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Part I

Part I. Mr. Robert Middelton …

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Part I

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  1. Part I Mr. Robert Middelton… Over the past few years, he noticed ...a slowly developing weakness initially in his hands and arms, now spreading to his leg muscles. He noted reduced dexterity in his fingers accompanied by muscle stiffness, occasional cramping, and wasting of hand and arm muscles.

  2. Clinical Examination (normal) Review of Systems: unremarkable..…Mr. Middelton is not aware of any tic bites or exposure to toxic agents.

  3. Labs normal

  4. Neurological Exam: Findings: Wasting of hand & arm musculature Sensory testing all normal Arms & legs: weakness with spasticity Reflexes: brisk with spasticity, Babinski sign Fasiculations (more on this later) Strength testing: Scale of 0-5 (full) 1/5 trace; 2/5 = movement weaker than gravity; 3/5 = movement against gravity; 4-/5, 4/5, 4+/5 = degree of power against active resistance. Conclusion: a disease of the motor system with complete sparing of the sensory systems.

  5. Amyotrophic lateral sclerosis (ALS): Lou Gehrig’s Disease

  6. Charcot’s Disease (1874) (based upon his clinical/anatomical method)

  7. Fundamentals of motor system Upper motor neurons Lower motor neurons

  8. Lower motor neurons Signal muscles to contract

  9. Upper motor neurons: control LMNs Select and initiate motor circuits resident in the cord. Releases programs from tonic inhibition.

  10. Corticospinal tract modulates reflexes

  11. Upper & lower motor neuron diseases have distinct presentations. Upper motor neurons Lower motor neurons

  12. Upper & lower motor neuron diseases with distinct presentations. Upper motor neurons Lower motor neurons

  13. Diseases of the lower motor neuron: polio Decreased tone, especially with passive mvt of limb, weakness, retardation of movement, hypo-reflexia& muscle wasting.

  14. Spinal Cord Histology

  15. Spinal Cord Histology Normal Polio

  16. Muscle Histology Normal Lower motor neuron disease Atrophy due to loss of torphic influence from lower motor neuron terminals.

  17. Upper & lower motor neuron diseases with distinct presentations. Upper motor neurons Lower motor neurons

  18. Upper motor neuron disease Cramped & spastic arm Increased tone, decreased motor control (clumsiness), weakness, cramping, hyper-reflexia.

  19. Normal spinal cord histology

  20. Normal spinal cord histology

  21. Upper motor neuron lesion: degeneration of corticospinal tract.

  22. Amyotrophic lateral sclerosis Charcot found both upper and lower motor neuron signs. On anatomical investigation, he noted muscle wasting (amyotrophy) and a hardening of the lateral corticospinal columns (lateral sclerosis)

  23. ALS Spinal Cord Histology

  24. Can confirm diagnosis with clinical electrophysiology. Clinical Electrophysiology: Nerve conduction studies: (normal) left and right median, ulnar, peroneal, tibial and sural nerves. All conduction velocities in the normal range. (Diagram at right.) • EMG: reduced number of motor units (vs. normal) for all muscles tested. (Shown below: spontaneous (involuntary) firing of large motor unit while muscle is a rest corresponding to a fasciculation.)

  25. Two Motor Units sharing a fascicle Motor Unit : an a-motorneuron & the muscle fibers it innervates

  26. Normal EMG Record from muscle under 3 conditions. Rest Exertion: Minimal Maximal

  27. Rest Minimal Maximal

  28. Fiber-type Grouping following denervation/reinnervation Normal

  29. Fasiculations

  30. ALS Incidence ~3/100,000 Males > females (1.6:1) Progressive with death 3-5 years following diagnosis Death results when brainstem motor neurons are affected resulting in cessation of breathing.

  31. Monitoring ALS Progression

  32. Genetics 5-10 % familial 13 genes identified 10-20 % of familial and 5 % of sporadic are SOD1

  33. Etiology of ALS: 3 models

  34. Why are motor neurons dying? Proposed ALS disease mechanisms.

  35. Therapeutics NMJ 2001 * Stem cell therapies.

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