1. Neuromuscular Junction Disorders Abdullah Al-Salti R3 AHD 9 march 2011

2. Neuromuscular junction

3. Myasthenia Gravis: a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. Age and Gender: Myasthenia gravis presents at any age. Female incidence peaks in the third decade of life, whereas male incidence peaks in the sixth or seventh decade. Myasthenia gravis presents at any age. Female incidence peaks in the third decade of life, whereas male incidence peaks in the sixth or seventh decade. The female-to-male ratio is said classically to be 6:4, but as the population has aged, the incidence is now equal in males and female The female-to-male ratio is said classically to be 6:4, but as the population has aged, the incidence is now equal in males and femaleInheritance: 1st degree relatives have 1000x the rest of general population 1st degree relatives have 1000x the rest of general population inc. jitter on SFEMG demonstrated in 33-45% of asymptomatic 1st degree relatives inc. jitter on SFEMG demonstrated in 33-45% of asymptomatic 1st degree relatives Inc. titres of AChR antibodies in up to 50% Inc. titres of AChR antibodies in up to 50% Myasthenia Gravis

4. Pathophysiology Immunoglobulin G (IgG) directed attack on the NMJ, aimed specifically at the nicotinic acetylcholine (ACH) receptor. Damage to the ACH receptor and postsynaptic membrane involves several steps. First, binding of the antibody to the receptor can directly block the binding of ACH. First, binding of the antibody to the receptor can directly block the binding of ACH. Second, there is a complement-directed attack, with destruction of the ACH receptor and post junctional folds. Second, there is a complement-directed attack, with destruction of the ACH receptor and post junctional folds. Third antibody binding can result in an increase in the normal removal of ACH receptors from the postsynaptic membrane. Third antibody binding can result in an increase in the normal removal of ACH receptors from the postsynaptic membrane. Resulting in a smaller endplate potential and a reduced safety factor of NMJ transmission.

5. Pathophysiology The MuSK The MuSK maintains the normal functional integrity of the NMJ maintains the normal functional integrity of the NMJ anti-MuSK antibodies may alter the normal maintenance of a high density of AChRs at the NMJ anti-MuSK antibodies may alter the normal maintenance of a high density of AChRs at the NMJ leading to reduced numbers of functional AChRs. leading to reduced numbers of functional AChRs. Thymus gland. Thymus gland. greater than 50% of anti – AChR-positive patients having thymic hyperplasia and 10% to 15% having a thymic tumor.

6. 1.HLA-DRW3, -B8, and -A1 predispose 2.a-subunit is the major T cell antigen

7. Etiology Acquired autoimmune Acquired autoimmune Drug-induced : D-penicillamine Drug-induced : D-penicillamine Transient neonatal (passive transfer of maternal anti-AChR antibodies) Transient neonatal (passive transfer of maternal anti-AChR antibodies) Congenital myasthenic syndrome Congenital myasthenic syndrome

8. Clinical presentation most commonly presents with weakness of extraocular muscles ptosis and/or diplopia, +/- photophobia most commonly presents with weakness of extraocular muscles ptosis and/or diplopia, +/- photophobia can mimic any pattern of ophthalmoplegia including pupil sparing IIIrd nerve palsy, internuclear ophthalmoplegia (INO) or sixth nerve palsy can mimic any pattern of ophthalmoplegia including pupil sparing IIIrd nerve palsy, internuclear ophthalmoplegia (INO) or sixth nerve palsy Bulbar involvement common eventually dysphagia, dysarthria, dysphonia (hypernasal or hoarse) Bulbar involvement common eventually dysphagia, dysarthria, dysphonia (hypernasal or hoarse) reduced facial expression, jaw fatigue reduced facial expression, jaw fatigue generally progresses over time so that within 2 years of onset of ocular MG, 90% have bulbar and proximal symmetric limb weakness generally progresses over time so that within 2 years of onset of ocular MG, 90% have bulbar and proximal symmetric limb weakness

9. Early Symptoms frequent purchase of new eyeglasses to correct blurred vision frequent purchase of new eyeglasses to correct blurred vision sleepy or sad facial appearance sleepy or sad facial appearance avoidance of difficult to chew foods avoidance of difficult to chew foods cessation of activities requiring specific muscles (e.g. singing) cessation of activities requiring specific muscles (e.g. singing) Presenting Symptoms ptosis or diplopia (2/3 of patients) ptosis or diplopia (2/3 of patients) present in almost all within 2 years of onset present in almost all within 2 years of onset difficulty chewing, swallowing, talking (1/6) difficulty chewing, swallowing, talking (1/6) limb weakness (1/10) limb weakness (1/10) Rarely limited to single muscle group Rarely limited to single muscle group Diurnal Variation Exacerbating Factors Clinical presentation

