Stanley Iyadurai, PhD MD. Assistant Professor of Neurology/Neuromuscular Medicine Nationwide Children s Hospital Myology Course 2015

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1 1 Stanley Iyadurai, PhD MD Assistant Professor of Neurology/Neuromuscular Medicine Nationwide Children s Hospital Myology Course 2015

2 Motor unit motor neuron, its axon, and nerve terminals, and muscle fibers the axon innervates Presynaptic nerve terminal No myelin sheath ACh is synthesized from Choline and Acetyl CoA by action of ChAT P/Q type calcium channels Synaptic vessels 6-10, 000 ACh molecules (quantum) Immediate (primary) store 1, 000 quanta of ACh Secondary store 10, 000 quanta, can resupply the primary store after a few seconds Tertiary store in the axon and cell body 100, 000

3 Synaptic space 50 nm Postsynaptic muscle membrane Clefts/folds, ACh R AChE is attached to collagen fibers of basement membrane, breaks down ACh to choline and acetate 20% of released ACh is hydrolyzed before binding to ACh R Choline is taken up be presynaptic nerve terminal through Na-dependent active transport mechanism

4 nerve axon synaptic vesicles axon terminal synaptic cleft junctional folds muscle fiber Engel et al 1976

7 Safety factor in NMJ transmission safety factor

8 Diseased endplate electrophysiology transmission failures safety factor

9 Resting state - release of single ACh quantum produces postsynaptic depolarization miniature EPP amplitude determined by amount of ACh Duration is determined by amount of time AChR that received the quantum is open AP depolarizes nerve terminal Calcium channel opens influx of Ca release of ACh

10 When EPP reaches threshold voltage, muscle fiber AP is produced (all-or-none) Quantal content number of synaptic vesicles (quanta) released M=N x P M quantal content N number of quanta immediately available at nerve terminal (~1000) P probability of quantal release (0.2 in nl)

11 M=N x P At rest Low P, high N---- low M----small number of quanta released ---- sub-threshold EPP AP in normal subject High P and N ---- high M ---- EPP reaches threshold muscle AP

12 Safety margin of NMJ Difference between actual EPP amplitude and EPP amplitude required to produce muscle AP Determined by quantal content, efficiency of AChE and AChRs High in normal subjects

13 Slow RNS (2-3 Hz) ACh quanta are progressively depleted from primary store Fewer quanta are released with each successive stimulation Corresponding EPP falls in amplitude but remains above threshold After first few seconds the secondary store begins to replace the depleted quanta with a subsequent rise in the EPP

14 Normal Myasthenia gravis

15 Rapid RNS (10-50 Hz) Depletion of primary store is counterbalanced by both mobilization from secondary store and accumulation of calcium 100 ms is needed for Ca to be pumped out Accumulation of Ca predominates over ACh depletion ---- increased amount of quanta being released ---- higher EPP

Voluntary muscle contraction 30-50 Hz Post-tetanic facilitation brief exercise (10 sec) Postsynaptic NMJ

May repair a low EPP developed after slow RNS Presynaptic NMJ disorders if baseline EPP is below threshold

17 Voluntary muscle contraction Hz Post-tetanic facilitation brief exercise (10 sec) Postsynaptic NMJ disorders higher EPP --- generation of MFAP. May repair a low EPP developed after slow RNS Presynaptic NMJ disorders if baseline EPP is below threshold --- facilitates EPP ---- generates MFAP Post-tetanic exhaustion after prolonged exercise NMJ disorders - slow RNS in 2-4 min can cause greater decline of EPP ---- no MFAP

18 Decrement at rest Post-tetanic facilitation after 10 sec of exercise Post-tetanic exhaustion after 1 min exercise (1,2,3 min after) Post-tetanic facilitation after 10 sec of exercise

20 IgG-directed attack on the nicotinic ACh receptor Abs are present in the serum of many MG patients Passively transferred Ab produce experimental myasthenia in animals Removal of Ab allows recovery Immunization of animals with ACh receptors produces Ab and experimental myasthenia

21 Autoantibodies: AChR Striational MUSK Seronegative Acetylcholine Receptor Antibodies Normal AChR density in controls Decreased AChR density in MG Fambrough et al, 1973

22 Normal Myasthenia gravis

23 Two alpha, one beta, delta and epsilon subunits Agrin, rapsyn and muscle-specific tyrosine kinase (MuSK) proteins important in clustering of AChR on postsynaptic membrane Two molecules of ACh are needed to bind to each alpha subunit to open AChR channel Sodium influx local depolarization (EPP) EPP size is proportional to the amount of ACh

24 Mechanism of Ab damage to AChR Ab binds to ACh receptor and directly blocks the binding of the ACh Complement-directed attack leading to destruction of AChR and postsynaptic folds Ab binding increases removal of AChR from postsynaptic membrane this leads to smaller endplate potential

25 Muscle fatigue and weakness EOM 50% at presentation/90% at diagnosis Proximal muscles symmetric Bulbar muscles Pathologic fatigability Transient neonatal MG Maternal Ab passed through placenta Self-limiting

1. Routine motor and sensory nerve conduction studies. Perform routine motor and sensory nerve conduction studies, preferably a motor and sensory nerve in one uppoer and one lower extremity.

