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Last Minute Review

Neuroimmunology — Last Minute Review

A last-minute review of high-yield facts — dense tables and one-liners for RITE/Board prep. Not a substitute for the full notes.

McDonald Criteria (2024 Revision) — MS Diagnosis

Criterion	2024 Requirement	How to Fulfill
DIS (Dissemination in Space)	≥1 T2 lesion in ≥2 of 5 CNS regions	Periventricular, cortical/juxtacortical, infratentorial, spinal cord, optic nerve (NEW) — need ≥2 of 5 areas
DIT (Dissemination in Time)	Not eliminated as a concept — can be satisfied by additional biomarkers at the time of a single clinical/radiographic event	DIT can be met by: new T2/Gd+ lesion on follow-up MRI, simultaneous Gd+ and non-enhancing lesions, or biomarkers (OCBs, kappa FLC, ≥6 central vein sign lesions, or paramagnetic rim lesions) at the time of a single event
RIS (Radiologically Isolated Syndrome)	Qualifies as MS ONLY when DIS is met AND there is additional supportive evidence, with no clinical or radiographic alternative	Requires: DIS fulfilled + (DIT shown on serial MRI, OR ≥2 CSF-specific OCBs, OR ≥6 central vein sign lesions / paramagnetic rim lesions) + no better alternative diagnosis

Key 2024 vs 2017 Changes

Feature	2017 Criteria	2024 Criteria
DIS regions	4 regions (periventricular, cortical/juxtacortical, infratentorial, spinal cord)	5 regions — optic nerve added as 5th location (via MRI orbits, OCT, or VEP)
DIT requirement	Strictly required for diagnosis	Removed as strict requirement — diagnosis possible after single event if other evidence supports
New biomarkers	OCBs only	OCBs + central vein sign, paramagnetic rim lesions, kappa free light chains (CSF)
RIS	Not diagnostic — must await symptoms	Can qualify for MS diagnosis if DIS + supportive biomarkers
Special populations	Limited guidance	Specific guidance for children and adults ≥50 years
CIS category	CIS = first event, not yet MS	Many former CIS cases now diagnosable as MS at first presentation

DIS Region (5 total)	Evidence
Periventricular	≥1 T2 lesion (same threshold as 2017)
Cortical/juxtacortical	≥1 lesion
Infratentorial	≥1 lesion
Spinal cord	≥1 lesion
Optic nerve (NEW)	MRI optic nerve lesion, abnormal OCT (RNFL thinning), or abnormal VEP

💎 Board Pearl

The 3 biggest 2024 updates: (1) Optic nerve = 5th DIS region (use MRI orbits, OCT, or VEP), (2) DIT can be substituted by biomarkers (OCBs, kappa FLC, ≥6 CVS lesions, PRL) at a single clinical/radiographic event — DIT is NOT eliminated as a concept, (3) RIS qualifies as MS ONLY when DIS is met AND additional supportive evidence is present (DIT on serial MRI, OR ≥2 CSF-specific OCBs, OR ≥6 CVS/PRL lesions), with no clinical or radiographic alternative. New supportive biomarkers: central vein sign (≥6 lesions or 40%+), paramagnetic rim lesions, and CSF kappa free light chains. Periventricular threshold remains ≥1 (same as 2017, NOT changed).

Diagnostic Criteria & Antibody-Testing Scores

Criterion / Score	Components	Threshold / Interpretation
APE2 score (Dubey 2017) Antibody Prevalence in Epilepsy and Encephalopathy	(1) New-onset refractory seizures, (2) autonomic dysfunction, (3) viral prodrome, (4) psychiatric features, (5) cognitive dysfunction, (6) temporal MRI changes, (7) CSF inflammation, (8) history of autoimmunity or cancer	Score ≥4 prompts neural antibody testing (sensitivity ~98%, specificity ~82%)
Graus 2016 — Possible Autoimmune Encephalitis	Subacute onset (<3 months) of working memory deficit, altered mental status, or psychiatric symptoms + ≥1 of: new focal CNS findings, seizures not explained by prior disorder, CSF pleocytosis (>5 WBC/µL), or MRI features suggestive of encephalitis	All criteria above + reasonable exclusion of alternative causes = Possible AE; upgrade to Definite when specific antibody identified or other criteria met
Graus 2021 PNS-Care Score Paraneoplastic Neurologic Syndromes	High-risk phenotypes: encephalomyelitis, limbic encephalitis, rapidly progressive cerebellar syndrome, opsoclonus-myoclonus, sensory neuronopathy, LEMS High-risk antibodies: Hu, Yo, CV2/CRMP5, Ri, Ma2, amphiphysin, SOX1, KLHL11, DNER/Tr Scoring 0–10 across phenotype + antibody + cancer + follow-up domains	Definite PNS ≥8; Probable 6–7; Possible 4–5
MOGAD 2023 Criteria	(1) Core clinical event (ON, myelitis, ADEM, cerebral monofocal/polyfocal deficit, brainstem/cerebellar syndrome, cortical encephalitis) + (2) MOG-IgG positive by cell-based assay (CBA) — clear positive serum titer typically >1:100, OR low/negative serum titer with supporting clinical/radiographic features + (3) exclusion of better diagnosis	Requires all three pillars; serum CBA preferred over fixed CBA or ELISA
IPND 2015 NMOSD Criteria	6 core clinical characteristics: (1) optic neuritis, (2) acute myelitis, (3) area postrema syndrome (intractable hiccups/nausea/vomiting), (4) acute brainstem syndrome, (5) symptomatic narcolepsy or diencephalic syndrome with typical NMOSD MRI lesions, (6) symptomatic cerebral syndrome with typical NMOSD MRI lesions	AQP4-IgG positive: ≥1 core characteristic + exclusion of alternatives AQP4-IgG negative / unknown: ≥2 core characteristics meeting strict MRI requirements; ≥1 must be ON, LETM, or area postrema syndrome; dissemination in space required

