Myasthenia Gravis 2015 Update Florida Osteopathic Medical Association 16th Annual Cardiovascular & Medicine Symposium April 30, 2015 Myasthenia Gravis 2015 Update Kenneth Hentschel, DO, PhD, FAANEM St. Vincent’s Spine & Brain Institute

Disclosures I have no financial relationships that impact on this activity

Learning Objectives To recognize the signs & symptoms of myasthenia gravis (MG) To understand the options for diagnosis of MG To identify treatment options for MG

Relevance Myasthenia gravis is a treatable disorder which should have no mortality Undiagnosed/untreated MG may be complicated by respiratory failure The prevalence of MG is 1:10,000 Diagnosis may be delayed 2y in 30% of MG patients Primary physicians are first line, well-positioned to make this diagnosis

Overview Normal neuromuscular transmission Pathophysiology Clinical signs & symptoms Classification Epidemiology Etiology & Provocation Diagnosis Evaluation Prognosis Management 5

Neuromuscular Transmission An action potential travels down the motor nerve axon to the presynaptic terminal causing a series of events leading to release of acetylcholine into the synapse ACh diffuses across the synapse where it may activate densely clustered postsynaptic nAChR on the muscle membrane

Neuromuscular Transmission Ach bound to the nAChR creates an mini- endplate potential, which depolarizes the muscle cell if the threshold is reached Acetylcholinesterase inactivates/hydrolyzes ACh from the synaptic area

Definition Myasthenia gravis is an autoimmune disorder of neuromuscular transmission which involves antibodies directed at the nicotinic acetylcholine receptor of skeletal muscles, leading to weakness

Pathophysiology In MG, Antibodies interact with the postsynaptic nAChR which leads to increased turnover of receptors, and damage to the postsynaptic membrane As a result, there are fewer functional receptors and simplified postsynaptic membrane Once the number of AChR is reduced to 30%, there is failure of neuromuscular transmission and symptomatic weakness Failure of NM transmission leads to a variety of clinical symptoms

Clinical Symptoms & Signs The hallmark of MG is fluctuating weakness Presenting symptoms: Ocular presentation in 50% Ptosis 25% Blurred vision/diplopia 25% Generalized weakness in 10% Extremity weakness in 10% Dysarthria, dysphagia in 10% Respiratory failure in 1%

Clinical Symptoms & Signs Typical Atypical Ocular Involved Spared Distribution Proximal > Distal Segmental Pain Painless Painful Sensation Normal Abnormal

Clinical Symptoms & Signs Modifying Factors/Timing: Worse with exercise, repetitive use…more prominent later in the day Palliated by rest…fewer symptoms in the morning Temporal Course: 80-90% have ocular symptoms by 1 month General progression: ocular => bulbar => axial => extremities 87% have generalized MG by 1 year after onset; 13% of ocular MG will never progress

Classification Myasthenia Gravis Foundation of America Class 1 = ocular Class 2 = ocular and mild systemic weakness Class 3 = ocular and moderate systemic weakness Class 4 = ocular and severe systemic weakness Class 5 = MG crisis, respiratory failure Subtypes: A, appendicular B, bulbar Does not apply to class 1

Epidemiology Gender ratio: female predominance 2:1 or 3:2 Means: female 28y & males 42y Occurs at any age: Young: 20-30y Older: 60-70y Prevalence: 1 in 10,000

Etiology Idiopathic autoimmune in most patients Genetic predisposition 90% of MGFA Class 2 or greater show antibodies Genetic predisposition HLA-B8 HLA-DRw3 HLA-DQw2 Autoimmune comorbidities RA SLE Pernicious anemia Thyroid

Etiology Iatrogenic D-penicillamine (Wilson’s, RA) Alpha interferon Bone marrow transplant (chronic graft v host dz)

Provocation Antibiotics Beta-blockers Lithium Aminoglycosides Telithromycin* Polymyxins Ciprofloxacin Erythromycin Ampicillin Beta-blockers Lithium Magnesium Verapamil Quinadine Chloroquine Prednisone Statins Phenytoin Neuromuscular blocking agents

Provocation Infection Thyroid dysfunction Surgery Immunization Uncontrolled diabetes Stress: physical or emotional Overheating

Diagnosis Appropriate clinical history PE showing probable ptosis, ocular mobility impairment and possibly fluctuating proximal weakness Differential diagnosis Brainstem disease (stroke, neoplasm) Myopathy (channelopathies) Lambert Eaton Myasthenic Syndrome Botulism Motor neuropathies

Diagnosis Acetylcholine receptor antibodies*** Binding, blocking, & modulating Highly specific (~100%) Class 2 MGFA or higher, 80-90% Ab+ Class 1 MGFA, 40-50% are Ab+ False positives Thymoma, LEMS, SCLC Penicillamine therapy

Diagnosis “Seronegative” if no AChR Ab detected Other antibodies: Anti-muscle specific kinase (MuSK*) 25% Anti-striated muscle Anti-striational MuSK phenotype Young females Bulbar predominant symptoms More difficult to treat; less responsive

Diagnosis Electrodiagnostic testing Repetitive nerve stimulation Highly variable among centers, MGFA class, n/m protocol used Ocular/Class 1: sensitivity 50% Nonspecific. False+ in motor neuron dz, myopathy, neuropathy Single fiber EMG Sensitivity 90% Few centers provide service

