Demyelinating diseases of the CNS (Week 3--Vinters)

Question 1

Multiple Sclerosis epidemiology

Answer 1

Demyelinating disease of the CNS (most common)

Young adults 20-40 years old

Females more

Question 2

How do you diagnose MS

Answer 2

No single diagnostic test for MS

Clinical diagnosis supported by laboratory testing

CNS lesions in more than 1 neuroanatomic location and on more than 1 occasion

MRI, evoked potentials (visual, somatosensory and brain stem), CSF analysis (IgG synthetic rate, more commonly, oligoclonal bands)

Patient may be given diagnosis of clinically definite MS, laboratory-supported definite MS, clinically probably MS or laboratory probably MS

Question 3

Clinically definite MS

Answer 3

2 attacks and clinical evidence of 2 separate lesions

OR

2 attacks, clinical evidence of 1 lesion and laboratory evidence of another lesion

Question 4

Laboratory-supported definite MS

Answer 4

2 attacks, either clinical or laboratory evidence of one lesion and CSF IgG or oligoclonal bands

OR

1 attack, clinical evidence of 2 separate lesions and CSF IgG or oligoclonal bands

OR

1 attack, clinical evidence of 1 lesion and laboratory evidence of another and CSF IgG or oligoclonal bands

Question 5

Clinically probably MS

Answer 5

2 attacks and clinical evidence of 1 lesion

OR

1 attack and clinical evidence of 2 separate lesions

OR
1 attack, clinical evidence of 1 lesion and laboratory evidence of another

Question 6

Laboratory-supported probably MS

Answer 6

2 attacks and CSF IgG or oligoclonal bands

Note: 2 attacks must involve different parts of the nervous system, must be separated by one month and must have each lasted at least 24 hours

Question 7

Expanded Disability Status Scale (EDSS)

Answer 7

Grading scale to document disability in an MS patient

Ranges from 0 (normal exam) to 10 (death due to MS)

2. 5 means minimal disability in 2 functional systems
3. 5 means requirement for constant bilateral assistance (canes, crutches, braces) to walk about 20 meters; severe disability in 2+ functional systems

Documentation that patient’s EDSS score is increased from one exam to the next is objective marker for disease progression

Question 8

Possible clinical courses of MS

Answer 8

Most (85%) begin with relapsing-remitting course which then gives way to secondary chronic progressive course (gradual increase in EDSS score but no more abrupt relapses)

Primary progressive course unusual and never associated with abrupt relapses (occurs in men with later onset of disease, 40+ years old)

Question 9

Neuropathologic lesions found within the CNS of MS patients

Answer 9

Usually patient will have both acute and chronic lesions at any given time

Acute: active inflammation (usually around venules) involving T lymphocytes and macrophages; demyelination with phagocytosis of myelin debris

Chronic: no infiltrative lymphocytes or macrophages, devoid of myelin at center, astrocytic proliferation and hypertrophy (astrogliosis) within centers and at periphery of demyelinating plaques, evidence of abortive attempts at remyelination found as sparse thin rims of myelin around axons

Question 10

General appearance of brain slice of patient with MS

Answer 10

MS plaques are well demarcated regions of demyelination with relative preservation of underlying axons (gelatinous areas surrounded by normal white matter)

Question 11

Are axons preserved in MS?

Answer 11

Used to be thought that axons were spared but recent data shows that there is significant axon loss

Pathogenesis of axonal injury not known but may be causesd by sustained influx of Na+ then Ca2+ into axons/neurons

Question 12

Rare variants of MS

Answer 12

Balo’s concentric sclerosis: concentric alternating bands of demyelinated/myelinated white matter

Fulminant/acute MS/Marburg variant: mass lesion

Devic’s disease/neuromyelitis optica: demyelination in optic nerve and spinal cord; AQP4 autoantibodies (often simultaneous)

Question 13

Does MS affect white or grey matter?

Answer 13

Of course affects white matter tracts but affects gray matter too, including cerebral cortex which may contribute to cognitive impairment

Note: not all people with MS get cognitive impairment, but IF there is cortex affected then they will

Question 14

Genetic and environmental causes of MS

Answer 14

We don’t know the etiology of MS!

Evidence for genetic causes: disease associated with immune response genes (HLA); increased risk for 1st degree relatives and more in monozygotic twins

Evidence for environmental causes: outbreaks of MS when immigrants come in; geographic distribution not uniform–less around equator; kids migrate before 15 adopt risk of region they migrated to but after 15 keep home risk (maybe environmental agent acts on developing immune system)

Question 15

Is there an asociated infectious agent for MS?