💎 Board Pearl

APE2 ≥4 = test for neural antibodies. Graus 2016 "Possible AE" is the entry-level umbrella criterion before subtype-specific antibodies define Definite. PNS-Care 2021 replaced the 2004 Graus criteria — uses a numeric score with high-risk phenotype + high-risk antibody + cancer + follow-up. MOGAD 2023: CBA is mandatory; ELISA-only positives are NOT acceptable. IPND 2015 NMOSD: AQP4− cases need stricter MRI criteria + ≥2 cores including ON, LETM, or area postrema.

MS vs NMOSD vs MOGAD

Feature	MS	NMOSD (AQP4+)	MOGAD
Antibody	None specific (OCBs in CSF)	AQP4-IgG (serum; 70–80% sensitivity by cell-based assay; lower by ELISA ~50–60%)	MOG-IgG (serum; CBA preferred)
Sex ratio (F:M)	~3:1	~9:1	~1:1
Age at onset	20–40	30–50	Bimodal: children + young adults
ON features	Unilateral, mild, retrobulbar, good recovery	Severe, often bilateral, posterior > anterior, poor recovery	Bilateral, anterior predominant, disc edema, perineural enhancement, good recovery
Myelitis	Short segment (<3 vertebral segments), peripheral	LETM (≥3 segments), central gray matter, bright spotty lesions	LETM, conus/lower cord predilection
Brain MRI	Dawson fingers, periventricular ovoid lesions perpendicular to ventricles	Often normal early; area postrema, periaqueductal, diencephalic, cloud-like enhancement	Fluffy bilateral cortical/deep WM, ADEM-like in children
Spinal MRI	Short lesions, dorsolateral, incomplete ring enhancement	LETM (≥3 segments), central cord, may enhance diffusely	LETM, conus involvement, can mimic NMOSD
CSF OCBs	Present >95%	Usually absent (~15–20%)	Usually absent
Relapse pattern	Relapses then progressive phase (SPMS)	Relapsing >90%; rarely monophasic	~50% monophasic, ~50% relapsing
Acute treatment	IV methylprednisolone	IV methylprednisolone + early PLEX	IV methylprednisolone (very steroid-responsive); PLEX if refractory
Maintenance treatment	DMTs (interferons, anti-CD20, S1P modulators, etc.)	Rituximab, eculizumab, satralizumab, inebilizumab, azathioprine, mycophenolate	No FDA-approved DMT; azathioprine, mycophenolate, rituximab if relapsing
MS DMTs harmful?	—	YES — interferons, fingolimod, natalizumab worsen NMOSD	Likely — interferons, fingolimod should be avoided
Prognosis	Variable; disability accrues over decades	Poor recovery per attack; cumulative disability from relapses	Generally good recovery per attack; better than NMOSD

Clinical Pearl

Do NOT treat NMOSD with MS DMTs — interferon-β, fingolimod, and natalizumab can worsen NMOSD attacks. Always confirm AQP4 status before starting MS-specific DMTs in patients with LETM or severe/bilateral ON.

💎 Board Pearl

Area postrema syndrome (intractable nausea/vomiting/hiccups) is nearly pathognomonic for NMOSD. MOG-IgG titers can become negative over time — persistent positivity predicts relapsing course. MOGAD optic neuritis shows characteristic perineural enhancement (around the nerve sheath, not just the nerve). NMOSD bright spotty lesions on T2 = high specificity.

