Other Autoimmune Encephalitides
Beyond NMDA receptor, LGI1, and CASPR2 encephalitis, a growing number of antibody-defined autoimmune encephalitis syndromes have been recognized. Each has distinct clinical features, tumor associations, and prognoses. These include antibodies targeting GABAB and GABAA receptors, AMPA receptors, DPPX, glycine receptors, IgLON5, GFAP, and GAD65. While individually less common, collectively they represent a substantial proportion of autoimmune encephalitis cases and emphasize the importance of panel-based antibody testing in appropriate clinical contexts.
Bottom Line
- GABAB receptor: Limbic encephalitis with prominent seizures; ~50% have SCLC; high cancer mortality
- GABAA receptor: Diffuse encephalitis with refractory status epilepticus; multifocal cortical/subcortical MRI lesions; ~30% with thymoma
- AMPA receptor: Limbic encephalitis with confusion, amnesia, seizures; ~70% with tumors (thymoma, SCLC, breast, ovarian)
- DPPX: Encephalitis with striking GI features (diarrhea, weight loss); myoclonus, hyperekplexia; good immunotherapy response
- Glycine receptor: Progressive encephalomyelitis with rigidity, myoclonus, and startle; wide age range; stiff person overlap
- IgLON5: Unique neurodegeneration-autoimmunity interface; sleep disturbance, bulbar dysfunction, movement disorders
- GFAP: Meningoencephalomyelitis with characteristic radial perivascular enhancement; 80% respond to steroids
- GAD65: Limbic encephalitis, stiff person syndrome, cerebellar ataxia, epilepsy; only high titers clinically relevant
GABAB Receptor Encephalitis
| Feature | Detail |
|---|---|
| IgG subclass | IgG1 |
| Demographics | Median age 61; M:F 1.5:1 |
| Clinical features | Limbic encephalitis with prominent seizures; new-onset refractory status epilepticus; rapidly progressive dementia (may mimic CJD) |
| MRI | ~70% abnormal; 45% mesial temporal T2/FLAIR hyperintensity |
| CSF | ~80% lymphocytic pleocytosis |
| EEG | 75% with ictal abnormalities |
| Cancer | ~50% with tumors, mostly SCLC |
| Outcome | 90% respond to immunotherapy; those with tumors have poorer prognosis due to malignancy |
GABAB receptor antibodies impair receptor function directly without causing internalization, representing a distinct mechanism from the receptor-internalizing IgG1 antibodies (NMDA-R, AMPA-R, GABAA-R). Some patients fulfill criteria for probable Creutzfeldt-Jakob disease, highlighting the importance of antibody testing in rapidly progressive dementias.
GABAA Receptor Encephalitis
| Feature | Detail |
|---|---|
| IgG subclass | IgG1 |
| Demographics | Median age 40; M:F 1:1; wide age range (2 months to 88 years) |
| Clinical features | Encephalitis with frequent status epilepticus; more diffuse (non-limbic) pattern |
| MRI | >80% with multifocal cortical and subcortical FLAIR abnormalities involving ≥2 brain regions — a highly suggestive imaging pattern |
| CSF | 25–50% pleocytosis with or without OCBs and elevated protein |
| Cancer | ~30% with thymoma |
| Outcome | Responsive to immunotherapy; ~10% mortality from status epilepticus or related complications |
The characteristic MRI pattern of multifocal cortical and subcortical lesions is highly suggestive and may be available before antibody results, providing an important diagnostic clue.
AMPA Receptor Encephalitis
| Feature | Detail |
|---|---|
| IgG subclass | IgG1 |
| Demographics | Median age 53; F:M 2:1 |
| Clinical features | Classic limbic encephalitis: confusion, amnesia, seizures, behavioral/psychiatric symptoms |
| MRI | ~85% abnormal; 67% bilateral mesial temporal involvement |
| Cancer | ~70% with tumors (thymoma, SCLC, breast cancer, ovarian cancer) |
| Outcome | Most patients improve from peak of disease (median mRS = 1 in survivors); ~15% mortality (often from malignancy) |
DPPX Encephalitis
| Feature | Detail |
|---|---|
| IgG subclass | IgG4 |
| Demographics | Median age 53; M:F 1.5:1 |
| Clinical features | Striking gastrointestinal features: diarrhea, significant weight loss (median 20 kg), constipation; encephalopathy with myoclonus, tremor, hyperekplexia (exaggerated startle); seizures, brainstem features |
| MRI | Normal or nonspecific |
| CSF | ~30% abnormal |
| Cancer | ~10% with B-cell neoplasm (gastrointestinal follicular lymphoma, CLL) |
| Outcome | 60–70% improve substantially with immunotherapy |
DPPX is expressed in both the brain and the enteric plexus, explaining the combined CNS and gastrointestinal manifestations. The significant weight loss preceding neurologic symptoms is a valuable clinical clue.
