Myasthenia gravis. Samuel Komoly MD PhD DSc

Myasthenia gravis Samuel Komoly MD PhD DSc

Myasthenia gravis - definition Painless fluctuating weakness of the striatal muscles (no tong or hearth muscle involvement) autoimmune disease

Myasthenia gravis importance (after Angela Vincent) MG is treatable Untreated it can be fatal (In the past, untreated MG carried a mortality rate of 30-70%. In the modern era, patients with MG have a near-normal life expectancy still 5% mortality rate of myasthenic crisis.) It can mimic untreatable diseases eg. motor neuron disease Average time to diagnosis is 6 YEARS On average, patient will see 4 doctors before diagnosis Best understood of all autoimmune disorders

MG learning objectives To recognize the clinical features To understand the pathogenesis To know how to investigate MG To have a working knowledge of the treatment options

Myasthenia types and LES Autoimmune myasthenia gravis (MG) Spontaneous (with or without thymus pathology) Neonatal (transient see on coming slide) Penicillamine induced (extremely rare) Hereditary (congenital) myasthenia (few families in Hungary) Lambert-Eaton myasthenic syndrome (LES) (20x less frequent than myasthenia gravis)

Myasthenia gravis epidemiology of 1.7 million inhabitant 202 MG patients (10-12/100 000 with MG (20 with thymoma) and 10 patients with LEMS (7 with small cell lung cancer) (J Neurol. 2003 Jun;250(6):698-701.)

Onset - 3 peaks 10 to 30 yrs (75% women) 60 to 75 yrs (60% men) Thymoma peak 40-50 yrs Message old man (or women) with double vision, difficulty of swallowing, ptosis, fatique of chewing concider MG (not only vertebrobasilar stroke)!

pregnancy A Batocchi et al article published in 1999 reported that the disease worsened in 10 (19%) of 54 patients. Approximately 60% of exacerbations occurred during the first trimester, and approximately 28% of patients deteriorated immediately after delivery. Premature delivery occurred in 4 (7.4%) of 54 patients. Cesarean delivery was performed in 16 pregnancies (30%). The study concluded that no correlation exists between MG severity before and during pregnancy.

Myasthenia gravis autoimmune disease Myasthenia gravis: passive transfer from man to mouse: Daily injections into mice of an ammonium sulfate-precipitated immunoglobulin fraction of serum from patients with myasthenia gravis: Some mice showed typical decremental responses on repetitive nerve stimulation, with reversal by neostigmine Toyka KV et al, Science 1975. 190(4212):397-9.

MG pathogenesis: AChR antibodies AChR abs IgG or IgM Target : any subunit AChR Fetal or adult receptors Recognize 1000s diff epitopes on one subunit Main immun.rregion: α subunit

Myasthenia gravis: pathomechanism axon terminal Acetylcholin antibody Acetylcholin receptor muscle Angela Vincent után

MG pathogenesis: thymus Thymus 75% abnormal 85% hyperplasia 15% thymoma 25% have no or a normal thymus

MG diagnosis Clinical Blood anti-achr and MuSK antibodies EMG Repetitive stimulation Single fibre (SFEMG) Edrophonium test (Tensilon) Other eg CT mediastinum, striated mu abs

MG clinical features Fluctuating muscle weakness Generalized MG 80% 90% : Eyes Ptosis + ophthalmoplegia 15% pure ocular MG 67% present with eye problems 80% : Swallowing and chewing 70% : Limb and trunk 5%: Respiratory muscles Ocular MG - 20%

MG eye signs

MG diagnosis Clinical Edrophonium test (Tensilon) EMG Repetitive stimulation Single fibre (SFEMG) Blood anti-achr and MuSK antibodies Other eg CT mediastinum, striated mu abs

MG diagnosis Tensilon challenge After i.v. Tensilon before

Tensilon (edrophonium) challenge test If muscle strength fails to improve following the maximum dose of edrophonium, probably the patient has another cause of weakness that is unrelated to myasthenia gravis. The effects of edrophonium are brief, and repeated doses may be required before oral anticholinesterase medication can take effect. In patients with less severe exacerbations, the degree of improvement with edrophonium may be subtle. Many authors recommend having several blinded observers assess the patient's response in these cases.

Tensilon (edrophonium) challenge test is useful in diagnosing MG A positive response is not completely specific for MG because several other conditions (eg, amyotrophic lateral sclerosis) may also respond to edrophonium with increased strength. Patients who respond generally show dramatic improvement in muscle strength, regaining facial expression, posture, and respiratory function within 1 minute. During this procedure, the patient must be monitored carefully because edrophonium can cause significant bradycardia, heart block, and asystole. The return of muscle weakness after edrophonium wears off combined with residual increased oral secretions can exacerbate respiratory distress and the risk of aspiration.