MS Disease-Modifying Therapies

DMT	Route	MOA	Monitoring	Key Risk	Efficacy Tier
Interferon-β	IM/SC (varies by formulation)	Immunomodulatory, ↓ BBB disruption	CBC, LFTs q3–6mo	Flu-like symptoms, hepatotoxicity, depression	Moderate
Glatiramer acetate	20 mg SC daily OR 40 mg SC 3×/week	MBP mimic → Th2 shift	None required	Injection site reactions, lipoatrophy, post-injection reaction	Moderate
Teriflunomide	PO daily	DHODH inhibitor → ↓ pyrimidine synthesis	LFTs monthly ×6mo then q6mo; TB test before start	Contraindicated in pregnancy (FDA letter categories retired 2015 with PLLR) — accelerated elimination with cholestyramine or activated charcoal if pregnancy occurs; hepatotoxicity; hair thinning	Moderate
Dimethyl fumarate	PO BID	Nrf2 pathway activation	CBC q6mo (lymphocytes!)	Lymphopenia → PML; GI; flushing. Consider holding/discontinuing if ALC <500 sustained ≥6 months.	Moderate
Fingolimod	PO daily	S1P modulator → lymphocyte sequestration in LN	First-dose 6hr cardiac monitoring; ophthalmology 3–4mo; CBC; LFTs	Bradycardia/AV block (first dose); macular edema; PML; VZV; rebound. Cardiac contraindications: recent MI / unstable angina / stroke / TIA / decompensated HF within 6 months; Mobitz II or higher AV block; QTc ≥500 ms. HR <55 = caution warranting prolonged monitoring.	High
Siponimod	PO daily (dose titration)	S1P1/S1P5 selective	CYP2C9 genotype before start; cardiac monitoring; ophthalmology	Bradycardia; macular edema; 3/3 genotype = contraindicated	High (approved for active SPMS)
Ozanimod	PO daily (7-day titration)	S1P1/S1P5 selective	CBC, LFTs, ECG, ophthalmology	Bradycardia; macular edema; avoid with MAOIs	High
Cladribine	PO short courses (Year 1 + Year 2 only)	Purine analog → selective lymphocyte depletion	CBC before each course; baseline cancer screening + HIV/HBV/HCV/TB/VZV screening	Lymphopenia; infections; theoretical malignancy risk (registries reassuring)	High (immune reconstitution)
Natalizumab	300 mg IV q4 weeks (or q6 weeks extended-interval per NOVA trial)	Anti-α4-integrin → blocks lymphocyte CNS entry	JCV Ab q6mo; MRI q3–6mo	PML (JCV+, prior IS, >2 years)	High
Ocrelizumab	First infusion: 300 mg IV ×2 doses (days 1 and 15); then 600 mg IV q6 months	Anti-CD20 (humanized) → B-cell depletion	Hep B screen; IgG levels; CBC	Infusion reactions; infections; breast cancer signal	High (first PPMS approval)
Ofatumumab	Loading: 20 mg SC at weeks 0, 1, 2; then 20 mg SC monthly starting week 4	Anti-CD20 (fully human)	Hep B screen; IgG levels	Injection reactions; infections; ↓ immunoglobulins	High
Alemtuzumab	IV ×5d (year 1), ×3d (year 2)	Anti-CD52 → profound lymphocyte depletion	CBC + TFTs monthly ×4 years after last dose; urinalysis monthly; skin exams	Secondary autoimmunity (thyroid 40%, ITP, anti-GBM); stroke; MI	High (REMS program)
Mitoxantrone	IV q3 months (lifetime dose limit)	Topoisomerase II inhibitor → immunosuppression	Cardiac echo + LVEF check before EACH dose; CBC	Cardiotoxicity (cumulative dose limit 140 mg/m²); AML risk ~0.3–0.8%	High (rarely used now)

PML Risk Stratification (Natalizumab)

Risk Factor	Detail
JCV antibody status	Negative = very low risk (~0.1/1000); positive = stratify further
JCV antibody index	>1.5 = significantly higher risk; ≤0.9 = lower risk among JCV+ patients
Prior immunosuppression	↑↑ risk if prior azathioprine, MTX, mitoxantrone, cyclophosphamide
Natalizumab duration	Risk ↑ after 24 months; highest at 24–72 months
Highest risk group	JCV Ab+ with index >1.5 + prior IS + >2 years → ~13/1000
Extended interval dosing	Q6–8 week dosing may ↓ PML risk (observational data)

💎 Board Pearl

JCV risk trifecta: anti-JCV Ab index >1.5, prior immunosuppression, natalizumab >2 years. S1P first-dose cardiac monitoring: required for fingolimod (6 hrs) and siponimod; ozanimod/ponesimod use gradual titration instead. Glatiramer acetate and interferon-β have the most reassuring pregnancy experience and may be continued in selected patients. Teriflunomide is contraindicated in pregnancy (FDA letter categories retired 2015 with PLLR) — requires accelerated elimination with cholestyramine or activated charcoal. Anti-CD20 agents do NOT deplete plasma cells (CD20−). Alemtuzumab monitoring continues 4 years after LAST dose. Rebound risk: S1P modulators and natalizumab carry high rebound if stopped without bridging. DMF PML: occurs with ALC <500 for >6 months — stop drug.

