Lambert-Eaton Myasthenic Syndrome (LEMS) PHM142 Fall 2018 Instructor: Dr. J. Henderson Date: 30 October, 2018 Lambert-Eaton Myasthenic Syndrome (LEMS) Presented by: Vanessa Bisson, Macy Chau, Peter Pham, Andy Kai Quan Wong

Muscle Contraction: Neuromuscular Junction Action potential reaches presynaptic terminal of motor neuron Calcium enters via voltage-dependent calcium channels (VGCC) Vesicles release acetylcholine (ACh) into synaptic cleft ACh binds post-synaptic receptors Muscle contraction 1 2 3 4 5

LEMS: Autoimmune Neuromuscular Junction Disorder 1950s: Edward Lambert and Lee Eaton Clinical presentation: Proximal muscle weakness Autonomic disturbance Two subgroups: LEMS + small cell lung carcinoma (SCLC) LEMS + no SCLC Epidemiology: Prevalence: 2.6 per 1,000,000 Incidence: 0.5 per 1,000,000 Demographics: 60% male Late age of onset LEMS + SCLC - LEMS as a consequence from cancer LEMS + no SCLC - genetic component https://www.ncbi.nlm.nih.gov/pubmed/27997683 https://www.hindawi.com/journals/ad/2011/973808/

Symptoms Weakness in upper legs and hips Weakness in upper arms and shoulders Breathing and swallowing problems Autonomic nervous system dysfunction Reference: https://www.mda.org/disease/lambert-eaton-myasthenic-syndrome

Diagnosis Physical exam Blood test Electromyography test Needle electromyography Single- fiber electromyography Nerve conduction velocity test Reference: https://www.google.ca/url?sa=i&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwibzurp-M3eAhWhct8KHd0QAsYQjRx6BAgBEAU&url=https%3A%2F%2Fneurologist-ahmedabad.com%2Fservices%2Femg-electromyography%2F&psig=AOvVaw2qN2WCyyxefhqzNaLsMPKD&ust=1542080787500765

Pathology Autoimmune Disease - half of cases are associated with Small Cell Lung Cancer IgG self reactive to Calcium ion channels in presynaptic neuron Figure 2 shows the normal calcium ion channels opening to allow vesicle docking and subsequent release of neurotransmitter acetylcholine to bind to the postsynaptic membrane. Ref: Hill, R., Wyse, G., & Anderson, M. (2012). Animal physiology (3rd ed.). New York: Sinauer Associates. Ref 2: Tim, R., Massey, J., & Sanders, D. (2000). Lambert-eaton myasthenic syndrome: Electrodiagnostic findings and response to treatment. The American Academy of Neurology, 54(1), 2176-2178.

Pathology Results in progressively decreased levels of acetylcholine release LEMS associated with various types of cancer Likely due to cross reactive cancer cell VGCC for healthy VGCC Figure 2: from left to right, shows the norma influx of calcium ions causing vesicle docking and neurotransmitter release, a self reacting IgG bound to the calcium ion channel thus decreasing neurotransmitter release, and the role of the drug 3,4DAP in reversing the treatment of LEMS Ref: Vincent, A., Lang, B., & Newsom-Davis, J. (1989). Autoimmunity to the voltage-gated caldum channel underlies the lambert-eaton myasthenic syndrome, a paraneoplastk disorder. Trends in Neuroscience, 12(12)

Pathology Figure 3 : A.) shows normal presynaptic neuron calcium ion channels. B.) Shows presynaptic neuron of a LEMS patient. Significant decrease in number of ion channels. Ref: Vincent, A., Lang, B., & Newsom-Davis, J. (1989). Autoimmunity to the voltage-gated caldum channel underlies the lambert-eaton myasthenic syndrome, a paraneoplastk disorder. Trends in Neuroscience, 12(12)

Treatments - Cholinesterase Inhibitors Pyridostigmine mostly used Inhibits the breakdown of acetylcholine at the neuromuscular junction Affects the autonomic nervous system as well - side effects include diarrhea, excessive saliva, abdominal cramps Usually only mildly effective Talk about + charge, BBB, reversibly carbamylates AChE ANS + why side effects happen

Treatments - Potassium Channel Blockers 3,4-diaminopyridine (DAP) most commonly used Often used in combination with pyridostigmine Allows neuromuscular junction electrical activity to last longer This in turn increases calcium influx and the release of acetylcholine Common side effects include paresthesias, dizziness, abdominal pain More effective than cholinesterase inhibitors How does it make electrical activity last longer? 3,4-DAP blocks potassium ion channels in membranes and facilitates synaptic transmission. The blocking of potassium ion channels prolongs the depolarisation during nerve action potentials, thereby increasing the open-time of voltage-gated calcium channels and consequently the influx of calcium ions into the nerve terminal. This increased calcium influx enhances the quantal neurotransmitter release which is calcium dependant.

Treatments - Immune Therapy Prednisone Slows disease progression - attacks autoimmunity Prednisone and azathioprine immunosuppressants most commonly used Intravenous immunoglobulin Decreases antibody production Blocks calcium channel antibodies from binding targets Plasma exchange Temporary removal of antibodies from blood Immunosuppression - increases susceptibility to other infections Azathioprine Shouldnt u be paying attentipn in class vannose???? NO Awk im working hard okay

Summary Described by Lambert and Eaton in 1950s Rare autoimmune disorder affecting higher proportion of males and late onset Two subgroups: LEMS + SCLC; LEMS + no SCLC Autoimmune disorder that targets calcium ion channels on the presynaptic neuron Results in decreased ACh release leading to weak muscle contraction Mainly affects the muscles and causes weakness Diagnosis: electromyography to test muscle and nerve reactivity Treatments include cholinesterase inhibitors, potassium channel blockers and immune therapy

References X) Sieb, J.P. (2012) 3,4-Diaminopyridine Phosphate in the Treatment of Lambert-Eaton Myasthenic Syndrome. European Neurological Review, 7(1), 56-61. Hill, R., Wyse, G., & Anderson, M. (2012). Animal physiology (3rd ed.). New York: Sinauer Associates. Tim, R., Massey, J., & Sanders, D. (2000). Lambert-eaton myasthenic syndrome: Electrodiagnostic findings and response to treatment. The American Academy of Neurology, 54(1), 2176-2178. Vincent, A., Lang, B., & Newsom-Davis, J. (1989). Autoimmunity to the voltage-gated caldum channel underlies the lambert-eaton myasthenic syndrome, a paraneoplastk disorder. Trends in Neuroscience, 12(12) Slightham, C. (2016). Lambert-Eaton Myasthenic Syndrome. Retrieved November 11, 2018, from https://www.healthline.com/health/lambert-eaton-syndrome M. (2017). Lambert-Eaton Myasthenic Syndrome (LEMS) - Signs and Symptoms. Retrieved November 11, 2018 from https://www.mda.org/disease/lambert-eaton-myasthenic-syndrome/signs-and-symptoms Abenroth, D. C., Smith, A. G., Greenlee, J. E., Austin, S. D., & Clardy, S. L. (2017). Lambert–Eaton myasthenic syndrome: Epidemiology and therapeutic response in the national veterans affairs population. Muscle and Nerve, 56(3), 421–426. https://doi.org/10.1002/mus.25520