10. Natural History Restricted to ocular muscles in 10% of patients. Restricted to ocular muscles in 10% of patients. 90% have progressive weakness over two years involving oropharyngeal and limb muscles. 90% have progressive weakness over two years involving oropharyngeal and limb muscles. 2/3 of patients reach remission within 1 year 2/3 of patients reach remission within 1 year Spontaneous remission can occur, usually early Spontaneous remission can occur, usually earlyStages 1. Active stage 1. brief period of fluctuation 2. more severe 2. Inactive stage 1. fluctuations attributable to fatigue, intercurrent illness 3. Burnt out stage (15-20 years) 1. fixed weakness 2. atrophic muscles Clinical presentation

11. Physical Findings Ocular Muscles Ptosis Ptosis assymetrical assymetrical covering ptotic lid may relieve contraction of opposite frontalis covering ptotic lid may relieve contraction of opposite frontalis passively lifting ptotic lid may cause opposite lid to fall passively lifting ptotic lid may cause opposite lid to fall varies during sustained activity varies during sustained activity may shift from eye to eye - pathognomonic may shift from eye to eye - pathognomonic edrophonium response edrophonium responseEOMs ³ N muscle without pupil involvement ³ N muscle without pupil involvement variable, fluctuating, and fatigable variable, fluctuating, and fatigable most severe in medial rectus most severe in medial rectus “ pseudo-INO ” “ pseudo-INO ” edrophonium may improve only one of several weak ocular muscles edrophonium may improve only one of several weak ocular muscles

12. Physical Findings Oropharyngeal Muscles Oropharyngeal Muscles altered facial appearance – depressed, snarl/sad altered facial appearance – depressed, snarl/sad examiner can manually open jaw against resistance examiner can manually open jaw against resistance impaired strength of eye closure impaired strength of eye closure nasal regurgitation nasal regurgitation difficulty swallowing difficulty swallowing hoarseness (larynx) hoarseness (larynx) nasal voice, especially after prolonged talking nasal voice, especially after prolonged talking Limb Muscles neck flexors > extensors neck flexors > extensors deltoids, triceps, wrist extensors, finger extensors especially affected deltoids, triceps, wrist extensors, finger extensors especially affected ankle dorsiflexors preferentially affected ankle dorsiflexors preferentially affected fatigability fatigability

15. Diagnostic Procedures

16. Tensilon test Measures ptosis, limitation of eye movement, or nasal speech preferred ptosis, limitation of eye movement, or nasal speech preferred limb muscles (requires maximum effort) limb muscles (requires maximum effort) Administration 2mg then wait 60s then 8mg then wait 60s 2mg then wait 60s then 8mg then wait 60s total dose 0.15mg/kg in children total dose 0.15mg/kg in children sc administration in newborns and infants (delayed 2-5 minutes) sc administration in newborns and infants (delayed 2-5 minutes) Test Characteristics 90% sensitivity not 100% specificity 90% sensitivity not 100% specificity motor neuron disease oculomotor nerve palsies Alternative Agents im neostigmine (longer duration of action) im neostigmine (longer duration of action) therapeutic trial of pyridostigmine therapeutic trial of pyridostigmine

17. Tensilon test

18. Antibodies Against Acetylcholine Receptors Value confirm diagnosis but cant predict severity neither predict thymoma Test Characteristics 80% sensitivity for generalized myasthenia (range 74-99%) 80% sensitivity for generalized myasthenia (range 74-99%) 55% sensitivity for ocular myasthenia 55% sensitivity for ocular myasthenia may rise with disease progression may rise with disease progression generally specific generally specific rare DDx rare DDxSLE Inflammatory neuropathy (CIDP) ALSRA Thymoma without MG Normal relatives of patients with MG

19. Ocular cooling Specificity?? Specificity?? Positive 80%, no positive response in patients with ptosis not due to myasthenia Positive 80%, no positive response in patients with ptosis not due to myasthenia Alternative to tensilon test Alternative to tensilon test Improvement in lid ptosis after the eye is cooled with ice pack 2 minutes Improvement in lid ptosis after the eye is cooled with ice pack 2 minutes

