11-26 NeuroPATH Myelin Diseases

Question 1

What makes CNS myelin?

Answer 1

oligodendrocytes

Question 2

leukodustrophies, general def

Answer 2

a group of enzymatic dzs result in myelin loss and death of oligodendroglial cells

Question 3

MS, gen def

Answer 3

chronic inflamm dz of CNS (not PNS!) causing:
—demyelination
—oligodendroglial death
—variable degrees of tissue damage

Question 4

Who get MS more often, men or women?

Answer 4

women

Question 5

What pattern do MS plaques show in RRMS?

Answer 5

none, totally random distribution in the CNS WM

Question 6

What do MS plaques look like pathologically?

Answer 6

Grossly: sharp-bordered areas that look like GM in the WM tracts

Histo: gliosis; late—>axonal death

TEM: no nice donut wrapping around large hole; see astrocytes invading (research: they are likely inhib re-mye, how to stop?)

Question 7

shadow plaques

Answer 7

initially sharp edges of myelin loss that show RE-myelination; active area of research

Question 8

Which immune cells come into plaque? What type of hypersensitivity reaction do you get?

Answer 8

CD4+ T-cells and MOs (remove degrading myelin); Type IV hypersensitivity

Question 9

What gene is most highly correlated across MS pts?

Answer 9

MHC Class II (presents Ags to T-cells)

Question 10

Natural history of Classical RRMS (Charcot’s)

Answer 10

Relapsing-Remitting predominates first
—Sx due to inflammation which starts as beads of T-cell/MO inflamm along small BVs w/in CNS
—With enough of this infall, demyelination happens, though there will still be slow transmission
—eventually you often get axonal death

Progressive Phase often follows later
—relapses do not full-recover; downward slope of sx/functioning

Question 11

Schilder’s Disease

Answer 11

bilateral dramatic massive demyelinating lesions; look sort of ring enhancing (r/o cancer, abscess?
**very rare

Question 12

Balo’s Concentric Sclerosis

Answer 12

big, lots of necrosis; layers of normal and devastated WM
—T-cell/MO inflamm
—oligos gone in demyelinated zones
—myelinated zones normal
—more common in asia

ripples on a pond/tree rings —> we don’t know why!

Question 13

ADEM (Acute Disseminated Encephalomyelitis)

Answer 13

umbrella term
—formerly many: post-vaccinial, p-infectious, p-measles, rabies post-vaccinial, transverse myelitis
—lots of triggers: snake bite, Campylobacter was biggie in China, others
—fulmanant, monophasic, perivenous (losing myeine around small venules) dz usu. s/p viral infx
—T-cell/MO inflamm cause breakdown of BBB seen on MRI
—if pt survives acute fulminant stage, usually full recover

Question 14

ADEM sub-type: Post-measles encephalitis

Answer 14

—big prob pre-vaccine; common in Peru today
—acute (wks-months after): large ring enchancing lesions w/ edema
—years after: very rare SSPE (subacute sclerosing panencephalitis): progressive, massive demye, years s/p

Question 15

ADEM sub-type: Acute Hemorrhagic Encephalomyelitis (Weston Hurst Dz)

Answer 15

—inflamm w/ T-cell and MOs but also PMNs
—vascular necrosis in addition to demyelination
—grossly: lots of tiny little hemorrhages in WM
—histo: demyelinated area with MO’s and T-cells + PMNs attacking art wall —>RBCs leaking out
——axons die (“are transected”) in adjacent areas

Question 16

Central Pontine Myelinolysis

Answer 16

—usually in pts w/ other illness first (usu w/ electrolyte imbalance**Frequently iatrogenic!!)
—locked-in syndrome—>coma—>death
—almost no one survives
—DON’T CORRECT ELECTROLYTES TOO QUICKLY
—no inflamm; oligos die and axons in area are transected
—MRI: someone punched out middle of pons bilaterally

Question 17

What are Leukodystrophies? Give 3 examples.

Answer 17

DYSmyelinating Dzs —> something wrong with myelin itself; usu inborn error of metabolism causing build-up of some metabolite and its precursors
—present in CNS b/c it uses these prots more
—All kind of present like really bad MS
—very rare; usually peds
1. globoid cell leukodystrophy (Krabbe’s dz)
2. metachromatic leukodystrophy
3. Pelizaeus-Merzbacher’s Dz

Question 18

globoid cell leukodystrophy (Krabbe’s dz)

Answer 18

—Developmental delay and psychomotor retardation, blindness, myoclonus, coma and death in 1-2 years
—Late infantile form is typical, but adult forms have been described - up to 73 yrs.
—Galactocerebroside-β-galactosidase = lost or mutated —> galactocerebroside builds up
—No inflamm but large MOs (“globoid cells”) appear perivascular
—Oligos die—>myeline bye
—Path: extensive loss of myelin

Question 19

metachromatic leukodystrophy

Answer 19

—Three types: late-infantile, intermed., juvenile.
—Loss of previous abilities, motor/gait problems. behavior problems, blindness and decr abilities in all modalities leading —> coma and death.
—classic: loss or deficiency of Aryl-sulfatase-A Chr. 22 – multiple mutations reported
—Sulphated lipid – cerebroside sulfate – accumulates in CNS (Also PNS) & kidney—> oligos die —> myelin lost
—Macrophages are abundant in the CNS removing debris, but no inflamm
—Name comes from stain purple stain—>mahogany brown

Question 20

Pelizaeus-Merzbacher’s Dz

Answer 20

—Neuro degen w/ blindness szs, spacticity —> death
—No inflamm present in CNS
—6 clinical types – vary from congenital type to slow adult form
—Age: neonate to 50s
—Most common mutation is gene duplication of PLP (proteolipid protein) gene on Xq22.33-22 (therefore more males
—Multiple others identified, some not in PLP exons
—PNS myelin not involved

Question 21

Spastic Parapalegia type 2

Answer 21

—Another PLP mutation
—Animal Models: Rabbit paralytic tremor, “rumpshaker” mouse, “jimpy” mouse
—PLP Knock-out mouse virtually normal
—Minor point mutations range from mild to severe
—Protein misfolding leading to accumulation in the ER and altered oligo apoptosis believed responsible