Demyelinating Diseases Flashcards
Multiple Sclerosis
chronic inflammatoy disorder characterized by progressive neurological decline that manifests in different clinical phenotypes
MS risk factors
gender (female)
family history
geograpahical latitude
low vitamin D levels
Chronic MS symptoms
fatigue exacerbated by heat (Uhthoff’s phenomenon) that improves with cooler temperatures
sleep disturbances, depression, euphoria, urinary retention, paroxysmal spasms, and cognitive decline
treatment for paroxysmal spasms in MS
carbamazepine
neuropsych testing in MS
deficits in long term memory (most common), verbal fluency, as well as speed and working memory
epilepsy and MS
rare complication, seen in only 2-5%
MS symptoms
broad spectrum of acute focal neurological symptoms, including but not limited to focal sensory or motor deficits, monocular visual loss, diplopia, and gait disturbance
MS diagnostic criteria
2017 McDonald Criteria
2017 McDonald Criteria
diagnosis based on patients that have evidence of demyelination with dissemination in space and time
can be based on clinical changes (relapse), feature son imaging, and CSF findings
Dissemination in Space (DIS)
development of lesions in two distinct anatomical locations indicating a multifocal disease process
Dissemination in Time (DIT)
appearance of new CNS lesions on imaging over time, or lesions of different appearance (bright vs dark) indicating new and old
oligoclonal bands in CSF now considered indication of DIT as well
remitting-relapsing MS (RRMS)
clearly defined attacks with neurologic recovery (complete or incomplete) between them
secondary progressive MS (SPMS)
seen in patients who initially had RRMS but now experiencing a gradual worsening regardless of occasional attacks
early aggressive treatment may delay this progression
primary progressive MS (PPMS)
progressive decline of neurological function without clearly defined attacks over the course of at least 1 year
Clinically Isolated Syndrome (CIS)
defined as a monophasic demyelinating episode in someone who otherwise has no clinical history of demyelinating disease
CIS treatment
initiation of a disease-modifying therapy (DMT) after CIS can delay time to a definitive diagnosis of MS
radiologically isolated syndrome (RIS)
diagnosed in a patient with an MRI that is consistent with MS but they have no clinical history of transient focal neurological deficits
when diagnosed, patients have a 33% chance of having a clinical demyelinating attack over the following two years
risk of MS is higher of oligoclonal bands are present in CSF
typical findings in CSF in MS
elevated protein
elevated CSF IgG index
oligocloncal bands in CSF that do not present in the serum
possibly slight elevation of WBC count (lymphocytic preodminant)
typical finding in MRI in MS
demyelinating lesions related to MS are ovoid, >3mm in diameter, and are typically located in particular regions: periventricular (Dawson’s fingers), juxtacortical, cortical, or spinal cord
acute: contrast enhance due to damage to blood brain barrier
chronic: hyperintense on T2/FLAIR sequences
typical demyelinating attacks
optic neuritis
transverse myelitis
optic neuritis presentation
presents with monocular decreased visual acuity, loss of color vision, and an afferent pupillary defect (APD) due to demyelinating lesion of the optic nerve
often painful with extraocular movements
children more likely to present with headache and bilateral symptoms
can be initial presentation of MS or NMO
optic neuritis funduscopic exam
swollen optic disc
optical coherence tomography (OCT) in optic neuritis
thinning of the retinal nerve fiber layer weeks to months after an acute attack
visual evoked potentials (VEPs) in optic neuritis
prolonged P100 latency, even in patients with distant histories of ON with no residual visual deficits
optic neuritis in DIT/DIS
not considered an event of dissemination in time/space
transverse myelitis presentation
presents with myelopathic findings (weakness, hyperreflexia, sensory symptoms, and occasionally bowel/bladder dysfunction)
Lhermitte’s sign - electric shock sensation down the neck/spine with neck flexion or extension may also be present
MRI in transverse myelitis
T2/FLAIR hyperintense lesion involving the spine +/- contrast enhancement based on the lesion’s acuity
Transverse myelitis as demyelinating presentation
can be initial presentation, however it is also important to exclude infectious, rheumatologic, postvaccination/postinfectious, and nutritional mimics of demyelinating disease
treatment if transverse myelitis related to inflammatory or idiopathic
once other etiologies ruled out, initiation of steroids
MS on gross anatomy
grey plaques within white matter representing loss of myelinated tissue
microscopic analysis of MS lesions
can gauge the chronicity of demyelinating plaque
active plaques microscopic analysis
destruction of oligodendroglia while sparing neurons and their axons, inflammatory infiltrates of the parenchyma and in the perivascular space, as well as macrophages containing myelin debris