20. Repetitive nerve stimulation ( CMAP) should be normal in patients with MG. ( CMAP) should be normal in patients with MG. With a small CMAP, LEMS should be considered. With a small CMAP, LEMS should be considered. Reproducible 10% decremental in amplitude when the first stimulus is compared to fourth or fifth Reproducible 10% decremental in amplitude when the first stimulus is compared to fourth or fifth skin temperature (i.e. 32 º C – 34 º C) before beginning RNS. skin temperature (i.e. 32 º C – 34 º C) before beginning RNS. hold anticholinesterases before test hold anticholinesterases before test more common in proximal muscles (facial, biceps, deltoid, trapezius) more common in proximal muscles (facial, biceps, deltoid, trapezius) may get some repair with exercise, but not an increment (unlike LEMS) may get some repair with exercise, but not an increment (unlike LEMS) RNS in hand/shoulder has sensitivity of 61% RNS in hand/shoulder has sensitivity of 61% 1. 76% in generalized myasthenia 2. 48% in ocular myasthenia

21. Repetitive nerve stimulation

22. SFEMG (MUAP) abnormalities suggestive of a NMJ disorder,unstable MUAP, small, short-duration. At least one symptomatic muscle At least one symptomatic muscle Increased jitter and blocking Increased jitter and blocking Jitter is greatest in weak muscles Jitter is greatest in weak muscles Measure 2 time locked motor units Measure 2 time locked motor units SENSITIVE: 99% sensitive for generalized and 97% sensitive for ocular SENSITIVE: 99% sensitive for generalized and 97% sensitive for ocular NONSPECIFIC NONSPECIFIC any other motor unit disease any other motor unit disease must perform EMG and NCS to exclude neuronopathy, neuropathy, myopathy must perform EMG and NCS to exclude neuronopathy, neuropathy, myopathy limb ­ jitter DOES NOT predict development of generalized myasthenia limb ­ jitter DOES NOT predict development of generalized myasthenia should examine 20 pairs in each muscle should examine 20 pairs in each muscle

24. Sensitivity testoculargeneralized tensilon60-95%72-95% Ach rec. Ab 1 50-75%70-95% Anti-Musk 50% of AchR - RNS50%75% SFEMG90-95%98-100% Ocular cooling 2 89%89%

26. Comparison of Diagnostic Techniques Tensilon test diagnostic if positive in patients with ptosis or ophthalmoparesis Tensilon test diagnostic if positive in patients with ptosis or ophthalmoparesis AChR Ab specific AChR Ab specific RNS confirms DNMJ transmission but nonspecific; often normal in mild or ocular disease RNS confirms DNMJ transmission but nonspecific; often normal in mild or ocular disease SFEMG sensitive but not specific SFEMG sensitive but not specific Other Diagnostic Procedures CT chest CT chest TFTs TFTs TB test prior to immunosupression TB test prior to immunosupression

27. Treatment

29. Treatment Cholinesterase Inhibitors Roles diagnostic diagnostic early, symptomatic treatment early, symptomatic treatment adjunct to immunomodulatory and immunosuppressive therapy. adjunct to immunomodulatory and immunosuppressive therapy. RARELY can be used as chronic treatment RARELY can be used as chronic treatment usually effect diminishes with time usually effect diminishes with timeDosingPyridostigmine longer duration of action longer duration of action initially 30-60mg q4-8 hours initially 30-60mg q4-8 hours 1.0mg/kg in infants and children 1.0mg/kg in infants and children available in serum (60mg/5ml) available in serum (60mg/5ml) available as nebulizer available as nebulizer RARELY produces normal strength and RARELY completely corrects diplopia RARELY produces normal strength and RARELY completely corrects diplopia

30. Treatment Cholinesterase Inhibitors Neostigmine initially 7.5-15.0mg q4-8h initially 7.5-15.0mg q4-8h 0.3mg/kg in infants and children 0.3mg/kg in infants and children available as IV and nebulizer available as IV and nebulizer Side Effects Smooth Muscle (muscarinic) NxVx NxVx cramps cramps diarrhea diarrhea Rx with loperamide, propantheline, glycopyrrolate, diphenozylate Rx with loperamide, propantheline, glycopyrrolate, diphenozylate Autonomic (muscarinic) ­ bronchial/oral secretions

31. Treatment Cholinesterase Inhibitors Cholinesterase Inhibitors Skeletal Muscle (nicotinic) weakness weakness Bromism (from Mestinon) acute psychosis acute psychosis rash rash measure bromine level measure bromine level Drug Interactions succinylcholine metabolized by acetylcholinesterase impaired metabolism can lead to potential arrythmias succinylcholine metabolized by acetylcholinesterase impaired metabolism can lead to potential arrythmias

