in adulthood treated with oral steroids. Both cases have low levels of AchR. antibodies initially. : ‘The Cochrane data in 2005 showed limited evidence from randomized controlled «rials which suggested that steroid treatment offers significant short term benefit in MG compared to placebo which supports conclusions from observational studies and expert opinion (Class IV).Nevertheless, steroids are used as the first line immunosuppressant drug when necessary (good practice point), Improvement with steroids in MG begin in 2 to 4 weeks with mean response to maximum benefit at 5-6 months. Thus one course of treatment has a duration of 6 to 8 months in a crescendo and decrescendo dosaging until the most effective dose is reached after which slow tapering Volume 15 No. 1 May 20 follows. For moderate to severe cases of generalized MG. is better to initiate oral prednisone at high doses (0,75 1,0mg/kg/day) in a hospital setting due to an anticipae worsening of weakness in the first 4 to 10 days of hi steroid treatment. For moderate cases in an out-patie setting, oral prednisone is started at 10-20 mg/day a increased every two wecks until your reich a 60 10 1 mgjday or until symptoms improve significantly. Ke the optimal dose of steroids for a month at the best mus: strength and start tapering every 2.t0 4 weeks gradually 3 t0 6 months depending on the maximum dose reache Forpatients who do notattain remission after one cou of prednisone treatment or who have symptom recurren low dose prednisone may be continued indefinitely using alternate-day reyimen such as 20mg/ 10 mg, or 1Omg/Sn ‘or 5 mg/Omg alternate days for several months or ye depending on the response or appearance of adverse even If adverse events appear or patients cannot be weaned fic steroids, or steroid doses remain high at 40 to 60 mr day, a second. immunosuppressant called steroid spari agent isadded. These are: azathioprine (the most popu with less side effects); cyclosporine, cyclophosphamic mycophenolate, tacrolimus mechorrexate. Recently af trials using rituximab in anti-MuSK positive MG a resistanc anti-AchRh antibody positive MG have shox favorable response. Icis recommended that prednisone be given as sing dose in the morning to mimic che natural diurnal corti cycle and to minimize the side effects Premature or rap tapering as well as excessive dose reduction or untim« withdrawal should be avoided, Wolfe and Gross ha recommended a tapering schedule for prednisone (Table Adequate time must be allowed forthe drugs to attain f therapeutic effect and maximum benefits. Adverse eves should als be anticipated and managed accordingly. Adverse events of steroids in about 2/3 of users are « following: Cushingoid features, bacterial, viral, and funy infections, hypertension, diabetes type 2, ostcoporos psychiatric disorders, hyperacidity, hair loss, cataracts, a ‘Table 1, Recommended Tapering Schedule f Prednisone In Myasthenia Gravis (Wolfe and Gross, J Clinical neuromuscul Disase, vol. 6. No. 2 Dec. 2004) Tan Day) Lega eg ean coy iokagame” e paa Sage soen ton peeked eee Buenie opathy cd $8 Wosing alternate day dosing, determine the average th [i dose over cwo days. For example: 100 mg every other day vac § mold correspond ro 50 mg per day. Thus, 100mg for odd nd sbaysand 50mg for even days may be insticured 00 Fe. AZATHIOPRINE (AZA) Azathioprine is the favored immunosuppressant aficr szeroids, Azathioprine is a purine antimetabolite that lipcerferes with T and B cell proliferation, Retrospective an 4). Seidies indicate that AZA is effective in 70-80% of patients ag, {But its benefit in MG may only be observedfrom 6 to 12 & AZA is initiated at 50 mg per day and can be used ba ec or in combination with Prednisone which is better ef de IF MG symptoms are not yet controlled, AZA ag sficrared upwardio a maximum dose of 2-3mg/kg per g or until WBC and RBC counts drops below normal. events are fluke symptoms at start of treatment, srotoxicity, leukopenia and infections, These are eeecible when AZA is discontinued. Some patients with 1e methyltransferase deficiency cannot completely olize AZA and a low dose might lead to toxicity. de is carly leukopenia at start of treatment, It is ol Sw monitor CBC monthly or measure the level of id jethyltransferase if available. Long term us AZA may lead 10 development of certain malignan: ice is dose and duration dependent. Fic regards co immunosuppresson, AZA is still the [baseline treatment often combined with steroids as ded by R. Gold, 2009, Sanders and Evoli, 2009 AZA is the fist choice immunosuppressant in FCLOPHOSPHAMIDE (CY) bamid has been used in severe and resistant ‘CY is a strong alkylating agent that acts on. gcell proliferation of T and B cells but more sreduce antibody production. According to “Ages, 2003, CY appears to be neatly like tion of remission although there ate no tials for chis drug on MG. Also smnay be outweighed by adverse events sists Guipaunes: THE Mebroal TaeaTwenT oF Non-trwonatous AuroiMMUNE GENERALIZED MvasTHena Gravis 9 such as severe myelosuppression, opportunistic infections, bladder toxicity infertility and neoplasms. Drachman etal, 2008 coined the cerm “rebooting” the immune system with cyclophosphamide by using a high dose of 200 mg/kg which climinates the mature immune system leaving hematopoietic precursors intact. He treated 12 patients with MG with high dose cyclophosphamide, Eleven of 12 experienced dramatic improvement from 5 months to 7.5 years, He suggested that high dose CY tweatmentbe followed up with immunosuppression, De Feo in 2002 used IV CY monthly in 12 MG patients on steroids vversus placebo and noted that IV CY resulted in reduction of sterdid dosages. MC Perezet al (198 Philippines) reported that cyclophosphamide may havea more specific therapeutic cffects than other immunosuppressive drugs used to treat ‘myasthenia as it has a more direct action on both T and B cells. He demonstrated a 28.6% stable remission out of 42 patients treated for 2 to 37 months. Five of nine patients (559) on CY alone achieved remission in 2 to 25 months of treatment. CY can be used intravenously during MG crisis at 500mg/m2 or 50mg/kg in 4 doses. For maintenance immunosuppression, an oral dose of 25 co 50 mg/day may be given with or without steroids. MC Perez et al used TV CY ac 200 mg IV dhily for 5 days and maintained orally at 100 mg per day ot a 3-Smg/kg/day until white blood cell count dropped to 4000 or below. From Cochrane data from a small RCT, CY wat reported to be statistically significant than placebo at 12 ‘months in 23 corticosteroids dependent MG patients (Class m CYCLOSPORINE A (CyA) Cyclosporine is the favored choice for steroid dependent MG asa steroid sparing drug nextoAZA. N. Kawaguchi (2011), reported that Cyclosporine is the favoured drug in Japan more than AZA.. Cyclosporine is an inhibicor of T helper function through blocking the calcincurin-medicated cytokine signalling. It has a much higher cost-to-benefic ratio than AZA with side effects of hypertension and renal damage. The recommended initial daily dose is 4-6 mg/kg in owo divided doses or 3-4 mg/kg depending on control of symptoms and appearance of side effects. CyA trough levels have to be determined regularly. Otherside effects are hirsutism, gum hyperplasia tremor and anemia,10 ‘Tue Prauirnne JouRNaL oF NevkoLocy From Cochrane daca in 2009, a meta-analysis of ‘gclosporine versus placebo from two trials (59 subjects) as ‘monotherapy (20) and with steroids (39) showed significant improvement in the cyclosporine group compared to placebo with a relative rate of improvement of 2.44. (Level Ja, Class I evidence) MYCOPHENOLATE MOFETIL (MyM or MME) MyM belongs to the newer immunosuppressant agents, that are being investigated for MG. Ie inhibits the pathway of de novo purine synthesis by blocking the enzyme inosine monophosphate dehydrogenase which is highly specific for proliferation of T and B lymphocytes that do not use the purine salvage pathway. It is also used in MG as a steroid sparing medication. A small double blind placebo controlled studyshowed that it is an effective adjunct, therapy for MG. Standard doses are 2000 to 3000 mg per day in two divided doses. MyM have similar efficacy vo ‘giclosporine but exhibits less toxicity. Main adverse events are gastrointestinal symptoms and myelosuppression ‘Yelv etl, 2008 used 1 gm twice daily MyM in Taiwanese MG patients and 4/6 patients improved in 12 months with steroid sparing effec Sanders etal 2008 reported the results ofa phase III randomized trial of MyM in MG with improvement as primary endpoint. 