Autoimmune Encephalitis
Autoimmune Encephalitis
What Do You Need to Know?
- Two antibody classes: Cell-surface antibodies (NMDA-R, LGI1, CASPR2, GABA-B, AMPA, DPPX) are directly pathogenic, immunotherapy-responsive, and carry better prognosis; intracellular/onconeural antibodies are T-cell mediated, poorly responsive to immunotherapy, and require tumor treatment
- Anti-NMDA-R encephalitis: Most common autoimmune encephalitis; young women; ovarian teratoma; staged progression (psychiatric → seizures → movement disorders → autonomic instability); extreme delta brush on EEG; ~80% good outcome with treatment
- Anti-LGI1: Older males; faciobrachial dystonic seizures (FBDS) are pathognomonic; hyponatremia (SIADH); AED-resistant but immunotherapy-responsive; rarely paraneoplastic
- Graus 2016 criteria: Possible autoimmune encephalitis requires subacute onset (≤3 months) of working memory deficits, altered mental status, or psychiatric symptoms plus ≥1 of: new focal CNS findings, seizures, CSF pleocytosis, or MRI suggesting encephalitis; definite requires specific antibody
- Always test BOTH serum AND CSF: NMDA-R antibodies may be negative in serum but positive in CSF in ~15% of cases
- Treatment ladder: First-line (steroids + IVIg or PLEX) → second-line (rituximab, cyclophosphamide) → tumor removal when applicable → long-term immunosuppression for relapsing cases
- Cancer screening is mandatory: CT body, pelvic/testicular ultrasound, whole-body PET-CT; repeat at 6–12 months if initially negative with cancer-associated antibody
Classification — Cell-Surface vs. Intracellular Antibodies
Fundamental Distinction
The single most important distinction in autoimmune encephalitis is antibody target location — this determines pathogenesis, treatment strategy, cancer association, and prognosis.
| Feature | Cell-Surface Antibodies | Intracellular/Onconeural Antibodies |
|---|---|---|
| Targets | NMDA-R, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX, IgLON5 | Hu (ANNA-1), Yo (PCA-1), Ri (ANNA-2), CV2/CRMP5, amphiphysin, Ma2 |
| Pathogenic mechanism | Directly pathogenic — receptor internalization, blockade, complement-mediated damage | T-cell mediated cytotoxicity — antibodies are biomarkers, not direct effectors |
| Neuronal damage | Potentially reversible — receptor dysfunction without neuronal death | Irreversible — cytotoxic T cells destroy neurons |
| Cancer association | Variable: NMDA-R (teratoma 20–50%); GABA-B (SCLC ~50%); LGI1 (<5%) | Strongly paraneoplastic: Hu (SCLC >80%); Yo (ovarian/breast); amphiphysin (breast, SCLC) |
| Immunotherapy response | Often excellent — >70% improve with first-line immunotherapy | Usually limited — neuronal damage is irreversible |
| Primary treatment strategy | Immunotherapy ± tumor removal | Tumor removal is primary; immunotherapy is adjunctive |
| Prognosis | Generally favorable with prompt treatment | Guarded — depends on tumor status and extent of neuronal loss |
💎 Board Pearl
- Cell-surface = treatable, intracellular = search for tumor — this is the highest-yield distinction on boards
- Cell-surface antibodies cause receptor dysfunction (reversible) while intracellular antibodies mark T-cell-mediated neuronal death (irreversible)
Graus 2016 Diagnostic Criteria
Possible Autoimmune Encephalitis
All three of the following criteria must be met:
- Subacute onset (rapid progression over ≤3 months) of working memory deficits, altered mental status, or psychiatric symptoms
- ≥1 of the following:
- New focal CNS findings
- Seizures not explained by a previously known seizure disorder
- CSF pleocytosis (WBC >5 cells/μL)
- MRI features suggestive of encephalitis (T2/FLAIR hyperintensity in medial temporal lobes or multifocal areas)
- Reasonable exclusion of alternative causes (infectious, metabolic, toxic, neoplastic)
