Demyelinating Disease Flashcards by Rai Christiana

Destruction of myelin sheaths of nerve fibers with relative sparing of other elements of the nervous system (axons, neuronal cell bodies, supporting structures) which are less affected

Demyelinating Disease

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Infiltration of inflammatory cells, particularly in a perivenous distribution

Demyelinating Disease

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Lesions that are primarily in the white matter, either in multiple small disseminated foci or in larger foci spreading from one or more centers

Demyelinating disease

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Chronic inflammatory demyelinating condition of CNS of unknown cause

Multiple Sclerosis

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Multiple sclerosis

Characteristics

Episodes (attacks) of focal disorders of the optic nerves, spinal cord and brain
remit to varying extent, recur over a period of many years, usually leading to progressive deficits

• Remission and relapse
• Evidence of > 1 discrete lesion in the CNS
• Discrete areas of damaged myelin (“plaques”) embedded in normal appearing tissue

• Neurologic manifestations have varied location and extent of demyelination

Separated in time and space

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Multiple sclerosis predilection

• Periventricular white matter - where subependymal veins line the ventricles (adjacent to bodies and atria of lateral ventricles)
• Corpus callosum
• Optic nerves and chiasm (rarely optic tract)
• Spinal cord - where pial veins lie next to or within the white matter; especially dorsal spinal cord
• But spare no part of the CNS
• Brainstem, cerebellar peduncles

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Sharply delineated tissue that is slightly depressed and stands out from the surrounding white matter due to its pink-gray color (result of myelin loss)
• Principally around periventricular white matter of brain, brainstem and spinal cord (do not extend beyond root entry zones of CN and spinal nerves)

Plaques

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Peak age of multiple sclerosis

30 y/o

First symptoms rarely occur before age 10 or after age 60

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Multiple sclerosis epidemiology

• Latitudinal gradient with
increased prevalence of MS
further from the equator in
both hemispheres

Black Americans have lower risk than whites at all latitudes but with same south to north gradient

F>M (2-3x)

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immunomodulatory properties and can prevent or ameliorate experimental allergic encephalomyelitis in mice

Vit D

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— correlation between sun exposure and dietary intake of Vit D vs risk of MS

Inverse

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Immigrated —- has similar risk to that of country

Before age 15

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Immigrated —- has similar risk with that of their birth place

After age 15

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Multiple sclerosis strongest genetic factors

HLAs

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Susceptible gene

HLA-DR locus on chromosome 6

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Multiple sclerosis Pathogenesis

Genetic, Environmental,, factors & Infectious triggers > Activation of myelin- reactive Th1/17 cells> Infiltration into CNS > BBB Breakdown + Immune cell recruitment > CNS tissue damage > Neurological dysfunction

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Multiple sclerosis is a — mediated disease

T cells

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• Antibody associated demyelination
•

B cell

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• Also act as APCs

B cell

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B cell location

Cell meninges & brain parenchyma

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Onset of multiple sclerosis

Acute or insidious
Vary in severity

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Sensory disturbance of multiple sclerosis

• Paresthesias, dysesthesia or hypoesthesia
• Intermittent or constant
• Can spread from one location to adjacent areas
• Common pattern: unilateral leg numbness that spreads to other leg and
ascends to pelvis, abdomen or thorax = SC involvement
• Lhermitte sign: on neck flexion, there is electrical or shock-like sensation traveling down the spine and radiates into one or more limbs
• Lesion is on cervical cord
• May evolve into chronic neuropathic pain

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on neck flexion, there is electrical or shock-like sensation traveling down the spine and radiates into one or more limbs

Lhermitte sign

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Motor symptoms of multiple sclerosis

• Second most common initial manifestation • Evolve over hrs or days • Limb weakness, loss of dexterity, gait disturbance + spasticity • Hyperreflexia, (+) Babinski • May be hyporeflexic if impedes the MSR

• 3rd most common presenting manifestation • Inflammation and demyelination of the optic nerve • Loss of vision affecting usually one eye evolving over hours or days

Optic neuritis

temporary appearance of new or worsening neurologi symptoms during elevations in temperatures due to reversible conduction block along demyelinated nerve fibers

