1. 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

2. 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

3. 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

4. Symptoms Weakness in upper legs and hips
Weakness in upper arms and shoulders
Breathing and swallowing problems
Autonomic nervous system dysfunction
Reference:

5. Diagnosis Physical exam Blood test Electromyography test
Needle electromyography
Single- fiber electromyography
Nerve conduction velocity test
Reference:

6. 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),

7. 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)

8. 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)

9. 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

10. 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.

11. 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

12. 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

13. References
X) Sieb, J.P. (2012) 3,4-Diaminopyridine Phosphate in the Treatment of Lambert-Eaton Myasthenic Syndrome. European Neurological Review, 7(1),
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),
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
M. (2017). Lambert-Eaton Myasthenic Syndrome (LEMS) - Signs and Symptoms. Retrieved November 11, 2018 from
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.