32. Corticosteroids Efficacy marked improvement or complete relief in 75% marked improvement or complete relief in 75% some improvement in 25% some improvement in 25% most improvement in 6-8 weeks most improvement in 6-8 weeks may become total remission even later may become total remission even later best response if treated early best response if treated early severity does not predict response severity does not predict response respond better with shorter disease duration and younger <50 respond better with shorter disease duration and younger <50 Initiation - standard begin with 1.5-2.0mg/kg/day begin with 1.5-2.0mg/kg/day given until sustained improvement (2 weeks) then changed to 100-120mg alternate days given until sustained improvement (2 weeks) then changed to 100-120mg alternate days Initiation - alternative begin at 20mg qd begin at 20mg qd increase in 10mg increments q1-2 weeks increase in 10mg increments q1-2 weeks then maintain constant until improvement is maximum then maintain constant until improvement is maximum used in ocular myasthenia used in ocular myasthenia

33. Corticosteroids Taper decrease to lowest dose necessary to maintain improvement by 20mg each month until dose is 60mg by 20mg each month until dose is 60mg by 10mg each month until dose is 20mg by 10mg each month until dose is 20mg by 5mg each 3 months until 10 every other day by 5mg each 3 months until 10 every other day if weakness occurs, increase prednisone or add another immunosuppressant if weakness occurs, increase prednisone or add another immunosuppressant do not d/c altogether do not d/c altogether Initial Worsening 1/3 of patients 1/3 of patients within 1st 7-10 days and lasts 6 days within 1st 7-10 days and lasts 6 days cover with ChE inhibitors cover with ChE inhibitors use initial PLEX and do in hospital if oropharyngeal weakness or respiratory insufficiency use initial PLEX and do in hospital if oropharyngeal weakness or respiratory insufficiency

35. Immunosupressants AzathioprineRegimen start 50mg/d start 50mg/d +50mg/d q7d +50mg/d q7d target 150-200mg/d target 150-200mg/dEfficacy improvement maintained improvement maintained ?synergistic with steroids ?synergistic with steroids may start simultaneous with steroids and taper steroids when azathioprine kicks in may start simultaneous with steroids and taper steroids when azathioprine kicks in effect takes 4-8 months effect takes 4-8 months maximum improvement within 12 months maximum improvement within 12 months 70-90% response rate – similar to steroids 70-90% response rate – similar to steroids

36. Immunosupressants Azathioprine severe allergic reaction (required discontinuation) severe allergic reaction (required discontinuation) 2 weeks after initiation 2 weeks after initiation 15-30% 15-30% flu-like symptoms and rash flu-like symptoms and rash GI irritation (use divided doses after meals or decrease dose) GI irritation (use divided doses after meals or decrease dose) leucopenia (monitor CBC q1wk x1m, q1m x1y, q3-6m after) leucopenia (monitor CBC q1wk x1m, q1m x1y, q3-6m after) Transaminitis Transaminitis stop only if >2x normal and can restart at lower dose once normalize stop only if >2x normal and can restart at lower dose once normalize no proven increase in malignancy in MG patient specifically (unlike in SLE) no proven increase in malignancy in MG patient specifically (unlike in SLE)

37. Immunosupressants CyclosporineRegimen begin at 5-6mg/kd div q12h begin at 5-6mg/kd div q12h trough levels after 1 month (allows tissue saturation) - aim for 75-150ng/ml trough levels after 1 month (allows tissue saturation) - aim for 75-150ng/mlEfficacy improvement in most patients taking CYA improvement in most patients taking CYA improve within 1-2 months improve within 1-2 months maximum improvement at >6months maximum improvement at >6monthsSFX Renal toxicity. Renal toxicity. HTN (monitor q1month until steady state) HTN (monitor q1month until steady state) ++drug interactions ++drug interactions

38. Immunosupressants CyclophosphamideUse severe, refractory MG severe, refractory MGRegimen 200mg/m2 q1month 200mg/m2 q1month titrate to changes in strength and side effects titrate to changes in strength and side effects 150-200mg/d po to total of 5-10g to relieve Sx 150-200mg/d po to total of 5-10g to relieve SxSFX alopecia alopecia cystitis cystitis leucopenia leucopenia NxVx anorexia NxVx anorexia

39. Immunosupressants Mycophenolate Mofetil Mycophenolate MofetilMechanism Selectively inhibits proliferation of B- and T- lymphocyte clones responding to antigenic stimulation Selectively inhibits proliferation of B- and T- lymphocyte clones responding to antigenic stimulation Suppresses formation of antibodies Suppresses formation of antibodiesEvidence Open label pilot study demonstrated role as adjunctive therapy in refractory MG Open label pilot study demonstrated role as adjunctive therapy in refractory MGDosing 2g/d div bid 2g/d div bidEfficacy Improvement as early as 2 weeks and usually seen within 2 months Improvement as early as 2 weeks and usually seen within 2 monthsRole Refractory MG Refractory MG Steroid sparing agent when imuran intolerable or ineffective Steroid sparing agent when imuran intolerable or ineffective Side Effects Diarrhea Diarrhea leukopenia leukopenia

