Multiple Sclerosis and Other CNS Inflammatory Demyelinating Diseases
Marcelo Matiello
Taha Gholipour
Rene A. Colorado
Riley M. Bove
Group of diseases of the CNS (see table below) in which destruction of myelin is a prominent feature along w/infiltration of inflammatory cells, particularly in a perivascular distribution. Lesions are primarily in white matter but variable degrees of neuronal and axonal degeneration may be seen, and in some diseases (e.g., NMO), tissue necrosis including vessels and axons is also possible.
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MULTIPLE SCLEROSIS (MS)
Definition: Most common autoimmune inflammatory demyelinating CNS disease, characterized by dissemination in time (multiple attacks) and space (different sites in the CNS). While there are no clinical features that are unique to MS, some are highly typical of the disease including sensory symptoms in limbs or face, visual loss, acute or subacute motor weakness, diplopia, gait and balance problems, Lhermitte sign, acute transverse myelitis, and pain. Typically presents in young adults w/two or more clinically distinct episodes of CNS dysfn w/at least partial resolution.
Pathophysiology: Complex genetic-environment interactions are suspected to increase susceptibility to disease. The roles of humoral and cellular immunity are not fully understood; however, it is known that activated T cells interact w/endothelial molecules and migration across the BBB is increased by proteinases. CD4+ T cells are reactivated after unknown antigen presented by the MHC class II; cytokines and chemokines lead to chemoattraction of B cells (intra-CNS production of Abs—oligoclonal bands seen on CSF analysis), monocytes, and CD8+; inflammatory cascade results in demyelination and axonal injury mediated by cytotoxic CD8+ and macrophages.
Epidemiology: Estimated prev: 400,000 US; 2.3 million worldwide; F:M 2:1; ages 20-40. Genetics: Monozygotic twins 20%-30% concordance; 20% MS pts have a relative w/MS. Assns: Caucasian, EBV antigen, HLA DRB1, low vitamin D/poor sunlight exposure, high BMI in childhood/adolescence, melanocortin receptor. More severe in African Americans.
Clinical Scenarios:
Clinically isolated syndrome (CIS) (NEJM 2002;346:158): Initial isolated CNS demyelination event (brain, brainstem, ON, or cord). Risk of → MS after CIS 38% @ 10 yr, 68% @ 14 yr. ↑ risk if initial MRI T2 hyperintense lesions, (T2H): (88% w/≥2 T2H vs. 19% if nl MRI, @ 14 yr). If first MRI shows ≥3 T2H or 1 contrastenhancing lesion (CEL): rate of new MRI abnls in first few months ˜80%-90%. After CIS repeat brain/spine MRI @ 3 & 6 mo, then annually. If new lesions, initiate Rx.
Radiologically isolated syndrome (RIS): Typical MRI but w/o clinical sx; repeat imaging at 3 mo, 6 mo; if new lesions, may initiate Rx. In 5-yr FU clinical events identified in 34% (˜10 of these fulfilled criteria for PPMS). Age <37 yr, male sex, and spinal cord involvement are predictors of symptom onset (PLoS One 2014;9(3):e90509).
RRMS: Relapsing remitting MS—85%-90% of initial course. Short-term relapse risk correlates w/enhancing lesions on baseline MRI & w/relapses over prior 2 yr.
PPMS: Primary progressive MS (older pts, African Americans).
SPMS: Secondary progressive MS (RRMS initially than becomes progressive after decades).
“Benign MS”: Low dz burden over >20 yr course; first few years are predictive. Female sex, early onset, and presentation w/optic neuritis and sensory symptoms are a/w favorable courses. Label “benign MS” is often temporary; disease may become disabling.
New classifications have been proposed based more simply on whether MS is active (new clinical attacks, new lesions, or enhancing lesions) and/or progressive (worsening on clinical evaluation) (Neurology 2014;83:278-286).
MS attack: Symptomatic inflammatory demyelinating event lasting >24 h w/objective clinical findings, >30 days from prior attack.