Landmark MS DMT Trials

Trial	Drug / Comparator	Population	Key Result
AFFIRM	Natalizumab vs placebo	RRMS	68% ↓ relapse rate; basis for approval
ASCEND	Natalizumab vs placebo	SPMS	Negative — no benefit on disability progression
OPERA I/II	Ocrelizumab vs IFN-β1a	RRMS	~46–47% ↓ ARR vs IFN; superior MRI outcomes
ORATORIO	Ocrelizumab vs placebo	PPMS	First positive PPMS trial — 24% ↓ 12-week confirmed disability progression
ASCLEPIOS I/II	Ofatumumab vs teriflunomide	RRMS	~50% ↓ ARR vs teriflunomide
ULTIMATE I/II	Ublituximab vs teriflunomide	RRMS	~50% ↓ ARR vs teriflunomide; faster infusion than ocrelizumab
BEYOND	High-dose IFN-β1b vs glatiramer	RRMS	No difference — both platforms equivalent
EXPAND	Siponimod vs placebo	SPMS (active)	21% ↓ 3-month confirmed disability progression; FDA approval for active SPMS
CLARITY	Cladribine vs placebo	RRMS	~58% ↓ ARR; basis for approval
TEMSO / TOWER	Teriflunomide vs placebo	RRMS	~31% ↓ ARR; ↓ disability progression
CARE-MS I/II	Alemtuzumab vs IFN-β1a	RRMS (CARE-MS I: treatment-naive; II: prior DMT)	Superior to IFN on ARR + disability; established alemtuzumab as high-efficacy
DEFINE / CONFIRM	DMF vs placebo (CONFIRM also vs glatiramer)	RRMS	~44–53% ↓ ARR; basis for DMF approval
MIST	HSCT vs DMT	Highly active RRMS	HSCT superior to DMT for time to disease progression; small RCT

Clinical Pearl

ORATORIO was the first positive PPMS trial — pivotal for ocrelizumab's PPMS indication. ASCEND was negative for SPMS (natalizumab does NOT help progressive disease without inflammation). EXPAND specifically established siponimod for active SPMS (those with relapses or MRI activity), not all SPMS.

Acute Relapse Treatment Protocol

Step	Treatment	Dose	Duration	Notes
First-line	IV Methylprednisolone	1 g IV daily	3–5 days	Speeds recovery but does NOT change long-term disability in MS; consider oral taper; very steroid-responsive in MOGAD
Second-line	PLEX (Plasma Exchange)	5–7 exchanges	Over 10–14 days	Start early for best response; especially effective in NMOSD and severe MS relapses refractory to steroids
Alternative second-line	IVIg	2 g/kg total	Over 2–5 days	Used when PLEX unavailable; check IgA deficiency before first infusion (anaphylaxis risk)
Rescue / refractory	Rituximab	1000 mg IV ×2 (days 0, 14)	Effect in weeks	For autoimmune encephalitis, refractory NMOSD, aggressive MS; Hep B screening mandatory
Rescue / refractory	Cyclophosphamide	500–1000 mg/m² IV	Monthly pulses	For PACNS induction, refractory autoimmune encephalitis, severe SLE; give MESNA for bladder protection

💎 Board Pearl

PLEX is most effective for NMOSD relapses and severe MS relapses refractory to steroids — start early (within days), delays significantly reduce efficacy. NMOSD FDA-approved maintenance therapies (AQP4+): eculizumab, ravulizumab (C5 inhibitor, q8wk maintenance; FDA-approved 2024), satralizumab, inebilizumab — all require AQP4-IgG positivity. Eculizumab/ravulizumab: MenACWY + MenB vaccines ≥2 weeks before first dose (if urgent, start antibiotic prophylaxis until 2 weeks post-vaccine). Check TPMT before azathioprine; check IgA before IVIg. Rituximab alternative NMOSD induction: 375 mg/m² weekly ×4 (lymphoma protocol); redose based on CD19/CD27+ memory B-cell repopulation.

Autoimmune Encephalitis — Antibody Table

Antibody	Target	Key Syndrome	Associated Tumor	Age/Sex	Treatment Response
Anti-NMDAR	GluN1 (NR1) subunit of NMDA receptor (cell-surface)	Psychiatric → seizures → dyskinesias → autonomic instability → central hypoventilation	Ovarian teratoma (young women)	Young women; F>>M	Excellent if treated early + tumor removal
Anti-LGI1	LGI1 (cell-surface)	Limbic encephalitis: memory loss, confusion, temporal seizures, hyponatremia (SIADH)	Rare (<10%)	Older men (50–70)	Good; responds to immunotherapy
Anti-CASPR2	CASPR2 (cell-surface)	Morvan syndrome (encephalitis + peripheral nerve hyperexcitability + autonomic dysfunction + insomnia)	Thymoma (~20%)	Older men	Good; may need prolonged therapy
Anti-GABA_B	GABA-B receptor (cell-surface)	Limbic encephalitis with prominent, refractory seizures	SCLC (~50%)	Older adults	Moderate; tumor treatment critical
Anti-AMPAR	AMPA receptor (cell-surface)	Limbic encephalitis; frequent relapses	Lung, breast, thymoma (~50–65%)	Older women	Good; high relapse rate
Anti-DPPX	DPPX (cell-surface)	Prodromal severe diarrhea/weight loss → encephalitis + hyperekplexia	Rare	Adults	Good
Anti-IgLON5	IgLON5 (cell-surface)	NREM/REM parasomnia + bulbar dysfunction + gait instability; tauopathy on pathology	None	Older adults; *HLA-DRB110:01 + DQB105:01*	Poor; progressive despite therapy
Anti-GlyR	Glycine receptor (cell-surface)	PERM (progressive encephalomyelitis with rigidity and myoclonus); stiff-person spectrum	Rare	Adults	Better than anti-GAD SPS

💎 Board Pearl

Faciobrachial dystonic seizures (FBDS) = pathognomonic for anti-LGI1 — brief, frequent, AED-resistant, immunotherapy-responsive. Treat early to prevent cognitive decline. Extreme delta brush on EEG (rhythmic delta + superimposed beta) = anti-NMDAR encephalitis. Anti-NMDAR encephalitis can follow HSV encephalitis (post-infectious autoimmune mechanism). Hyponatremia + limbic encephalitis = think LGI1. CSF antibody more sensitive than serum for NMDAR; serum more sensitive for LGI1.