40. Plasma Exchange Roles sudden worsening of myasthenic symptoms for any reason sudden worsening of myasthenic symptoms for any reason rapidly improve strength before surgery rapidly improve strength before surgery concomitantly with high dose steroids concomitantly with high dose steroids chronic intermittent Rx in refractory MG chronic intermittent Rx in refractory MGProtocol 2-3L of plasma 3x per week until improvement plateaus (usually after 5-6 exchanges) Adverse Effects cardiac arrhythmias cardiac arrhythmias Lightheadedness Lightheadedness Chills Chills Obscured vision Obscured vision Pedal edema Pedal edema Hemorrhage (removal of coagulation factors) Hemorrhage (removal of coagulation factors) Hypercoagulation (removal of antithrombin III) Hypercoagulation (removal of antithrombin III) Coagulation defects corrected within24h Coagulation defects corrected within24h

41. IVIG Indications Similar to PLEX Similar to PLEXMechanisms blocks Fc receptors on macrophagesm blocks Fc receptors on macrophagesm anti-idiotype Ab against AChR antibodies anti-idiotype Ab against AChR antibodies Protocol 2g/kg over 2-5 days SFX Headache, fever and chills, alopecia, aseptic meningitis, leucopenia retinal necrosis, renal failure.

42. Treatment

43. Other Types Of Myasthenia Gravies

44. Transitory Neonatal Myasthenia clinical features hypotonic hypotonic onset within hours of birth but can be delayed up to 3 days onset within hours of birth but can be delayed up to 3 days feed poorly in 1st 3 days feed poorly in 1st 3 days can get weak cry and lack of facial expression in 50% can get weak cry and lack of facial expression in 50% 15% have limited EOM and ptosis 15% have limited EOM and ptosis respiratory insufficiency rare respiratory insufficiency rare worsens for first few days then improves worsens for first few days then improves last 2-12 weeks (usually 2 weeks) last 2-12 weeks (usually 2 weeks) neonatal antibodies have half life of 2-3 weeks and not detected after 5 months neonatal antibodies have half life of 2-3 weeks and not detected after 5 months recovery is complete recovery is complete

45. Transitory Neonatal Myasthenia diagnosis tensilon test OR RNS tensilon test OR RNS high AChR in neonate blood high AChR in neonate bloodtreatment ChE for swallowing or breathing - just before feeding ChE for swallowing or breathing - just before feeding neostigmine im before feeding neostigmine im before feeding can also give via NG tube at 10 times parenteral level can also give via NG tube at 10 times parenteral level PLEX if respiratory weakness (rare). PLEX if respiratory weakness (rare).

46. Anti-Musk Myasthenia Epidemiology 25% of all MG patients are seronegative 25% of all MG patients are seronegative 40% of seronegative MG patients are MuSK positive (about 10% overall) 40% of seronegative MG patients are MuSK positive (about 10% overall) M=F M=F Same age of onset as usual myasthenia Same age of onset as usual myasthenia Normal Function of MuSK Tyrosine kinase Tyrosine kinase Regulates and maintains AChR at NMJ Regulates and maintains AChR at NMJ Clinical Features – Differences from Typical Myasthenia More involvement of neck, shoulder, respiratory More involvement of neck, shoulder, respiratory Less limb Less limb More bulbar More bulbar Increased risk of myasthenic crisis in 1st 2 years Increased risk of myasthenic crisis in 1st 2 years Greater proportion in more severe category Greater proportion in more severe category Outcome similar, but require more steroids Outcome similar, but require more steroidsTreatment Treatment generally the same Treatment generally the same Can respond to thymectomy Can respond to thymectomy Less likely to have thymic hyperplasia Less likely to have thymic hyperplasia

47. Genetic Myasthenic Syndromes Congenital Myasthenia Genetics several genetic defects Epidemiology 2:1 male predominance Causes Deficiency of muscle acetylcholine receptors at the end plate Deficiency of muscle acetylcholine receptors at the end plate Some have AChR mutations Some have AChR mutations Some have deficiency of rapsyn (receptor-associated protein at the synapse) Some have deficiency of rapsyn (receptor-associated protein at the synapse) Abnormalities of acetylcholine resynthesis or immoblilization Abnormalities of acetylcholine resynthesis or immoblilization Reduced end plate acetylcholinesterase Reduced end plate acetylcholinesterase Impaired AChR function Impaired AChR function

48. Genetic Myasthenic Syndromes Congenital Myasthenia Clinical Features ophthalmoparesis and ptosis developing in infancy ophthalmoparesis and ptosis developing in infancy incomplete at onset incomplete at onset progresses to complete paralysis during infancy or childhood progresses to complete paralysis during infancy or childhood mild facial paresis mild facial paresis limb weakness mild compared to opthalmoplegia limb weakness mild compared to opthalmoplegia respiratory distress unusual respiratory distress unusual symptoms may not fluctuate much symptoms may not fluctuate much

