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Neuromuscular junction
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Neuromuscular junction

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    Neuromuscular junction Neuromuscular junction Presentation Transcript

    • Neuromuscular Junction Chris Robinson, DO Department of Neurology Loyola University Medical Center 2012.
    • Brief Review
    • THE MOTOR UNIT• A single motor unit contains 1 motor neuron and all the muscle fibers it innervates• Cell bodies of motor neurons located in brainstem and spinal cord• Axons of neurons are myelinated to propagate action potential at high velocity• When an action potential is produced, all muscle fibers contract simultaneously
    • THE MOTOR UNIT
    • Review• Cortical input descends through white matter tracts to synapse in the ventral gray matter.• Efferent’s from the ventral horn exit via ventral rami and exit through peripheral nerves.• Peripheral nerve travels to muscle terminus, where myelin sheath ends and axons divide into terminal boutons localized to specific muscle sites
    • Review• Distribution of lower motor neurons in the ventral horn – Motor neurons controlling flexors lie dorsal to extensors – Motor neurons controlling axial muscles lie medial to those controlling distal muscles
    • Review• Two Types of Muscle Fiber – Extrafusal fibers: Innervated by alpha motor neurons – Intrafusal fibers: Innervated by gamma motor neurons
    • Review• Gamma Loop• Golgi Tendon Organ – Regulate muscle tension and proprioception
    • Neuromuscular Junction
    • Terminal Axon (Presynaptic Cleft)• Consists of numerous vesicles contain AcH, as well as voltage gated Ca2+ channels – When an action potential spreads over the terminal, these channels open and calcium ions diffuse to the interior of the nerve terminal. – The calcium ions, exert an attractive influence on the acetylcholine vesicles, drawing them to the neural membrane adjacent to the dense bars. – The vesicles then fuse with the neural membrane and empty their acetylcholine into the synaptic space
    • Synaptic Cleft• Within the synaptic cleft lies AcH, AcHe, Nicotinic Ach Receptor, and Voltage Gated Na+ Channel• AcH binds to ligand gated (nicotinic) receptor, stimulating Na+ influx• Na+ influx from ligand gated ion channel generates end plate potential (EPP)• Following equilibrium potential of AcH receptors, AcHe binds and hyrolyzes AcH
    • Post-Synaptic Receptors1. AcH Receptor a. Contains 5 subunits (most importantly 2 alpha subunits) b. 1 AcH molecule must bind to both alpha subunits to activate c. Allows for influx of Na+ to depolarize2. MUSK Receptor a. Receptor tyrosine kinase, needed specifically for NMJ formation b. Allows for recruitment of AcH receptors to post-synaptic membrane3. Voltage Gated Na+ Channel a. Propogates endplate potential throughout sarcolemma
    • Neuromuscular Junction Disroders
    • Disorders of the Motor Unit• Motor neuron disease• Peripheral nerve disorders• Neuromuscular junction disease• Muscle disease
    • NMJ Disorders• Myasthenia Gravis• Lambert-Eaton Syndrome• Neuromyotonia• Botulinum Toxin
    • Myasthenia Gravis• A autoimmune neuromuscular disorder that leads to a breakdown in communication between neural input and muscle contraction• Can be paraneoplastic from malignant thymoma (sero-positive AcH Ab)• Involves antibodies (Ab) against nicotinic acetylcholine receptors (nAChR) and Muscle- specific Tyrosine Kinase (MuSK)• Leads to muscle weakness and fatigability, generally non-fatal
    • Myasthenia Gravis• Epidemiology: – Disease of young woman ( <40 y/o) and old men (> 65 y/o). – Often associated w/ other autoimmune disorders – More likely to occur with: a. Family history b. Coexisting thyroid disease
    • Myasthenia Gravis• Signs and Symptoms:• Muscle fatigue that worsens with activity and improves with rest• Ptosis• Difficulty speaking (dysarthia)• Trouble with making facial expression and swallowing (dysphagia)• Other muscles can be affected: – Myasthenic crisis occurs if there is paralysis of respiratory muscles • Ventilation
    • Myasthenia Gravis• Mechanisms1) Binding and Activation of Complement • Ab 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
    • Myasthenia Gravis• Mechanisms• 2) Antigenic Modulation (accelerated degradation of AChR) – Ab can crosslink two antigenic molecules – Leads to accelerated endocytosis and degradation – Leads to reduction of AChR at the NMJ
    • Myasthenia Gravis• Mechanisms• 3) Functional AChR Block – Ab binding to ACh binding sites – Block AChR binding site – Cause failure of neuromuscular transmission
    • Myasthenia Gravis• Diagnostic Tests:• 1) Clinical Tests – Edrophonium (diagnostic drug) – Ice-pack test (cooling decreases activity of acetylcholinesterase) – Have patient do sustained task (e.g. look up)• 2) Assays of Serum Ab (blood tests) – Anti-AChR – 85% MG patients – Anti-MuSK – detectable in 30-40% patients with Anti-AChR-negative MG• 3) Electrodiagnostic Tests – Electromyography (EMG) – Repetitive stimulation of peripheral nerves – Single fiber EMG – very sensitive
    • Myasthenia GravisTx Modalities:Modulation of Neuromuscular TransmissionCholinesterase Inhibitors (e.g., Pyridostigmine, Binding to Acetylcholinesterase (AChE) to inhibitNeostigmine, Ambenonium) the degradation of acetylcholineGeneral ImmunosuppressionAzathioprine 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 lymphocytesTacrolimus Lowers AChR antibody for patients who have undergone thymectomy and were using steroid and receiving cyclosporineCyclophosphamide 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.
