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neuro.encephalitis-anti-nmdar.v1PRODUCTION
neuro.encephalitis-anti-nmdar.v1

Anti-NMDA Receptor Encephalitis

neurologyacutesubacuteadultpediatricpregnancy
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12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Acute / subacute neuropsychiatric syndrome with psychiatric prodrome + seizures + movement disorder + autonomic instability + AMS → suspect anti-NMDAR encephalitis (Graus 2016 IRCNS PMID 26906964)

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Autoimmune encephalitis pathway activated

Patient inputs (16)

Bimodal — young female (15-45 y) classic; pediatric peak (post-HSV); less teratoma association in pediatric (Graus 2016 PMID 26906964)

Anti-NMDAR strongly female predominant (~80%); ovarian teratoma association ~50% in young women (Dalmau)

Post-HSV biphasic course — up to 27% of HSV survivors develop anti-NMDAR 1-6 wk after recovery (Armangué 2018 PMID 30049614)

AMS → coma progression typical without treatment; GCS baseline + serial

Psychiatric prodrome (psychosis, mania, paranoia, agitation) — 70% present first to psychiatry; common diagnostic delay

CSF anti-NMDAR IgG via cell-based assay (CBA) — GOLD STANDARD; serum less sensitive; Graus 2016 criteria (PMID 26906964)

CSF — lymphocytic pleocytosis (often 20-100), normal-mild protein, OCB+ in ~60%; rule out HSV PCR + autoimmune AE panel

HSV PCR MANDATORY to rule out HSV encephalitis (mimic + post-HSV trigger); empiric acyclovir until result

Pelvic US + MRI for ovarian teratoma in young women (~50% association); CT chest/abdomen/pelvis if older / atypical to screen for occult malignancy (Dalmau)

MRI brain often normal in anti-NMDAR (50%); T2/FLAIR mesiotemporal hyperintensity in 30%; rule out HSV temporal lobe necrosis

EEG — extreme delta brush ~30% pathognomonic; cEEG if persistent AMS or refractory seizures

>70% have seizures; ~30% develop status epilepticus; route to neuro.status-epilepticus.core.v1 if status (Titulaer 2013 PMID 23290630)

Orofacial dyskinesia + dystonia + chorea — distinctive feature; clonazepam + valproate; AVOID typical antipsychotics (extreme sensitivity)

Autonomic storms (BP/HR/temperature lability, hypoventilation, hypersalivation) — ICU monitoring; dexmedetomidine preferred

Required before cyclophosphamide / MMF / methotrexate initiation

Rituximab / B-cell depletion pre-screen

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (8)

8 need judgement
  • informationallife_threateningicu_severe_with_dyskinesia_autonomic
    ICU phenotype — orofacial dyskinesia + autonomic storms (BP/HR/temperature lability + hypoventilation) + status — dexmedetomidine for agitation, clonazepam + valproate for dyskinesia (Dalmau)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereclassic_psychiatric_prodrome_young_female
    Young female (15-45 y) with subacute psychiatric prodrome → seizures → movement disorders → autonomic + AMS — classic anti-NMDAR pentad; pelvic US for ovarian teratoma ~50% (Graus 2016 PMID 26906964)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereovarian_teratoma_associated_paraneoplastic
    Anti-NMDAR with ovarian teratoma found on pelvic US/MRI — TUMOR REMOVAL MANDATORY (improves outcome significantly; ~50% of young women); + first-line immunotherapy (Dalmau)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepediatric_anti_nmdar_post_hsv_or_idiopathic
    Pediatric anti-NMDAR — post-HSV triggered more common than adult; less ovarian teratoma association; pediatric dosing methylpred 30 mg/kg/d (max 1 g); IVIG preferred adjunct (PMID 34301820)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepost_hsv_anti_nmdar_biphasic_1_to_6_wk
    Biphasic neurological relapse 1-6 wk after HSV encephalitis recovery — anti-NMDAR autoimmune encephalitis; up to 27% of HSV survivors; psychiatric prodrome + new seizures + dyskinesia (Armangué 2018 PMID 30049614)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepregnancy_with_nmdar_encephalitis
    Pregnancy + anti-NMDAR encephalitis — IVIG safer than PLEX; cyclophosphamide CONTRAINDICATED in pregnancy; rituximab Cat C; MFM + neuro coordination
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevererefractory_to_first_line_rituximab_cyclophosphamide
    No improvement at 4 wk on first-line steroid + IVIG + PLEX + tumor removal — escalate to second-line rituximab 1 g × 2 + cyclophosphamide 750 mg/m² monthly × 6 mo (Titulaer 2013 PMID 23290630)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatechronic_relapsing_form_maintenance_rituximab
    Relapsing anti-NMDAR ≥2 events ≥3 mo apart (~12% of cases) — long-term maintenance rituximab q6 mo × 2 y + steroid-sparing (AZA/MMF)
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

