LambertEaton Myasthenic Syndrome LEMS Dr Sadik ALGhazzawi MRCP

Lambert-Eaton Myasthenic Syndrome (LEMS) Dr Sadik AL-Ghazzawi MRCP FRCP UK

Muscle Contraction: Neuromuscular Junction 1. Action potential reaches presynaptic 2. 3. 4. 5. 1 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 2 3 4 5

LEMS: Autoimmune Neuromuscular Junction Disorder ● 1950 s: 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 Incidence: 0. 5 per 1, 000 ● Demographics: ○ ○ 60% male Late age of onset

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=2 ah. UKEwibzurp. M 3 e. Ah. Whct 8 KHd 0 QAs. YQj. Rx 6 BAg. BEAU&url=https%3 A%2 F%2 Fneurologist-ahmedabad. com%2 Fservices%2 Femgelectromyography%2 F&psig=AOv. Vaw 2 q. N 2 WCyyxefhqz. Na. Ls. MPKD&ust=1542080787500765

Pathology ● ● Autoimmune Disease - half of cases are associated with Small Cell Lung Cancer Ig. G 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 (3 rd 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 Ig. G bound to the calcium ion channel thus decreasing neurotransmitter release, and the role of the drug 3, 4 DAP 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)

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

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

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