4496 of MyM treated (68) and 39% of placebo (88) achieved improvement which ‘was not significant. C. Phan et al 2008 summarized cwo RCT’s (176 and 80 MG patients) that failed to prove its efficacy in MG at 36 weeks and 12 weeks of treatment. ‘Three retrospective studies showed improvement in 73% of 85, 75% of 36, 59% of 32 MG patients. (Class III) ‘TACROLIMUS Tacrolimus is similar to cyclosporine in its T-helper cell action but is ielatively less toxic. It likewise ink interleukin-2 production via the calcineurin-mediated pathway. S. Sathasivamin 201 | reviewed seven open labelled studies on 396-MG patients treated with thymectomy and ‘other immunosuppresants showed improvement in 29% - 87%of their population. However, he mentioned one study that reported no significant clinical improvement in nine ccorticosteroid-dependent generalized MG patients trated ‘with low-dose tacrolimus for 5 years. In an open label study Volume 15 No.1 May 2011 by Nagaishi et al in 2008 used ‘Tacrolimus in 7 steroid dependednt MG at 3 mg per day for 2 years showed long term improvements in all patients that allowed replacement of steroids. Sustained benefit was seen in anti-ryanodine- receptor-positive MG patients. Tacrolimus is given at 0.1 mg. g/day. Adverse events are the following: hyperglycemia, hypertension, headache, hyperkalemia, nephrotoxicity, diarshea and nausea and vomiting, Tacrolimus can be considered a third line of treatment and appears to reduce the need for other immunosuppressant and plasmapheresis. (Class IV) METHOTREXATE (MTX) Reports of use of methotrexate in resistant MG cases dates back several decades specially by Mertens et al in 1969, There are no RCT on methotrexate. MTX is used effectively in autoimmune diseases like Crohn’ disease, psoriasis and cheumatoid arthritis. MTX is an analog of folicacid and isan antiproliferative drug chat interferes with DNA synthesis.A single blinded trial by Heckmann et al, (2011 South Africa) using MTX versus AZA in 24 patients showed that prednisone dosage was halved in MTX than in AZA after 12 months. Improvement started at 10 mos of MTX treatment.(Class IV) Recommended dosage is 15mg weekly for 2 weeks and then 20 mg weekly thereaficr. An ongoing study by R. Barohn et al in the USA. will be completed in 2013, Adverse events with methotrexate are the following: bone marrow suppression ,hepacotoxicity, alopecia, neoplasms, general body discomfort, dizziness, oral sores, diarthes, chest pain, confusion, visual changes. RITUXIMAB Rituximab is the only monoclonal antibody that is B- fe cell dicected that targets the CD20 antigen on B cells and thus modulates B cell activation. Rituximab is used in the} treatment of non-Hodgkins lymphoma. Interest in MG started in 2004, Nowak et al in 2011 reported sustaine: clinical improvement in all 14 refractory generalized) MG after a follow-up of 2 years using 375mg/m2. Each cycle consisted of one infusion per week for 4 weeks. Prednisone dosage was decreased as much as 93.8% after 3 coutses of treatment and AchRvantibody titers decreased a mean of 52.1% after 2 cycles. There is evidence thmab may be:beneficial in MG, but it should only Be used in severe refractory cases not responding to usual gost of the medication and adverse events including _ peutropenia, infections and risk of progressive multifocal "Igokoencephalopathy plus fever, chills, nausea, vomiting, “Bashing and bronchospasm. “Myasthenic crisis is defined. as extreme weakness of wary muscles including respiratory muscles resulting hypoxia, hypercapnia and reduced tidal volume that id only be teversed by endotracheal intubation sitive pressure mechanical ventilation. Timely cory support is imporcant to save MG crisis patients en faxality. Myasthenia crisis results from weakness of cr airway muscles leading to airway obstruction and ion as weakness of respiratory muscles results in ced tidal volumes. Twenty percent of MG patients nce myasthenic crisis within the first two years of ess. Precipitating factors for myasthenic crisis include: Ections, aspiration, sepsis, surgical procedures, rapid g of steroids, steroid initiation and. exposure to gs that compromise neuromuscular transmission, and “ necretions in the setting arene a eels eliminate the possibility of a cholinergic crsis.Insert nasogastric tube as wel | Elective intubation of a crisis patient is better than “emergency intubation. Thus respiratory function coring is importanc wich patients presenting with paca. Inspiratory function is measured by both vital “VC less than 1 liter (or <20-25 mL/kg) or an NIF <20cm H2O indicates significant respiratory weakness defines myasthenic crisis, Expiratory function red by positive expiratory force (PEF) which a -<40cm H2O may indicate criss. Regardless of cs. the need for mechanical ventilation ina dyspncic patient defines criss. In the absence of pulmonary gesion tests, observation on the patient is important using accessory respiratory muscles indicates ous GUIDELINES: THE Mepicat‘TReaTMeNT oF Non-riyMoMaTous AUTOIMMUNE GENERALIZED MYASTHENI inspiratory muscle weakness; a weak coughing reflex: or difficulty counting 1 to 20 ina single breath which indicates weakness of expiratory muscles, Other signs of moderate to severe bulbar weakness is summarised in table 2 below. Table 2. Useful signs of