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1 Last Minute Review 2 Multiple Sclerosis 3 Disease-Modifying Therapies 4 NMOSD & MOGAD 5 Systemic Diseases 6 Autoimmune Encephalitis 7 Paraneoplastic Syndromes 8 CNS Vasculitis 9 Other Neuroimmunology Topics
Clinical › Immunology

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 antibody-defined autoimmune encephalitis overall, particularly in patients <45 years; young women; ovarian teratoma (~38% overall, ~50% in women 18–45, <10% in girls <14 and males); staged progression (psychiatric → seizures → movement disorders → autonomic instability); extreme delta brush on EEG; 81% achieve mRS 0–2 at 24 months with first- and second-line therapy (Titulaer 2013)
  • 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
🚩 Don’t Miss — Test-Day Priorities
  • Anti-NMDAR in a young woman: Viral prodrome → psychiatric symptoms → seizures → orofacial dyskinesias → autonomic instability & central hypoventilation; ovarian teratoma in ~50% of women 18–45; CSF antibody more sensitive than serum; tumor removal is critical
  • HSV encephalitis is a known NMDAR trigger: Worsening at a median of ~27 days (weeks to a few months) after HSV → check NMDAR antibodies and treat with immunotherapy, NOT more acyclovir
  • LGI1 — older man + FBDS + hyponatremia: Faciobrachial dystonic seizures (brief, frequent, ASM-resistant) precede limbic encephalitis by weeks to months; SIADH-driven hyponatremia in ~60%; rarely paraneoplastic; treat early to prevent cognitive decline
  • CASPR2 — Morvan syndrome: Encephalopathy + neuromyotonia + severe insomnia + dysautonomia; thymoma in 30–40% of Morvan cases; only autoimmune encephalitis with simultaneous central AND peripheral involvement
  • GABA-B + refractory status epilepticus + older adult → screen for SCLC (~50–60% paraneoplastic); good immunotherapy response for encephalitis, prognosis driven by tumor
  • AMPAR = relapsing limbic encephalitis: ~60–65% paraneoplastic (SCLC, breast, thymoma); long-term immunosuppression usually required
  • DPPX — prodromal diarrhea/weight loss + encephalopathy + hyperekplexia/myoclonus/PERM: GI prodrome is nearly unique; minimal tumor association
  • High-titer GAD65 (>10,000 IU/mL or >20 nmol/L): Stiff-person syndrome, cerebellar ataxia, temporal lobe epilepsy ± type 1 diabetes; intracellular target → poor immunotherapy response; low titers are non-specific
  • IgLON5 = parasomnia + sleep-disordered breathing + bulbar dysfunction + gait/chorea: Tauopathy at autopsy; the major exception to the “cell-surface = immunotherapy-responsive” rule
  • GFAP astrocytopathy: Meningoencephalomyelitis with linear radial perivascular gadolinium enhancement in white matter; steroid-responsive
  • Surface vs intracellular is the highest-yield distinction: Surface (NMDAR, LGI1, CASPR2, GABA-B, AMPA, DPPX, GFAP) = pathogenic, reversible, immunotherapy-responsive; Intracellular (Hu, Yo, Ri, Ma2, CV2/CRMP5, amphiphysin, GAD) = T-cell mediated, irreversible, strongly paraneoplastic