26 1. Routine motor and sensory nerve conduction studies. Perform routine motor and sensory nerve conduction studies, preferably a motor and sensory nerve in one uppoer and one lower extremity. CMAP amplitudes should be normal. If CMAP amplitudes are low or borderline, repeat distal stimulation immediately after 10 seconds of exercise to exclude a presynaptic NMJ transmission disorder (e.g., Lambert-Eaton myasthenic syndrome) Only 5-15% of MG patients has small CMAP amplitudes Ensure integrity of the nerve which will be used for RNS

27 2. Repetitive nerve stimulation and exercise testing. Perform slow RNS (2-3 Hz) on at least one proximal and one distal motor nerve. Always try to study weak muscles. If any significant decrement (>10%) is present, repeat to ensure decrement is reproducible. If there is no significant decrement at baseline, exercise the muscle for 1 minute, and repeat RNS at 1, 2, 3, and 4 minutes looking for a decrement, secondary to post-exercise exhaustion. If at any time a significant decrement is present (at baseline or following post-exercise exhaustion), exercise the muscle for 10 seconds and immediately repeat RNS, looking for post-exercise facilitation (repair of the decrement). RNS is abnormal in 50-70% of generalized MG patients

29 3. Needle electromyography (EMG). Perform routine EMG of distal and proximal muscles, especially weak muscles. Patients with moderate to severe myasthenia gravis may display unstable or short, small, polyphasic motor unit action potentials. Recruitment is normal or early. Needle EMG must exclude severe denervating disorders or myotonic disorders, which may display an abnormal decrement on RNS. Two reasons: exclude severe denervating disorders (i.e. MND, polyneuropathy) show evidence of NMJ disorder

SF-EMG in the extensor digitorum communis and, if necessary, one other muscle, looking for jitter and

Normal SF-EMG in a clinically weak muscle excludes an NMJ disorder.

30 4. Single-fiber EMG (SF-EMG). If the above are normal, or equivocal in a patient strongly suspected of having myasthenia gravis, perform SF-EMG in the extensor digitorum communis and, if necessary, one other muscle, looking for jitter and blocking. It is always best to study a weak muscle. Normal SF-EMG in a clinically weak muscle excludes an NMJ disorder. No clinical correlate to jitter may be abnormal even in patients w/o overt clinical symptoms. Sensitivity 95-99% for generalized MG, but low specificity Often done on EDC Normal SF-EMG in clinically weak muscle rules out MG At least 20 single-fiber pairs. Jitter in >10% of pairs - abnormal

33 Single Fiber Electromyography Normal jitter Trigger on this rise

34 Single Fiber Electromyography Abnormal jitter Trigger on this rise Blocking Figure courtesy of W. David Arnold, MD

35 Autoantibodies: AChR Striational MUSK Seronegative Acetylcholine Receptor Antibodies ~80% of MG ~100% of thymoma-mg Heterogeneity of actions: binding, blocking, activating Major pathogenic actions: Activate complement, membrane attack complex (MAC) Cross-link AChR, leading to increased turnover

36 Autoantibodies: AChR Striational MUSK Seronegative Striational Antibodies ~33% of MG ~90% of thymoma-mg patients Also seen in autoimmune liver disease, lung cancer, rarely in Lambert-Eaton syndrome Pathogenic role uncertain Bind skeletal and cardiac muscle in a cross-striational pattern. Many targets: RYR1, titin, rapsyn, myosin

37 Autoantibodies: AChR Striational MUSK Seronegative Muscle-Specific Kinase Antibodies ~10% of cases Rarely associated with thymoma May worsen with AChE inhibitors Clinical features differ: Rarely seen in ocular MG Subgroup with early respiratory failure, head drop Many indistinguishable from AChR-MG

38 Autoantibodies: AChR Striational MUSK Seronegative Seronegative Myasthenia Gravis ~10% of cases Clinically similar to AChR positive MG ~60% have AChR Ab detected with more sensitive laboratory techniques

39 Enhance NMJ Transmission Thymectomy Immune Therapy Acetylcholine Esterase Inhibitors Pyridostigmine (Mestinon) is the most commonly used: Edrophonium (Tensilon) traditionally administered in a bedside diagnostic test. Diarrhea and abdominal cramping are common dose-limiting side effects.