Anti-NMDAR encephalitis escalating immunotherapy + tumor removal + supportive (Graus 2016 PMID 26906964; Titulaer 2013 PMID 23290630; Titulaer 2013 PMID 23290630)
axis: anti_nmdar_first_second_third_line_immunotherapystep 1 - Step 1 — First-line immunotherapy + tumor removal (Graus 2016 PMID 26906964; Titulaer 2013 PMID 23290630)
Selected step "Step 1 — First-line immunotherapy + tumor removal (Graus 2016 PMID 26906964; Titulaer 2013 PMID 23290630)" — Confirmed or strongly suspected anti-NMDAR encephalitis with neuropsychiatric syndrome
  • methylprednisolone
    first line
    corticosteroid_pulse
    1 g IV daily × 5 d adult (30 mg/kg/d × 5 d pediatric, max 1 g/d) • IV • daily × 5 d (max: 5 g cumulative)
    triggers: acute_anti_nmdar
    First-line acute pulse; combine with IVIG or PLEX; Graus 2016 PMID 26906964; Titulaer 2013 PMID 23290630
    rxcui 6902
  • IVIG
    first line
    pooled_human_IgG
    0.4 g/kg/day × 5 d (total 2 g/kg) • IV • daily × 5 d
    triggers: acute_anti_nmdar, pregnancy_with_nmdar, pediatric_anti_nmdar
    First-line combo with steroid; preferred in pediatric + pregnancy; Titulaer 2013 PMID 23290630
    rxcui 1426680
  • plasmapheresis (PLEX)
    first line
    apheresis
    5 cycles q48h over 10 d • IV/large-bore • q2 days × 5
    triggers: severe_anti_nmdar_or_ivig_alternative
    Alternative to or addition to IVIG for severe presentation; large-bore IV / temporary line; ~50-70% improvement
  • ovarian teratoma removal
    first line
    surgical_oncologic
    triggers: teratoma_found_on_pelvic_imaging
    Tumor removal MANDATORY when found — improves outcome significantly (Dalmau; ~50% young women); without removal, immunotherapy alone less effective
  • prednisone
    add on
    corticosteroid_oral_taper
    60 mg PO daily × 2-4 wk then taper over 4-6 mo • PO • daily slow taper
    triggers: post_pulse_taper_anti_nmdar
    Maintenance taper after IV pulse; slower than MS-flare to prevent relapse; bridge to steroid-sparing
    rxcui 8640

outpatient playbook — drug actions (6)

  1. 1. rituximab maintenance
    1 g IV q6 mo × 2 y • IV • q6 mo
    trigger: Refractory or relapsing anti-NMDAR
    Titulaer 2013 PMID 23290630
  2. 2. prednisone taper continuation
    Per taper schedule down to 5-10 mg/d then off • PO • daily taper
    trigger: Post-acute maintenance
    Slow taper over 4-6 mo
  3. 3. azathioprine or MMF (steroid-sparing)
    AZA 2-3 mg/kg/d OR MMF 1-3 g/d • PO • daily / BID
    trigger: Steroid-sparing maintenance
    TPMT + CBC + LFT monitoring; MMF pregnancy CONTRAINDICATED
  4. 4. levetiracetam (continued if seizure history)
    1000-1500 mg PO BID • PO • BID
    trigger: Seizure history
    Long-term AED
  5. 5. sertraline (post-anti-NMDAR depression)
    25-200 mg PO daily • PO • daily
    trigger: PHQ-9 ≥10
    Common sequelae
  6. 6. quetiapine low-dose (residual psychiatric)
    25-100 mg PO daily • PO • daily
    trigger: Residual psychiatric
    AVOID typical antipsychotics

