March 3, 2016 C. Ulane, MD, PhD Myasthenia gravis

Case#1 30yo woman presents with several months of shortness of breath on exertion, diplopia at the end of the day and after reading for a significant period of time, and her parents note that her speech is slurred by the end of the day or after she is talking for awhile. She also reports generalized fatigue and weakness. She has never had these symptoms in the past.

Clinical symptoms of myasthenia gravis Hallmark: fluctuating weakness brought on by exertion, improves with rest Ocular 40% initial, 85% eventual Bulbar (dysarthria, dysphagia, difficulty chewing) prominent in 20% Generalized

Case continued PMH: extensive psychiatric history (bulimia, PTSD, ADD, possible personality disorder and substance abuse), no prior surgeries MEDS: Adderall, dilaudid, NKDA SH: lives with a friend on the UES, denies t/e/d, was working until 1 month ago when developed shortness of breath

Epidemiology Prevalence: 14 per 100,000 Familial cases rare; first degree relatives with increased incidences of other autoimmune diseases (SLE, RA, thyroid), HLA Thymoma 10%, thymic hyperplasia 60%

Case#1 continued EXAM: general physical exam-unremarkable MSE-intact CNs-no ptosis, no fatigueable upgaze, diplopia on lateral gaze in both directions with subtle incomplete abduction of each eye, no dysarthria

Case#1 continued Motor-very mild proximal arm and leg weakness, with a component of give-way weakness DTRs-2+symmetrical, toes downgoing Sensory exam, coordination and gait are all normal

Exam findings in MG Pattern of weakness: Ocular: 17% If restricted to ocular for 2-3 years, unlikely to generalize Ocular and generalized: 50% Ocular and bulbar: 13% Ocular and limb: 20%

Case#2 88yo man with no significant PMH presents with 4-5 months of dysarthria and dysphagia. He notes that the symptoms are worse at the end of the day, and he also has blurry vision when reading at night. Dysarthria worsens after he has been talking for awhile, and improves if he rests. He denies limb weakness and walks several miles every day. He has lost ~10lbs due to difficulty eating, but has a good appetite.

Case#2 continued EXAM General physical exam: thin man in NAD MSE-normal CNs-no ptosis, normal EOMs but diplopia on endgaze, +significant dysarthria, nasal speech, increased salivation, mild tongue weakness Motor-full strength throughout DTRs-2+symmetric, toes downgoing, negative Hoffmann’s, Babinski Sensory-normal Coordination/gait-normal

Exam findings in MG Pattern of weakness: Ocular: 17% If restricted to ocular for 2-3 years, unlikely to generalize Ocular and generalized: 50% Ocular and bulbar: 13% Ocular and limb: 20%

Diagnostic Work-up for MG AchR antibodies Found in 75-80% of patients with generalized symptoms, 50% of patients with ocular 88% sensitive, 97-98% specific MuSK antibodies 7-10% of all patients, prominent oropharyngeal symptoms Poor response to cholinesterase inhibitors “Seronegative”: 10% Lrp4 (low-density lipoprotein receptor related protein)

Table 89-2: Diagnostic testing for myasthenia gravis Laboratory Test Comments Acetylcholine receptor (AchR) antibodies AchR binding AchR blocking AchR modulating   80-85% of all MG 50% of ocular MG Binding most common Blocking positive in ~10% of MG with negative binding Modulating positive in <1% of MG with negative binding MusK antibodies 10% of all MG 50% of AchR-negative MG Other antibodies Striational (titin, RyR, myosin, actin) LPR4, agrin Present in 75-85% of thymomatous MG May be associated with more severe disease (titin, RyR) Found in other disorders Electrodiagnostic Test Nerve Conduction Studies Repetitive nerve stimulation reveals decrement (> 10%) Sensitivity 53-100% in generalized MG Sensitivity 10-48% in ocular MG Not specific Single-fiber EMG Most sensitive test for MG (>95%) but not specific (~70%) Radiology Computed tomography of the chest 10% thymoma

Electrophysiological testing in MG Nerve conduction studies with repetitive stimulation: 60% sensitive Single fiber EMG: 90-99% sensitive, less specific

Meriggioli, Matthew N. CONTINUUM: Lifelong Learning in Neurology Volume 15(1) Myasthenic Disorders and ALS February 2009 pp 35-62

Results-Case#1 (30F) AchR binding, blocking, modulating antibodies are negative MuSK antibody negative EMG/NCS with repetitive stimulation were performed

Neuromuscular Junction Neuroscience:  Genomics reaches the synapse Cori Bargmann Nature 436, 473-474(28 July 2005) doi:10.1038/436473a