significant muscle weakness from MGFA, Artificial ventilator support is mandatory in all MG ctisis patients, Once intubated, patients should be placed on an assisted setting (AC Mode) with tidal volumes of 6-10 cc/kg ideal body weight and pressure( PEEP) support of 5-15cm H20 to prevent atelectasis, and to minimize the work of breathing. Maintain normal minute ventilation OF 6-10 liters and pCO? at 40 mmHg (Meyer etal, 2002) The patient shall’ undergo 5 or 6 exchanges of plasmapheresis or 20 5 doses of IV immunoglobulin. Response to treatment generally occurs after 2 days with plasma exchange (PE) and 4-5 days with IV Ig. Some evidence exists that plasma exchange may be more effective than IV Ig. A multicentre retrospective study using 5-6 cycles of PE completed every other day to 400mg/kg/day of IV Ig given for 5 days found DE to be more effective. Patients who received PE. hhad more clinical improvement after 1 week,becter respiratory starus at 2 weeks and better functional uttcome at one month. However, an increased number ‘of complications mostly infections and cardiovascular instability were seen in the PE group. Start high dose oral steroids via NGT with gasttoprotection. Corticosteroids are used in conjunction with cither PE or IVIg . High dose steroids at 60-100 mg/day ot 1 0 1.5 mg/kg/day via nasogastric tube may be initiated in a crisis patient. Effectvity of steroids are sen after 10 0 14 days afte initia2 ‘Tue Pemirrine Journal. or NeuRoLocy ‘on steroids are improved at 3 weeks. Restart oral PB gradually via NGT on the 4th to 6h day in the ICU. Restarting PB will prepare patient for excubation as muscle strength improves after PE or IV Ig. Start at a low dose (30 mg chree times daily) and gradually increase as the necd arises. Stare weaning from che respirator as muscle stzength increase. Neurological assessment of bulbar muscle weakness and measurement of ftigability in an incubated patient is difficult co assess, Parameters for weaning include: adequate and sustained eye closure, tongue protrusion, head life at least 5 cm, lip closure and adequate cough reflex. Pulmonary function test criteria for weaning include: VC> or = 10mi/kg. maximum inspiratory 10 cm H20 and maximum expiratory {0 cm F120. Readiness for extubation is largely judged of the basis of patient performance during weaning, The single best predictor of successful extubation is the ability of the patient to tolerate ‘weaning tials with minimal pressure support (< or = 5 ‘cm H20) for extended periods of time (12 to 24 hours) ‘Tracheostomy should be performed early (2 weeks) if prolonged intubation is anticipated. “Twenty five percent of patients are extubated on day 7 and 50% are extubated at 13 days. Risk factors for prolonged intubation (>14 days) are as follows: age >50 years, VC<25ml/kg and serum bicarbonate level>30mmol/L. at start. Also those with thymoma have longer intubation duration. Maximal expiratory pressure has been shown to predict extubation success. Respiratory muscle training by respiratory therapist Extubation success is assisted by a respiratory physiotherapist. Once muscle strength improves the respiratory therapist should star the respiratory exercises to prevent atelectasis and improved diaphragmatic muscle strength. Continuous cardiac monitoring should be maintained on MG crisis patients in the ICU. Eleven to 14% of MG crisis patients developed archythmias such as atrial fibrillation, ventricular fibrillation and even asystole. Most of this patients hhad underlying heare diseases or others were given IV anticholinesterases Volume 15 No. 1 May 8. Nutrition of the MG crisis patient shoul. maintained. Nutrition should be adequately addressed to av negative energy balance which willincerfece with we: from the respirator. It is emphasized that nuciit support of the critically ill is a primary therap regimen. R. Ramprasad and M. Kapoor, 2012 s that nutrition supporcis geared on improving mets response co stress, preventing oxidative cellular i and modulating the immune response. From the Canadian guidelines nutritional support for venti patients is enteral nutrition involving the follox rate of advancement of caloric requirement, ches gastric residuals, motility agents, elevation of the to 30degrees, probiotics and bolus administra V. Huberlant and JC Preiser 2009 teview adder use of glatam in cases of sepsis as it atven inflammation and the heat-shock protein resp Carbohydrate feedings should be guided by gh levels as hyperglycemia is associated with mosbidit mortality. Recommended protein feeding is 1.2 protein/kg/day. Vitamin supplements are also ad PLASMAPHERESIS IN