WORKUP FOR MS
DDx broad, MUST r/o MS mimics. Institute w/u early; goal: start appropriate Rx to prevent further attacks and possibly alter the disease course.
H&P: Ask about systemic sx (skin involvement, arthralgias); recent infxns, fevers, or vaccinations; prior episodes of motor/visual/sensory loss; recent trauma; family Hx.
Serum tests (depending on presenting syndrome): NMO Ab (more likely to be positive in LETM (longitudinal extensive transverse myelitis), severe or bilateral ON), Lyme (if in endemic region), RPR, B12, HIV, ESR, ANA, ACE, HTLV-1 (in progressive myelopathies) to r/o other etiologies.
CSF: WBC <50; IgG index = (CSF IgG/CSF albumin)/(serum IgG/serum albumin); nl range 0.34-0.66; elevated in MS (also elevated in ddx: SSPE, viral encephalitis, CADASIL, HIV, SLE, NMO, ADEM, ALD) Oligoclonal bands (OCB): shows bands exclusive to CSF, (may also be present in: SLE, APLAS, Sjögren, sarcoidosis). For both tests, a serum sample should be send at the same time as CSF.
MRI: T1 axial w/gadolinium, T2/FLAIR axial & sagittal. Brain: Multifocal WM lesions, usually >3 mm. Corpus callosum involvement is quite specific. Acute plaques = fade after 4-6 wk. T2 hyperintense lesions (T2H): Stable, shrink, or grow. Dawson fingers: Periventricular ovoid lesions w/long axis perpendicular to ventricles. T1 hypointensities “Black holes”: Old plaques; may persist × years; represent axonal loss. Spinal cord: Lesions in up to 80% pts, usually cervical, <1 cord segment, peripheral; may be asx.
2010 MCDONALD DIAGNOSTIC CRITERIA FOR MS (ANN NEUROL 2011;69(S):292-302)
In the past, as a rule, a dx of MS was not determined unless there was clinical hx of two or more relapses and evidence on examination of more than one discrete lesions of the CNS (dissemination in time and space). Currently, MRI aids capacity to identify clinically silent lesions, of different ages, as key part of dx criteria. Current diagnostic criteria are shown in the table.
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Red flags suggestive of possible alternative dx (Neurology 2007;13:13). (1) Hearing loss, especially b/l, (2) onset <10 yo or >50 yo; progressive or stroke-like onset, (3) serum: ESR >80; CSF: protein >100 mg/dL, WBC > 50 mm3, + PMNs; or nl CSF, (4) MRI: Negative, u/l lesions, (5) Systemic: Coexisting systemic/autoimmune d/os; + PNS sx, (6) Psych Hx, prominent deficits w/o concurrent objective findings or + MRI, (7) Atypical MRI: Extensive gray matter involvement, anterior temporal lobes, punctate, tumor-like mass lesions, spinal cord lesion extent >3 vertebral segments, diffusion restriction.
COMMON MANIFESTATIONS OF MS & DDX
ON (ddx: NMO, idiopathic, sarcoidosis, toxic; mimics: retinal artery occlusion, retinal detachment, acute glaucoma).
Brainstem sx: (1) Internuclear ophthalmoplegia (INO) (ddx: infarcts, e.g., CADASIL, lacunes; myasthenia gravis, trauma, syphilis, Lyme, meds (phenothiazines, TCA), SDH, brainstem, & fourth vent tumor); (2) oculomotor dysfn; diplopia (ddx: Wernicke encephalopathy); (3) trigeminal neuralgia (ddx: idiopathic; posterior fossa tumor); (4) facial nerve palsy (ddx: idiopathic; Lyme; sarcoidosis); (5) generalized brainstem processes (ddx: CPM, Behcet’s); (6) vertigo, nystagmus, oscillopsia (ddx: broad); (7) cerebellar ataxia (ddx: spinocerebellar ataxia, ADEM, post-VZV cerebellitis, Wernicke syndrome, vit E deficiency).