Definite Autoimmune Encephalitis
- Requires identification of a specific neural antibody (cell-surface or intracellular) in serum and/or CSF
- OR: meets criteria for a specific antibody-defined syndrome (e.g., definite anti-NMDA-R encephalitis)
Definite Anti-NMDA-R Encephalitis (Graus Criteria)
Probable diagnosis if ≥4 of the following major groups of symptoms develop within 3 months:
- Abnormal (psychiatric) behavior or cognitive dysfunction
- Speech dysfunction (pressured speech, verbal reduction, mutism)
- Seizures
- Movement disorder, dyskinesias, or rigidity/abnormal postures
- Decreased level of consciousness
- Autonomic dysfunction or central hypoventilation
Definite = probable criteria + positive NMDA-R IgG antibodies (serum or CSF)
Definite Autoimmune Limbic Encephalitis
All four of the following:
- Subacute onset (≤3 months) of working memory deficits, seizures, or psychiatric symptoms suggesting temporal lobe involvement
- Bilateral MRI T2/FLAIR abnormalities restricted to medial temporal lobes
- ≥1 of: CSF pleocytosis, EEG with epileptic or slow-wave activity involving temporal lobes
- Reasonable exclusion of alternative causes
💎 Board Pearl
- Graus criteria key threshold: Subacute onset (≤3 months) + cognitive/psychiatric/behavioral change + at least 1 supportive feature (seizures, CSF pleocytosis, MRI changes, focal CNS findings) = possible autoimmune encephalitis
- A normal MRI does NOT exclude the diagnosis — MRI is normal in up to 50% of NMDA-R encephalitis
Anti-NMDA-R Encephalitis
Overview
- Most common autoimmune encephalitis overall
- Demographics: Young women (median age ~21); F:M ratio 4:1; also affects children and men
- Tumor association: Ovarian teratoma in 20–50% of women >18 years; rare in children (<5%) and men
- Mechanism: IgG antibodies cause NMDA receptor internalization → decreased receptor density at synapse
Staged Clinical Progression
| Stage | Timing | Features |
|---|---|---|
| 1. Prodromal | Days 1–14 | Headache, fever, malaise, upper respiratory symptoms — often mistaken for viral illness |
| 2. Psychiatric | Weeks 1–2 | Psychosis, hallucinations, agitation, paranoia, personality change, anxiety — often seen by psychiatry first |
| 3. Seizures | Weeks 2–3 | Generalized tonic-clonic or focal seizures; may develop status epilepticus |
| 4. Movement disorders | Weeks 2–4 | Orofacial dyskinesias (lip smacking, chewing, grimacing), choreoathetosis, dystonia, stereotypies — hallmark of disease |
| 5. Decreased consciousness | Weeks 3–8 | Catatonia, unresponsiveness, central hypoventilation (may need intubation), autonomic instability (tachy/bradycardia, blood pressure swings, hyperthermia) |
| 6. Recovery | Months | Gradual improvement in reverse order of symptom onset; may take months to years |
Diagnostics
- MRI: Normal in ~50%; when abnormal → T2/FLAIR hyperintensity in mesial temporal lobes, cortex, or cerebellum
- CSF: Lymphocytic pleocytosis (80%), oligoclonal bands (60%), elevated IgG index; CSF antibody testing is more sensitive than serum
- EEG: Diffuse slowing; extreme delta brush (rhythmic delta at 1–3 Hz with superimposed beta bursts) — seen in ~30%, fairly specific for NMDA-R encephalitis
- Antibody: Anti-NMDA-R IgG in CSF (gold standard) — serum can be negative in ~15%
Treatment & Prognosis
- First-line: IV methylprednisolone + IVIg or PLEX + tumor removal if teratoma found
- Second-line (if no improvement in 2 weeks): Rituximab or cyclophosphamide
- ~80% achieve good outcome (mRS ≤2) with treatment; recovery may take 12–18 months
- Relapse rate: 12–20%; higher if no tumor removed or no second-line therapy
- Post-HSV NMDA-R encephalitis: Develops 2–6 weeks after HSV encephalitis; clinical worsening after initial improvement → requires immunotherapy, NOT more acyclovir