Paraneoplastic Antibodies — Intracellular (Poor Prognosis)

Antibody	Syndrome	Associated Tumor	Response to Immunotherapy
Anti-Hu (ANNA-1)	Sensory neuropathy, encephalomyelitis, limbic encephalitis, autonomic neuropathy	SCLC	Poor — most common paraneoplastic Ab; multifocal dysfunction
Anti-Yo (PCA-1)	Subacute pancerebellar degeneration (irreversible Purkinje cell loss)	Ovarian, breast	Poor — essentially irreversible once established; treat tumor first
Anti-Ri (ANNA-2)	Opsoclonus-myoclonus-ataxia, brainstem encephalitis	Breast, SCLC	Partial — may improve with tumor treatment
Anti-CV2 (CRMP5)	Chorea + peripheral neuropathy, optic neuritis, uveitis	SCLC, thymoma	Poor — chorea + neuropathy combo is characteristic
Anti-amphiphysin	Stiff-person syndrome, encephalomyelitis	Breast, SCLC	Poor — paraneoplastic SPS variant (vs anti-GAD65 SPS)
Anti-Ma2 (Ta)	Limbic/diencephalic encephalitis, narcolepsy, vertical gaze palsy	Testicular germ cell (young men); lung (older)	Moderate — better prognosis if testicular tumor (curable)
Anti-SOX1	Lambert-Eaton myasthenic syndrome, cerebellar ataxia	SCLC	Poor — often co-occurs with anti-VGCC; supports SCLC association
Anti-GAD65	Stiff-person syndrome, cerebellar ataxia, temporal lobe epilepsy	Rarely paraneoplastic (thymoma, SCLC if tumor); usually autoimmune	Variable — very high titers (>10,000) = neurological; low titers = type 1 DM

Clinical Pearl

Intracellular antibodies (Hu, Yo, Ri, CV2, amphiphysin, Ma2) = T-cell mediated neuronal destruction = poor response to immunotherapy = FIND AND TREAT THE TUMOR. Cell-surface antibodies (NMDAR, LGI1, CASPR2, AMPAR, GABA-B, VGCC) = antibody-mediated = potentially reversible with immunotherapy + tumor removal.

💎 Board Pearl

Young man + limbic encephalitis + hypersomnia + vertical gaze palsy = anti-Ma2 → check for testicular tumor. Opsoclonus-myoclonus in adults = anti-Ri or lung cancer; in children = neuroblastoma. LEMS: anti-VGCC (P/Q-type), SCLC ~60%, proximal weakness + areflexia + facilitation on high-frequency rNS, treat with 3,4-DAP. Neurological symptoms often PRECEDE cancer diagnosis by months to years.

Systemic Autoimmune Diseases — Neuro Manifestations

Disease	CNS Features	PNS Features	Key Test	Treatment
Neurosarcoidosis	CN VII palsy (most common CN), leptomeningeal enhancement, hypothalamic/pituitary lesions (DI), chronic meningitis, myelopathy (dorsal subpial)	Small fiber neuropathy (most common PNS), mononeuritis multiplex	Chest CT (bilateral hilar LAD); ACE (low sensitivity ~60%); non-caseating granulomas on biopsy; PET-CT for biopsy targets	Steroids → MTX/AZA/MMF → infliximab (refractory)
Neuro-Behçet	Brainstem/diencephalic encephalitis, cerebral venous sinus thrombosis, cranial neuropathies	Rare	Clinical criteria (oral ulcers + 2 of: genital ulcers, eye lesions, skin lesions, pathergy); HLA-B51	Steroids + azathioprine; anti-TNF for refractory; anticoagulation for CVST
SLE (neuropsychiatric)	Psychosis, seizures, cognitive dysfunction, stroke (antiphospholipid), transverse myelitis, chorea, aseptic meningitis	Peripheral neuropathy, cranial neuropathies	ANA, anti-dsDNA; antiphospholipid antibodies (anticardiolipin, β2-GP1, lupus anticoagulant)	Steroids + cyclophosphamide (severe); anticoagulation for APS
Sjögren syndrome	Myelitis (can mimic NMOSD — check AQP4), cognitive dysfunction, CNS lymphoma risk	Sensory neuropathy (small fiber or sensory ganglionopathy), trigeminal neuropathy	Anti-SSA/Ro + minor salivary gland biopsy (focus score ≥1) carry classification weight (2016 ACR/EULAR); anti-SSB/La may coexist but isolated SSB is no longer a serologic criterion; Schirmer test supports	Steroids, rituximab; treat neuropathy symptomatically
IgG4-related disease	Orbital pseudotumor (most common neuro), hypertrophic pachymeningitis, hypophysitis, perineural disease	Cranial nerve palsies	↑ Serum IgG4; biopsy: storiform fibrosis, >10 IgG4+ plasma cells/HPF	Steroids (very responsive); rituximab for refractory