Diagnosis “Tensilon”/edrophonium test Acetylcholinesterase inhibitor Monitor patient weakness, ptosis or ocular motility in response to IV medication Subjective, non-specific Complications Respiratory failure Syncope Bradycardia Hypotension

Evaluation If ocular & seronegative, check MRI brain & orbits to exclude structural lesion CXR/CT chest to evaluate for thymoma Thymectomy has resulted in delayed improvements, even remission in some General consensus Perform Thymectomy if thymoma present Consider Thymectomy if 10-55y, class 3-5 MGFA, and not well controlled medically Transsternal approach for total gland removal

Prognosis/Clinical Course By 1 month after onset 80% with Class1 will progress to systemic symptoms If Class 1 does not progress in the first year, it is unlikely to ever progress Maximal weakness usually occurs by year 3 Spontaneous remission occurs in 15-20%

Management Symptomatic: Acetylcholinesterase inhibition Decreases breakdown of ACh, leaving more active neurotransmitter to act in the synapse Indicated for MGFA classes 1-4 Side effects through muscarinic AChR Diarrhea, cramps Salivation, diaphoresis Bradycardia?

Management Acetylcholinesterase inhibition Pyridostigmine (Mestinon) Start dose: 30mg po q4-6h Onset: 30 min, peak 1-2h Forms: Tablet, elixor Goal dose: 60mg po q4-6h Sustained release (Timespan180mg) for qhs use if needed Caution: overuse may provoke cholinergic crisis Depolarized blockade of nAChRs NTE 1500mg/d

Management Immunomodulatory For Class 3-5 myasthenia gravis Reduces the immune-mediated neutralization of AChR and simplification of postsynaptic membrane Steroids Steroid-sparing medications Thymectomy Plasmaphersis & IVIG

Management Prednisone Very inexpensive & pretty fast For MGFA classes 2-5 Dose: 60-80 mg/d, po, divide dose Hospitalize: beware 50% worsen ~day3, for a few days, before improving 10% can be severe, respiratory failure 80% will response to steroids (50% marked) Onset range: 12h-2 mo., usually by 2 wks

Management Prednisone Max improvement by 9 months After improvement, wean to lowest effective dose Decrease by 10mg every 1-2 months Many complications: Cushingoid changes, hypertension Weight gain, diabetes Edema, osteoporosis, Cataracts Prednisone bridge to steroid sparing agents

Management Mycophenolate mofetil (Cellcept) Steroid sparing immunosuppressant Purine inhibitor of B & T cell proliferation 75% MG patients respond Onset: 3 months Start dose: 250mg po BID Goal dose: 1000mg PO BID Well tolerated, monitor for GI & heme toxicity

Management Azathioprine (Imuran) Steroid sparing immunosuppressant Cytotoxic purine inhibitor of T lymphocytes 50% MG patients respond Onset: 4-8 months Start dose: 50mg PO QD Goal dose: 150mg PO QD Monitor for liver & hematologic toxicity

Management Cyclosporine Steroid sparing immunosuppressant 50% MG patients respond Onset: 2 months Start dose: 3-5mg/kg/d, divided BID Monitor for renal toxicity, hypertension and med-med interactions

Management Emergent/acute therapy For rapidly progressive disease, MG crisis, impending respiratory failure Plasmaphersis: removes AChR antibodies IVIG: possible immunoneutralization

Management Plasmapheresis 2-3L plasma/exchange, QOD, until improvement, usually 3-5 exchanges Often improving by 2nd exchange Max improvement at 2-3wks later Moderate-marked efficacy Duration: 1-2 months Requires dialysis grade catheter (Quinton) Complications: HoTn, bradycardia, lytes, pneumothorax, infection, hemolysis

Management IVIG 0.4g/kg/d x 5 days Often improving by 3rd infusion Max improvement at 2-3wks later Moderate efficacy Duration: 1-2 months Complications: fever, chills, malaise, aseptic meningitis, renal failure, stroke Pretreat with Tylenol & diphenhydramine

Summary Clinical signs & symptoms involve fluctuating fatigable weakness, usually involving the eyes, and frequently progressing to other body areas Diagnosis of MG may be confirmed by serologic antibody testing*, electrodiagnostic tests, or sometimes pharmacologic challenge

Summary MG treatment is tailored for the individual, usually involving symptomatic acetylcholinesterase inhibition (Class 1-4 MG), and frequently immunomodulatory therapies. Emergent treatment of MG crisis may utilize plasmapheresis or IVIG, in the ICU setting

References Medscape: Myasthenia gravis. Aashit Shah. Updated 5/2/14. Editor: N Lorenzo. Accessed 3/28/15. http://emedicine.Medscape.com/article/1171206-overview Practical Neurology, by Jose Biller. 4th Edition. Lippincott, Williams & Wilkins, Philadelphia PA 2012. Chapter 48: Disorders of the Neuromuscular Junction, by R Pascuzzi & CL Bodkin, pp. 559-569. 39

Thank You Kenneth Hentschel, DO, PhD, FAANEM St Vincent’s Spine & Brain Institute Office phone: 308-7959 General neurology or subspecialty referrals: 308-7149 doctor.hentschel@gmail.com