💎 Board Pearl
- Extreme delta brush on EEG = think NMDA-R encephalitis — rhythmic delta with superimposed beta; ~30% of cases; fairly specific
- Young woman + psychiatric symptoms + seizures + orofacial dyskinesias = NMDA-R encephalitis — always check for ovarian teratoma
- Recovery occurs in reverse order of symptom progression — autonomic stability returns first, psychiatric symptoms last
- Post-HSV worsening at 2–6 weeks = NMDA-R antibodies from viral neuronal destruction exposing antigens — treat with immunotherapy, not antivirals
Anti-LGI1 Encephalitis
Overview
- Demographics: Older males (median age ~65); M:F ratio 2:1
- Cancer association: Rare (<5%); thymoma reported
- Mechanism: LGI1 antibodies disrupt LGI1-ADAM22/ADAM23 interaction at synapse → increased neuronal excitability
- Previously misattributed to “VGKC antibodies” — the true target is LGI1 (or CASPR2), not the voltage-gated potassium channel itself
Key Clinical Features
| Feature | Details |
|---|---|
| Faciobrachial dystonic seizures (FBDS) | Pathognomonic; brief (<3 sec), very frequent (up to 100/day); unilateral arm + ipsilateral face contraction; ASM-resistant; immunotherapy-responsive |
| Hyponatremia | 60–70% of patients; due to SIADH; often <130 mEq/L |
| Limbic encephalitis | Memory impairment, confusion, temporal lobe seizures; may follow FBDS by weeks to months |
| MRI | Mesial temporal T2/FLAIR hyperintensity (uni- or bilateral); may progress to mesial temporal sclerosis |
| EEG | Often normal during FBDS (>50%); temporal IEDs or subclinical seizures |
| Seizures | >90% prevalence; AED-resistant; rapid response to immunotherapy |
FBDS: The Critical Early Window
- FBDS typically precede cognitive decline by weeks to months
- Prompt immunotherapy at the FBDS stage may prevent progression to full limbic encephalitis
- Frequently misdiagnosed as myoclonus, tics, or PNES because EEG is normal in >50%
Treatment
- First-line: Corticosteroids (excellent response); IVIg
- Relapse rate: 20–35%, most during steroid taper → many require prolonged immunosuppression
- Residual cognitive impairment (especially memory) common even after seizure control
💎 Board Pearl
- FBDS = LGI1 until proven otherwise — pathognomonic; brief, frequent, ASM-resistant, immunotherapy-responsive
- Hyponatremia + seizures + older male = think LGI1 — hyponatremia from SIADH in 60–70%
- FBDS with normal EEG does NOT equal non-epileptic events — the brief duration and subcortical origin mean scalp EEG is often negative
- “VGKC antibodies” without LGI1 or CASPR2 specificity are non-specific and should not be used to diagnose autoimmune encephalitis
Anti-CASPR2 Encephalitis & Morvan Syndrome
Overview
- Demographics: Older males predominate (median age ~65)
- Cancer association: Thymoma in 20–40%
- CASPR2 (contactin-associated protein-like 2): Located at juxtaparanodal region of myelinated axons → disruption causes peripheral nerve hyperexcitability and CNS dysfunction
Clinical Spectrum
| Syndrome | Features |
|---|---|
| Morvan syndrome | The classic tetrad: encephalopathy + neuromyotonia + severe insomnia + dysautonomia; also pain, weight loss, hyperhidrosis |
| Limbic encephalitis | Memory impairment, seizures, confusion; mesial temporal FLAIR changes |
| Peripheral nerve hyperexcitability (neuromyotonia) | Muscle cramps, stiffness, fasciculations, myokymia; EMG: spontaneous motor unit discharges (doublets, triplets, multiplets) |
| Neuropathic pain | Prominent neuropathic pain, often preceding encephalopathy |
Morvan Syndrome Diagnostic Clues
- Combination of central (encephalopathy, insomnia) and peripheral (neuromyotonia, pain, dysautonomia) features is hallmark
- Insomnia is severe — can progress to agrypnia excitata (complete inability to sleep)
