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) ArmsDeltoidsBicep s TricepsWrFlexWrExtFingFlexInfraspinatus Right4+4-4 4+4 Left434454-3 LegsPsoasQuad s HamsTAGlutMa x GastrocToeExtToeFlexGlutMed Right4+5 554 Left4+554-4+554 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 neuronsLower 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. 10 Corticospinal tract modulates reflexes

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

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

13. 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. 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 neuronsLower motor neurons

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

19. 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. 25 Two Motor Units sharing a fascicle Motor Unit : an  -motorneuron & the muscle fibers it innervates

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

27. 27 Rest Minimal Maximal

28. 28 Normal Fiber-type Grouping following denervation/reinnervation

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.

36. Therapeutics NMJ 2001 * Stem cell therapies.