MG diagnosis Clinical Edrophonium test (Tensilon) EMG Repetitive stimulation Single fibre (SFEMG) Blood anti-achr and MuSK antibodies Other eg CT mediastinum, striated mu abs

MG diagnosis - EMG Repetitive stimulation >10% decrement at 3Hz Single fibre EMG Jitter and blocking

MG diagnosis - autoantibodies Blood anti-achr abs Generalized MG - 80-90% positive Ocular MG - around 50% positive Other autoantibodies MuSK in generalized MG 10% positive Striated muscle antibodies Others

Szeropozitív Myasthenia gravis Post synapticus membrán i Itt blokkol az autoantitest (Natrium csatorna)

Szeronegatív myasthenia gravis i izom specifikus receptor thyrosin kinase (Musk) ellenanyag

MG - natural history Spontaneous remission < 10% Without treatment 1/3 die With treatment 95% of patients reach remission Ocular MG - fewer than 15% develop generalized MG after first 2 years

MG - management Aim for treatment 95% patients can lead normal life Now fewer than 5% die from MG cf 33% died before immunosuppression

MG - medical therapy Symptomatic - Anticholinesterase Pyridostigmine (Mestinon) Definitive - Immunosuppression Prednisolone Azathioprine Combined therapy Other - methotrexate, cyclosporin, mycophenolate Acute treatment Plasma exchange Intravenous immunoglobulin

Plasmapheresis is an expensive procedure used in patients in myasthenic crisis. Together with steroids, plasmapheresis is a very effective treatment. It consists of 3-6 exchanges of 2-3 L over 1-2 weeks. It is safe during pregnancy and has even saved patients during fulminant crises. Plasmapheresis can result in premature delivery because of large hormone shifts. Other complications can occur from hypovolemic reactions or allergies.

Intravenous immunoglobulin is also useful in patients in myasthenic crisis. It is thought to interfere with anti-achr antibodies. It is infused at 0.4 g/kg/d for 5 consecutive days. Improvement is noticeable in 3-21 days and lasts as long as 3 months.

MG - medical therapy Symptomatic - Anticholinesterase Pyridostigmine (Mestinon) Definitive - Immunosuppression Prednisolone (gradually increasing the dose) Azathioprine (2.5 mg/day late delayed effect) Combined therapy (aza+metilpredisolon) Other - methotrexate, cyclosporin, mycophenolate Acute treatment Plasma exchange Intravenous immunoglobulin

Take home messages Myasthenia gravis is treatable Without (or with inadequat) treatment can be fatal (30%) First symptoms: oculo-pharingeal weekness in 80-90% Two peeks: young --- old age: increasing!! Dg: clinical, Tensilon test, EMG, antibodies, Th.: Long term (combined) treatment!

Acetilkolin receptor alegységei main immunogen region embrionális felnıtt

APPENDIX

Myasthenia gravis (egyik) felosztása Szeropozitív MG (85%) = AchR ellenes ellenanyagok inaktiválják az AchR-okat (α- alegység, main immunological region ) Szeronegatív MG (15%) = izom specifikus receptor thyrosin kinase (Musk) ellen termelıdı ellenanyagok mutathatók ki

MG diagnosis - imaging CT/MRI chest to look at thymus

Many patients develop depression or comorbid depressive episodes. Bupropion (Wellbutrin XL) has been studied extensively and may be a good addition for these patients.

MG - thymectomy Elective procedure Indications Method Thymoma Most AChR antibody positive generalized cases < 45 yrs? Other patients Trans-sternal

medications reported to cause exacerbations of MG Antibiotics - Macrolides, fluoroquinolones, aminoglycosides, tetracycline, and chloroquine Antidysrhythmic agents - Beta-blockers, calcium channel blockers, quinidine, lidocaine, procainamide, and trimethaphan Miscellaneous - Diphenylhydantoin, lithium, chlorpromazine, muscle relaxants, levothyroxine, adrenocorticotropic hormone (ACTH), and, paradoxically, corticosteroids

Thyroid disorders may be seen in as many as 10% of patients with MG, and symptoms of hyperthyroidism or hypothyroidism may be present.

MG summary MG causes fluctuating muscle weakness MG is an antibody-mediated autoimmune disorder Diagnosis is clinical and confirmed by blood tests and EMG Treatment aims to induce remission

MG reference Vincent A et al. Myasthenia gravis. Lancet 357:2122-2128, 2001

Myasthenia gravis epidemiológia of 1.7 million inhabitant 202 MG patients (10-12/100 000) with MG (20 with thymoma) and 10 patients with LEMS (7 with SCLC) (J Neurol. 2003 Jun;250(6):698-701.) Osztályunkon évente 160-180 esetben kiírási dg a myasthenia gravis (10 év alatt 3 Lambert- Eaton syndroma)