  • Treatment ladder: First-line steroids + IVIg or PLEX + tumor screen/removal → second-line rituximab or cyclophosphamide; ICU support for autonomic instability/central hypoventilation in NMDAR
🔍 Buzzwords & Pathognomonic FindingsClinical · Imaging / EEG · Antibody / tumor associations
Clinical phenotype
  • Orofacial dyskinesias + autonomic storm + central hypoventilation in a young woman → anti-NMDAR
  • Faciobrachial dystonic seizures (FBDS) + hyponatremia in older man → anti-LGI1
  • Morvan syndrome (encephalopathy + neuromyotonia + insomnia + dysautonomia) → anti-CASPR2
  • Refractory status epilepticus in older adult with limbic encephalitis → anti-GABA-B
  • Relapsing limbic encephalitis → anti-AMPAR
  • PERM (progressive encephalomyelitis with rigidity & myoclonus) / hyperekplexia + prodromal diarrhea → anti-DPPX (also GlyR)
  • Stiff-person syndrome → anti-GAD65 (non-paraneoplastic) or anti-amphiphysin (paraneoplastic, breast)
  • Non-REM + REM parasomnia + sleep-disordered breathing + bulbar dysfunction → anti-IgLON5
  • Subacute cerebellar degeneration in woman with breast/ovarian cancer → anti-Yo (PCA-1)
  • Opsoclonus-myoclonus syndrome in an adult → anti-Ri (ANNA-2)
  • Brainstem/diencephalic encephalitis + narcolepsy-like hypersomnia + vertical gaze palsy in young man → anti-Ma2
  • Sensory neuronopathy + limbic encephalitis + autonomic neuropathy in smoker → anti-Hu (ANNA-1)
    • Imaging / EEG signs
  • Extreme delta brush on EEG → anti-NMDAR
  • Normal MRI in ~50% despite florid encephalopathy → anti-NMDAR
  • Bilateral mesial temporal T2/FLAIR hyperintensity (limbic encephalitis pattern) → LGI1, GABA-B, AMPA (and HSV mimicker)
  • Multifocal cortical FLAIR + refractory status → anti-GABA-A
  • Linear radial perivascular gadolinium enhancement in white matter → anti-GFAP astrocytopathy
  • Striatal T2 hyperintensity → anti-DPPX or anti-CV2/CRMP5 (chorea)
  • Diencephalic / hypothalamic / brainstem T2/FLAIR → anti-Ma2
    • Antibody / tumor associations
  • Anti-NMDAR + ovarian teratoma → anti-NMDAR encephalitis (young women)
  • Anti-LGI1 (rarely thymoma) → FBDS + limbic encephalitis + SIADH
  • Anti-CASPR2 + thymoma → Morvan syndrome
  • Anti-GABA-B + SCLC → limbic encephalitis with status epilepticus
  • Anti-AMPA + thymoma / lung / breast → relapsing limbic encephalitis
  • Anti-Ma2 + testicular germ cell tumor → limbic/diencephalic/brainstem encephalitis (young men)
  • Anti-Yo (PCA-1) + ovarian/breast → paraneoplastic cerebellar degeneration
  • Anti-Hu (ANNA-1) + SCLC → sensory neuronopathy, limbic encephalitis, autonomic neuropathy
  • Anti-Ri (ANNA-2) + breast / SCLC → opsoclonus-myoclonus / brainstem encephalitis
  • Anti-CV2 / CRMP5 + SCLC or thymoma → chorea + optic neuritis + peripheral neuropathy
  • Anti-amphiphysin + breast → SPS-like syndrome (paraneoplastic SPS)
  • Anti-Tr / DNER + Hodgkin lymphoma → paraneoplastic cerebellar degeneration
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 ~38% overall, ~50% in women 18–45); GABA-B (SCLC ~50–60%); 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:

  1. Subacute onset (rapid progression over ≤3 months) of working memory deficits, altered mental status, or psychiatric symptoms
  2. ≥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)
  3. Reasonable exclusion of alternative causes (infectious, metabolic, toxic, neoplastic)

Definite Autoimmune Encephalitis

  • Most commonly defined by 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 autoimmune limbic encephalitis can also be diagnosed WITHOUT a specific antibody when the full Graus criteria are met: subacute onset (<3 months) of working memory deficits/seizures/psychiatric features plus bilateral medial temporal T2/FLAIR abnormalities plus CSF pleocytosis OR temporal-lobe EEG abnormalities, with reasonable exclusion of alternatives

Definite Anti-NMDA-R Encephalitis (Graus Criteria)

Probable diagnosis if ≥4 of the following major groups of symptoms develop within 3 months:

  1. Abnormal (psychiatric) behavior or cognitive dysfunction
  2. Speech dysfunction (pressured speech, verbal reduction, mutism)
  3. Seizures
  4. Movement disorder, dyskinesias, or rigidity/abnormal postures
  5. Decreased level of consciousness
  6. 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:

  1. Subacute onset (≤3 months) of working memory deficits, seizures, or psychiatric symptoms suggesting temporal lobe involvement
  2. Bilateral MRI T2/FLAIR abnormalities restricted to medial temporal lobes
  3. ≥1 of: CSF pleocytosis, EEG with epileptic or slow-wave activity involving temporal lobes
  4. 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 antibody-defined autoimmune encephalitis overall, particularly in patients <45 years
  • Demographics: Young women (median age ~21); F:M ratio 4:1; ~35–40% of NMDA-R cases are pediatric (Titulaer 2013)
  • Tumor association: Ovarian teratoma in ~38% overall; ~50% in women aged 18–45; <10% in girls <14 and males (Titulaer 2013)
  • 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 at 10–14 days): Rituximab or cyclophosphamide
  • 81% achieve mRS 0–2 (good outcome) at 24 months with first- and second-line therapy (Titulaer 2013); 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: Typically develops within weeks to a few months (median ~27 days) 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 within weeks to a few months (median ~27 days) = 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% 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%
  • 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 10–20% overall; up to 30–40% in Morvan syndrome
  • 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 ~50–60% — 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: ~60–65% 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
  • ~60–65% 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
Anti-GAD65 (High-Titer) Neurological Syndromes

Overview

  • GAD65 (glutamic acid decarboxylase 65) — intracellular enzyme that synthesizes GABA; antibody target in a spectrum of neurological syndromes
  • Antigen location is intracellular — antibodies are biomarkers rather than directly pathogenic, and immunotherapy response is generally poor compared to cell-surface antibody syndromes
  • High-titer threshold: >10,000 IU/mL by RIA or >20 nmol/L — low-titer GAD65 is non-specific (seen in type 1 diabetes and healthy individuals)
  • Demographics: Female predominance; often coexists with type 1 diabetes, thyroid autoimmunity, or other polyglandular autoimmunity

Clinical Spectrum

Syndrome Features
Limbic encephalitis Subacute memory impairment, temporal lobe seizures; mesial temporal T2/FLAIR; tends to be more indolent than cell-surface limbic encephalitides
Cerebellar ataxia Progressive cerebellar syndrome (gait/limb ataxia, dysarthria); may be isolated or overlap with other GAD65 syndromes
Stiff-person syndrome (SPS) Axial and limb rigidity, painful spasms, hyperlordosis; classic high-titer GAD65 syndrome
Refractory epilepsy Drug-resistant temporal lobe epilepsy; may present without overt encephalopathy
💎 Board Pearl
  • High-titer GAD65 (>10,000 IU/mL or >20 nmol/L) + limbic encephalitis / cerebellar ataxia / SPS / refractory epilepsy — consider the GAD65 spectrum
  • GAD65 is intracellular → poor immunotherapy response — in contrast to cell-surface antibody syndromes; mirrors the classical onconeural rule
  • Low-titer GAD65 is non-specific — seen in type 1 diabetes; do not over-interpret without a compatible neurological syndrome and a high titer
Hashimoto Encephalopathy / SREAT

Overview

  • SREAT = Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis; historically “Hashimoto encephalopathy”
  • Diagnosis of exclusion — requires ruling out infectious, metabolic, structural, neoplastic, and specific antibody-defined autoimmune encephalitides
  • Elevated anti-TPO and/or anti-thyroglobulin (Tg) antibodies are required, but these are not specific and do not establish causality — many euthyroid individuals carry them
  • Thyroid function is typically normal or only mildly abnormal at presentation — encephalopathy is not explained by thyroid hormone status

Clinical Features

  • Subacute encephalopathy with fluctuating cognition, confusion, behavioral change
  • Seizures, myoclonus, tremor, ataxia, stroke-like episodes
  • CSF: mildly elevated protein in ~80%; pleocytosis less common
  • MRI: usually normal or non-specific white matter changes
  • EEG: diffuse slowing; epileptiform discharges in a subset

Treatment & Prognosis

  • Dramatic steroid response is often present, but lack of objective response should prompt reassessment for mimics (AE, prion, infection, malignancy, metabolic, psychiatric) rather than simply concluding SREAT is wrong
  • IV methylprednisolone followed by oral taper; IVIg or PLEX in refractory cases
  • Many patients require prolonged immunosuppression to prevent relapse
💎 Board Pearl
  • SREAT = diagnosis of exclusion — positive thyroid antibodies (anti-TPO and/or anti-thyroglobulin) alone do NOT establish SREAT (they are common in the general population, ~10%, and in many healthy euthyroid individuals). Diagnosis requires exclusion of more specific autoimmune (cell-surface and intracellular antibody-defined AE), infectious, toxic-metabolic, and prion (CJD) causes
  • Lack of objective steroid response should prompt reassessment for mimics — autoimmune encephalitis (cell-surface/intracellular antibodies), prion disease, infection, malignancy, metabolic disease, or primary psychiatric disease. SREAT remains a diagnosis of exclusion; do not over-call when steroid response is absent
  • Anti-TPO/Tg antibodies are biomarkers of thyroid autoimmunity, not direct CNS pathogens — the underlying CNS mechanism remains uncertain
Classical Onconeural (Intracellular) Antibodies