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Young female (15-45 y) with subacute psychiatric prodrome (psychosis, mania, paranoia) → seizures → movement disorders → autonomic instability + AMS (Graus 2016 IRCNS PMID 26906964); Biphasic neurological relapse 1-6 wk after HSV encephalitis — psychiatric + dyskinesia + new seizures (Armangué 2018 PMID 30049614); Orofacial dyskinesia + autonomic storms (BP/HR/temperature lability) + AMS — ICU phenotype (Dalmau).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Anti-NMDA Receptor Encephalitis** (neuro.encephalitis-anti-nmdar.v1).
Phenotype framing: Anti-NMDAR encephalitis (paraneoplastic with teratoma vs idiopathic vs post-HSV biphasic) / HSV encephalitis (PCR pivot) / other autoimmune AE (LGI1/CASPR2/GABA-B/AMPA/DPPX/IgLON5) / primary psychiatric disease / NMS / serotonin syndrome / catatonia (treat with benzo trial) / drug-induced (PCP, ketamine, methamphetamine) / paraneoplastic intracellular (Hu/Ma2/Ri) / metabolic encephalopathy / CJD / Hashimoto encephalopathy
Scope: Acute / subacute neuropsychiatric syndrome with psychiatric prodrome + seizures + movement disorder + autonomic instability + AMS → suspect anti-NMDAR encephalitis (Graus 2016 IRCNS PMID 26906964)

No severity triggers fired against current inputs.

Plan

Regimen axis: **Anti-NMDAR encephalitis escalating immunotherapy + tumor removal + supportive (Graus 2016 PMID 26906964; Titulaer 2013 PMID 23290630; Titulaer 2013 PMID 23290630)** — step "Step 1 — First-line immunotherapy + tumor removal (Graus 2016 PMID 26906964; Titulaer 2013 PMID 23290630)".
1. methylprednisolone 1 g IV daily × 5 d adult (30 mg/kg/d × 5 d pediatric, max 1 g/d) IV daily × 5 d (corticosteroid_pulse, first line) — First-line acute pulse; combine with IVIG or PLEX; Graus 2016 PMID 26906964; Titulaer 2013 PMID 23290630
2. IVIG 0.4 g/kg/day × 5 d (total 2 g/kg) IV daily × 5 d (pooled_human_IgG, first line) — First-line combo with steroid; preferred in pediatric + pregnancy; Titulaer 2013 PMID 23290630
3. plasmapheresis (PLEX) 5 cycles q48h over 10 d IV/large-bore q2 days × 5 (apheresis, first line) — Alternative to or addition to IVIG for severe presentation; large-bore IV / temporary line; ~50-70% improvement
4. ovarian teratoma removal (surgical_oncologic, first line) — Tumor removal MANDATORY when found — improves outcome significantly (Dalmau; ~50% young women); without removal, immunotherapy alone less effective
5. prednisone 60 mg PO daily × 2-4 wk then taper over 4-6 mo PO daily slow taper (corticosteroid_oral_taper, add on) — Maintenance taper after IV pulse; slower than MS-flare to prevent relapse; bridge to steroid-sparing

Setting playbook (outpatient) — Primary neurology / neuropsychiatry / autoimmune encephalitis clinic q3-6 mo — relapse surveillance + DMT + cognitive rehab + comorbidity + pregnancy planning (Graus 2016 PMID 26906964)
6. rituximab maintenance 1 g IV q6 mo × 2 y IV q6 mo — Refractory or relapsing anti-NMDAR (Titulaer 2013 PMID 23290630)
7. prednisone taper continuation Per taper schedule down to 5-10 mg/d then off PO daily taper — Post-acute maintenance (Slow taper over 4-6 mo)
8. azathioprine or MMF (steroid-sparing) AZA 2-3 mg/kg/d OR MMF 1-3 g/d PO daily / BID — Steroid-sparing maintenance (TPMT + CBC + LFT monitoring; MMF pregnancy CONTRAINDICATED)
9. levetiracetam (continued if seizure history) 1000-1500 mg PO BID PO BID — Seizure history (Long-term AED)
10. sertraline (post-anti-NMDAR depression) 25-200 mg PO daily PO daily — PHQ-9 ≥10 (Common sequelae)
11. quetiapine low-dose (residual psychiatric) 25-100 mg PO daily PO daily — Residual psychiatric (AVOID typical antipsychotics)