Glycine Receptor Encephalitis
| Feature | Detail |
|---|---|
| IgG subclass | IgG1/IgG3 |
| Demographics | Median age 50; M:F 1:1; wide age range (1–75 years) |
| Clinical features | Three main syndromes: (1) stiff person syndrome; (2) progressive encephalomyelitis with rigidity and myoclonus (PERM); (3) limbic encephalitis. Prominent auditory/tactile startle responses, spasms, stiffness, brainstem dysfunction, dysautonomia |
| MRI | Brain: ~30% abnormal; spinal cord: ~20% abnormal |
| CSF | ~40% pleocytosis; 20% OCBs |
| EMG | 60% with continuous motor unit activity, spontaneous/stimulus-induced activity, neuromyotonia |
| Cancer | ~15% with thymoma; coexisting GAD antibodies in 10% |
| Outcome | Good outcomes in survivors (median mRS 1); ~10% mortality |
Unlike many autoimmune encephalitides with acute onset, glycine receptor encephalitis often has a chronic onset and may not meet criteria for “possible autoimmune encephalitis,” similar to LGI1 and CASPR2 disease.
IgLON5 Disease
A Unique Neurodegeneration-Autoimmunity Interface
IgLON5 disease bridges autoimmunity and neurodegeneration, featuring both neural antibodies and prominent tau deposition. Patients present over months to years with features resembling neurodegenerative conditions, making this a critical consideration in atypical neurodegenerative presentations.
| Feature | Detail |
|---|---|
| IgG subclass | IgG1/IgG4 |
| Demographics | Median age 64; M:F 1:1; HLA-DRB1*10:01 and HLA-DQB1*05:01 in 87% |
| Clinical features | Sleep disorder (both REM and non-REM parasomnias, sleep apnea); bulbar syndrome; progressive supranuclear palsy-like syndrome; cognitive syndrome with or without chorea |
| MRI | ~80% normal; ~15% brainstem atrophy; 5% bilateral hippocampal atrophy |
| CSF | ~30% pleocytosis (early stages); elevated protein ~50%; OCBs ~10% |
| Pathology | Tau deposition alongside neuronal surface antibodies |
| Outcome | ~50% respond to early immunotherapy; poor outcomes (including death) common with later treatment |
GFAP Astrocytopathy
| Feature | Detail |
|---|---|
| Demographics | Median age ~45–50; M:F ~1:1 |
| Clinical features | Encephalitis, meningoencephalitis, myelitis, optic disc edema; variable presentation |
| MRI | Characteristic cerebral radial perivascular enhancement in ~50% of patients — a highly distinctive finding |
| Cancer | ~25% (teratoma, carcinoid, glioma, adenocarcinoma) |
| Coexisting antibodies | NMDA receptor or AQP4 antibodies may coexist |
| Pathogenicity | GFAP is an intracellular antigen; antibodies are unlikely to be directly pathogenic but serve as a marker of immunotherapy-responsive illness |
| Outcome | 80% have good improvement with immunotherapy (median mRS 1.5 at 1 year); 20–50% relapse |
The radial perivascular enhancement pattern on brain MRI is highly suggestive of GFAP astrocytopathy and can direct diagnostic testing before antibody results are available.
GAD65 Antibody-Associated Disorders
| Feature | Detail |
|---|---|
| Demographics | Median age mid-40s; F:M 3:1 |
| Clinical spectrum | Limbic encephalitis, stiff person syndrome, focal onset seizures/epilepsy, cerebellar ataxia, cognitive impairment, myelopathy |
| Cancer | <10%; SCLC, neuroendocrine, thymic, and breast cancer (more likely in patients with limbic encephalitis) |
| Coexisting antibodies | GABAB receptor (paraneoplastic), GABAA receptor, glycine receptor (without cancer) |
| Pathogenicity | GAD65 is intracellular; antibodies are likely nonpathogenic biomarkers of an autoimmune process |
| Immunotherapy response | Variable: 73% sustained response in stiff person spectrum; 25% in epilepsy; cerebellar ataxia with high titers (>500 nmol/L) predicts poor outcome |
GAD65 Antibody Interpretation
- Low GAD65 titers (<20 nmol/L) are common in the general population, primarily in patients with type 1 diabetes, and are not clinically significant for neurologic disease
- Only high titers in the context of a compatible clinical phenotype are diagnostically meaningful
- Complete immunotherapy response is rare — this is one of the more treatment-refractory autoimmune neurologic disorders
- Coexisting cell-surface antibodies (GABAB, GABAA, glycine receptor) should be actively sought, as they may be the more relevant target and predict better immunotherapy response
Diagnostic Approach to Less Common Encephalitides
When to Suspect These Entities
- Refractory status epilepticus: Consider GABAB, GABAA receptor antibodies
- Rapidly progressive dementia mimicking CJD: Consider GABAB receptor, AMPA receptor encephalitis
- Severe weight loss + diarrhea + encephalopathy: Consider DPPX antibodies
- Stiff person phenotype with brainstem involvement: Consider glycine receptor antibodies
- Sleep disorder + bulbar dysfunction + movement disorder (chronic course): Consider IgLON5 antibodies
- Meningoencephalomyelitis with radial enhancement: Consider GFAP antibodies
- Stiff person syndrome or refractory epilepsy: Consider GAD65 antibodies (high titers)
- Panel-based testing is recommended, as clinical overlap exists and coexisting antibodies are common
References
- Irani SR. Autoimmune encephalitis. Continuum (Minneap Minn). 2024;30(4):995-1020.
- McKeon A, Pittock SJ. Overview and diagnostic approach in autoimmune neurology. Continuum (Minneap Minn). 2024;30(4):960-994.
- Lancaster E, Lai M, Peng X, et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9(1):67-76.
- Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor. Lancet Neurol. 2014;13(3):276-286.
- 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. Brain. 2014;137(Pt 8):2240-2251.