The$Neuromuscular$Junc0on:$ … · · 2018-04-04– Ocular$vs.$Generalized$ ... Myasthenic$Crisis$ • Treatment ... – Signs$of$cholinergic$dysautonomia

The Neuromuscular Junc0on: Neurophysiology and Common

Disorders Nicholas J. Silvestri, M.D.

Assistant Professor of Neurology

Neuromuscular Transmission

•  Presynap0c events •  Events in the synap0c cleC •  Post-‐synap0c events

Presynap0c Events

•  Synthesis and degrada0on of ACh

Choline Acetyltransferase

Acetyl CoA + Choline à Acetylcholine

Presynap0c Events

•  ACh packaged into vesicles in discrete units called quanta – Each quantum contains ~ 10,000 molecules of Ach

•  Quanta are located in 3 separate stores –  Primary store: ~1000 quanta available for immediate release

–  Secondary store: ~10,000 quanta that can resupply primary store aCer several seconds

–  Ter0ary store: ~100,000 quanta distant from NMJ

Presynap0c Events

•  Presynap0c nerve terminal lined with ac0ve zones which are specific sites on membrane where vesicles aQach and release ACh into synap0c cleC

Pre-‐Synap0c Events

•  AP invades and depolarizes nerve terminal

•  Voltage gated Ca++ channels open, allowing influx of Ca++

•  Ca-‐dependent binding of vesicles to terminal membrane occurs –  Rela0vely slow, lasts 0.5msec (of total 0.75msec for NMJ

transmission)

•  Near-‐synchronous release of up to 200 quanta –  Number of quanta released propor0onal to concentra0on of Ca

++

Synap0c Events

•  Synap&c cle+ – Space between nerve terminal and depression in the postsynap0c membrane into which the terminal fits

– Site of hydrolysis of ACh by acetylcholinesterase (AChE)

Post-‐synap0c Events

•  Post-‐synap&c membrane –  Region of muscle fiber membrane across from the nerve

terminal, a.k.a. endplate •  1 endplate per fiber, number increases with reinnerva0on

–  Contains mul0ple infoldings called secondary cleCs •  Nico0nic ACh receptors concentrated on crests of folds •  AChE concentrated in depths of cleCs

–  ACh receptor is a transmembrane glycoprotein which binds 2 ACh molecules, opening a central channel in the receptor for a few msec, allowing Na+ to enter down its electrochemical gradient

NMJ Ultrastructure

Nico0nic ACh Receptor


•  ACh diffuses across synap0c cleC and binds to ACh receptors, genera0ng an end plate poten0al (EPP)

•  If the EPP > threshold for genera0ng an AP, all-‐or-‐none depolariza0on of the muscle membrane occurs –  Threshold around 40-‐60 mV


•  Propogated AP pentrates T tubule system, triggering muscle fiber contrac0on

•  EPP terminated via hydrolysis of ACh by AChE within a few msec

Disorders of the NMJ

•  Myasthenia gravis •  Congenital Myasthenic Syndromes

•  Lambert-‐Eaton Myasthenic Syndrome

•  Botulism

•  Miscellaneous disorders of the neuromuscular junc0on

Myasthenia Gravis

n Incidence: 1-‐9 per million q F>M (7:3 in young age group, 1:1 in older)

q F peak at ages 20-‐24 and 70-‐74 years q M peak at ages 30-‐34 and 70-‐74 years

n Prevalence: 25-‐142 per million

n 10% cases present in childhood (juvenile myasthenia)

MG

•  Pathophysiology –  In 85% pa0ents with generalized MG and 50% pa0ents with ocular MG, an0bodies directed against ACh receptors •  Binding an0bodies-‐ most common •  Blocking an0bodies •  Modula0ng an0bodies

– MuSK an0bodies – Other an0bodies

MG

•  Pathophysiology –  In the case of an0bodies to ACh receptors, damage to the NMJ occurs from: •  Accelerated degrada0on of ACh receptors •  Blocking ac0ve sites on ACh receptors •  Damaging ACh receptors with the aid of complement

MG

•  Thymic pathology – 40-‐70% of pa0ents with autoimmune MG have evidence of thymic hyperplasia

– 10-‐15% of pa0ents with autoimmune MG have underlying thymoma

MG

•  Presen0ng Symptoms – Ocular: Ptosis, diplopia – Bulbar: Dysphagia, dysarthria, dysphonia, jaw fa0gue

– Respiratory: Dyspnea, orthopnea – Generalized: Neck, limb weakness – Dis0nc0ve feature is fluctua0ng nature of symptoms, producing a dynamic rather than sta0c disorder

MG

•  In the vast majority of pa0ents (90%), ocular symptoms are first manifesta0on

•  Generaliza0on ul0mately occurs in two-‐thirds of pa0ents with OMG, the majority within 2 years

•  In most pa0ents, the severity of disease lessens with 0me and remissions are possible

