{ The Evaluation of Weakness in the Electromyography Lab Anthony Chiodo, MD, MBA University of Michigan Health System AAPMR Meeting, San Diego

 38 year old right handed woman comes in with a chief complaint of weakness  Noticed it first in her inability to complete her usual circuit training program over the last month  Subsequently affected her aerobic exercise program and day to day home management activities Case Study

 She does not think there has been any numbness or tingling  She has not noticed it affecting one area of the body first but is uncertain  She has had no new pain, no fever or chills, no change in bowel or bladder control

 Past medical history is remarkable for hypothyroidism for which she takes synthroid  Family history is significant for a maternal grandmother with rheumatoid arthritis, paternal grandparents with diabetes mellitus and heart disease, father with hypertension, mother with hypothyroidism

 Deep tendon reflexes are 1+  Pin sensation and light touch is symmetric  Strength testing shows shoulder and hip girdle muscles in the 3-4 range, hamstrings 3, elbows 4, hands and feet 4+ to 5  There is no tenderness and no pain with ROM Physical Examination

{ Differential Diagnosis

{ Neuromuscular Junction Disorders Anthony Chiodo, M.D.

 Motor disorder  Defect affecting the relationship between the distal motor axon and muscle  Defect can be pre-synaptic, synaptic, or post- synaptic  Acquired disorders are pre- or post-synaptic NMJ Disorders: Nature of the Abnormality

 Normal distally and conduction Sensory Nerve Conduction Studies

 Post-synaptic: Normal  Pre-synaptic: inability to achieve transmission: decreased motor evoked amplitudes but normal latency and conduction Motor Nerve Conduction Studies

 Pre-synaptic: if no motor units are seen with activation, fibrillation potentials and positive waves are possible  Botulism  Otherwise, decreased amplitude motor units of varying amplitude and rapid recruitment  Post-synaptic: varying amplitude motor units with rapid recruitment  If myasthenia gravis: may see proximal fibrillation potentials and positive waves Routine Needle Examination

{ Repetitive Nerve Stimulation Physiology is Key to Understanding

 Molecules = Quanta X # Released(p)  Typical Quanta = several thousand acetylcholine molecules, generate MEPP, amplitude 1 mV  P typically around 60 quanta released per nerve stimulus  Muscle action potentials at 7-20 mV Presynaptic Acetylcholine Stores

 Reserve: 300,000 quanta  Mobilization: 10,000 quanta  Immediate Release: 1,000 quanta Types of Acetylcholine Stores

 Mobilization store: 1500 msec  Reserve: 3-4 minutes Time Availability

 Decreased quanta released per nerve stimulation  Synaptic vesicle fusion time(Ca++ dependent) is msec  Maximal decrement at 2-3 Hz  No decrement at 10 Hz  Normal decrement < 8% Concept of Decrement

 1 st stimulus: 60 quanta  2 nd stimulus: 56 quanta  3 rd stimulus: 53 quanta  4 th stimulus: 55 quanta as reserve quanta become available  Accounts for decrease in EPP and results in increase risk of failure (blocking) over four repetitive stimulations at 2 Hz At 2 Hz Repetitive Stimulation

 Other Disorders NMJ Transmission  Myotonia  Neurogenic Disorders with Denervation/Reinnervation  Rapidly Progressive ALS  Polyneuropathy  Mononeuropathy  Radiculopathy What Other Disorders Have a Decrement To Low Frequency Repetitive Nerve Stimulation?

 Yes, temperature  Increased decrement and blocking at increased temperature due to increased acetylcholinesterase activity  May account for the fact that the effect is more pronounced in proximal muscles Are there any physiological parameters that effect this finding?