Uhthoff phenomenon

impaired proprioception from spinal cord dorsal columns

Romber sign

Dysconjugate eye movements • Depending on which eye muscles are affected

Diplopia

Most common diplopia

Internuclear opthalmoplegia-mlf lesion

bilateral exotropia, bilateral INO

WEBINO

Weak slow adduction of the affected eye with abduction nystagmus of the contralateral eye

Internuclear ophthalmoplegia - MLF syndrome

• May be fleeting or lasts for days • Associated with other brainstem signs and symptoms

Vertigo

• Can occur as a consequence of exertion (neuromuscular fatigue), manifestation of depression, consequence of insomnia • Out of proportion to physical activities

Fatigue

• Trigeminal neuralgia secondary to MS - bilateral, constant duration, involvement of V1 and sensory loss

Facial pain

tonically contracted and incapable of complete feeling

Spastic bladder

fails to contract and overflows

Denervated bladder

Incontinence due to sphincter dysfunction or bowel spasticity and fecal urgency

Bowel dysfunction

• Erectile and ejaculatory dysfunction • Difficulty achieving orgasms, decreased vaginal lubrication and sensation • Decreased libido

Sexual dysfunction

Peripheral facial palsy • Intraparenchymal emerging fibers

Facial weakness

• Hallmark of the disease • Paroxysmal • Tonic spasms of a limb or face often preceded by paresthesias or dysesthesias • Spasms are brief, painful and distressing • Can occur at night and in clusters • Can be elicited by movements, hyperventilation or other precipitating factors

Flexor spasms

• Short term memory, attention, concentration, information processing, problem solving, multitasking and language • Emotional lability • 50-60% depression

• Neuropsychiatric dysfunction

• Tongue weakness from lower brainstem dysfunction, spastic dysarthria from corticobulbar lesions, scanning dysarthria from cerebellar dysfunction

Dysarthria

• Chronic flickering contractions of the orbicularis oculi or other muscles of facial expression • Injury to facial nerve within brainstem or to corticobulbar tracts

Facial myokymia

• Brief, repetitive, stereotyped attacks of neurologic dysfunction • Trigeminal neuralgia, tonic spasms • Due to ephaptic spread of abnormal discharges form demyelinated fibers • Acute inflammation or chronic damage • Spontaneous or provoked

Paroxysmal symptoms in MS

S&S improve partially or completely followed by a variable latent period same abnormalttes or then by recurrence of the appearance of new ones in other parts of the CNS

Relapsing-remitting

Initially relapsing profile becoming steadily progressive in later stages

Secondary progressive

> 40 onset, progressive

Primary progressive

patients develop symptoms due to plaque formation

Relapses/flares/attacks

periods of recovery due to resolution of acute inflammation, myelin repair and plastic reorganization

Remission

Location of plaques

(corpus callosum or periventricular white matter)

• 85% of patients • Relapses/flares/attacks - patients develop symptoms due to plaque formation • Most plaques are in clinically silent areas (corpus callosum or periventricular white matter) • Remission - periods of recovery due to resolution of acute inflammation, myelin repair and plastic reorganization • Complete recovery vs sustained neurologic deficits due to irreversible axonal and myelin injury (40%) • Plaque accumulation in clinically silent areas will eventually result in impairments

Relapsing remitting MS

• First demyelinating event • Develop MS vs no further evidence of demyelinating disease • Risk of having a 2nd attack after 14 yrs of follow-up is 88% if there are any lesions present on the initial brain MRI and only 19% if the initial brain MRI is normal

Clinically isolated syndrome

• More than half of RRMS develop SPMS • Insidiously progressive neurologic impairments • Frequency of relapses decrease • Median time from diagnosis of RRMS to SPMS is 15-19 years • Time from disease onset to requiring a cane,