MG CRISIS. Plasmapheresisis considered asa short term creat modality for MG. It is designed to remove circul antibodies from the plasma temporarily. ‘There techniques of standard plasmapheresis- on-line plasm separator by a centrifuge or by a plasma separator 1 membrane filtration. Clinical effeces are observed it than 24 hours up to 48 hours the longest due to ren oF autoantibodies. ‘Total cost is prohibitive. Complications from the procedure are as foll cardiovascular reactions, electrolyte imbalance, s¢ thrombosis, thrombophlebitis, pulmonary embe and subacute bacterial endocarditis. Maffeis et al (2 ‘enumerated the following side effects: perioral ting trembling, dizziness, hypotension, hypocalcemia, all reactions. Pneumothorax, thrombosis and infection ‘complications from placement of central catheter. ‘The Cochrane data in 2002 showed no adequate but many case series reporting short term benefit plasma exchange specially in myasthenic crisis (Cla evidence) from an AAN guideline, cecommendatior plasmapheresis is neither supported or refuted due to of RCT evidence. (recommendation LevelU).RAVENOUS IMMUNOGLOBULIN SMG CRISIS Gajdos in 2008 said that there is now convincing a lence that IV Ig is effective in MG. The potential al [fy srechanisms of action include: inhibie Fe receptor and ie igen presenting cells; neutralize blocking cffects of dd [f{, autoantibodies to AchR. In a clinical trial by Gajdos in 1997, 1 p/kg dose is as effective as 2glkg dose. given in 105 days. Onset of benefit is usually between 4-5 days 13. BBP and even at 19 days. ‘Total cose is approximately 250,000 xd ff & 300,000 for a S0kg patient. Adverse events include: & [Ff Beadaches, fluid overload, aseptic meningitis, renal failure, ig Siromboric complications such as MI and stroke, Patients d mith IgA deficiency can develop anti-IGA antibodies 1. ff sszsing anaphylactic reaction in subsequent treatments te fe Disadvantages of this treatment are the follos ing: a tency of the response, high cost and insufficient 3 bility oF IV Ig. «Hee From Cochrane data in 2003 there was one study dF epmparing IVIg and placebo in mild to moderate MG and 8 [fhe result was negative. In another study, comparing IV Ig IV methylprednisolone in 33 MG crisis patients, also «negative results for significance, (Class IV evidence) : ies in 2005 (23 patients) and in 2002 (24 Pesens) of a series of MG crisis showed that infection . LRTI and UTD was the most common precipitant jents had plasmapheresis and 1 received IV Ig. The Zan ICU stay was 15 days, Six patients died due to camonia and sepsis. >IRATORY THERAPY IN GENERALIZED. AUTOIMMUNE MG Bashy respiratory therapy may prevent myasthenic crisis Efe devcloping respiratory muscle strength and endurance, es ‘muscle deterioration in MG changes breathing ens. Inspiratory muscle training may improve mace thereby preventing morbidity and mortality in is surgical procedures for early respirator weaning ec al in 2005 instituted inspiratory muscle and breathing retraining in 27 generalized MG ‘over 8 weeks successfully improved respiratory ssessus Guibiunes: Tie Mepicat Taearvent oF NoN-THYMOMATOUS AUTOMMUNE GeNERALiZéD Mrasueta Gravis 13 muscle strength, chest mobility, respiratory pattems and endurance. SUMMARY OF RECOMMENDATIONS 1, Mestinon is given to all newly diagnosed mg patients, (Level ©) 2. Thymectomy is considered the next option. Level C) 3, Prednisone is started in patients who have moderate to severe weakness despite intake of pyridostigmine Bromide. (Level C) 4, Other immunosuppressant is started for steroid dependent patients and to patients who do not achieve significant improvement. Azathioprine is the favored next immunosuppressant to prednisone. (evel C) others follow such as: cyclosporin (level A); cyclophosphamide (level B); mycophenolate mofetil (level ©); tacrolimus (level ©); methotrexate (level U); and rituximab (level C). They are all effective but the tisk of adverse events is high as well as the cost of 5. Management of an mg patient in crisis should be in an icu setting with the ventilator machine, Alevel C) mestinon is temporarily withdrawn, Both plasmapheresis and ivig are effective in myasthenic crisis (evel U); however, both treatment carries complications * and the cost of treatment is prohibitive Figure 1, FLOWCHART: TREATMENT OF GENERALIZED NON ‘THYMOMATOUS AUTOIMMUNE SEROPOSITIVE, MYASTHENIA GRAVIS NEWLY DIAGNOSED GENERALIZED MG as —a MID * MopERAre* PYRIDOSTIGMINE _ PYRIDOSTIGMINE _ PYRIDOSTIGMINE (ORAL ‘Tmnscroun RAsumAaess PREDNISONE PREDNISONE PREDNISONE AZATHIOPRINE THYMECTOMY OTHERIMMUNO DRUGS OTHER IMMUNO aucs *See Appendix tt