 Acetylcholine Receptor Antibodies  Normal number of MEPP’s  MEPP amplitude decreased by 80%  Post-activation facilitation  Post-activation exhaustion Myasthenia Gravis

 Increased calcium in endplate increases the quanta released  Decrement decreased, small increase in motor evoked amplitude Post-activation Facilitation

 Depletion of mobilization and immediate release stores, before reserve store becomes available  Decreased receptor excitability  Characteristic of Myasthenia Gravis Post-activation Exhaustion

 Recording surface 25 mcm to pick up from single muscle fiber  Quantify the differences in time of onset of firing of two muscle fibers from the same motor unit  Jitter is the mean difference in this firing onset time  Blocking is the rate of failure of a muscle fiber from firing with it’s motor unit SFEMG

 Pre- and post- synaptic neuromuscular junction disorders  Ongoing neuropathic processes: motor neuron disease, neuropathy, radiculopathy Diagnoses with Increased Jitter

 Hallmark: Fluctuating weakness  Diplopia  Ophthalmoplegia  Ptosis  Facial Weakness  Dysphagia  Vocal cord weakness  Respiratory muscle weakness  Pelvic floor muscle weakness Myasthenia Gravis Clinical Symptoms

 I:Ocular  IIA:Mild generalized  IIB:Moderate generalized  III:Acute severe with bulbar symptoms  IV:Late severe  V:Muscle atrophy Clinical Classifications of Myasthenia Gravis Severity: Osserman

 Active:5-7 years  Inactive:10 years  Burned Out:Slow improvement seen  40-50% of ocular myasthenics will become generalized in the first 2 years Clinical Course in Myasthenia Gravis

 Antibodies: 80% generalized, 55% ocular  Seronegative: 70% with anti-MuSK Ig  Rep Stim: 76% generalized, 48% ocular  Limb SFEMG: 89% generalized, 60% ocular  Facial SFEMG: 92% ocular Myasthenia Gravis Diagnosis

 Evaluate/treat other autoimmune disorders: RA, thyroid, B-12  Pacing  High K+ diet  Avoid excessive heat>cold  Watch for cyclic changes in women  Avoid botox, quinamm, aminoglycosides, tetracyclines, anesthetic agents, anticonvulsants Preventing Exacerbations in Myasthenia Gravis

 Mestinon: Acetylcholinesterase inhibitor  Prednisone  Imuran, Cytoxan, Cyclosporine, Mycophenolate  Therapeutic Plasma Exchange  Thymectomy  AchR-based Immunoadsorbants  Mucosal injection of AchR-recombinant fragments  IG to proinflammatory cytokine IL-18 and costimulatory factor CD40L  Create viral manipulated antigen presenting cells that express AchR to present to AchR-specific T- cells and activate Fas ligand “guided missile” Myasthenia Gravis Treatment

 Creatine plus resistance exercise with normal treatment in mild MG shows improved strength and muscle mass  Isometric exercise effective in improving strength in mild MG Exercise in Myasthenia Gravis

 Increased acetylcholinesterase activity  Decreased sensitivity of acetylcholine receptors  More rapid presynaptic acetylcholine depletion  Can explain proximal>distal weakness Effect of Temperature in Myasthenia Gravis

 Antibodies prevent pre-synaptic Ca++ influx prevents quanta release  Decreased number of MEPP’s of normal amplitude  Decrement to low frequency rep stim due to many muscle fibers activated near-threshold so decreased release is miniscule but significant  Post-exercise facilitation due to increased Ca++ in cell resulting in increased quanta release with next nerve stimulus Myasthenic Syndrome

 Immunogenic: responds to TPE, prednisone, and 2,4-DAP  Tumorogenic: responds to cancer therapy Eaton-Lambert Types

 Food, wound or infantile  Markedly decreased pre-synaptic release due to botulinum toxin binding to and entry into the nerve terminus membrane  Cleave proteins in synaptic vesicle membrane inhibiting release  Complete binding may result in no increment to exercise  Complete binding may lead to fibrillation potentials and positive waves Botulism

 LEMS: hallmark is marked incremental response with exercise  AIDP  Critical illness myopathy Botulism Differential Diagnosis

Does not include neonatal myasthenia gravis  Presynaptic: failed production, storage and mobilization of acetylcholine  Acetylcholine receptors: decreased number, decreased binding, prolonged binding/opening  Congenital absence of acetycholinesterase Congenital Myasthenia Gravis

Thank you!