recovery phase microscopic analysis
recruited oligodendrocyte precursor cells remyelinate active plaques leading to reduced myelin density and thin myelin sheaths
- almost half of chronic MS plaques will show some degree of remyelination
- remyelinated plaques are known as “shadow plaques”
chronic inactive plaques in microscopic analysis
sharply demarcated hypocellular plaques with myelin loss and glial scar formation via astrocytes
stain for myelin
luxol fast blue (LFb)
acute treatment in MS first line
high dose steroid therapy: IV methylprednisolone (1gm per day for 3-5 days) +/- prednisone taper
- oral steroids have been shown to have equal benefit and can be used first line, but typically not recommended for acute optic neuritis given risk of recurrence in either eye seen in the optic neuritis treatment trial (ONTT)
acute treatment in MS second line
if IV steroids fail to improve symptoms, providers can try plasma exchange (PLEX)
- has more established data for acute MS exacerbation treatment than dose IVIG
acute treatment in MS DMTs
not recommended as the sole treatment for acute MS exacerbations
disease-modifying therapies: forms
oral
injectables
infusions
Oral DMTs
dimethyl fumarate
diroximel fumarate
fingolimod
siponimod
ozanimod
ponesimod
teriflunomide
cladribine
injectable DMTs
interferons
glatiramer acetate
ofatumumab
infusion DMTs
mitoxantrone
alemtuzumab
natalizumab
ocrelizumab
dimethyl fumarate: efficacy
moderate to high
dimethyl fumarate: mechanism of action
reduces toxic oxidative stress through activation of the nuclear 1 factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway
may also suppress pro-inflammatory cytokines
dimethyl fumarate: side effects
flushing (most common), nausea, diarrhea, and leukopenia
treatment for dimethyl fumarate flushing
aspirin by inhibiting the prostaglandin pathway
dimethyl fumarate: monitoring
interval complete blood counts and liver function testing should be done to monitor for medication-related complications
diroximel fumarate
approved for relapsing-remitting MS
fewer GI side effects
same MOA
fingolimod efficacy
moderate to high efficacy
fingolimod: mechanism of action
sequesters lymphocytes in lymph nodes, thereby reducing the number of lymphocytes in peripheral circulation and the central nervous system
performed by downregulating sphingosine-1-phopsphate receptors (S1PR) expressed on lymphocytes in secondary lymphoid tissue
fingolimod similar MOA to:
siponimod, ozanimod, ponesimod
fingolimod mnemonic
FINGolimod using its long FINGers to sequester lymphocytes, via sFINGosine-1-phosphate receptor downregulation on lymphoid tissue
fingolimod: side effects
first dose bradycardia, AV block, QT prolongation due to activation of S1PRs on atrial myocytes
macular edema
fingolimod: monitoring
EKG monitoring and observation required during first dose
frequent ophthalmologic examinations
fingolimod: rare fatal side effects
infections: cryptococcus meningitis, disseminated varicella-zoster, herpes simplex encephalitis, and PML
fingolimod: sudden cessation risk
severe rebounding of disease
siponimod: approved for
relapsing-remitting MS
siponimod: mechanism of action
downregulates sphingosine-1-phosphate receptors (S1PR) expressed on lymphocytes in secondary lymphoid tissue, like fingolimod
siponimod: side effects
macular edema
bradycardia - risk reduced by slow daily titration of medication, c/i in known bradycardic patients
siponimod monitoring
CYP2C9 and funduscopic testing required prior to initiation due to significant variability in metabolism and macular edema, respectively
- certain CYP2C9 variants require greatly reduced dose while some patients with homozygous variants should not receive the drug at all
teriflunomide efficacy
mild effectiveness
teriflunomide mechanism of action
reduces T- and B-cell activation, proliferation, and function by inhibiting pyrimidine synthesis for DNA replication by blocking dihydroorotate dehydrogenase
teriflunomide side effects
leukopenia, alopecia, GI symptoms
hepatotoxicity
category X for pregnancy due to teratogenicity
teriflunomide mnemonic
TERIflunomide is TERRIble for baby development
cladribine mechanism of action
purine antimetabolite
cladibrine side effects
leukopenia, malignancy, teratogenicity
interferons effectiveness
mild effectiveness
interferons mechanism of action
nonselective immunomodulation
interferons side effects
myalgias, flu-like symptoms, injection site reactions
interferons risk
decreased effectiveness over time due to formation of neutralizing antibodies with prolonged use
glatiramer acetate effectiveness
moderate effectiveness
glatiramer acetate mechanism of action
selective immunomodulation
glatiramer acetate side effects
tends to be better tolerated than interferons
lipoatrophy at injection sites
no risk for the formation of neutralizing antibodies, unlike beta-interferons or natalizumab
ofatumumab mechanism of action
monoclonal antibody to CD20 B-cells