💎 Board Pearl

Neurosarcoidosis: facial nerve palsy is the most common cranial neuropathy; can be bilateral. Serum ACE is neither sensitive nor specific — do not use to rule in or out. Non-caseating granulomas = gold standard finding. Infliximab (NOT etanercept) for refractory neurosarcoidosis — etanercept can paradoxically worsen sarcoidosis. Bilateral facial palsy differential: sarcoidosis, Lyme, GBS, HIV, lymphoma.

CNS Vasculitis — PACNS vs RCVS vs Susac

Feature	PACNS	RCVS	Susac Syndrome
Presentation	Insidious: headache, cognitive decline, strokes in multiple territories	Acute: recurrent thunderclap headaches over days to weeks	Subacute: encephalopathy + vision loss + hearing loss
Headache pattern	Chronic, progressive, dull	Thunderclap (<60 seconds to peak); recurrent; often triggered by Valsalva, exertion, sex	Variable; may be mild or absent
Imaging	Multifocal infarcts in different vascular territories; white matter lesions; mass-like lesions possible	Convexity SAH; posterior predominant edema (like PRES); infarcts if severe	Snowball lesions in CENTRAL corpus callosum (pathognomonic); periventricular white matter lesions
Angiography	Beading/stenosis (~60% sensitivity); can be normal (small vessel)	Diffuse segmental vasoconstriction (beading); REVERSIBLE within 12 weeks	Branch retinal artery occlusions on fluorescein angiography
CSF	Elevated protein, pleocytosis in ~90%; ESR/CRP often NORMAL	Usually NORMAL	Markedly elevated protein (often >100 mg/dL) helps distinguish from MS; mild pleocytosis possible
Biopsy	Gold standard (leptomeninges + cortex); 25% false-negative rate	Not indicated	Not indicated
Treatment	Cyclophosphamide + corticosteroids induction; AZA/MMF maintenance	Calcium channel blockers (nimodipine/verapamil); remove triggers; NO immunosuppression	Aggressive: IVMP + IVIg + PLEX; MMF/AZA maintenance; antiplatelet
Prognosis	Chronic, relapsing; can be fatal without treatment	Self-limited (resolves in 1–3 months); generally good	Variable; early aggressive treatment improves outcomes

💎 Board Pearl

RCVS = thunderclap headache + reversible vasoconstriction (resolves in 3 months); triggers include triptans, SSRIs, cannabis, postpartum. Do NOT immunosuppress RCVS — it is NOT a vasculitis. Susac = encephalopathy + BRAO + sensorineural hearing loss (clinical triad). Susac snowball lesions are in the CENTRAL corpus callosum; MS lesions are at the callosal-septal interface (Dawson fingers). PACNS brain biopsy: need leptomeninges + cortex in sample; 25% false-negative rate.

Other Neuroimmunology Conditions

Condition	Key Features	Diagnosis	Treatment
ADEM	Monophasic; children >> adults; post-infectious/post-vaccination; encephalopathy REQUIRED; large fluffy bilateral WM lesions + deep gray matter (thalamus). Pathology pearl: ADEM = perivenular demyelination; MS = perivascular (around larger Virchow-Robin veins)	Clinical: polyfocal deficits + encephalopathy + large lesions; MOG-IgG positive in many pediatric cases; OCBs usually absent	IV methylprednisolone → PO taper; IVIg or PLEX if refractory
Transverse myelitis	Acute/subacute bilateral motor + sensory + autonomic spinal cord dysfunction; sensory level; urinary retention	Spinal MRI (T2 hyperintensity ≥2 segments for idiopathic); CSF pleocytosis; rule out compressive, NMOSD, MS, MOG	IV methylprednisolone; PLEX if refractory; address underlying cause
NMOSD-associated ON	Severe, often bilateral; posterior > anterior; poor recovery; chiasmal involvement; AQP4+	AQP4-IgG serum; MRI orbits (long-segment enhancement, often posterior/chiasmal)	IV methylprednisolone + early PLEX; long-term: rituximab/eculizumab/satralizumab/inebilizumab
Stiff-person syndrome	Progressive axial rigidity + painful spasms (triggered by startle/emotion); exaggerated lumbar lordosis; anti-GAD65 (very high titers >10,000)	Anti-GAD65 (high titer); anti-amphiphysin (if paraneoplastic → breast/SCLC); EMG: continuous motor unit activity at rest	Diazepam/baclofen (symptomatic); IVIg (immunotherapy of choice); rituximab; tumor treatment if paraneoplastic
Hashimoto encephalopathy (SREAT)	Subacute encephalopathy (cognitive decline, seizures, myoclonus, stroke-like episodes); anti-TPO/anti-TG antibodies; DRAMATICALLY steroid-responsive	Diagnosis of exclusion; elevated anti-TPO/anti-TG; EEG: diffuse slowing; CSF: elevated protein; normal thyroid function often	High-dose corticosteroids (dramatic response = diagnostic clue); steroid-sparing agents if relapsing
Immune checkpoint neurotoxicity	Anti-PD-1/PD-L1/CTLA-4 therapy; myasthenia gravis (most common NMJ), GBS, encephalitis, myositis, aseptic meningitis, transverse myelitis; can overlap (myasthenia + myositis + myocarditis)	Temporal relationship to checkpoint inhibitor; antibody testing; EMG/NCS; MRI. ICI-MG: mandatory troponin + ECG given MG + myositis + myocarditis triad (can be fatal)	Hold checkpoint inhibitor; IVIg or PLEX first-line for ICI-MG (steroid monotherapy can paradoxically worsen initially); high-dose steroids added; permanent discontinuation for grade 3–4
CLIPPERS	Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; ataxia, diplopia, dysarthria; punctate/curvilinear Gd-enhancing lesions in pons → "peppering" pattern	MRI: punctate gadolinium-enhancing lesions centered on pons; biopsy: perivascular T-cell infiltration; exclude lymphoma	Corticosteroids (dramatic response); steroid-sparing (MTX, MMF); relapses on taper common
Bickerstaff brainstem encephalitis	Ophthalmoplegia + ataxia + encephalopathy (altered consciousness); overlap with GBS and Miller Fisher; anti-GQ1b antibodies	Anti-GQ1b (positive in ~65%); CSF albuminocytologic dissociation; MRI brainstem lesions possible; EEG: diffuse slowing	IVIg or PLEX (as for GBS); generally good prognosis

