Multiple SclerosisD. Gelb11.09.06

I. upper vs. lower motor neuronA. cortical fiber synapses in spinal cord (upper motor neuron)B. post-synaptic neuron goes from spinal cord out to muscle (lower motor neuron)C. upper motor neuron lesion: weakness without fasciculations and atrophyD. lower motor neuron lesion: weakness, atrophy, fasciculations (spontaneous muscle twitching) E. reflex arc:

1. sensory fiber measures length of muscle and sends information to spinal cord2. synapses on lower motor neuron 3. lower motor neuron lesion shows reduced reflex4. reflex arc is tonically suppressed from above5. upper motor neuron lesion reduces suppression and reflex will be hyperactive

F. a given disease process may involve both the upper and lower motor neurons G. lesion below L1-2 cannot cause upper motor neuron symptoms because there are only nerve roots (purely lower motor

neuron process) II. clinical:

A. multiple lesions separated in space and time B. multifocal, subacute inflammatoryC. typical lesion sites

1. spinal cord 50% a. numbness, paresthesias (Lhermitte’s), pain, weakness, stiffness, clumsiness, bladder/bowel disturbance,

impotenceb. Lhermitte’s phenomenon: when patient bends neck forward, he/she feels an electric shock running down the back

(herniated disk, vitamin B12 deficiency, MS - anything that affects the posterior columns) 2. optic nerve 25% (blurred vision, loss of vision, eye pain)3. brainstem/cerebellum 20% (diplopia, dysarthria, dysphagia, clumsiness, vertigo, numbness, weakness)4. almost any neurological symptom can occur

D. symptoms by frequency1. focal weakness (40%)2. vision loss (22%)3. paresthesias (21%)4. diplopia (12%)5. vertigo (5%)6. urinary symptoms (5%)

E. internuclear ophthalmaplegia (INO): 1. gaze centers point both eyes in the same direction (cortical lesion will affect both eyes)2. nuclear lesion (nuclei of cranial nerves) can affect only one eye3. ex. to move eyes to the left, cortex needs to use right medial rectus (III) and left lateral rectus (VI)4. pontine gaze center (parapontine reticular formation PPRF): coordinates between different nuclei to move eyes

coordinately5. lesion in 6th nerve lesion - still disrupts 3rd nerve pathway because it has to go through the 6th nerve nucleus first6. ophthalmoplegia: eye weakness

7. MLF (median lateral fasciculus): joins 6th and 3rd nerve nuclei in pons and midbrain (respectively)

F. clinical course

1. classic: relapsing and remittinga. episode of CNS problem

i. transverse myelitis - common episodeii. weakness on one side of the bodyiii. INO

b. either return to baseline or not quitec. episodes continued. after 10 years, 50% of these evolved to secondary progressive (50% relapsing-remitting)

2. secondary chronic progressive: after a certain period of time remitting stops 3. primary progressive (10-20%): progression from the onset of illness

G. diagnosis - imaging (MRI)1. may be in either brain or spinal cord (sometimes show old asymptomatic lesions) 2. pathologic hallmark: demyelinating plaque (bright spots in the white matter)

III. pathology: multiple lesions separated in space and time, specifically inflammatory lesions of white matter A. gross pathology: gray patches in white matter, looks like gray matter (frequently near ventricle)B. microscopic pathology

1. white matter lesionsa. loss of myelin in lesion area (attacks oligodendrocytes) b. can also affect the axons (even early in the disease)

i. preserved but reduced (less dense) ii. neuron cell bodies are spared - attacks axons

2. inflammatory processa. perivascular lymphocytesb. macrophage infiltrationc. reactive astrocytosis d. degenerated myelin sitting in the plaques

3. 4 patterns for demyelinating plaquesa. I: sharply demarcated area of perivenous demyelination, many T-cells and macrophagesb. II: same, plus massive deposition of activated complementc. III: ill-defined edges, marked reduction of myelin-associated glycoprotein (MAG)d. IV: same as I, except oligodendrocytes depleted

IV. pathophysiology: inflammatory demyelination

A. mechanism1. T-cells in blood get activated2. migrate across blood-brain barrier3. enter CNS4. present antigen to macrophage that is similar to myelin antigens5. cells then attack myelin

B. question: was T-cell activated due to damage, or due to deranged T-cells1. immune activation could be primary or secondary2. if primary, could be specific CNS problem or a generalized problem with immune system3. many believe it is a primary problem involving the CNS

C. underlying cause1. environmental factors

a. increased prevalence with increased distance from equatorb. mini-epidemics (frequently correlate with epidemics of other disease in animals)c. moving to a different place between ages 1-15 changes risk to risk of individuals that were born in that area

2. genetic factorsa. concordance rate for monozygotic twins 30% (200 times background rate)b. concordance rate for dizygotic twins 5%c. first-degree relatives have 25-fold higher risk of MS than general population

V. diagnosisA. clinical: multiple lesions separated in space and timeB. when necessary (non are 100% specific or sensitive, they just alter the probabilities based on clinical suspicion)

1. MRI a. brainb. spinal cordc. sometimes too specific

2. LP (CSF)a. oligoclonal bandsb. increased IgG index = [(IgGCSF/albuminCSF)/(IgGserum/albuminserum)]

3. evoked potentials a. EEG recordingb. time-locked to stimulus

i. visualii. auditoryiii. somatosensory (arms or legs)

c. averaged over multiple stimuli (sharpens signal and reduces noise) d. looking for a lesion that is undetectable clinically

C. diagnostic dilemma: single episode1. by definition not MS2. MS is very likely if

a. typical syndrome

b. diffuse MRI changes3. must distinguish from acute disseminated encephalomyelitis (ADEM)

a. typically associated with antecedent infection (sometimes vaccination)b. abrupt onset, progreses over hoursc. fever, headache, stiff neck, reduced consciousness common

4. neuromyelitis optica (Devic’s): isolated optic neuritis and transverse myelitis without other signs or symptoms of MS VI. treatment

A. disease-modifying agents - fewer relapses, relapses are less severe (early treatment is significantly beneficial) 1. interferon-β-1a (Avonex): low dose, IM q week2. interferon-β-1a (Rebif): high dose, sub-q 3 times a week3. interferon-β-1b (Betaseron): high dose, sub-q every other day4. glatiramer acetate (Copaxone): sub-q daily5. mitoxantrone (Novantrone): IV, every 3 months (chemo drug with cardiac toxicity) 6. natalizumab (Tysabri): inhibitor of an integrin (complication: polyfocal leuko-encephalopathy - PML)

B. acute exacerbations1. steroids hasten recovery2. not clear if dependent on:

a. specific steroid medicationb. dosec. route

3. no evidence of long-term benefit C. symptomatic treatment

1. spasticitya. physical therapyb. baclofen or tizanidinec. botulinum toxin

2. fatiguea. amantidineb. modafinilc. methylphenidate

3. tremor, incontinence, constipation, pain, depression