Spinal cord sx: Transverse myelitis (TM) (ddx: Acute: NMO (LETM), idiopathic, epidural abscess, spinal epidural hematoma, spinal AVM, mycoplasma; slowly progressive myelopathy: Structural causes: Cervical stenosis, syrinx, epidural tumor; others: Spinal AVM, dural venous fistula, HTLV1, HIV myelopathy, Cu or Zn deficiency, hereditary spastic paraparesis, adrenomyeloneuropathy).
Pain syndromes: (1) Trigeminal neuralgia; (2) Lhermitte sign: Neck flex → electrical sensation; in ˜10% MS pts @ presentation (ddx: cervical stenosis, spinal cavernous angioma or tumor; ↓ B12); (3) tonic spasms (ddx: NMO, spinal strokes); (4) HA (e.g., secondary migraine; ddx broad); (5) back pain; (6) dysesthetic limb(s); (7) brief painful focal szs.
Cognitive changes: Initial deficits include attention and processing speed. Depression, memory loss; aphasia, mania, personality changes (ddx: ADEM, lupus cerebritis, viral encephalitis, HIV, PML, CADASIL, metachromatic leukodystrophy, adrenoleukodystrophy). Many MS pts have functional sx early in dz.
MANAGEMENT OF ACUTE MS ATTACKS
Ddx attack: Pseudorelapse (recrudescence of previous syndrome 2/2 infection or fatigue). Bladder infxn > tooth infxn > URI; also, r/o other common neurologic causes, e.g., disk herniation; routine w/u (minimal): U/A, ESR, CBC, CXR (looking for infectious trigger). Uhthoff phenomenon (worsening of neurologic symptoms when body gets overheated—hot weather, exercise, fever, saunas, etc.). Sx and symptoms disappear or improve w/cold shower and air-conditioning.
For most attacks, IV methylprednisolone (Solu-Medrol) 1 g/day × 3 days typically; 5 days if ongoing evolution of symptoms at day 3 or severe attack (or 1,250 mg PO prednisone). Check PPD. Give Ca/vit D, PPI, insulin SS w/FS AC + HS while in house & if on taper. Speeds recovery, does not improve long-term outcomes. ± 10-14 days PO prednisone taper (rarely done).
Plasmapheresis: 5-7 courses of 1-1.5 plasma volume exchanges. Used in fulminant cases that are refractory to steroids. Neurology 46(6):878-886.
Disease-modifying therapies (DMTs) in CIS and RRMS
Utility: Decrease severity & number of relapses, steroid courses, & hospital stays, may alter dz course.
Principles of use: (1) Start early; aggressive w/u of CIS and RIS. (2) Selection based on compliance likelihood, tolerance of side effects. (3) If breakthrough, increase dose or switch DMT. (4) Check MRI 6 M & 12 M after starting DMT, may need to change dose
or Rx. (5) Limited data on safety w/pregnancy & breast-feeding; usually d/c DMTs & trial of steroids or IVIg for relapses.
or Rx. (5) Limited data on safety w/pregnancy & breast-feeding; usually d/c DMTs & trial of steroids or IVIg for relapses.
Injectables
Beta Interferons (IFNs):
MOA: Enhance suppressor T cells, decrease release of metalloproteinases & proinflamm cytokines, prevent helper T cell adhesion to BBB, down-regulate antigen presentation.
SE/AE/monitoring: Overall good safety profile. Injection site inflamm, HA; Flulike sx, rhinitis, fatigue. Rare: Depression/suicide, szs, thyroid abnls, decrease plts, lymphopenia, elevated LFTs, symptomatic hepatitis. Check CBC & LFTs @ baseline, 1 mo, 3 mo, 6 mo; then q6mo. TFTs q6mo. Think developing neutralizing antibody (Nab) if more relapses/new T2 lesions. Consider switch to alternate class of DMT if pos. If Nab neg, no further testing.
Dosage and key clinical trials: Beta IFN-1a 30 &mgr;g IM qwk (Avonex). Trials: CIS CHAMPS and 22 or 44 &mgr;g SC 3×/wk (Rebif) titrate over 4 wk. Pivotal trial for RRMS: PRISMS (Lancet 1998;352(9139):1498); for CIS: ETOMS (Lancet 2001:357(9268):1576-1582).