Answer 15

No single agent associated with MS

May be that we haven’t found it/them yet and may be that there is none

Broad immunosuppressive therapy is beneficial in MS (maybe not a causative agent)

Maybe various viruses activate autoimmunity to myelin in nonspecific ways

Question 16

Experimental autoimmune encephalomyelitis (EAE)

Answer 16

Animal model for MS

EAE in SJL strain of mice is particularly useful as MS model since is characterized by relapsing remitting disease course with gradual progression

Mice immunized with myelin proteion (MBP) so create antibodies to MBP –> after 10-14 days are sacrificed and draining lymph node cells (LNCs) placed in culture with MBP (LNCs will attack MBP, and be “MBP stimulated LNCs”) –> MBP stimulated LNCs transferred to naive recipient mouse (LNCs attack naive mouse’s MBP) –> mice develop inflammatory demyelinating lesions within the CNS 7-10 days after transfer

Question 17

What types of cells are necessary for the transfer of disease in EAE?

Answer 17

CD4+ lymphocytes that are specific for myelin proteins MBP, PLP, etc (if specific for ovalbumin, disease will NOT be transferred)

Question 18

What must the myelin specific T lymphocytes produce to transfer disease?

Answer 18

T lymphocytes must produce TH1 cytokines (IFN gamma, TNF) upon activation with antigen

Probably because these cytokines act on endothelial cells of BBB to increase permeability and permit entry of immune cells from blood into CNS (possibly a key initiating event in MS)

Note: TH2 cytokines are protective

Question 19

Full explanation of immunopathogenesis of MS

Answer 19

CD4+ myelin protein specific circulating T lymphocytes are in activated state –> produce TH1 cytokines (IFN gamma, TNF) –> cytokines cause opening of BBB –> T lymphocytes and macrophages enter CNS and cause inflammation and myelin injury –> demyelination

Not clear how axonal injury occurs

Question 20

Use of MRI in neuro-imaging MS

Answer 20

Serial MRIs show that MS lesions appear and/or enlarge even when patient is clinically stable

Gadolinium enhancement on T1 images indicates areas of active inflammation as lymphocytes and macrophages open the BBB early in lesion development

T2 images show enlarging lesions and atrophy, axonal loss late in disease process

Patient will have heterogeneous picture of lesions with some actively inflamed and others chronic and associated with gliosis and axonal loss

Progression shows less gadolinium enhancement and more atrophy on MRI

Question 21

MS treatment

Answer 21

Acute: solu-medrol followed by prednisone taper over 2 weeks

Prophylaxis: interferon beta, IFN-1b, Betaseron; interferon beta, IFN-1a, avonex; copolymer 1 (copaxone), glatiramer acetate

Question 22

Non-MS demyelinating lesions (rare)

Answer 22

Leykodystrophies

Progressive multifocal leukoencephalopathy (PML)

Central pontine myelinolysis (CPM)

Acute disseminated encephalomyelitis (ADEM)

Question 23

Leukodystrophies

Answer 23

Dysmyelinating disorders

Rare, usually present in infants and children but sometimes adults

Progressive neurologic decline with spasticity

Result from breakdown of abnormally formed myelin

Most cases due to well-characterized genetic abnormalities of enzymes important in forming and maintaining normal CNS myelin

Neuropathology shows diffuse white matter pallor, brain atrophy, affects both cerebral hemispheres symmetrically

VERY rare

Question 24

Progressive multifocal leukoencephalopathy (PML)

Answer 24

Destructive myelin lesions usually asymmetrical within cerebral hemispheres

Unlike MS because show patchy “moth-eaten” areas of myelin (poorly demarcated regions) with cystic areas of injury (may look like infarct) and myelinated fiber loss (can also involve brainstem and cerebellum) caused by opportunistic infection of the brain by papovavirus (JC virus) in immunosuppressed patients

Most commonly seen in AIDS patients

Rare

Question 25

Central pontine myelinolysis (CPM)

Answer 25

Central region of well demarcated demyelination in mid-pons, and axonal injury in severe cases

Linked to rapid correction of severe hyponatremia (“osmotic demyelinating syndromes”)

Brainstem of 8-10% of orthotopic liver transplant patients in autopsy

Clinical correlates not well characterized, but probably flaccid quadriparesis if corticospinal tracts (pass thru basis pontis) affected

In some, can be shown by MRI and is reversible

Toxic leukoencephalopathies result from action of toxins on CNS myelinated axons (recreational drugs or chemotherapeutic agents)

Softening of area by palpation on autopsy specimen if severe

Question 26

Acute disseminated encephalomyelitis (ADEM)

Answer 26

Occurs a few weeks after vaccination or systemic viral infection

Resolves 1-6 months

Neuropathologically perivenous areas of demyelination throughout CNS and variably extensive lymphocytic infiltrates

Probably clinically reversible

No macroscopic changes on gross inspection of brain, only congested blood vessels and questionable areas of demyelination

Very rare

Question 27

How is spinal cord affected by MS

Answer 27

Spinal cord is affected by MS

MS plaques do NOT respect tract boundaries (it is NOT Wallerian Degeneration)

Just get demyelination of a big part of the spinal cord including many different spinal tracts