Case Discussion: Multiple Sclerosis Flashcards
MS
def
Multiple sclerosis is a chronic demyelinating disease of adults characterized by multifocal development and accumulation of plaques of demyelination in the CNS. Multiple lesions in time and space is the sine-qua-non of multiple sclerosis.
MS
Clinical course
Extremely Variable:
(1) Classic: acute onset, relapsing/remitting with eventual burn-out of active disease (“RRMS” = relapsing/remitting multiple sclerosis)
(2) Chronic progressive or primary progressive multiple sclerosis (PPMS)
(3) Secondary progressive multiple sclerosis (SPMS)
Diagnosis of MS
Clinical history and examination: multiple CNS lesions in time and space
CSF examination
(1) mild pleocytosis (5-50 lymphs) during acute attack
(2) increased protein with high IgG
(3) oligoclonal bands (persistent) – Bands seen on electrophoresis of CSF representing antibodies produced within the CNS/CSF
MRI shows multiple plaques, active plaques may enhance
MS
Diagnostic criteria
Pg. 373
Do it
MS
Common clinical manifestations
i) Optic neuritis: visual loss
ii) Limb weakness
iii) Sensory symptoms (paresthesias, hypesthesia)
iv) Cerebellar ataxia
v) Nystagmus
vi) Diplopia (CN VI palsy or INO)
MS
Age of onset/sex/epidemiology
Age 15-50, peak in 20’s
F = 2x males
E: temperate climates
MS
genetics
(1) Most common in white northern Europeans
(2) Family risk (4% risk of 1st degree relative, 26% monozygotic twin concordance) is most likely due to multiple unlinked genes
(1) Multiple sclerosis incidence increases with latitude
(2) Multiple sclerosis risk correlates with geographic location prior to age 15
Multiple sclerosis incidence correlates with HLA type - MHC locus on chromosome 6, MHC class II HLA-DR2 haplotype DR15, DQ6
MS
Tx
methylprednisone
Infusion of high dose methylprednisolone may shorten the course of an acute exacerbation of multiple sclerosis, but probably has no long-term effect on the course of the disease. Monthly infusions are sometimes used in rapidly progressive disease.
MS
β-interferons
Beta-interferons (Betaseron, Avonex, Rebiff) are effective in reducing the severity and frequency of exacerbations
(1) Beta-interferons are thought to interfere with the actions of interferon gamma, which appears to provoke exacerbations
(2) Following binding to specific cellular receptors, interferons lead to synthesis of over 2 dozen proteins that contribute to viral resistance
MS
Tx
glatiramer
Glatiramer (Copaxone) is effective in multiple sclerosis patients and in experimental allergic encephalomyelitis (EAE)
(1) Glatiramer is a mixture of random polymers of four amino acids, L-alanine, L-glutamic acid, L-lysine, and L-tyrosine
(2) The effect is probably related to inhibition of the immune response to myelin basic protein and possibly other myelin antigens
(3) Glatiramer has been shown to at least partially cross-react with myelin basic protein on a cellular and humoral level
MS
Tx
mitoxantrone
Mitoxantrone (Novantrone) is effective at slowing the progression of chronic progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis. It is an antibiotic-class antineoplastic
MS
Tx
Natalizumab
Natalizumab (Tysabri) is indicated for the treatment of relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations
(1) Natalizumab is a recombinant humanized immunoglobulin-4 (IgG4) monoclonal antibody produced in murine myeloma cells directed against alpha(4) integrin
(2) Inhibition of alpha(4) integrin results in at least partial blockade of immune-cell adhesion to vascular endothelium and subsequent tissue migration of lymphocytes
(3) May prevent inflammatory cells from crossing the blood-brain barrier
(4) Carries a risk of activating latent JC virus causing fatal progressive multifocal leukoencephalopathy (PML)
MS
Tx
Fingolimod
Fingolimod is an oral medication indicated to treat relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
(1) Fingolimod hydrochloride is metabolized (via sphingosine kinase) to the active metabolite fingolimod phosphate, which is a sphingosine 1- receptor modulator. By binding to sphingosine 1-phosphate receptors 1, 3, 4, and 5, fingolimod phosphate prevents lymphocytes from exiting lymph nodes which reduces the lymphocyte count in the peripheral blood. The exact mechanism of action of fingolimod in patients with multiple sclerosis is unknown; however, it may work by reducing lymphocyte migration to the central nervous system.