Beta IFN-1b 8 MIU (0.25 mg) SC qod (Betaseron and newer Extavia) titrate over 6 wk. Trials for RRMS IFNB MS Study (Neurology 1993;43(4):655-666); for CIS BENEFIT (Neurology 67(7):1242-1249).
Pegylated interferon beta-1a (Plegridy) formed by attaching a polyethylene glycol (PEG) group to the N-terminus of IFN beta. Has prolonged half-life and consequently a reduced dosing. Approved for RRMS, ADVANCE trial (Lancet Neurol 2014;13(7):657-665).
Glatiramer acetate (GA, Copaxone)
MOA: Synthetic polypeptides; may bind to MHCs as decoy for myelin proteins causing shifting immune response from TH1 to TH2.
Dosage and key trials: 20 mg SC daily and new 40 mg SC dosing 3×/wk. Copolymer 1 Multiple Sclerosis Study Group trial (Neurology 1995;45(7):1268)
SE: Very good safety profile. Flushing, local injection site rxn. Localized lipoatrophy.
Oral
Dimethyl fumarate (DMF, Tecfidera)
MOA: Unclear neuroprotective and immunomodulatory properties.
Dosing: Starting dose 120 mg PO bid; increased to 240 mg PO bid after 7 days.
Key trials: DEFINE: DMF vs. placebo (NEJM 2012;367(12):1098-1107), and COMFIRM DMF vs. GA vs. placebo.
SE: Flushing and gastrointestinal symptoms, including diarrhea, nausea, and abdominal upset. May decrease lymphocyte counts, CBC should be in first 6 mo and then yearly. Should be discontinued if lymphocytopenia develops. Isolated cases of PML have been reported.
Fingolimod (Gilenya)
MOA: Modulates the sphingosine-1-phosphate receptor and impairs lymphocyte migration, resulting in sequestration in the lymph nodes.
Key trials: FREEDOMS (NEJM 2010;362:387-401)—fingolimod vs. placebo; TRANSFORMS (N Engl J Med 2010;362:402-415)—fingolimod vs. IFN beta 30 mcg IM weekly—two deaths in the high-dose fingolimod group (disseminated VZV infection and HSV encephalitis).
SE/AE: Headache, diarrhea, elevated LFTs, fatigue, cough, HTN. Less common but potentially serious are bradyarrhythmia and AV block (usually first dose effect), macular edema (reversible), skin cancers, VZV infections, and paradoxical worsening of MS disease activity w/severe MS relapses. Isolated cases of PML have been reported. Contraindicated for pts w/active ischemic or conductive heart dz (unless treated w/a pacemaker) or Rx w/antiarrhythmic drugs. Considered second-line Rx.
Dosage: 0.5 mg PO qd. Before start: check CBC, LFT, EKG, perform ophthalmologic exam, skin exam for precancerous skin lesions, VZV serology and vaccination if Ab titers neg/low at least 1 mo before fingolimod. 1st dose should be given w/q1h BP and HR for 6 h where symptomatic bradycardia can be managed; w/EKG obtained at the end of the 6-h observation. Ophthalmologic exam should be repeated in 3-4 mo after starting fingolimod and routinely in pts w/diabetes mellitus or a history of uveitis. Consider shingles vaccine in anyone approaching the age of 60, <1 mo prior to start.
Teriflunomide (Aubagio)
MOA: Inhibits de novo pyrimidine synthesis needed for the proliferation of activated lymphocytes.
Dosing and key trials: 7 or 14 mg once a day; TEMSO trial compared to placebo (NEJM 2011;365:1293-1303); TEMSO II.
SE/AE/monitoring: Diarrhea, nausea, hair thinning, and elevated ALT. Teriflunomide is pregnancy category X. Pts w/known liver disease may not be treated w/teriflunomide. Obtain baseline LFTs; screen for latent TB, pregnancy test. Monitor ALT levels monthly for 6 mo; discontinue if drug-induced liver injury is suspected and for women who are pregnant, also men and women who are planning to conceive. Pregnancy should be avoided until the serum concentration of teriflunomide is <0.02 mg/L. Manufacturer recommends an “accelerated washout protocol” if need to decrease levels fast.