Secondary progressive MS

Median time from diagnosis of RRMS to SPMS is

15-19 y/o

Time from disease onset to requiring a cane to walk

15-22 y/o

• 10-15% of patients • Progressive from onset without relapses or remissions, but fluctuations occur • Typically present with insidious onset of asymmetric leg weakness or gait disturbance • Visual loss at onset is rare • M=F • Older age of onset (40 yrs vs 30yrs in RRMS) • Develop ambulatory disability 50% faster • Dx: MS plaques on brain MRI and oligoclonal bands or elevated IgG index in CSF

Primary progressive

Least common

Primary Progressive Relapsing

Quantifies components of neurologic examination as functional scale scores and takes into account the extent of ambulatory disability and limitations in self care

• Expanded Disability Status Scale (EDSS)

Multiple sclerosis dx

Clinical criteria MRI +/- CSF

Multiple sclerosis Type of MRI

T2 and T2 FLAIR

. T2 and T2 FLAIR hyperintensities that have a round or ovoid appearance located within the

corpus callosum and the periventricular, juxtacortical, deep white matter and subcortical white matter • Pons, floor of the 4th ventricle, cerebellar peduncles, cerebellar hemispheres

Linear or flame-like streaks oriented perpendicular to the lateral ventricles

Dawson’s fingers

Cranial MRI signifies active inflammation and disruption of BBB. Typically resolves after 1-3 weeks

Contrast uptake (homogenous or ring enhancement) of acute plaques

T1 shows areas of relative— that correspond to increased T2 signals = chronic

hypointensity (T1 black holes)

Plaques seen on

T2 or T1

Spinal cord volume loss of

both central gray and white matter tracts •

Intermedullary lesion

C5-C6

Plaques description in spine

oriented longitudinally along the cord, often with dorsal location, spanning one or 2 vertebral cord segments

CSF Analysis

• Elevated total IgG • Elevated IgG ratio • Increased IgG synthesis rate • Increased IgG index • Presence of 2 or more oligoclonal bands in the CS that are not present in the serum sample

% Mild lymphocytic pleocytosis

% Normal/mildly elevated protein

Multiple sclerosis Evoked potentials

Sensitive in detecting clinically silent lesions • VEP - asymmetric delay of P100 and conduction block • SSEP - delays or blocks

Diagnostic criteria

Mc Donald Criteria "Separated in time and space"

Rare fulminant disease that presents with acute or subacute neurologic dystunction

Tumefactive MS

• Cranial MRI: large edematous lesions with nass effect and contrast enhancement (at least one large lesion > 2cm) • Appearance similar to brain tumor

Tumefactive MS

Acute-onset fulminant demyelinating course relentless in progression, which may lead to death in a matter of months

Marburg Variant MS

• Monophasic • Cranial MRI: multiple T2 FLAIR hyperintensities that coalesce to form confluent, large plaques in the hemisphere and brainstem • Edematous and enhancing • Massive macrophage infiltration, axonal injury and necrosis • CSF analysis: usually normal to slightly elevated WBC, less common oligoclonal bands

Marburg Variant MS

Characterized by alternating bands of demyelinated white matter and nearly normal white matter • Onion bulb and whorled appearance

Balo Concentric Sclerosis

Present with headache, altered mental status, seizure, incontinence and other signs of increased ICP and mass effect before focal signs • Pathognomonic concentric rings seen in tissue samples and MRI

Baloconcentric Sclerosis

Cranial MRI • T1: alternating hypo and isointense rings • T2: alternating iso and hyperintense rings • GE: enhancement at the periphery • Eventually evolve to homogeneous tumefactive or more typical demyelinating lesions

Balo Concentric Sclerosis

Inflammation of the spinal cord resulting to motor and sphincter impairment with sensory level • Bilateral, cause more severe weakness compared to MS myelitis • Presenting manifestation of MS in 1-2%

Acute Transverse Myelitis

Acute transverse myelitis causes

Infections • Collagen vascular diseases • Sarcoidosis • Idiopathic inflammatory disease • Presenting manifestation of neuromyelitis optica

Long segment (3 or more) *short segment - uncommon

Transverse myelitis

Both halves Greater than 2/3 of the cord

Transverse myelitis

Short segment

Myelitis

Involve less than half of the cross sectional area

Myelitis

Uncommon: whole transverse or anterior portion only Lesions in other segments of the cord and brain