Clinical Pearl

ADEM = monophasic, children, post-infectious, large fluffy lesions, encephalopathy REQUIRED for diagnosis. If "ADEM" recurs, think MOGAD or MS. Multiphasic ADEM = second event ≥3 months after first; if ≥2 non-ADEM events → likely MOGAD or MS. SREAT (Hashimoto encephalopathy) is a diagnosis of exclusion — the dramatic steroid response is the diagnostic clue. Checkpoint inhibitor neurotoxicity: watch for MG + myositis + myocarditis overlap (can be fatal).

Additional High-Yield Entities — Tumefactive MS, LEMS, PRES

Entity	Key Features	Diagnosis	Treatment / Notes
Tumefactive MS	Lesions ≥2 cm; incomplete / open-ring enhancement (opens toward cortex); mass effect; T2 hypointense rim; relatively little edema for size	MRI features above; consider biopsy if atypical (rule out lymphoma, glioma, abscess); CSF OCBs often positive; MRS may show elevated choline	IV methylprednisolone → PLEX if refractory; may need long-term DMT after — can be first MS presentation or in established MS
LEMS (Lambert-Eaton)	Proximal weakness, areflexia at baseline, autonomic dysfunction (dry mouth, erectile dysfunction); post-exercise facilitation (reflexes return / strength ↑ after brief exercise); SCLC association ~60%	Anti-VGCC (P/Q-type) antibody; EMG: low CMAP at rest, ≥60% increment on high-frequency RNS (20–50 Hz) or post-exercise; anti-SOX1 supports paraneoplastic origin	3,4-DAP (amifampridine) first-line; pyridostigmine adjunct; IVIg/steroids/rituximab for refractory; SCLC screening with FDG-PET annually ×2 years if no tumor at diagnosis
PRES (Posterior Reversible Encephalopathy Syndrome)	Headache, seizures, altered mental status, cortical blindness/visual disturbance. Triggers: hypertension, eclampsia, calcineurin inhibitors (tacrolimus, cyclosporine), chemotherapy (bevacizumab, cisplatin), sepsis, autoimmune disease	MRI: posterior parieto-occipital vasogenic edema (T2/FLAIR hyperintense, no restricted diffusion); can involve frontal lobes, brainstem, cerebellum in atypical cases. Can overlap with RCVS	Reversible with BP control and trigger removal; treat seizures (AEDs short-term); avoid further BP swings. Atypical/severe cases may have hemorrhage or restricted diffusion (worse prognosis)

💎 Board Pearl

Tumefactive MS: open-ring enhancement opens toward cortex — classic feature distinguishing from neoplasm/abscess. T2 hypointense rim = peripheral macrophages. LEMS: post-exercise facilitation distinguishes from MG (which fatigues). 3,4-DAP blocks K+ channels → prolongs depolarization → more Ca2+ entry → more ACh release. PRES + thunderclap headache + reversible vasoconstriction = PRES-RCVS overlap (common in postpartum / sympathomimetic exposure).