INFUSION
Natalizumab (Tysabri)
MOA: Monoclonal Ab against &agr;-4-integrin on lymphocytes, preventing migration to CNS. Dosing: 300-mg infusion IV q4wk. Contraindicated in pregnancy.
Key trials: AFFIRM trial (NEJM 2006;354:899-910) as monotherapy and in SENTINEL (NEJM 2006;354:911-923) in combination w/IFN SC showed strong anti-inflammatory effect in preventing new relapses and new MRI lesions.
SE/AE: Increased risk of infections including herpes, infusion reactions, HA, fatigue, pruritus, arthralgias, cholelithiasis. Development of neutralizing antibodies to natalizumab possible. Antibodies to natalizumab: check if no clinical response to Rx or if ongoing active lesions; if Abs present, discontinue natalizumab.
Rare: Progressive multifocal leukoencephalopathy (PML) in pts exposed to JC virus. Serum serology for JCV-Ab commercially available and encouraged to test prior to discussing Rx w pt. risk of seroconversion, check every 6 M while on natalizumab. The length of Rx, JCV titer, and prior immunosuppression increase risk. Testing CSF for JCV DNA also recommended after 2 yr or if symptoms/imaging concerning for PML. Other opportun infections observed. Rare cases of melanoma have been reported but association not yet proven.
MRI brain w contrast q6mo for PML surveillance recommended. Dermatologic and ophthalmologic exam at baseline, w/follow-up during Rx as needed; check baseline LFT then q6mo. Stopping natalizumab can be a/w rebound severe increased inflammatory activity and in some cases immune reconstitution inflammatory syndrome (IRIS); some centers use glucocorticoids as a bridge to other Rxs if discontinuation needed.
Alemtuzumab (Lemtrada)
MOA: Humanized monoclonal Ab leads to depletion of CD52-expressing T cells, NK cells, and monocytes.
Key trials: CARE-MS compared alemtuzumab to IFN (44 &mgr;g SC 3x per wk); CARE-MS II alemtuzumab vs. IFN or GA.
Dosage: IV 12 mg daily for 5 consecutive days (total 60 mg) at the start of Rx; then 12 mg daily for 3 days (total 36 mg) 12 mo later.
SE/AE/monitoring: Infusion reactions (90% of pts) HA, rash, nausea, fever. Herpes infections (16%-18%)—need prophylactic acyclovir (during alemtuzumab infusion and for 28 days after w/acyclovir 200 mg PO bid) and prophylaxis for Pneumocystis jirovecii pneumonia (PCP) (e.g., trimethoprim-sulfamethoxazole 80-160 mg daily) during Rx and for several weeks after Rx. Thyroid autoimmunity (16%-30%) seen at longer follow-up. Due to frequent SE, reserved for pts w/RRMS who have an inadequate response to two or more first-line Rx. In the United States, requires special registration through a restricted distribution program. Surveillance for bone marrow suppression, infections, and autoimmune disorders is necessary.
OTHER TREATMENTS
Vitamin D: Blood levels of “25-hydroxyvitamin D” should be obtained, w/current goal levels in MS, in the middle range of normal. Otherwise, usual dose is 1,000 IU for levels between 20 and 35 ng/mL and 2,000 IU daily for levels below 20 ng/mL. Vitamin D3 supplements are preferable (more active biologically, raises blood levels more effectively, and is more stable on the shelf than D2).
Glucocorticoids—IV glucocorticoid bolus, typically 1,000 mg of methylprednisolone, is used at many institutions for the Rx of primary or secondary progressive MS alone (e.g., monthly) or in combination w/other immunomodulatory or immunosuppressive medications. RCT data are limited and conflicting. Some providers use during periods of staying off Rx due to pregnancy or to prevent relapses in periods of increased risk of relapses.
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