- Dysautonomia: hyperhidrosis, tachycardia, blood pressure instability, urinary dysfunction
💎 Board Pearl
- Encephalopathy + neuromyotonia + insomnia + dysautonomia = Morvan syndrome = CASPR2 — always check for thymoma
- CASPR2 is the only autoimmune encephalitis antibody that characteristically causes both central and peripheral nervous system involvement simultaneously
- Distinguished from LGI1 by: peripheral nerve hyperexcitability, pain, and thymoma association (LGI1 has FBDS, hyponatremia, and is rarely paraneoplastic)
Anti-GABA-B Encephalitis
Overview
- Demographics: Older adults (median ~60 years)
- Cancer association: SCLC in ~50% — always screen
- Mechanism: Antibodies against GABA-B receptor (inhibitory) → loss of GABAergic inhibition → seizures
Key Clinical Features
- Prominent early seizures — often the presenting symptom
- Status epilepticus is common and may be the initial presentation
- Limbic encephalitis with memory loss and confusion
- MRI: Mesial temporal T2/FLAIR hyperintensity (similar to LGI1)
- Good immunotherapy response for the encephalitis component
- Prognosis often dictated by underlying malignancy (SCLC)
💎 Board Pearl
- Limbic encephalitis + prominent early seizures/status epilepticus + older adult = think GABA-B — always screen for SCLC
- GABA-B and LGI1 can look similar on MRI (mesial temporal FLAIR); distinguish by: GABA-B has more prominent seizures, SCLC association, and no FBDS/hyponatremia
Anti-AMPAR Encephalitis
Overview
- Demographics: Middle-aged to older adults; slight female predominance
- Cancer association: ~70% paraneoplastic — SCLC, breast cancer, thymoma
- Mechanism: Antibodies against AMPA receptor (excitatory glutamate receptor) → receptor internalization
Key Clinical Features
- Limbic encephalitis with memory impairment and confusion
- Relapsing course is characteristic — distinguishes AMPAR from other limbic encephalitides
- Seizures in 40–60%
- Psychiatric symptoms (psychosis, personality change)
- MRI: Mesial temporal T2/FLAIR signal changes
- Responds to immunotherapy but frequently relapses → long-term immunosuppression often required
💎 Board Pearl
- Relapsing limbic encephalitis + cancer (SCLC/breast/thymoma) = think AMPAR — the relapsing course is the hallmark distinguishing feature
- ~70% are paraneoplastic — one of the highest cancer association rates among cell-surface antibodies
Anti-DPPX Encephalitis
Overview
- DPPX (dipeptidyl-peptidase-like protein-6): Auxiliary subunit of Kv4.2 potassium channels
- Demographics: Middle-aged adults; male predominance
- Cancer association: Low; B-cell lymphoma reported rarely
Key Clinical Features
| Phase | Features |
|---|---|
| Prodromal (GI) | Diarrhea, weight loss, GI dysmotility — often precedes neurological symptoms by weeks to months; may be misdiagnosed as GI disease |
| Neurological | Encephalopathy (agitation, confusion, paranoia); hyperekplexia (exaggerated startle); myoclonus; tremor; progressive cognitive decline |
| Autonomic | Dysautonomia; PRES (posterior reversible encephalopathy syndrome) reported |
💎 Board Pearl
- Prodromal GI symptoms (diarrhea + weight loss) followed by encephalopathy + hyperekplexia + myoclonus = think DPPX
- The prodromal GI phase is nearly unique to DPPX and is the most common board-tested distinguishing feature
- Hyperekplexia (exaggerated startle response) in the setting of encephalitis should prompt testing for DPPX antibodies
Anti-IgLON5 Disease
Overview
- Unique among autoimmune encephalitides: Features of both autoimmunity AND neurodegeneration (tauopathy at autopsy)
- Demographics: Older adults (median ~60); slight male predominance
- Cancer association: None known
- Strong HLA association: HLA-DRB1*10:01 and HLA-DQB1*05:01