    • Myasthenia Gravis• Tx Modalities Cont.RAPIDLY-ACTINGIMMUNOTHERAPIESThymectomy Surgery to remove thymus gland (site of T cells maturation)Plasmapheresis Removal of antibody and replacement of antibody-free plasmaIntravenous Immunoglobulin (IVIg) A concentrated solution of immunoglobulins composed primarily of IgG of different donors. The mechanism is numerous and includes cytokine inhibition and competition with autoantibodies.
    • Lambert-Eaton Myasthenic Sx (LEMS)• Paraneoplastic Sx associated w/ Ab to Voltage Gated Ca2+ presynaptic motor terminals, autonomic terminals, and cerebellar purkinje cells• Leads to reduction of Ca2+ influx, thus insufficient AcH is released to initiate an end plate potential• Repeated impulses increase Ca2+ influx, and eventually enough AcH is released to generate an action potential
    • Lambert-Eaton Myasthenic Sx (LEMS)• Epidemiology- 10 fold less common than MG- 60% of cases associated w/ SCLC (3% of all SCLC cases)- NMJ sx may precede radiologic dx of tumor by several years- Non-cancer associate LEMS may occur in children or adults w/out any specific autoimmune predilection
    • Lambert-Eaton Myasthenic Sx (LEMS)• Clinical Features:- Proximal > Distal Limb Weakness- Initially presents w/ difficulty walking (proximal limb weakness)- Occular, Bulbar, and Respiratory weakness uncommon- Autonomic sx such as dry mouth, constipation, impotence, and bladder urgency
    • Lambert-Eaton Myasthenic Sx (LEMS)• Diagnosis:- Anti-VGCC (voltage gated Ca2+ channel) Ab detected in ~90% cases (specific)- EMG – w/ repetitive stimulation or voluntary contraction, evidence of increased action potentials
    • Lambert-Eaton Myasthenic Sx (LEMS)• Tx:- 3,4 diaminopyridine (3,4-DAP), which blocks presynaptic potassium channels, thereby increasing the opening time of theavailable VGCC- Mestinon (pyridostigmine)- Effective tx of cancer insult
    • Neuromyotonia• Acquired or paraneoplastic sx (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 myokemia
    • Neuromyotonia• Clinical Features:- Mean age of onset 30-40 years- Skeletal Muscle over activity resulting in twitching or myokemia- Pt’s may complain of fasciculations, muscle cramps, or stiffness
    • Neuromyotonia• Diagnosis:- Anti VGKC Antibodies – immunoassay detects Ab in ~ 50% of cases- EMG – classic findings are spontaneous doublet, triplet, or multiple discharges from motor nerves
    • Neuromyotonia• Treatment:- Many pt’s gain sx relief from downregulation of VGKC through use of AED’s. (Tegretol, Dilantin, and Lomtrigine)- PLEX has much greater short term benefit over IVIG- Resistant cases have shown to benefit from prednisolone + imuran combination
    • Botulism• Disperses widely via vascular sx• Neurotoxin secreted from clostridium botulinum• Binds in NMJ at presynaptic bulb• Enters terminus through endocytosis and destroys formation of Ach, affecting its release
    • Botulism• Clinical Features:1. Bilateral Cranial Nerve Abnormalities2. Symmetric Descending Weakness3. No sensory deficits w/ exception of blurry vision4. Absence of Fever5. The pt remains responsive
    • Botulism• Dx:- ELISA or mouse toxicity- EMG – decreased CMAP amplitude in 2 separate muscles, and 20% facilitation of CMAP amplitude during tetanic stimulation
    • Botulism• Tx:1. Age > 1 year – equine serum botulism antitoxin2. Age < 1 year – Human derived botulinum imunnoglobulin
    • Thank You