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Disorders of the neuromuscular junction

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Disorders of the neuromuscular junction include Myasthenia gravis, Lambert-Eaton myasthenic syndrome, Botulism, Tetanus, Strychnine intoxication, Organophosphates poisoning and neuromyotonia. Pharmacology of the NMJ is also reviewed in brief.

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Disorders of the neuromuscular junction

  1. 1. Disorders of the Neuromuscular Junction Daniel Vela-Duarte, MD Department of Neurology Loyola University Medical Center October 2013
  2. 2. Differential diagnosis of flaccid paralysis Anterior horn disease Disorders of the NMJ  Polyemyelitis  Amyotrophic lateral sclerosis  Myasthenia gravis  Lambert-Eaton disease (Myasthenic syndrome)  Botulism  Snake, scorpion, spider bites Peripheral neuropathy Disorders of muscle  Guillain-Barre syndrome  Diphteric neuropathy  Heavy metals, biologic toxins, drug intoxication  Acute intermittent porphyria  Vasculitic neuropathy  Critical illness neuropathy  Lymphomatous neuropathy        Hypokalemia Hypophosphatemia Inflammatory myopathy Critical illness myopathy Acute Rhabdomyolisis Acid maltase deficency Periodic paralysis Acute myelopathy (Spinal shock phase)  Space-occupying lesions or Acute transverse myelitis
  3. 3. Mechanisms of disease.  Binding and Activation of Complement • • • Antibody binds to AChR activating complement cascade Leads to the formation of a Membrane Attack Complex (MAC) Triggers localized destruction of post-synaptic NMJ – Destroying muscle morphology
  4. 4. Mechanisms of disease. cont’d  Antigenic Modulation (accelerated degradation of AChR)  Antibody can crosslink two antigenic molecules  Leads to accelerated endocytosis and degradation  Leads to reduction of AChR at the NMJ
  5. 5. Mechanisms of disease. cont’d  Functional AChR Block  Ab binding to ACh binding sites  Block AChR binding site  Cause failure of neuromuscular transmission
  6. 6. Myasthenia Gravis. Epidemiology  Myasthenia gravis is one of the most frequent, autoimmune diseases of the neuromuscular junction (NMJ)  Frequent in young woman  (<40 years old) and old men (> 65 years old).  15% of patients experience a myasthenic crisis during the course of disease. The vast majority of patients with generalized MG (~85%) and pure ocular MG (~50%) will have antibodies to the skeletal nicotinic acetylcholine receptor (AChR)   8-10% of patients with generalized form will have Ab’s to musclespecific tyrosine kinase receptor (MuSK)
  7. 7.  Take-home points on: “natural course of the disease”   Generalized myasthenia gravis will develop in more than 50% of patients who present with ocular MG, typically within 2 years. Prednisone  40-60 mg/daily, followed with the dosage tapered for 5-6 weeks  Daily or alternate-day doses of 2.5 to 10mg to prevent diplopia  Tensilon Test  Mean dose of edrophonium (Tensilon) was 3.3mg for ptosis and 2.6mg for ocular motor dysfunction. Therefore, the test should be administered using increments of 1 -2mg.  Generalized MG developed within 2 years in 4/58 treated (7%) and 13/36 untreated (36%) pts
  8. 8. Symptoms. Generalized presentation
  9. 9. Myasthenia Gravis. Five new things… Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.  Plasmapheresis vs IVIg  No difference in between both, fewer adverse events with IVIg (Neurology 2011;76:2017-2023)  Both treatments are equally effective for myasthenic crisis, but PLEX seems superior for crisis requiring ventilatory support.  Higher frequency of extubation with PLEX ?  0.4g/kg for 3-5 days or 1g/kg for 2 days
  10. 10. Myasthenia Gravis. Five new things (2) Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.  MuSK phenotype  Role in AChR clustering at the postsynaptic neuromuscular junction  It makes up ~40% of AChR-negative MG pts  Female predominance: 78% - 100 women  The majority of case series report poor response to cholinesterase inhibitors  Poor response to thymectomy
  11. 11. Myasthenia Gravis. Five new things (3) Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.  New (and old treatment strategies)  Thymectomy Not indicated for ocular myasthenia  Role of thymectomy for non-thymomatous myasthenia gravis. (Ongoing trial - Aug 2015)   Rituximab Indicated for refractory myasthenic pt  Dramatic response in MuSK patients  B-cell depletion. Population levels monitoring 
  12. 12. Myasthenia Gravis. Five new things (4) Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.  Myasthenia gravis and pregnancy  1/3 of women will experience exacerbations of symptoms during 1st trimester and puerperium  Treatment should be individualized Mild disease: Pyridostigmine <600mg/day are safe for the fetus  Corticosteroid poses little, if any teratogenic risk. They CAN be continued.  Azathioprine, IVIg, PLEX are safe  Avoid Mycophenolate. 
  13. 13. Myasthenia Gravis. Five new things (5) Statland JM, Ciafaloni E., Neurol Clin Pract. 2013 Apr;3(2):126-133.  New antibody testing  10% of patients remain Ab negative  Lrp4: low density lipoprotein receptor-related protein 4. (Described in 2011) Arch Neurol. 2012 Apr;69(4):445-51  The protein is required for agrin-induced activation of MuSK.  thought to induce clustering of synaptic-vesicle related proteins in the NJM.  3-50% of seronegative patients were found to be Ab positive to Lrp4