ofatumumab effectiveness
proven to be more effective than teriflunomide in randomized drug trials
ofatumumab side effects
injection site irritation, upper respiratory infections, headache
ofatumumab screening
hepatitis B and low immunoglobulins should be done prior to initiating therapy
mitoxantrone mechanism of action
type II topoisomerase inhibitor
mitoxantrone approved for
secondary progressive MS
mitoxantrone side effects
dose-related cardiotoxicity
alopecia, menstrual irregularity, amenorrhea, and leukopenia
category D for pregnancy
mitoxantrone monitoring
pretreatment cardiac output screening is advised, and monitoring should occur with the first treatment
alemtuzumab mechanism of action
monoclonal antibody targeting of the CD-52 receptor on activated T- and B-lymphocytes, leading to cytotoxic and complement-mediated depletion
alemtuzumab side effects
lymphopenia and autoimmune-related syndromes including thyroid disease (30-40%), thrombocytopenia (1%), and anti-glomerular basement membrane-related nephropathy
natalizumab effectiveness
highly effective
natalizumab mechanism of action
monoclonal antibody targeting of alpha 4-integrin which is expressed on activated T-lymphocytes, which blocks the transmigration of T-cells across the blood-brain barrier
natalizumab side effects
progressive multifocal leukoencephalopathy (PML)
natalizumab risk of PML
usually fatal opportunistic infection of CNS within oligodendrocytes due to reactivation of latent JC polyomavirus infection
risks include: positive anti-JC virus antibodies before initiating therapy, prior use of immunosuppressive therapy, and more than 24 months of natalizumab therapy
natalizumab monitoring
JCV titers checked before starting therapy
JC viral positive patients can still undergo treatment, however the risk for PML increases when the duration of therapy is greater than 2 years
natalizumab treatment for PML
discontinuation of natalizumab
PLEX used to accelerate drug clearance
restoration of immune function may result in immune reconstitution inflammatory syndrome (IRIS)
natalizumab sudden cessation
without transition to another therapy can lead to worsening of symptoms
ocrelizumab approved for
primary progressive and relapsing-remitting MS
ocrelizumab mechanism of action
binds CD20 B-cells leading to cell-mediated cytotoxicity
ocrelizumab side effects
increased risk of infection
dalfampridine mechanism of action
inhibition of voltage-dependent potassium channels causes improved nerve conduction
dalfampridine treatment associated with
improvements in strength, ambulation, and endurance
dalfampridine monitoring/contraindications
renally cleared, so patients with CKD are at risk for toxic blood levels, so should be avoided in ESRD
contraindicated in patients with epilepsy
rebounding demyelinating disease
seen with the cessation of fingolimod or natalizumab when no substitute medication is initiated
often presents within a few months of discontinuation
symptoms include fulminant encephalopathy and focal neurological deficits
treatment includes high dose steroids and/or PLEX
tumefactive MS
presents with a large >2cm demyelinating lesion with incomplete ring enhancement, mass effect, minimal surrounding edema, and low cerebral blood volume
- may be difficult to differentiate from brain tumor, ADEM, or abscess
- tumors often more significant surrounding edema and higher cerebral blood volume than TMS
- biopsy sometimes required to confirm the diagnosis
tumefactive MS pathology
foamy microphages containing phagocytosed myelin debris
marburg variant disease (acute/fulminant MS)
fulminant form of MS with large tumefactive lesions, associated with high mortality rate
relatively unresponsive to therapy but high dose steroids and PLEX may help
marburg variant disease pathology
more macrophage infiltrates and necrosis than typical MS
Balo’s concentric MS
imaging will show concentric alternating bands of preserved myelination with alternating areas of demyelination
also described as “onion bulbs” when seen pathologically
Schilder’s disease
seen primarily in childhood
lesions will be large in size, contrast-enhancing, and usually involve the centrum semiovale
pregnancy with MS
generally safe
- children born from parents with MS have a 3-5% risk of developing MS themselves
relapse rates decrease over duration of pregnancy and increase postpartum
pregnancy and breastfeeding have no effect on overall disease progression
pregnancy with MS: ok meds
glatiramer acetate and interferon beta are felt to be safest options for pregnancy
high dose corticosteroids can be used for acute relapses during pregnancy and are not teratogenic
pregnancy with MS: avoid meds
DMTs should be discontinued or avoided if possible during pregnency, especially if patient is taking teriflunomide or motixantrone
MS mimics
infectious
inflammatory
other demyelinating disease
other
MS mimics: infection
HIV
Lyme
Neurosyphilis
Bartonella infection
PML
Whipple’s disease
MS mimics: inflammatory disease