(2) Bradycardia has been reported and may be asymptomatic; monitoring is recommended for 6 hours after the first dose in all patients or in any patient who discontinued fingolimod for more than 2 weeks and plans to restart it. Atrioventricular block may occur, and blood pressure increases and hypertension have been reported.
Neuromyelitis optica
chars
Neuromyelitis optica (Devic’s disease) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord NMO is considered a severe variant of multiple sclerosis (MS) Brain lesions develop in 60% of patients with otherwise typical NMO A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier
Myelinopathies
Basic categories
Primary: disease process directly affects myelin or myelin-producing cell
Secondary: myelin loss or damage is secondary to damage to axon or neuron
MS
variants
Subclinical/self-limited
Acute fulminant (Marburg variant)
Childhood onset with massive demyelination
Neuromyelitis optica (devic variant: SC, optic nerves)
Diseases affecting myelin
Immune-mediated
MS
Acute disseminated encephalomyelitis
AIDP
CIDP
Classifications of myelinopathy
viral
PML
Classifications of myelinopathy
Toxic/metabolic damage
Central pontine myelinolysis
Radiation-induced leukoencephalopathy
Demyelinating peripherals neuropathies due to therapeutic drugs
Lead poisoning
Classifications of myelinopathy
Vascular (genetic)
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts + leukoencephalopathy)
Classifications of myelinopathy
Inheritied metabolic
Leukodystrophies
Many more
Chars of MS plaques
Discrete foci of primary demyelination, not defined by anatomic system:
Demyelination is usually complete
Plaques are usually perivenous
MS plaques
Areas of predilection
Periventricular white matter
Subpial white matter (SC, optic pathways)
Gray-White Junction
MS
Evolution of inflammatory lesion
Individual plaque: acute → resolving → gliotic
Possible fate of acute plaque: Partial remyelination Enlargement Evolution into chronic lesion with oligo/axonal loss Burn out phase: demyelinated glial scar
MS
CSF findings
Increased protein
↑IgG, oligoclonal bands
Diseases with similar pathology to acute MS
Experimental allergic encephalomyelitis (animal)
Acute Disseminated encephalomyelitis
Acute monophasic disease usually triggered by systemic viral infections or immunization
PML vs MS
plaques
Lesions may mimic MS plaques but are more destructive and do not enhance
Central pontine myelinolysis
def
Acute destructive disease affecting myelin due to over rapid correction of hyponatremia
Central pontine myelinolysis
Pathology/clinical manifestations
P: Localized breakdown of myelin, usually in midline of basis pontis
CM: rapidly evolving quadriplegia due to bilateral damage to corticospinal tract myelin
Leukodystrophies
def
Group of rare inherited diseases, whose principal manifestations are due to damage to myelin
Leukodystrophies
Clinical features
-Most are autosomal recessive, have an early onset, and are eventually lethal
Subgroups:
Normal early neurological development followed by loss of milestones and neurological regression
Abnormal neurologic development
Leukodystrophies
pathology
usually results in diffuse, symmetric white matter damage
Leukodystrophies
classification
Defects of myelin degredative enzymes (LSD):
Metachromatic leukodystrophy
Krabbes globoid cell leukodystrophy
Defects of molecules forming myelin (dysmyelinating diseases):
Pelizaeus-merzbacher disease
Others:
Canavans disease
Alexanders disease
Major patterns of primary myelin disease
list
MS pattern (randomly scattered plaques in CNS)
ADEM/AIDP patterns (numerous tiny foci)
Leukodystrophy pattern (diffuse symmetrical)