Overview

  • Intracellular antigens → antibodies are biomarkers; pathogenesis is T-cell mediated cytotoxicity → irreversible neuronal loss
  • Strongly paraneoplastic — identification mandates aggressive cancer search (CT, PET-CT, age- and sex-appropriate screening)
  • Immunotherapy response is poor — tumor treatment is the cornerstone; immunotherapy is adjunctive

Onconeural Antibody Reference Table

Antibody Classical Syndrome(s) Associated Cancer(s)
Hu (ANNA-1) Encephalomyelitis, sensory neuronopathy, limbic encephalitis, cerebellar degeneration, autonomic neuropathy SCLC (>80%)
Ri (ANNA-2) Brainstem encephalitis; opsoclonus-myoclonus syndrome (OMAS); cerebellar/oculomotor dysfunction Breast, SCLC
Yo (PCA-1) Paraneoplastic cerebellar degeneration (PCD) Ovarian, breast
CV2 / CRMP5 Sensorimotor neuropathy, optic neuritis, chorea, limbic encephalitis, cerebellar ataxia SCLC, thymoma
Ma2 Limbic/diencephalic/brainstem encephalitis; narcolepsy-like hypersomnia; vertical gaze palsy Testicular germ cell tumor (young men)
Amphiphysin Stiff-person-like syndrome; encephalomyelitis; sensory neuropathy Breast, SCLC
Tr / DNER Paraneoplastic cerebellar degeneration (PCD) Hodgkin lymphoma
💎 Board Pearl
  • Ri = brainstem encephalitis / OMAS, breast or SCLC; Yo = PCD, ovarian/breast; Tr/DNER = PCD, Hodgkin lymphoma
  • CV2/CRMP5 is the “multifocal” onconeural antibody — sensorimotor neuropathy, optic neuritis, chorea; SCLC or thymoma
  • Amphiphysin = SPS-like syndrome with breast cancer or SCLC — distinguishes from GAD65-SPS (no tumor, female, intracellular but non-paraneoplastic)
  • Ma2 in a young man → testicular germ cell tumor — testicular ultrasound and PET-CT; orchiectomy may be required even with normal imaging
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 (~38% overall; ~50% in women 18–45; <10% in girls <14 and males) Excellent; 81% mRS 0–2 at 24 months (Titulaer 2013)
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 (10–20% overall; 30–40% in Morvan) 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 (~50–60%) 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 (~60–65%) 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 (~60–65%), GABA-B (~50–60%), 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

APE2 Score (Antibody Prevalence in Epilepsy and Encephalopathy)

  • APE2 score (Dubey 2017) — clinical prediction tool that estimates the probability of detecting a neural-specific autoantibody in patients with epilepsy or encephalopathy of unclear etiology
  • Sensitivity ~98%, specificity ~82% for predicting antibody positivity
  • Cutoff ≥4 prompts neural antibody testing (serum + CSF panels)
  • Variables include: new-onset rapidly progressive mental status change; neuropsychiatric changes; autonomic dysfunction; viral prodrome; faciobrachial dystonic seizures; facial dyskinesias; treatment-resistant seizures; CSF inflammation; MRI suggestive of encephalitis; systemic cancer history

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 10–14 days; 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 (81% mRS 0–2 at 24 months, Titulaer 2013) 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 10–14 days → 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

References

  1. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15(4):391–404.
  2. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018;378(9):840–851.
  3. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis. Lancet Neurol 2013;12(2):157–165.
  4. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7(12):1091–1098.
  5. Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 2010;133(9):2734–2748.
  6. Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede LGI1 antibody limbic encephalitis. Ann Neurol 2011;69(5):892–900.
  7. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010;9(1):67–76.
  8. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009;65(4):424–434.
  9. Boronat A, Gelfand JM, Gresa-Arribas N, et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 2013;73(1):120–128.
  10. Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5. Sleep 2014;37(10):1543–1550.
  11. Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology 2017;88(18):1736–1743.
  12. Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83(1):166–177.
  13. Bien CG, Vincent A, Barnett MH, et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 2012;135(Pt 5):1622–1638.
  14. Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 2012;79(11):1094–1100.
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