49. Genetic Myasthenic Syndromes Congenital Myasthenia Diagnosis subcutaneous injection of edrophonium  transitory improvement in ocular motility subcutaneous injection of edrophonium  transitory improvement in ocular motility RNS RNS Decrement found in some limb muscles Decrement found in some limb muscles May be necessary to test proximal or facial muscles if limbs normal May be necessary to test proximal or facial muscles if limbs normal SFEMG SFEMGTreatment ChE inhibitors improve limb weakness in many forms ChE inhibitors improve limb weakness in many forms Ocular muscle weakness less responsive Ocular muscle weakness less responsive Some children respond to DAP Some children respond to DAP

50. Congenital Myasthenic Syndrome with Episodic Apnea (Familial Infantile Myasthenia) Clinical Features Similar problems in other siblings Similar problems in other siblings generalized hypotonic at birth +/- arthrogryposis generalized hypotonic at birth +/- arthrogryposis respiratory insufficiency and feeding difficulty at birth respiratory insufficiency and feeding difficulty at birth repeated episodes of life-threatening apnea and feeding difficulty neonatally repeated episodes of life-threatening apnea and feeding difficulty neonatally may require ventilation may require ventilation usually improves within weeks of birth, allowing weaning from ventilation usually improves within weeks of birth, allowing weaning from ventilation episodes may persist throughout infancy and even into adulthood episodes may persist throughout infancy and even into adulthood sudden bouts of respiratory distress with intercurrent illness sudden bouts of respiratory distress with intercurrent illness ocular function usually normal ocular function usually normal

51. Congenital Myasthenic Syndrome with Episodic Apnea (Familial Infantile Myasthenia) Diagnosis edrophonium test - 0.15mg/kg edrophonium test - 0.15mg/kg decremental RNS decremental RNSTreatment ChE inhibitors improve strength in most children - long term to prevent episodes of apnea at time of intercurrent illness ChE inhibitors improve strength in most children - long term to prevent episodes of apnea at time of intercurrent illness DAP + pyridostigmine works for children from several families DAP + pyridostigmine works for children from several families many require mechanical ventilation many require mechanical ventilation

52. Slow-Channel Congenital Myasthenic Syndrome EpidemiologyRARE Genetics and Molecular Biology AD AD Prolonged open time of Ach channel Prolonged open time of Ach channel Clinical Features Normal at birth Normal at birth Onset always after infancy Onset always after infancy onset may be delayed until adult life onset may be delayed until adult life can present in 20 ’ s can present in 20 ’ s begins with weakness of cervical and scapular muscles begins with weakness of cervical and scapular muscles slowly progressive weakness of arm leg neck facial muscles slowly progressive weakness of arm leg neck facial muscles exercise intolerance exercise intolerance ophthalmoparesis ophthalmoparesis Rare to have ptosis, bulbar dysfunction, leg weakness Rare to have ptosis, bulbar dysfunction, leg weakness atrophy of affected muscles atrophy of affected muscles

53. Slow-Channel Congenital Myasthenic Syndrome Course progresses slowly progresses slowly many patients do not present until after age 10 many patients do not present until after age 10Diagnosis decremental RNS decremental RNS repetitive discharges after nerve stimulation (like ChE inhibitor toxicity) repetitive discharges after nerve stimulation (like ChE inhibitor toxicity) muscle Bx – type I predominance, group atrophy, tubular aggregates, abrnomal end-plate configurations muscle Bx – type I predominance, group atrophy, tubular aggregates, abrnomal end-plate configurations

54. Slow-Channel Congenital Myasthenic Syndrome Treatment not effective not effective ChE inhibitors ChE inhibitors Thymectomy Thymectomy Immunosuppression Immunosuppression May be effective May be effective Quinidine sulfate improves strength Quinidine sulfate improves strength Fluoxetine equally effective Fluoxetine equally effective

55. Fast Channel Myasthenic Syndromes Pathophysiology Ach receptor/channel complex does not let in sufficient sodium Ach receptor/channel complex does not let in sufficient sodium Mechanisms Mechanisms Channel open for too short a time Channel open for too short a time Channel takes long time to open up Channel takes long time to open up Ach does not bind sufficiently long to receptor Ach does not bind sufficiently long to receptor Channel requires too much energy to switch from inactive to active state Channel requires too much energy to switch from inactive to active stateTreatment Responds well to 3,4 DAP and anticholinesterases. Responds well to 3,4 DAP and anticholinesterases. Ephedrine may help Ephedrine may help