Vaccine Guidance in Immunosuppressed MS / NMOSD

Vaccine Type / Issue	Guidance
LIVE vaccines to AVOID on immunosuppression	MMR, varicella (chickenpox), yellow fever, oral typhoid (Ty21a), BCG, intranasal influenza (LAIV), oral polio — avoid on anti-CD20, S1P modulators, natalizumab, alemtuzumab, cladribine
Timing of live vaccines	Complete live vaccines ≥4 weeks before initiating DMT; consider VZV vaccination (Shingrix is non-live, preferred) before high-efficacy DMT
Inactivated / subunit vaccines	Acceptable on DMT but reduced response on anti-CD20 — give ≥2 weeks before next infusion or 4–6 months after the last infusion to maximize antibody response
Routine vaccines recommended	Annual influenza (inactivated), pneumococcal (PCV15/20 + PPSV23), Shingrix (recombinant zoster), Tdap, HPV per ACIP
Screening before anti-CD20	HBV screening mandatory (HBsAg, anti-HBc, anti-HBs); reactivation risk; HIV; tuberculosis; baseline immunoglobulins
Eculizumab / ravulizumab specific	MenACWY + MenB ≥2 weeks before first dose; if urgent treatment must precede full vaccination, add antibacterial prophylaxis until vaccination is complete. Vaccination does not eliminate meningococcal risk — counsel on prompt evaluation for any febrile illness
COVID-19 vaccines	mRNA / protein-based (non-live) — recommended; reduced humoral response on anti-CD20 but T-cell response preserved

💎 Board Pearl

Live vaccines + anti-CD20 / S1P / natalizumab = avoid. Complete needed live vaccines ≥4 weeks BEFORE starting therapy. For anti-CD20, time inactivated vaccines to maximize B-cell window (give ≥2 weeks before next dose, or 4–6 months after). HBV screening is mandatory before rituximab/ocrelizumab/ofatumumab/ublituximab. Shingrix (non-live) is preferred over Zostavax (live) in immunocompromised. Eculizumab/ravulizumab require BOTH MenACWY and MenB.

Key Numbers & Board Traps

Fact	Value / Detail
McDonald DIS requirement (2024)	≥1 T2 lesion in ≥2 of 5 regions (periventricular, cortical/juxtacortical, infratentorial, spinal cord, optic nerve) — harmonized with Section 1
OCB bands needed	≥2 CSF-specific oligoclonal bands (not matched in serum)
MS relapse definition	Symptoms lasting ≥24 hours, occurring ≥30 days after previous attack, not explained by fever/infection
JCV index threshold	Anti-JCV Ab index >1.5 = high PML risk on natalizumab
Natalizumab PML risk factors	JCV Ab+ (index >1.5) + prior immunosuppression + duration >2 years → ~13/1000
NMOSD LETM definition	≥3 contiguous vertebral segments of T2 signal on spinal MRI
AQP4-IgG sensitivity in NMOSD	70–80% by cell-based assay (CBA); lower by ELISA (~50–60%); seronegative NMOSD exists
NMDAR encephalitis F:M ratio	~4:1 overall; higher in teratoma-associated (nearly all female)
Rituximab redosing interval	Every 6 months; monitor CD19/CD20 counts for B-cell reconstitution
MS pregnancy relapse pattern	Relapses ↓ in 3rd trimester; ↑↑ rebound in first 3 months postpartum
Fingolimod first-dose monitoring	6-hour continuous cardiac monitoring (ECG + BP); risk of bradycardia/AV block; do not use if resting HR <55
Siponimod CYP2C9 genotyping	3/3 = contraindicated; required before starting
Alemtuzumab monitoring duration	Monthly CBC + TFTs + urinalysis for 4 years after LAST dose
Teriflunomide washout	Cholestyramine 8 g TID ×11 days OR activated charcoal 50 g BID ×11 days as alternative; confirm levels <0.02 mg/L ×2 (two weeks apart) before conception
DMF ALC threshold for PML	Stop if ALC <500 for >6 months
Anti-GAD65 titer threshold	Low (<20) = type 1 DM; very high (>10,000) = neurological (SPS, ataxia, epilepsy)
PPMS progression requirement	≥1 year of progressive disability (not a single time point)
CIS conversion risk with OCBs	OCBs + ≥2 T2 lesions = ~90% convert to MS within 20 years
Eculizumab / ravulizumab vaccines	MenACWY + MenB vaccines ≥2 weeks before first dose; if urgent, start antibiotic prophylaxis until 2 weeks post-vaccine. Ravulizumab = C5 inhibitor, q8wk maintenance, FDA-approved for AQP4+ NMOSD in 2024.
PACNS biopsy false-negative rate	~25% (sampling error); need leptomeninges + cortex in specimen
RCVS resolution	Vasoconstriction resolves within 1–3 months (by definition)

💎 Board Pearl

NMOSD + MS DMTs = disaster (interferons, fingolimod, natalizumab can worsen NMOSD). PML is not just natalizumab (also DMF, fingolimod, rituximab). FBDS are NOT epilepsy — they respond to immunotherapy, not AEDs. Etanercept can paradoxically worsen sarcoidosis (use infliximab). GCA + vision loss = start steroids BEFORE biopsy. Anti-NMDAR encephalitis can follow HSV encephalitis. Teriflunomide + pregnancy = cholestyramine washout required. IVIg + IgA deficiency = anaphylaxis risk. ADEM requires encephalopathy — if absent, it is not ADEM.

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