Myelitis

Attacks of ON can be bilateral or unilateral, severe with poor recovery 2. Myelitis is severe and transverse and is LONGITUDINALLY EXTENSIVE involving 3 or more contiguous vertebral segments 3. Intractable nausea, vomiting or hiccups

Neuromyelitis Optica Spectrum Disorder (Devic disease)

Aggressive inflammatory disorder characterized by recurrent attacks of optic neuritis and myelitis • Affect 4-10/100,000 persons • F>M (3:1) • Typically begins in adulthood (4th decade) but can occur at any age

Neuromyelitis Optica Spectrum Disorder (Devic disease)

Neuromyelitis Optica Spectrum Disorder (Devic disease) • Brain lesions can be present: only around ventricles

• Hypothalamus - endocrinopathy • Area postrema - intractable vomiting or hiccups • Cerebral hemispheres - focal symptoms, encephalopathy and seizure • Can be asymptomatic • Often not destructive and can resolve completely

extensive demyelination, axonal damage and contain inflammatory infiltrate consisting of macrophages, B lymphocytes, eosinophils and granulocytes • Immunoglobulin and products of complement activation are deposited in distinctive perivascular rim and rosette pattern • Gray and white matter of spinal cord are necrotic

Acute NMO Lesion

Nmo dx criteria

1. Optic neuritis 2. Acute myelitis 1. Spinal cord MRI lesion extending three or more contiguous vertebral segments 2. Initial brain MRI with fewer than four white matter lesions or three lesions if one is periventricular 3. NMO-IgG seropositivity

Loc of damaged neuron cell

Optic nerve 2) Brainstem Spinal cord

Devic disease spinal mri

Focal enhancing areas of swelling and tissue destruction extending over 3 or more segments and on axial cuts, centered on the gray matter of the cord

Devic disease CSF analysis

• Pleocytosis with neutrophils and eosinophils • Oligoclonal bands not common (<30%)

• Main water channel in CNS • Primarily located in perivascular and subpial astrocytic foot processes and expressed in high levels in the opti lerves, hypothalamus, brainstem, periventricular regions and gray matter of spinal cor • Localized to the foot processes of astrocytes in close apposition to endothelial surfaces, as well as at paranodal regions near the nodes of Ranvier

• Aquaporin 4 (AQP4)

Sensitive and highly specific Present in 70% of NMOSD patient's serum or CSF • Fix complement to mediate astrocyte injury • (+) - higher risks of relapses; more than half within 1 year if untreated (-) - may be positive for anti-myelin oligodendrocte glycoprotein Ab (Anti-MOG)

Aquaporin 4 IgG (Anti-AQP4)

Devic disease Associated with highly specific autoantibody directed against AQP4

anti-AQP4

Monophasic illness characterized by multifocal inflammation and demyelination • Rapid onset • More common in children • Associated with recent rabies or small pox vaccination (post vaccination encephalomyelitis) and recent infection (post infectious encephalomyelitis • Often follows exanthems ie chickenpox and measles • Autoimmune response to myelin basic protein

Acute Disseminated Encephalomyelitis (ADEM)

Onset of Acute Disseminated Encephalomyelitis (ADEM)

Rapid

Acute Disseminated Encephalomyelitis (ADEM) Infections

(post infectious encephalomyelitis)

fulminant and devastating form of ADEM with microvascular hemorrhages

Acute hemorrhagic leukoencephalitis (Hurst disease)

Presents as ON, myelitis or anti-AQP4 seronegative NMO in adults • Bilateral, synchronous ON and myelitis • Papillitis or swelling of nerve head (us MS or MO) • Extensive cord involvement • Presents as ADEM in children • Defined by presence of anti-MOG Ab

Anti-Myelin Oligodendrocyte Glycoprotein Demyelination

• Recurrent bouts of ON with unknown etiology • Diagnosis of exclusion • Imaging studies of CNS are normal or nonspecific other than findings related to ON • Laboratory studies are normal

Chronic Relapsing Inflammatory Optic Neuropathy (CRION)