Non-pharmacologic actions:
- Cognitive rehab + memory aids + structured routines
- Neuropsych eval at 6 + 12 + 24 mo
- Speech / occupational / physical therapy
- Pre-DMT vaccinations
- Bone health (DEXA, vitamin D)
- Pregnancy planning
- Driving re-evaluation per cognition + AED
- Vocational rehab + functional capacity assessment
- Mental health referral if PHQ-9 ≥10

AVOID / contraindication checks:
- CSF_anti_NMDAR_via_CBA_gold_standard (serum less sensitive)
- Send_CSF_anti_NMDAR_BEFORE_immunotherapy_if_feasible (titer lowered by steroid + IVIG)
- Ovarian_teratoma_removal_MANDATORY_when_found (improves outcome significantly)
- AVOID_typical_antipsychotics_haloperidol_fluphenazine (extreme NMS like sensitivity)
- HSV_PCR_MANDATORY_to_rule_out_HSV_encephalitis_mimic_or_trigger
- Second_line_rituximab_plus_cyclophosphamide_if_no_response_at_4_weeks (Titulaer 2013 PMID 23290630)
- Dexmedetomidine_preferred_over_benzo_for_ICU_agitation
- Cyclophosphamide_CONTRAINDICATED_in_pregnancy
- HBV_VZV_TB_screen_before_rituximab
- Pediatric_methylpred_30_mg_per_kg_per_d_max_1g
- Annual_pelvic_US_for_2_years_if_no_teratoma_initially (occult teratoma may emerge)

Monitoring

Regimen monitoring:
- Daily neuro exam + GCS + CASE if available
- cEEG if status / persistent AMS / refractory seizure (extreme delta brush ~30%)
- Continuous telemetry for autonomic storms
- CBC + CMP + glucose + LFT during steroid
- CD19/CD20 + IgG q3-6 mo on rituximab
- CSF re-test at 4-6 wk if no clinical improvement (anti-NMDAR titer)
- Pelvic US annually × 2 y if no teratoma initially found
- Cognitive battery at 3 + 6 + 12 + 24 mo (75% return to baseline at 2 y)
- Pregnancy / postpartum surveillance
- AED levels if applicable

Setting (outpatient) monitoring:
- CBC + LFT + IgG q3-6 mo on DMT
- CD19/CD20 q3-6 mo on rituximab
- Anti-NMDAR CSF titer at 6-12 mo if symptoms
- Annual MRI brain if persistent
- Pelvic US annually × 2 y
- Cognitive battery 3/6/12/24 mo

Follow-up plan: Cognitive rehab (memory + executive + attention deficits common post-recovery — 75% return to baseline at 2 y); neuropsychiatry (depression / behavioural change frequent); speech / occupational / physical therapy; AED management if seizure history; pregnancy planning + postpartum surveillance; psych follow-up for late-onset psychosis or relapse; PHQ-9 + cognitive battery at 3 + 6 + 12 + 24 mo
- Close-out criterion: Long-term plan + specialty referrals documented

Monitoring phase: Daily neuro + GCS during acute; cEEG if status / persistent AMS; continuous telemetry for autonomic; CBC + LFT + glucose during steroid; CSF re-test at 4-6 wk if no clinical improvement; CD19/CD20 + IgG q3-6 mo on rituximab; surveillance for relapsing course (~12% recur within 2 y); annual pelvic US for 2 y if no teratoma found initially