NMJ Transmission At rest, small number of quanta released (dependent on EC calcium and temperature) Nerve action potential opens VGCC (P/Q type) leading to calcium influx at presynaptic terminal Ach vesicles fuse, release Ach which diffuses across synaptic cleft and binds AchR Threshold EPPinflux of calcium and muscle fiber contraction

Quantal Content: Low Frequency -Normal -Myasthenia -LEMS

Normal RNS: Pre and Post Exercise

3 Hz RNS in Myasthenia Gravis A: Baseline B: After 10 sec exercise (postex facilitation) C/D: 2 and 3 min after 60 sec exercise (postex exhaustion) E: after 10 sec exercise again (postex facilitation/repair of decrement)

Results continued EMG/NCS: repetitive stimulation of the distal median-APB system is negative (4% decrement at rest, 6% after exercise), repetitive stimulation of the proximal spinal accessory-trapezius system is consistent with post-synaptic NMJ dysfunction (9% decrement at rest, 17% decrement at 3minutes post-exercise) Distal: decrement of 10%, proximal: 15%

Single-Fiber EMG (SFEMG)

Normal Jitter Increased Jitter Jitter + Blocking

Case#2 continued 88yo man with fluctuating dysarthria AchR binding, blocking, modulating antibodies, MuSK antibodies all negative NCS-rep stim negative EMG-scattered fasciculations but no active denervation or chronic neurogenic changes; tongue EMG normal Trial of pyridostigmine-no improvement

Treatment *highly individualized* Pyridostigmine (acetylcholinesterase inhibitor) 60mg, titrate to effect Extended release Side effects: diarrhea, increased salivation, nausea, diaphoresis

Treatment-steroids Steroids (in 1960s-1970s ACTH was used) No RCTs for steroids, but multiple case series, anecdotal evidence Steroids compared to other immunosuppressives in RCTs

Treatment-steroids Alternate day or daily dosing , when achieve remission maintain for ~1month, followed by long, slow taper over months May have initial worsening in first 2 weeks (50%) Titrate up (start 20mg) goal of 60-80mg

Steroid-Sparing Agents Mycophenolate mofetil (blocks purine synthesis) Case reports, open label studies show benefit (reduction in symptoms, medication doses) Maximal improvement ~6wks Recent RCT showed no benefit High cost, risk for late malignancies Azathioprine (purine analog) Benefit is at 1-2yrs Monitor CBC, LFTs

Steroid-Sparing Agents Cyclosporine (calcineurin inhibitor) Benefit within~1mo, limited by renal toxicity Rituximab (anti-CD20) Case series, esp in MuSK Methotrexate (inhibits DNA synthesis) Case reports Cyclophosphamide (DNA cross-linker)

Significant bulbar dysfunction Dysarthria, dysphagia Table 89-3: Signs of Impending Respiratory Failure in MG VC=vital capacity, NIF=negative inspiratory force, MEP=maximal expiratory pressure Clinical Features Significant bulbar dysfunction Dysarthria, dysphagia Impaired gag reflex Tachypnea, dyspnea Use of accessory muscles Paradoxical breathing Single breath count < 15 Poor cough Impaired secretion clearance Laboratory Signs Pulmonary function tests: VC < 15-20ml/kg (or VC < 1L) NIF > -20cm H20 MEP < 40cm H20 tidal volume < 4-5ml/kg Laboratory: pCO2 > 50mm Hg *hypoxia is a late finding

Treatment IVIg Plasma exchange RCT evidence for benefit when rapid improvement needed Plasma exchange Similar effectiveness when compared to IVIg Can be used on monthly basis if MG is severe or not tolerating other agents

Treatment Thymectomy Thymomasurgery Non-thymomatous, autoimmune: controversial Improves outcome (medication-free remission, asymptomatic w/ or w/o meds) Control population, severity of MG, age/sex Currently ongoing trial of thymectomy plus prednisone vs prednisone alone

Case#3 67yo woman with DM, HTN, CAD (s/p CABG and DES), CHF, interstitial lung disase (on home O2/bipap), pulmonary HTN, and myasthenia gravis (Ach binding antibody positive, rep stim negative x2, SFEMG with increased jitter) Diplopia, ptosis, proximal weakness, SOB

Case#3 continued No response to mestinon Admitted for IVIg, steroids (renal insufficiency and volume overload with IVIg) Did not tolerate mycophenolate mofetil Multiple exacerbations requiring intubation, plasma exchange, IVIg On steroids, continued to worsen, significant weight gain, difficult to control DM

Medications which may worsen MG Calcium channel blockers (long-term use) Beta blockers Quinolones Penicillamine Aminoglycosides Macrolides H2 antagonists GBP, PHT