MG

•  Exam –  Ocular signs

•  Ptosis, diplopia on tes0ng of EOM, weakness of eye closure, over-‐contrac0on of frontalis

–  Bulbar signs •  Jaw weakness, facial diplegia, palatal weakness, tongue weakness

–  Respiratory signs •  Respiratory rate, use of accessory muscles, ease of speech

–  Neck strength –  Limb strength

•  Examine for fa0gability

MG

•  Diagnos0c Work-‐up –  An0body tes0ng

•  ACh receptor an0bodies in 85% GMG, 50% OMG •  MuSK an0bodies in roughly 10% GMG, rare OMG

–  Thyroid func0on studies –  EMG and Nerve Conduc0on Studies –  Evalua0on for thymic pathology

•  CT or MRI of the chest –  Edrophonium (Tensilon) test –  Ice pack test

MG 3 Hz Repetitive Nerve Stimulation

Single Fiber EMG

MG

•  Treatment – Ocular vs. Generalized – Acetylcholinesterase inhibitors – Prednisone – Steroid-‐sparing agents –  IVIg – Plasmapheresis

MG

•  Treatment of Ocular MG –  Ini0ally, pyridos0gmine

–  If symptoms refractory to pyridos0gmine and impac0ng quality of life, prednisone

MG

•  An0-‐acetylcholinesterase medica0ons –  Most commonly used is pyridos0gmine (Mes0non)

–  Transiently inhibits AChE from metabolizing ACh

–  Ini0ated at dose of 30-‐60mg q6h

–  Gradually 0trated to effect, most adults requiring 60-‐120mg q4-‐6h

–  Doses exceeding 600mg/day typically ineffec0ve and produce side effects

MG

•  Side effects of an0-‐acetylcholinesterase medica0ons – Nausea, vomi0ng – Abdominal cramping – Diarrhea – Sialorrhea – Bradycardia – Encephalopathy (rare) – Cholinergic crisis (rare)

MG

•  Treatment of Generalized MG –  Ini0al treatment with pyridos0gmine and prednisone

–  Subsequent treatment with steroid sparing agent •  Azathioprine •  Cyclosporine •  Mycophenolate mofe0l •  Tacrolimus •  IVIg

–  Thymectomy if thymoma present or in young pa0ents with thymic hyperplasia

Myasthenic Crisis

•  Strictly defined as respiratory failure due to myasthenia gravis, though impending respiratory failure also qualifies

•  Causes: infec0on, illness, surgery, trauma, stress, medica0ons

•  More commonly occur within 3 years of ini0al diagnosis of MG

•  Diagnosis –  Largely based on history and exam –  Assessment of pulmonary func0on (spirometry)

Myasthenic Crisis

•  Treatment – Protec0on of airway

•  Endotracheal intuba0on and ven0la0on versus non-‐invasive posi0ve pressure ven0la0on

•  Signs of impending respiratory failure: –  Rapid progression of weakness –  Neck flexor weakness –  Inability to converse in complete sentences –  Use of accessory muscles –  Tachypnea –  Spirometry: NIF < -‐30cc, FVC < 15cc/kg or declining trend in these parameters

Myasthenic Crisis

•  Treatment – Directed treatment toward inci0ng event if iden0fiable (e.g. infec0on)

– Prudent to hold an0-‐acetylcholinesterase drugs – Plasmapheresis

Medica0ons that can worsen MG •  Anesthe0cs: Chloroprocaine, Diazepam, Ether, Halothane, Ketamine, Lidocaine •  Neuromuscular blocking agents: Propanidid, Procaine, Botox, Magnesium •  An0bio0cs: Aminoglycosides, Amikacin, Gentamicin, Kanamycin, Neomycin,

Ne0lmicin, Paromomycin, Spec0nomycin, Streptomycin, Tobramycin, Fluoroquinolones, Ampicillin, Clarithromycin, Clindamycin, Colis0n, Erythromycin, Lincomycin, Quinine, Telithromycin, Tetracyclines

•  An0convulsants: Gabapen0n, Phenytoin, Trimethadione •  An0psycho0cs: Chlorpromazine, Lithium ,Phenothiazines •  An0rheuma0c drugs: Chloroquine, Penicillamine •  Cardiovascular drugs: Beta blockers, Bretylium, Procainamide, Propafenone,

Quinidine, calcium channel blockers •  Glucocor&coids •  Ophthalmologic drugs: Betaxolol, Echothiophate, Timolol, Tropicamide,

Proparacaine •  Other drugs: An0cholinergics, Carni0ne, Cholinesterase inhibitors, Deferoxamine,

Diure0cs, Eme0ne (Ipecac syrup), Interferon alpha, Iodinated contrast agents Oxytocin, An0retroviral protease inhibitors, Sta0ns,Thyroxine

•  Narco0cs •  Oral contracep0ves

Congenital Myasthenic Syndromes

•  Presynap0c disorders –  Choline acetyltransferase deficiency –  Paucity of synap0c vesicles