41 Improve NMJ Transmission Thymectomy Immune Therapy Thymectomy With thymoma: always remove, variable effects on symptoms Without thymoma: controversial Older series (before medical immunosuppression) indicate higher remission rates in thymectomized MG Newer series indicate no significant difference from controls Reported remission rates after thymectomy range from 11 to 32%

42 Treatment Approach: Improve NMJ Transmission Thymectomy Immune Therapy Immune Therapies for MG Rapid: plasmapheresis, IVIG Long-term: Corticosteroids (prednisone) Steroid-sparing agents: azathioprine (Imuran) mycophenolate mofetil (CellCept) cyclosporine/tacrolimus (Prograf) Investigational biologics: rituximab, belimumab, eclizumab

Neuromuscul Disord. 2015 Aug;25(8):651-2.

43 Neuromuscul Disord Aug;25(8): doi: /j.nmd Epub 2015 Apr 22.

44 Reduced release of ACh from presynaptic terminal IgG Ab against presynaptic voltage-gated Ca channels Passive transfer IgG from LEMS pts to animals causes same symptoms

45 Rare, 70% male, 30% female Proximal muscle weakness (esp legs) and fatigability DTR are reduced or absent Autonomic symptoms (dry mouth) Paresthesias Bulbar symptoms are mild

46 Muscle facilitation After 10 sec exercise power and DTR are increased SCLC expresses VGCC--- starts autoimmune process Found in 60% of LEMS, esp males >40, smokers Other pts (younger women) primary autoimmune disease VGCC Ab testing is available

47 Slow RNS before and after exercise decrement will be there in both conditions but baseline CMAP amplitude is significantly larger after exercise

49 Must be suspected in any patient with small CMAP amplitude on NCS at rest with normal sensory responses Repeat after 10 sec exercise Few patients can have signs of both MG and LEMS (AChR AB and CMAP amplitude facilitation after exercise)

50 Find and treat any underlying malignancy AChE inhibitors 3,4-diaminopyridine Immune therapy as in MG

51 Exotoxin of Clostridium botulinum (A,E,F) blocks presynaptic release of ACh at both somatic and autonomic synapses NMJ and parasympathetic blockade Food, wound infection 2-72 hrs after Infantile botulism 2/2 GI tract colonization with Clostridia bacteria

52 Nausea, vomiting, abdominal pain Blurred vision, diplopia, dysarthria Rapidly progressive descending weakness --- flaccid areflexic quadriparesis with ophthalmoplegia Pupils paralyzed in 50% Ileus, decreased salivation

53 Similar to LEMS Similar to LEMS

55 Inherited defect of NMJ transmission, rare Not immune-mediated Usually presents in early childhood EO, bulbar and proximal muscles are often affected Heterogeneous NCS/EMG results Single impulse may cause repetitive CMAP potential Morphologic and in vitro electrophysiological analysis of an NMJ from biopsied muscle

56 Disorder Onset Ocular Sx? Bulbar Sx? Reflexes Autonomic Sx? Sensory Sx? GI Sx? MG Subacute Yes Yes Normal No No No LEMS Subacute +/- +/- Reduced +/- +/- No Botulism Acute Yes Yes Normal Yes No Yes CMS Congenital Yes +/- Normal No No No Disorder CMAP amplitude Decrement in 3 Hz Increment in 50 Hz SF- EMG Repetitive CMAP Fibs/PSW? MG Normal Yes No Abn No No Nml LEMS Decreased Yes Yes Abn No No Nml Botulism Decreased Yes Yes* Abn No Yes Nml CMS Normal Yes No Abn Yes* No Nml MUAP

59 Before treatment After treatment

60 Distribution of Weakness: Ocular (~25%) can mimic CN III, IV, or VI palsy, INO Bulbar Dysphagia, dysarthria, dysphonia, aspiration, OSA Limb Proximal > Distal Upper > Lower extremity Respiratory Can lead to respiratory failure (<10%)

Neuromuscular Junction Testing ELBA Y. GERENA MALDONADO, MD ACTING ASSISTANT PROFESSOR UNIVERSITY OF WASHINGTON MEDICAL CENTER

Neuromuscular Junction Testing ELBA Y. GERENA MALDONADO, MD ACTING ASSISTANT PROFESSOR UNIVERSITY OF WASHINGTON MEDICAL CENTER Objectives Neurophysiology Electrodiagnostic Evaluation Clinical Application