  14. 14. Thymomatous myasthenia gravis
  15. 15. Treatment modalities. Modulation of Neuromuscular Transmission Cholinesterase Inhibitors (e.g., Pyridostigmine, Neostigmine, Ambenonium) Binding to Acetylcholinesterase (AChE) to inhibit the degradation of acetylcholine General Immunosuppression Azathioprine Acts through purine synthesis inhibition thus inhibiting T and B lymphocyte division. Cyclosporine Inhibits protein phosphatase (calcineurin) role in activating T cells of the immune system. Mycophenolate Mofetil (CellCept) Inhibits de novo purine synthesis in lymphocytes Tacrolimus Lowers AChR antibody for patients who have undergone thymectomy and were using steroid and receiving cyclosporine Cyclophosphamide High doses help repopulate the immune system with new lymphocytes by removing old ones from the bone marrow. Methotrexate Inhibits the metabolism of folic acid which leads to T cell destruction and production.
  16. 16. Lambert-Eaton myasthenic syndrome Epidemiology  10 fold less common than myasthenia gravis   60% of cases associated with small cell lung CA Syndrome may precede radiologic diagnosis of tumor by several years
  17. 17. Lambert-Eaton Sx. Diagnosis  Clinical Features:  Proximal > Distal limb weakness  Initial presentation with difficulties to walk. (proximal limb weakness)  Occular, Bulbar, and Respiratory weakness is uncommon  Autonomic symptoms such as dry mouth, constipation, impotence, and bladder urgency (Lack of Ach)
  18. 18. Lambert-Eaton Sx. Treatment   3,4 diaminopyridine (3,4-DAP) Blocks presynaptic potassium channels, thereby increasing the opening time of the available Voltagegated Calcium channesls  The blocking of K+ channels prolongs the depolarisation during nerve action potentials, thereby increasing the open-time of voltage-gated Ca2+ channels and consequently the influx of Ca2+ into the nerve terminal. This increased Ca2+ influx enhances the quantal neurotransmitter release which is Ca2+ dependant.  Mestinon (Pyridostigmine)  Effective treatment of cancer
  19. 19. Lambert-Eaton myasthenic syndrome
  20. 20. Neuromyotonia  Acquired or paraneoplastic syndrome  SCLC or Thymoma involving antibodies to VGKC (voltage gated K+ Channel) at presynaptic membrane  Inhibition of VGKC prolongs depolarization, thereby increasing AcH release  Increased AcH hyperexcites postsynaptic membrane, resulting in twitching or myokymia
  21. 21.  Where is the site of action of the following toxins in the neuromuscular junction?  Botulism,  Tetanus,  Organophosphorates,  Strychnine
  22. 22. Botulism. Mechanism of disease JAMA. 2001 Feb 28;285(8):1059-70.
  23. 23. Botulism. Mechanism of disease JAMA. 2001 Feb 28;285(8):1059-70.
  24. 24. Tetanus. Mechanism of disease 1. 2. 3. 4. Peripheral nerve terminal binding Endocytosis of toxin Retograde axonal transport Release of the toxin into the presynaptic space 5. Binding to the membrane of the inhibitory interneuron. 6. Endocytosis Translocation of toxin into cytosol Inhibtion of the VAMP complex (Essential for synaptic vessicle fusion) 7. 8.
  25. 25. Tetanus. Mechanism of disease  Clostridium tetani  Tetanospasmin  Sustained muscular rigidity and, in severe cases, reflex spasms.   Early manifestations of generalized tetanus are rigidity of the masseter muscles (lockjaw) and facial muscles, with straightening of the upper lip or risus sardonicus. Autonomic instability, mostly hypersympathetic state, may occur in severe cases. "The contracted" Opisthotonus, By Sir Charles Bell (1809) Contracted body of a soldier suffering from tetanus.
  26. 26. Strychnine (Nonanticoagulant Rodenticide) Mechanism • Antagonizes glycine, an inhibitory neurotransmitter released by postsynaptic inhibitory neurons in the spinal cord. • Binds to the chloride ion channel (Inhibitory synapse) causing increased neuronal excitability and exaggerated reflex arcs. Clinical features • • Muscular stiffness and painful cramps precede generalized muscle contractions Extensor muscle spasms, and opisthotonus. • Muscle contractions are intermittent and easily triggered by emotional, auditory, or minimal physical stimuli. Repeated and prolonged muscle contractions often result in hypoxia, hypoventilation, hyperthermia, rhabdomyolysis, myoglobinuria, and renal failure. • . •
  27. 27.  What are the diagnostic criteria of critical illness myopathy? Major diagnostic features 1. Sensory nerve amplitudes >80 % of the lower limit of normal in 2 or more nerves 2. Needle EMG with short-duration, low-amplitude MUPs with early or normal full recruitment, with or without fibrillation potentials 3. Absence of a decremental response on repetitive nerve stimulation 4. Muscle histopathologic findings of myopathy with myosin loss Supportive features 1. Motor amplitudes <80 % lower limit of normal in 2 or more nerves without conduction block 2. Elevated serum CK (best assessed in the first week of illness) 3. Demonstration of muscle inexcitability
  28. 28.  What are the characteristics of the episodes seen in familial hypokalemic periodic paralysis?