56. LEMS Epidemiology Epidemiology usually after 40 ’ s usually after 40 ’ s has been reported in children has been reported in children M=F M=F 50% have underlying malignancy (80% of these SCLC) 50% have underlying malignancy (80% of these SCLC)Immunopathology antibodies to VGCCs antibodies to VGCCs disorganization of motor nerve terminal active zone particles disorganization of motor nerve terminal active zone particles SCLC cells contained high concentrations of VGCCs and SCLC VGCC are inhibited by LEMS sera SCLC cells contained high concentrations of VGCCs and SCLC VGCC are inhibited by LEMS sera Clinical Features Weakness proximal muscles, especially legs proximal muscles, especially legs oropharyngeal and ocular relatively spared (although can be affected) oropharyngeal and ocular relatively spared (although can be affected) objective weakness mild compared to severity of symptoms objective weakness mild compared to severity of symptoms weakness improves briefly after exercise, then returns with sustained activity weakness improves briefly after exercise, then returns with sustained activity absent DTR which are enhanced by repeated muscle contraction or repeated tapping of tendon absent DTR which are enhanced by repeated muscle contraction or repeated tapping of tendon can present as prolonged paralysis following use of neuromuscular blocking agents in surgery can present as prolonged paralysis following use of neuromuscular blocking agents in surgery

57. Clinical Features Autonomic Features dry mouth common dry mouth common impotence impotence postural hypotension postural hypotension Temperature Dependence worse in heat worse in heat avoid hot showers or baths avoid hot showers or bathsDiagnosis edrophonium not as effective as seen in MG edrophonium not as effective as seen in MG EMG/NCs – most sensitive in distal muscles EMG/NCs – most sensitive in distal muscles Neoplastic Workup Neoplastic Workup bronchoscopy bronchoscopy PET scan PET scan LEMS

58. NCS NCS CMAP amplitudes low Repetitive Nerve Stimulation and Exercise Testing >10% decrement in CMAP amplitude on slow repetitive nerve stimulation (3Hz) between 1st and 4th potential >10% decrement in CMAP amplitude on slow repetitive nerve stimulation (3Hz) between 1st and 4th potential >40% (often >100%) increase in distal CMAP amplitude after 10 seconds of maximal voluntary exercise. >40% (often >100%) increase in distal CMAP amplitude after 10 seconds of maximal voluntary exercise. >40% (often>100%) increase in distal CMAP amplitude after high frequency (30-50Hz) repetitive nerve stimulation >40% (often>100%) increase in distal CMAP amplitude after high frequency (30-50Hz) repetitive nerve stimulationEMG generally normal generally normal motor unit action potentials may be unstable; may be short, small, or polyphasic (i.e. myopathic); may have normal or early recruitment motor unit action potentials may be unstable; may be short, small, or polyphasic (i.e. myopathic); may have normal or early recruitmentSFEMG increased jitter and blocking increased jitter and blocking LEMS

59. Treatment ChE Inhibitors may work in occasional patients may work in occasional patients pyridostigmine 30-60mg q6h x several days pyridostigmine 30-60mg q6h x several days major benefit is relief of dry mouth major benefit is relief of dry mouth Guanidine Hydrochloride increases release of Ach increases release of Ach add on agent to mestinon add on agent to mestinon temporary improvement in strength in many patients with LEMS temporary improvement in strength in many patients with LEMS start 5-10mg/kg/d div 4-6h apart start 5-10mg/kg/d div 4-6h apart increase to maximum of 30mg/kg/d q3d increase to maximum of 30mg/kg/d q3dSFX BM suppression,RTA,Chronic interstitial nephritis,Cardiac arrhythmia,Hepatic toxicity,Pancreatic dysfunction,Paresthesiae,Ataxia.Confusion,Mood changes LEMS

60. TreatmentDAP 5-25mg tid-qid 5-25mg tid-qid facilitates release of Ach from motor nerve terminals facilitates release of Ach from motor nerve terminals synergistic with pyridostigmine synergistic with pyridostigmine PLEX and IVIG can provide transitory improvement can provide transitory improvement ( Immunosupression,prednisone,azathioprine,cyclosporine) not as good as in MG not as good as in MG Severe Weakness PLEX/IVIG 1st PLEX/IVIG 1st Prednisone and imuran added after improvement begins Prednisone and imuran added after improvement beginsPrognosisvariable LEMS