Key Clinical Features
| Domain | Features |
|---|---|
| Sleep disorders | Non-REM parasomnias (finalistic movements, vocalizations); REM sleep behavior disorder; obstructive sleep apnea; stridor |
| Bulbar dysfunction | Dysphagia, dysarthria, stridor, vocal cord paralysis — major cause of morbidity/mortality |
| Movement disorder | Gait instability, chorea, orofacial dyskinesias, progressive supranuclear palsy-like features |
| Cognitive | Cognitive decline, typically subcortical pattern |
| Autonomic | Dysautonomia (less prominent than other autoimmune encephalitides) |
Pathology & Prognosis
- Tauopathy at autopsy: Neuronal deposits of hyperphosphorylated tau in hypothalamus, tegmentum, hippocampus — unique overlap of autoimmune and neurodegenerative pathology
- Poor immunotherapy response — in contrast to most other cell-surface antibody syndromes
- Progressive course in many patients despite treatment
- Death often from respiratory complications (aspiration, sleep apnea)
💎 Board Pearl
- Non-REM + REM parasomnias + sleep apnea + bulbar dysfunction + gait instability = think IgLON5
- IgLON5 is the only autoimmune encephalitis with tauopathy at autopsy — bridges autoimmunity and neurodegeneration
- IgLON5 is the major exception to the rule that cell-surface antibodies = good immunotherapy response
Comprehensive Antibody Comparison Table
| Antibody | Target Type | Demographics | Key Clinical Features | MRI Findings | Cancer Association | Treatment Response |
|---|---|---|---|---|---|---|
| NMDA-R | Cell-surface (ionotropic glutamate receptor) | Young women (median ~21); F:M 4:1 | Staged: psychiatric → seizures → orofacial dyskinesias → autonomic instability → coma; extreme delta brush | Normal in ~50%; mesial temporal or cortical T2/FLAIR | Ovarian teratoma (20–50% in women >18) | Excellent; ~80% good outcome |
| LGI1 | Cell-surface (secreted neuronal protein) | Older males (median ~65); M:F 2:1 | FBDS (pathognomonic); hyponatremia (SIADH); limbic encephalitis; AED-resistant seizures | Mesial temporal T2/FLAIR (uni- or bilateral) | Rare (<5%) | Good; rapid response to steroids; relapses common (20–35%) |
| CASPR2 | Cell-surface (juxtaparanodal) | Older males (median ~65) | Morvan syndrome: encephalopathy + neuromyotonia + insomnia + dysautonomia + pain; limbic encephalitis; PNH | Mesial temporal T2/FLAIR or normal | Thymoma (20–40%) | Good; combined CNS + PNS features respond |
| GABA-B | Cell-surface (inhibitory receptor) | Older adults (median ~60) | Limbic encephalitis with prominent early seizures/status epilepticus | Mesial temporal T2/FLAIR | SCLC (~50%) | Good for encephalitis; prognosis depends on tumor |
| GABA-A | Cell-surface (inhibitory receptor) | All ages; children and adults | Refractory status epilepticus; rapidly progressive encephalopathy | Multifocal cortical FLAIR (distinctive) | Thymoma (occasional) | Moderate; often requires aggressive immunotherapy |
| AMPAR | Cell-surface (excitatory receptor) | Middle-aged to older; slight female predominance | Limbic encephalitis; relapsing course; memory impairment | Mesial temporal T2/FLAIR | SCLC, breast, thymoma (~70%) | Good initially but frequent relapses |
| DPPX | Cell-surface (K+ channel subunit) | Middle-aged; male predominance | Prodromal GI symptoms (diarrhea, weight loss) → encephalopathy + hyperekplexia + myoclonus | Often normal | Low (B-cell lymphoma rare) | Moderate; may require prolonged immunotherapy |
| IgLON5 | Cell-surface (neuronal adhesion) | Older adults (median ~60) | Non-REM/REM parasomnias, sleep apnea, bulbar dysfunction, gait instability; tauopathy | Often normal; brainstem atrophy late | None | Poor (exception to cell-surface rule) |