Sjogren’s syndrome
Systemic lupus erythematosus (SLE)
Sarcoidosis (intramedullary lesions are most often found in the cervical cord)
Behcet’s disease
CNS vasculitis (primary or secondary)
Susac’s syndrome
MS mimics: other demyelinating disease
ADEM
NMO
Leukodystrophies
MS mimics: other
CADASIL
B12 deficiency
neuromyelitis optica spectrum disorder (NMOSD)
inflammatory CNS disorder distinct from MS
most commonly associated with antibodies to aquaporin-4 (APQ4)
NMO core clinical characteristics
optic neuritis (longitudinal/chiasmal lesion)
longitudinally extensive transverse myelitis (LETM) is defined by a single lesion involving 3 or more vertebral segments
brainstem/diencephalic lesions
area postrema syndrome
NMO diagnosed based on what criteria
2015 Wingerchuk criteria
what to check when NMO suspected
antibodies to aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG)
AQP4
water channel localized in the CNS at the endfeet of astrocytes
MOG
found on oligodendrocytes
NMO CSF findings
oligoclonal bands often absent
NMO pathologic findings
perivenous infiltration of lymphocytes, inflammation, and demyelination
NMO Treatment: acute
high dose steroids, then PLEX or IVIG if symptoms are steroid-resistant
NMO treatment: long term
IVIG
immunosuppressants (azathioprine, mycophenolate)
monoclonal antibodies (if anti-AQP4 antibody positive)
monoclonal antibodies in NMO treatment
inebilizumab
satralizumab
eculizumab
inebilizumab mechanism of action
CD19-directed antibody
satralizumab mechanism of action
interleukin-6 (IL-6) receptor antagonist
eculizumab mechanism of action
complement-binding monoclonal antibody
acute disseminated encephalomyelitis (ADEM)
aka postinfectious encephalomyelitis
monophasic autoimmune illness that presents abruptly with headaches, fever, and widespread CNS demyelination and occurs primarily in children and young adults
ADEM resolution
symptoms usually resolve within a week without residual neurologic deficits
children more likely to make a complete recovery than adults
ADEM onset
7-14 days after environmental exposure
most commonly occurs after viral URI but can occur after immunizations as well
MRI in ADEM
multiple bilateral hyperintense T2-weighted lesions with poor margins and variable enhancement
hyperacute variant of ADEM
acute hemorrhagic leukoencephalitis (Hurst’s disease)
unlike traditional ADEM will show hemorrhagic lesions radiologically
pathology: perivenous infiltration of lymphocytes, inflammation, and demyelination
ADEM vs MS/NMO
acute demyelinating lesions for MS are perivascular
acute demyelinating lesions for ADEM are perivenular
progressive multifocal leukoencephalopathy (PML)
usually fatal infection of oligodendrocytes caused by reactivation of latent JC polyomavirus
PML presentation
subacute progressions of encephalopathy, focal motor deficits, ataxia, diplopia, and/or hemianopia
PML: CNS infection
established via hematogenous dissemination of the latent virus in the kidneys which then crosses the blood-brain barrier
PML: who is at risk
patients with impaired immune systems: HIV, leukemia, and those on immunosuppresive agents (chemotherapy/monoclonal antibodies)
JCV positive patients risks
natalizumab is high risk of causing PML when treatment is greater than 2 years
if on immunosuppressive medications at time of diagnosis should have medications discontinued and then consider PLEX to remove drug from circulation
HIV-related PML
started on HAART therapy
restoration of immune function may result in immune reconstitution inflammatory syndrome (IRIS),
immune reconstitution inflammatory syndrome (IRIS)
presents with worsening neurologic symptoms and contrast enhancing cerebral edema
IRIS occurs 3-6 weeks after treatment for PML and should be treated with high-dose IV steroids followed by an oral slow taper regimen
PML: imaging
non-enhancing FLAIR lesions preferentially involving the white matter without mass effect
PML: pathology
demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei with intranuclear inclusions
immunohistochemistry staining for the JC virus is considered the gold standard for diagnosis
PML monitoring
JC virus PCR titers can also be used for diagnostic purposes and should be performed before biopsy if clinical suspicion is high
central pontine myelinolysis
aka osmotic demyelination syndrome due to rapid correction of hyponatremia leading to demyelination of the base of the pons
extrapontine demyelinating lesions are infrequent but when present they are seen at cortical gray-white matter junctions
central pontine myelinolysis seen in
alcoholics, end-stage renal disease, chronically malnourished patients, and patients undergoing hepatic transplant
central pontine myelinolysis presentation
acutely with AMS, hypotension, and hypoventilation with progression to pseudobulbar palsy and quadriparesis
severe cases can progress to a locked in syndrome
no available therapies, but many patients improve over time
what can be used for both ulcerative colitis and MS?
ozanimod
