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.

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

Labs normal

 Neurological Exam: Findings:

Wasting of hand & arm musculatureSensory testing all normalArms & legs: weakness with spasticityReflexes: brisk with spasticity, Babinski signFasiculations (more on this later)

Arms Deltoids Biceps

Triceps WrFlex WrExt FingFlex Infraspinatus    

Right 4+ 4- 4 4- 4+ 4 4+    

Left 4 3 4 4 5 4- 3                       Legs Psoas Quad

sHams TA GlutMa

xGastroc ToeExt ToeFlex GlutMed

Right 4+ 5 4+ 4+ 4+ 5 5 4 4+Left 4+ 5 5 4- 4+ 5 5 4 4+

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. 

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

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

Fundamentals of motor systemUpper motor neurons Lower motor neurons

Lower motor neurons

Signal muscles to contract

Upper motor neurons: control LMNs

Select and initiate motor circuits resident in the cord. Releases programs from tonic inhibition.

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Corticospinal tract modulates reflexes

Upper & lower motor neuron diseases have distinct presentations.

Upper motor neurons Lower motor neurons

Upper & lower motor neuron diseases with distinct presentations.

Upper motor neurons Lower motor neurons

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Diseases of the lower motor neuron: polio

Decreased tone, especially with passive mvt of limb, weakness, retardation of movement, hypo-reflexia & muscle wasting.

Spinal Cord Histology

Spinal Cord Histology

Normal Polio

Muscle Histology

Normal Lower motor neuron disease

Atrophy due to loss of torphic influence from lower motor neuron terminals.

Upper & lower motor neuron diseases with distinct presentations.

Upper motor neurons Lower motor neurons

Cramped & spastic arm

Upper motor neuron disease

Increased tone, decreased motor control (clumsiness), weakness, cramping,  hyper-reflexia. 

Normal spinal cord histology

Normal spinal cord histology

Upper motor neuron lesion: degeneration of corticospinal tract.

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)

ALS Spinal Cord Histology

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.)

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Two Motor Units sharing a fascicle

Motor Unit : an a-motorneuron & the muscle fibers it innervates

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Rest

Minimal

Maximal

Normal EMG

Exertion:

Record from muscle under 3 conditions.

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Rest

Minimal

Maximal

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Normal

Fiber-type Grouping following denervation/reinnervation

Fasiculations

ALS

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

Monitoring  ALS Progression

Genetics

5-10 % familial13 genes identified10-20 % of familial and 5 % of sporadic are SOD1

Etiology of ALS: 3 models

Why are motor neurons dying? Proposed ALS disease mechanisms.

Therapeutics

NMJ 2001

* Stem cell therapies.