| Hu (ANNA-1) | Intracellular (nuclear) | Older adults; smokers | Encephalomyelitis, sensory neuropathy, limbic encephalitis, cerebellar degeneration | Variable; temporal FLAIR or cerebellar atrophy | SCLC (>80%) | Poor; treat tumor primarily |
| Ma2 | Intracellular (nuclear) | Young men | Limbic/diencephalic encephalitis; narcolepsy-like hypersomnia; vertical gaze palsy | Diencephalic/hypothalamic/brainstem T2/FLAIR | Testicular germ cell tumor | Moderate; better than other intracellular (young patients, treatable tumor) |
💎 Board Pearl
- Highest cancer associations: AMPAR (~70%), GABA-B (~50%), Hu (>80%), Ma2 (testicular) — these always require aggressive cancer screening
- Lowest cancer associations: LGI1 (<5%), DPPX (rare), IgLON5 (none) — but still screen all patients
- GABA-A is unique: Multifocal cortical FLAIR pattern (not mesial temporal) + refractory status epilepticus
Diagnostic Workup
Systematic Evaluation
- Testing should be performed before immunotherapy whenever possible — treatment may reduce antibody titers and cause false negatives
- Always send BOTH serum AND CSF antibody panels simultaneously
| Test | Details | Key Considerations |
|---|---|---|
| Serum antibody panel | NMDA-R, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX, IgLON5; intracellular panel (Hu, Yo, Ri, CV2, amphiphysin, Ma2) | Cell-based assays (CBA) preferred for surface antibodies; higher sensitivity/specificity than immunoblot |
| CSF antibody panel | Same panel as serum; also oligoclonal bands, IgG index, cytology | NMDA-R may be negative in serum but positive in CSF (~15%) — CSF is gold standard for NMDA-R |
| CSF routine | Cell count, protein, glucose, cultures, HSV/VZV PCR | Lymphocytic pleocytosis (10–100 cells) in ~80% of NMDA-R; must exclude infectious encephalitis first |
| Brain MRI | Epilepsy protocol with coronal FLAIR through temporal lobes | Mesial temporal FLAIR (LGI1, GABA-B); multifocal cortical (GABA-A); normal in ~50% of NMDA-R |
| EEG | Continuous video-EEG if encephalopathic; routine EEG otherwise | Extreme delta brush (NMDA-R); temporal IEDs; subclinical seizures; FBDS may have no EEG correlate |
| CT chest/abdomen/pelvis | Cancer screening — mandatory in ALL patients | SCLC (GABA-B, AMPA, Hu); thymoma (CASPR2, AMPA) |
| Pelvic ultrasound or MRI | Women with NMDA-R antibodies | Ovarian teratoma detection; transvaginal preferred |
| Testicular ultrasound | Young men with Ma2 or NMDA-R antibodies | Testicular germ cell tumor (Ma2); testicular teratoma (NMDA-R, rare) |
| Whole-body PET-CT | If CT negative but high-risk antibody | Higher sensitivity for small/occult tumors; repeat at 6–12 months if initially negative |
Serum vs. CSF Sensitivity
| Antibody | Preferred Specimen | Notes |
|---|---|---|
| NMDA-R | CSF (gold standard) | ~15% serum-negative/CSF-positive; CSF titers correlate better with disease activity |
| LGI1 | Serum (more sensitive) | May be negative in CSF; serum titers usually higher |
| CASPR2 | Serum (more sensitive) | Similar to LGI1; serum typically more informative |
| GABA-B, AMPA | Both (send paired) | Concordance is generally high |
| Intracellular | Serum (usually sufficient) | High serum titers; CSF adds limited value |
💎 Board Pearl
- Always send BOTH serum AND CSF — NMDA-R can be serum-negative/CSF-positive in ~15%; LGI1 can be CSF-negative/serum-positive
- Cell-based assay (CBA) is the gold standard for cell-surface antibodies — tissue-based assays (rat brain immunohistochemistry) are used for screening but less specific
- A normal MRI does not exclude autoimmune encephalitis — up to 50% of NMDA-R cases have normal MRI
- Repeat cancer screening at 6-month intervals for ≥2 years in patients with high-risk antibodies and initial negative screen
Treatment
First-Line Immunotherapy
| Agent | Dose/Regimen | Key Points |
|---|---|---|
