Demyelinating Diseases and MS - Milo Flashcards
What are the types of demyelinating diseases?
• Multiple sclerosis
– Chronic relapsing encephalomyelopathic forms
– Acute multiple sclerosis (Marburg type)
– Diffuse cerebral sclerosis (encephalitis peraxialis diffusa) of Schilder and concentric sclerosis of Balo
• Neuromyelitis optica (Devic)
• Acute disseminated encephalomyelitis
– Following measles, chickenpox, smallpox, mumps, rubella, influenza, and other viral and some bacterial (Mycoplasma, Rickettsia, etc) infections
– Following rabies or smallpox and rarely other types of vaccination (postvaccinal)
• Acute and subacute necrotizing hemorrhagic encephalitis
– Acute encephalopathic form (hemorrhagic leukoencephalitis of Hurst)
– Subacute necrotic myelopathy
What is seen in microscopic and gross pathology of MS?
• INACTIVE PLAQUES
– DEPLETION OF :
• MYELIN
• OLIGODENDROCYTES
• AXONS
– ASTROGLIOSIS REPLACES ABOVE
• SHADOW PLAQUES
– PLAQUES UNDERGOING “REMYELINATION”
– NO DISCRETE BORDERS
– DIFFUSE THINLY MYELINATED FIBERS
– INCOMPLETE REMYELINATION DUE TO REPEATED
ATTACKS
– AXONS ARE PRESERVED
What are the associated symptoms with plaques in common sites in MS?
Optic nerves:
Optic neuritis: impaired vision, eye pain with movement, cecocentral scotoma, afferent pupillary defect, decreased color vision (lose red)
Spinal cord (myelitis):
Weakness, paraplegia, spasticity, tingling, numbness,
sensory level, Lhermitte’s sign, bladder and sexual
dysfunction
Medulla/Pons:
Diplopia, vertigo, dysarthria, nystagmus, trigeminal
neuralgia, intranuclear ophthalmoplegia (MLF)
Cerebellum:
Ataxia, intention tremor, dysarthria, nystagmus
Cerebral hemispheres/CC:
Large variety of symptoms, cognitive deficits, but
also many “silent” lesions
What are emotional disorders in MS and their putative pathogenesis?
Depression: Bitemporal demyelination, Psychological factors
Bipolar disorder: Bitemporal demyelination, Genetic vulnerability
Euphoria: Bifrontal demyelination
Emotional incontinence: Corticobulbar tracts
Psychosis: Frontal-limbic disconnection, Temporal-limbic demyelination
How does migration affect risk of MS?
If an adolescent moves from a high risk to low risk or visa versa before age 15 adopt the risk of MS associated with their new home.
Those who migrate after age 15 retain the risk of their childhood home.
May be related to viral or environmental etiology.
What are focal cognitive syndromes in MS and what white matter lesions are they associated with?
Verbal memory deficit: Left temporal
Aphasia (non-fluent): Left frontal
Alexia with agraphia: Left temporal-parietal
Conceptual reasoning deficit: Bifrontal
Cerebral disconnection: Corpus callosum and bihemispheric
What are the patterns of disability over time in MS?
Relapsing-remitting (usually returns to baseline, usually for first 10 years)
Secondary-progressive (periods of remittance not returning to baseline, usually due to axonal loss after 10 years of relapsing-remitting, often in men over 40 with progressive myelopathy)
Primary-progressive (steady deterioration)
Progressive-relapsing (deterioration with periods of worsening, <5%)
How is MS diagnosed?
• Clinical features
- Multiple events disseminated in time and space
- Lesions in the CNS white matter
- Exclusion of other diseases
• Cerebrospinal fluid (CSF)
-IgG and oligoclonal bands
• Evoked potentials (VEP, SEP, BERA-if there is a delay)
• Magnetic resonance imaging (MOST SENSITIVE- shows periventricular lesions, ovoid lesions, involvement of corpus collosum, infratentorial structures or U-fibers adjacent to cortex or temporal lobe, gadoliniium enhancement of active lesions that break BBB but most subclinical).
What do oligoclonal bands in CSF indicate?
Present in 90% of MS patients (60% at diagnosis)
Once positive they stay positive
Supports MS diangosis but seen in other diseases (there should be no Ig in normal CSF):
Inflammatory
• MS
• SLE
• Sjorgen’s syndrome
• Behcet’s disease
• Polyarteritis nodosa
Others
• Sarcoidosis
• CVA
• GBS
Infectious
• Viral encephalitis
• Lyme’s disease
• Neurosyphilis
• Chr. Fungal meningitis
• SSPE
• PRPE
What are the goals of MS therapy?
• Treating acute relapses
• Preventing relapses
• Slowing disease progression and
accumulation of disability
• Delaying progressive phase
• Improving quality of life
What are the treatments for MS?
IFN don’t cross BBB, affect periphery, upregulate MHCII molecules, enhance TH2, injection site reactions most common
- SC IFNβ-1b (Betaferon, Betaseron)-injected each day subcutaneously
- Avonex-IFNβ-1a- IM 1/week
- Rebif IFNβ-1a -SC 3/week
- IV Mitoxantrone - immunosuppressive (dangerous)
For acute therapy:
Steroids (IV Methylprednisolone):
Mainly shorten relapse but don’t prevent the next attack-Most commonly oral prednisone, 5 days
Selective Adhesion Molecule Inhibitors (SAMs):
Tysabri/Natalizumab:
Monoclonal antibodies against alpha-4 WBCs (causing inflammation in BBB)
Block VLA4 Ag and prevent interaction of endothelial molecules
Better clinical effect than IFN
Long halflife given only 1/week
Can cause defective immune surveillence against infection-PML (progressive multifocal leukoencephalitis in 1/500 pts) caused by JC virus (usually dormant in kidneys)
Fingolimod:
Oral treatment
Traps lympthocytes in lymph nodes, decreases brain atrphy by entering BBB, increased remission 55% and decreases disability by 35%.
First line in US but second in Israel d/t infection increase (downregulates immune system and maybe malignancy longterm)
Glatiramer Acetate: mimicks antigen presented to T-cells on myelin to attacks drugs instead of myelin and downregulates specific Th2 cell that recognizes myelin and generates others. Only reduces relapses by 33%. Can cause MI like symptoms.
Symptomatic treatment for depression, etc.
What are the side effects of IFN-beta
Common:
– Injection site
reactions
– Flu-like syndrome
Less common:
– Headache
– Depression (?)
– Skin necrosis
– Menstrual irregularity
– Weakness and spasticity
– Anemia and leukopenia
– Hepatotoxicity
What are the diagnostic criteria for MS?
The following 6 criteria are essential for a diagnosis of “definite MS”:
1. Age between 10-50 yrs
2. Objective abnormalities on exam
3. Two or more separate lesions in the CNS
4. CNS disease must reflect white matter involvement
5. Consistent time course
Attacks last > 24 hrs; spaced 1 mo apart
Slow/stepwise progression > 6 mo
6. No better explanation by a physician competent in clinical neurology
Clinical criteria:
1 Gd enhancing lesion or 9 T2 lesions
>= 1 Infratentarial lesion
> =1 Juxtacortical lesion
>= 3 Periventricular lesions