61. Botulism Pathophysiology Pathophysiology botulinum toxin block release of Ach from motor nerve terminal botulinum toxin block release of Ach from motor nerve terminal 8 types of toxin 8 types of toxin types A and B cause most occurrences of botulism in US types A and B cause most occurrences of botulism in US type E transmitted in seafood type E transmitted in seafood Clinical Features Course Course NxVx 1st Sx of food-borne botulism NxVx 1st Sx of food-borne botulism Neuromuscular Sx begin 12-36h after exposure Neuromuscular Sx begin 12-36h after exposure Ocular : blurred vision and impaired pupillary reflexes Ocular : blurred vision and impaired pupillary reflexes Motor : weakness and decreased DTRs Motor : weakness and decreased DTRs Autonomic : dry mouth,constipation,urinary retention Autonomic : dry mouth,constipation,urinary retention

62. Botulism Diagnosis Diagnosis Tensilon Test positive in 1/3 of patients positive in 1/3 of patients do not distinguish botulism from other causes do not distinguish botulism from other causesMicrobiological Botulinium toxin in stool Botulinium toxin in stool C. Botulinium culture from stool C. Botulinium culture from stool Wound cultures and serum for Botulinium toxin Wound cultures and serum for Botulinium toxinEMG/NCS 1. reduced CMAP in at least 2 muscles 2. at least 20% facilitation of CMAP amplitude during titanic stimulation 3. persistence of facilitation at least 2 minutes after activation 4. no postactivation exhaustion SFEMG Jitter and blocking Jitter and blocking Sensitivity 100%,Poor specificity Sensitivity 100%,Poor specificity

63. Botulism Treatment bivalent (type A, B) or trivalent (A, B, E) antitoxin bivalent (type A, B) or trivalent (A, B, E) antitoxin antibiotics NOT effective antibiotics NOT effective supportive therapy supportive therapy ChE inhibitors NOT beneficial ChE inhibitors NOT beneficial DAP improves strength but not respiratory function DAP improves strength but not respiratory functionPrognosis Most patients make complete recovery within 2-3 months Most patients make complete recovery within 2-3 months If sever einvolvement, may not return to normal for a year If sever einvolvement, may not return to normal for a year

64. Venoms Clinical Features progressive, symmetrical muscle weakness progressive, symmetrical muscle weakness oculomotor/eyelids most often oculomotor/eyelids most often neck flexion, and pelvic and pectoral girdles next neck flexion, and pelvic and pectoral girdles next bulbar or respiratory if severe bulbar or respiratory if severe cognition and sensation preserved cognition and sensation preserved DTR preserved, or minimally diminished DTR preserved, or minimally diminishedMechanisms initial augmentation of Ach release with subsequent depletion initial augmentation of Ach release with subsequent depletion facilitation of Ach release without subsequent depletion of neurotransmitter facilitation of Ach release without subsequent depletion of neurotransmitter depletion of Ach release depletion of Ach release blockade of post junctional Ach receptor blockade of post junctional Ach receptor Specific Venoms Funnel Web and Black Widow Spiders (latrodectism) facilitation of neurotransmitter release by depolarization of presynaptic terminal

65. Venoms Tick Paralysis Microbiology dermacentor andersoni,dermacentor variabilis dermacentor andersoni,dermacentor variabilis Clincial Features Clincial Features usually children <5yo usually children <5yo similar to GBS similar to GBS ocular motor palsies and papillary abnormalities <GBS ocular motor palsies and papillary abnormalities <GBSMechanism postsynaptic blockade of neurotoxin Diagnosis CSF protein normal CSF protein normal NCS normal or mild slowing of NCV NCS normal or mild slowing of NCV decreased CMAP decreased CMAP high frequency RNS may be normal or abnormal incremental response high frequency RNS may be normal or abnormal incremental responseTreatment remove tick usually lead to rapid recovery remove tick usually lead to rapid recovery Australian variant may have continued worsening for another 1-2 days Australian variant may have continued worsening for another 1-2 days

66. Other Neurotoxins Affecting The NMJ Marine neurotoxins Marine neurotoxins are rare and come primarily from poisonous fish (stonustoxin), a few mollusks (conotoxins), and dinoflagellates. Heavy metal intoxication Heavy metal intoxication is a rare cause of neuromuscular toxicity. is a rare cause of neuromuscular toxicity. Ingestion of contaminated grain used for flour in bread. Ingestion of contaminated grain used for flour in bread. produced weakness with characteristic decremental responses produced weakness with characteristic decremental responses partial reversal with ChE inhibitors. partial reversal with ChE inhibitors. Organophosphates Organophosphates impair neuromuscular transmission by irreversibly inhibiting acetylcholinesterase. impair neuromuscular transmission by irreversibly inhibiting acetylcholinesterase. producing a depolarizing neuromuscular block. producing a depolarizing neuromuscular block.

67. Neuromuscular Junction Disorders