| IV methylprednisolone | 1 g/day × 3–5 days; then oral prednisone taper over 3–6 months | Rapid anti-inflammatory effect; first agent initiated in most cases |
| IVIg | 0.4 g/kg/day × 5 days (total 2 g/kg) | Immunomodulatory; can be combined with steroids; may repeat monthly for maintenance |
| PLEX (plasma exchange) | 5–7 exchanges on alternate days | Most effective for cell-surface antibodies (removes pathogenic IgG); consider first-line in fulminant presentations |
- First-line agents are typically combined: steroids + IVIg OR steroids + PLEX
- Assess response at 2 weeks; if insufficient improvement → escalate to second-line
Second-Line Immunotherapy
| Agent | Dose/Regimen | Key Points |
|---|---|---|
| Rituximab | 375 mg/m2 weekly × 4 OR 1000 mg × 2 doses (2 weeks apart) | B-cell depletion; onset within 2–4 weeks; preferred first second-line agent; monitor CD19/CD20 counts |
| Cyclophosphamide | IV pulse 750 mg/m2 monthly × 3–6 | Reserved for rituximab-refractory cases; significant toxicity (hemorrhagic cystitis, myelosuppression, infertility) |
Tumor Removal
- Essential when paraneoplastic etiology is identified — immunotherapy alone is often insufficient
- Ovarian teratoma resection in NMDA-R encephalitis improves outcomes and reduces relapse
- Thymectomy for thymoma-associated CASPR2 or AMPA
- SCLC treatment (chemotherapy/radiation) for GABA-B, AMPA, Hu syndromes
- Tumor removal should proceed in parallel with immunotherapy, not sequentially
Long-Term Immunosuppression
| Agent | Dose | Notes |
|---|---|---|
| Rituximab maintenance | Every 6 months; guided by CD19/CD20 recovery | Preferred for relapsing NMDA-R, LGI1, CASPR2 |
| Mycophenolate mofetil | 1000–1500 mg BID | Steroid-sparing; onset 2–3 months; monitor CBC, LFTs |
| Azathioprine | 2–3 mg/kg/day | Onset 3–6 months; check TPMT genotype before starting (myelosuppression risk) |
- Continue immunotherapy ≥1–2 years minimum; taper guided by clinical stability and antibody titers
- Relapsing cases (especially AMPA, LGI1) may require indefinite immunosuppression
Treatment Response by Antibody
| Antibody | Immunotherapy Response | Relapse Rate | Special Considerations |
|---|---|---|---|
| NMDA-R | Excellent (~80% good outcome) | 12–20% | Better with early second-line + tumor removal; recovery may take ≥12 months |
| LGI1 | Good; rapid steroid response | 20–35% | Most relapses during steroid taper; residual cognitive impairment common |
| CASPR2 | Good | Moderate | Thymectomy when thymoma present |
| GABA-B | Good for encephalitis | Variable | Prognosis driven by underlying SCLC |
| AMPAR | Good initially | High (frequent relapses) | Long-term immunosuppression usually needed |
| IgLON5 | Poor | N/A (progressive) | Exception to cell-surface = treatable rule; tauopathy component |
| Intracellular | Poor | N/A (irreversible damage) | Tumor treatment is primary; immunotherapy adjunctive |
Clinical Pearl
- Do not delay immunotherapy while awaiting antibody results in patients with rapidly progressive encephalopathy, refractory status epilepticus, or high clinical suspicion. Obtain samples before treatment whenever possible, but treatment should not be withheld for pending results — early treatment is the strongest predictor of good outcome.
💎 Board Pearl
- Treatment ladder: First-line (steroids + IVIg/PLEX) → re-assess at 2 weeks → second-line (rituximab > cyclophosphamide) → long-term immunosuppression
- Tumor removal improves outcomes and reduces relapse rates — always pursue in parallel with immunotherapy
- PLEX is most effective for cell-surface antibodies because it directly removes pathogenic IgG from circulation
- Check TPMT before azathioprine — homozygous TPMT deficiency causes life-threatening myelosuppression
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