•  Synap0c disorders –  End plate AChE deficiency

•  Postsynap0c disorders –  Primary kine0c defect +/-‐ AChR

deficiency –  Primary AChR deficiency +/-‐ kine0c

defect –  Rapsyn deficiency –  Sodium channel myasthenia –  Plec0n deficiency –  Dok-‐7 myasthenia

Lambert-‐Eaton Myasthenic Syndrome

•  Rare •  Presenta0on

– Pa0ents typically complain of weakness and easy fa0gability, predominantly of proximal lower extremi0es

– Oculobulbar symptoms less common than in MG – Cholinergic dysautonomia

LEMS

•  Exam – Signs of cholinergic dysautonomia

– Proximal muscle weakness, improved with repe00ve tes0ng (facilita0on)

– Hyporeflexia, improved with facilita0on

LEMS

•  Pathophysiology – An0bodies directed against P/Q voltage-‐gated calcium channels on presynap0c membrane at both NMJ and preganglionic parasympatheic nerve terminals

LEMS

•  Roughly two-‐thirds of cases associated with underlying malignancy – Most common underlying malignancy is SCLC (90%, others include lymphoprolifera0ve disorders, breast, ovarian, and pancrea0c ca)

•  Diagnosis typically precedes that of malignancy by ~10 months

LEMS

•  Diagnos0c work-‐up – An0body tes0ng

•  85-‐90% of pts have an0-‐P/Q voltage-‐gated Ca channel an0bodies (both paraneoplas0c and non-‐paraneoplas0c)

•  ~10% of pts also have an0-‐ACh R an0bodies – Electrodiagnos0c studies – Evalua0on for malignancy

•  CT torso

LEMS

50 Hz RNS

Pre- and post-tetanic stimulation (10 seconds of maximal voluntary contraction)

LEMS

•  Treatment – Of malignancy-‐ pa0ents may improve

– An0-‐acetylcholinesterase drugs may produce a modest effect (variable)

– 3,4 diaminopyridine – ?Immunosuppression (steroids, IVIg, plasmapheresis)

Botulism

•  Caused by toxin of Clostridium botulinum – Gram posi0ve, rod-‐shaped, obligate anaerobe – A, B, E strains of toxin most common

•  Can be acquired via several routes: – Wound – Food borne –  Infan0le – Hidden (suspected gastrointes0nal) –  Inhala0onal

Botulism

•  Pathophysiology – Neurotoxins produced by C. botulinum degrade proteins necessary for docking and fusion of ACh vesicles to the synap0c membrane, thereby preven0ng release into the synap0c cleC

Botulism

•  Presenta0on – Neurologic: Dysphagia, xerostomia, diplopia, dysarthria begin acutely and progress over 12-‐36 hours with rostral to caudal progression of weakness eventually involving limbs and/or respiratory muscles

– Gastrointes0nal: Nausea, vomi0ng, diarrhea followed by cons0pa0on, abdominal cramps

– Anxiety

Botulism

•  Exam – Ptosis, ophthalmoplegia, facial diplegia, palatal and tongue weakness

– Limb weakness and hypo-‐ to areflexia

– Evalua0on of respiratory func0on – Signs of dysautonomia: e.g. poorly reac0ve pupillary light response, bradycardia

Botulism

•  Differen0al Diagnosis – Myasthenia gravis

– Guillain-‐Barre syndrome – Tick paralysis – Poliomyeli0s

– LEMS – Heavy metal intoxica0on – Brainstem stroke

Botulism

•  Diagnos0c work-‐up – Toxin

•  Serum in foodborne •  Stool in infan0le • Wound scrapings in wound

– EMG/NCS

Botulism

•  Treatment – Suppor0ve care

•  Respiratory monitoring, intuba0on as necessary •  Gastrointes0nal symptoms

– An0-‐toxin •  Equine serum trivalent botulism an0toxin (A, B, E) is available in the United States through State Health Departments or the CDC

•  Early treatment – An0bio0cs

•  Unproven but oCen given for wound botulism

Botulism

•  Most pa0ents require hospitaliza0on for 1 to 3 months for suppor0ve care

•  Mortality rate ~5%

Other Causes of Neuromuscular Junc0on Dysfunc0on

•  Drug-‐induced MG (penicillamine, amiodarone) •  Aminoglycoside an0boi0cs

•  Hypermagnesemia •  Envenoma0ons (various snakes, scorpions, spiders,

cobras, kraits) •  Certain forms of 0ck paralysis •  Agents designed for chemical warfare

•  Prolonged neuromuscular blockade (curare-‐like agents in the cri0cally ill)

Ques0ons?

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The$Neuromuscular$Junc0on:$ … · · 2018-04-04– Ocular$vs.$Generalized$ ... Myasthenic$Crisis$ • Treatment ... – Signs$of$cholinergic$dysautonomia