Disposition

Current setting: outpatient — Primary neurology / neuropsychiatry / autoimmune encephalitis clinic q3-6 mo — relapse surveillance + DMT + cognitive rehab + comorbidity + pregnancy planning (Graus 2016 PMID 26906964)

Disposition criteria:
- Continue indefinite neurology + neuropsychiatry q3-6 mo for 2-5 y minimum
- Admit for acute relapse
- Discharge from chronic DMT after 2-5 y stable

Escalation triggers (move to higher acuity):
- Breakthrough relapse on rituximab → consider switch or escalate to tocilizumab / bortezomib
- New psychiatric / seizure / dyskinesia → ED + steroid pulse
- IgG <500 + recurrent infection → IVIG / pause rituximab
- Pregnancy confirmed → MFM + neuro coordination
- Severe depression / suicidality → urgent psych

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] ICU phenotype — orofacial dyskinesia + autonomic storms (BP/HR/temperature lability + hypoventilation) + status — dexmedetomidine for agitation, clonazepam + valproate for dyskinesia (Dalmau)
- [SEVERE] Young female (15-45 y) with subacute psychiatric prodrome → seizures → movement disorders → autonomic + AMS — classic anti-NMDAR pentad; pelvic US for ovarian teratoma ~50% (Graus 2016 PMID 26906964)
- [SEVERE] Anti-NMDAR with ovarian teratoma found on pelvic US/MRI — TUMOR REMOVAL MANDATORY (improves outcome significantly; ~50% of young women); + first-line immunotherapy (Dalmau)

Citations

- Graus 2016 Lancet Neurol autoimmune-encephalitis clinical diagnostic criteria (PMID 26906964) + Titulaer 2013 Lancet Neurol NMDAR treatment & prognostic cohort n=577 (PMID 23290630) + Dalmau 2008 Lancet Neurol original NMDAR case series n=100 (PMID 18851928) + Abboud 2021 JNNP autoimmune-encephalitis management consensus (PMID 33649022 / 33649021) + Armangué 2018 Lancet Neurol post-HSV autoimmune encephalitis (PMID 30049614) + Nosadini 2021 paediatric NMDARE international consensus (PMID 34301820). [depth-pass-2 2026-05-18: prior 6/6 anchor PMIDs were PubMed-MCP-confirmed mis-attributions — corrected; see neuro.encephalitis-anti-nmdar.v1._research-bundle.md] [PMID:26906964](https://pubmed.ncbi.nlm.nih.gov/26906964/)
- Cited evidence (PMID 23290630) [PMID:23290630](https://pubmed.ncbi.nlm.nih.gov/23290630/)
- Cited evidence (PMID 18851928) [PMID:18851928](https://pubmed.ncbi.nlm.nih.gov/18851928/)
- Cited evidence (PMID 33649022) [PMID:33649022](https://pubmed.ncbi.nlm.nih.gov/33649022/)
- Cited evidence (PMID 33649021) [PMID:33649021](https://pubmed.ncbi.nlm.nih.gov/33649021/)

Last reconciled with current guidelines: 2026-05-22.
References
  • Graus 2016 Lancet Neurol autoimmune-encephalitis clinical diagnostic criteria (PMID 26906964) + Titulaer 2013 Lancet Neurol NMDAR treatment & prognostic cohort n=577 (PMID 23290630) + Dalmau 2008 Lancet Neurol original NMDAR case series n=100 (PMID 18851928) + Abboud 2021 JNNP autoimmune-encephalitis management consensus (PMID 33649022 / 33649021) + Armangué 2018 Lancet Neurol post-HSV autoimmune encephalitis (PMID 30049614) + Nosadini 2021 paediatric NMDARE international consensus (PMID 34301820). [depth-pass-2 2026-05-18: prior 6/6 anchor PMIDs were PubMed-MCP-confirmed mis-attributions — corrected; see neuro.encephalitis-anti-nmdar.v1._research-bundle.md] — PMID:26906964
  • Cited evidence (PMID 23290630) — PMID:23290630
  • Cited evidence (PMID 18851928) — PMID:18851928
  • Cited evidence (PMID 33649022) — PMID:33649022
  • Cited evidence (PMID 33649021) — PMID:33649021