Thymus eltávolítás és MG viszonya Thymus eltávolítás utáni hónapokban-években a betegek megközelítıen 25%-a javul A thymus eltávolítás a MG-t NEM gyógyítja meg, t.i. a receptor specificus autoreaktívt-lymphocyták már legyártódtak a thymusban. A thyemctomia csak újabb sejtek képzıdését szünteti meg A már képzıdött memória T-sejtek élettartama ismeretlen, de valószínő, hogy évekig, évtizedekig aktívak maradnak Utóbbira utalnak azok a MG-os betegek, akikben hosszú évek, néha évtizedek tünetmentessége után alakult ki tüneti relapsus

Lambert-Eaton Myasthenia Syndroma (LEMS) (praesynapticus Ca csatorna) of 1.7 million inhabitant 202 MG patients and 10 patients with LEMS (7 with SCLC) J Neurol. 2003 Jun;250(6):698-701. Osztályunkon évente 160-180 esetben kiírási dg a myasthenia gravis (10 év alatt 3 Lambert- Eaton syndroma)

Autoimmun kórképek (autoimmun ioncsatorna betegségek J. Newsom-Dawis) Myasthenia gravis (postsynapticus Nacsatorna) Lambert-Eaton Myasthenia Syndroma (LEMS) (praesynapticus Ca csatorna) Autoimmun neuromyotonia (Isaac s syndroma) (praesynapticus Kálium-csatorna)

Lamert-Eaton sy Neuromuscularis junctio

Lambert-Eaton Myasthenia Syndroma (LEMS)- klinikum rendszerint proximalis izomgyengeséggel kezdıdik, de lehet szemmozgás, -nyelés zavar is gyakran van autonóm zavar (szájszárazság, obstipatio, impotencia) reflexeltérések (renyhe, areflexia, esetenként posttetániás potenciáció)

Lambert-Eaton Myasthenia Syndroma (LEMS)- klinikum 60%-ban kissejtes tüdırákkal társul a LEMS, a tüdırák felfedezését évekkel megelızheti! kissejtes tüdırákban a LEMS elıfordulása 3%(?) (Small cell lung carcinoma was diagnosed in 1593 patients, 7 (0.44 %) of whom developed LEMS). LEMS nemcsak paraneoplasias jelenség, Ca-csatorna elleni ellenanyag 90%-ban kimutatható Napi gyakorlatban diff dg: EMG

Lambert-Eaton Myasthenia Syndroma (LEMS)- terápia C-LEMS-ben specifikus tumorterápia ez rendszerint a LEMS tüneteiben is enyhülést hoz 3,4-diaminopyridin 4x10mg-4x20mg (feszültségfüggı kálium-csatorna blokkoló) guanidin (csontvelıt deprimál, vesekárosító) pyridostigmin minimális hatás C-LEMS immunoszuppresszív kezelés = szteroid NC-LEMS immunoszuppresszív kezelés = kombinált (azathioprin-szteroid) kezelés PE, IVIG súlyos esetben szóba jön

Isaac s sy Neuromuscularis junctio

Neonatal myasthenia because of transfer of maternal autoantibodies

Örökletes kórképek ( congenitalis myastheniák ) Abicht A, Stucka R, Karcagi V, Herczegfalvi A, Horvath R, Mortier W, Schara U, Ramaekers V, Jost W, Brunner J, Janssen G, Seidel U, Schlotter B, Muller-Felber W, Pongratz D, Rudel R, Lochmuller H. A common mutation (acetylcholine receptor) epsilon subunit (1267delG) in congenital myasthenic patients of Gypsy ethnic origin. Neurology. 1999 Oct 22;53(7):1564-9.

Örökletes kórképek ( congenitalis myastheniák ) Postsynapticus AchR hiány ( leggyakoribb CMS 60%-a) slow-channel syndroma (> 10 eset) fast-channel syndroma (5 eset) rapsyn mutációk (3 eset) plectin mutáció (1 eset)

Egyéb myasthenia szindrómák neonatalis MG átmeneti állapot! (MG mamák újszülötteinek 12%-a) Gyógyszer indukálta (?) MG: penicillaminindukálta MG, gyógyszer elhagyása után a tünetek remisszióba kerülnek, alpha interferon? Motoros neuron betegség (ALS) kezdeti szakaszában?

Congenitális myasthenia szindrómákkal kihez forduljunk? Igen ritka betegségek Dr. Hercegfalvi Ágnes (Bethesda Gyermekkórház) Dr. Horváth Rita (Dél-pesti Kórház Neurológia)

Összefoglalás: autoimmun ioncsatorna betegségek (J. Newsom-Dawis) Myasthenia gravis (postsynapticus Na-csatorna) 1000 beteg Mo-n Lambert-Eaton Myasthenia Syndroma (LEMS) (praesynapticus Ca csatorna) néhány tucat (?) beteg MO-n Autoimmun neuromyotonia (Isaac s syndroma) (praesynapticus Kálium-csatorna) 1-2 beteg?? Diff dg: klinikum+emg Terápia: hozzáértés és TÜRELEM

Szeronegatív myasthenia gravis i izom specifikus receptor thyrosin kinase (Musk) ellenanyag