Autoimmune Encephalitis
Immune-mediated brain inflammation presenting with cognitive or psychiatric changes, seizures, movement disorders and autonomic dysfunction.
Autoimmune Encephalitis
Autoimmune encephalitis (AE) is a group of inflammatory brain diseases caused by immune responses against neuronal antigens, involving pathogenic surface antibodies and/or T-cell-mediated injury. The name itself tells you the disease: "auto" = self, "immune" = immune system, "encephalitis" = inflammation of the brain ("encephalon" = brain, "-itis" = inflammation). So the brain is being attacked by the patient's own immune system rather than by an infectious pathogen.
"Autoimmune encephalitis is a differential diagnosis of patients presenting with fever and confusion" — it is crucial to consider AE whenever you see a young patient (especially a young woman) with subacute neuropsychiatric symptoms, seizures, and movement disorders that do not respond to antipsychotics or antivirals [1].
Key Distinction: Infectious vs. Autoimmune Encephalitis
Infectious encephalitis (e.g., HSV) involves direct viral invasion and destruction of neurons. Autoimmune encephalitis involves antibody- or T-cell-mediated attack on neuronal antigens. The distinction is critical because the treatments are opposite: antivirals for the former, immunosuppression for the latter. In practice, you often start empirical acyclovir AND investigate for AE simultaneously, because HSV encephalitis itself can trigger secondary anti-NMDAR encephalitis.
2. Epidemiology
- AE is increasingly recognised as a significant cause of encephalitis — in many series it is now as common as, or more common than, any single infectious cause of encephalitis.
- "Rare" in absolute terms but increasingly diagnosed with better antibody assays [1].
- Anti-NMDAR is a major recognised subtype, particularly in younger patients; relative subtype frequency varies with age and population.
- In the California Encephalitis Project, anti-NMDAR encephalitis was found to be more common than any single viral aetiology in patients < 30 years old.
- Anti-NMDAR disease often affects young women and children; this does not describe every AE subtype.
- Anti-NMDAR encephalitis: median age ~21 years, female predominance (~80% female). When associated with ovarian teratoma, almost exclusively in women of reproductive age.
- Anti-LGI1 encephalitis: older adults (median ~60 years), slight male predominance (~65% male).
- Anti-CASPR2 encephalitis: older males (median ~60–70 years).
- Anti-GAD65 encephalitis/stiff-person spectrum: female predominance, middle age.
Consider AE across age groups. NMDAR disease is especially important in children and young adults; LGI1 disease is a key treatable cause of subacute cognitive decline in older adults. Do not infer local incidence from referral-centre experience.
| Risk Factor | Mechanism | Associated AE Subtype |
|---|---|---|
| Ovarian teratoma | Teratoma contains nervous tissue expressing NMDA receptors → breaks immune tolerance → cross-reactive antibodies attack brain NMDA receptors | Anti-NMDAR encephalitis [1] |
| Other tumours (SCLC, thymoma, breast, testicular) | Tumour expresses neuronal antigens → paraneoplastic antibody production | Classical paraneoplastic (anti-Hu, anti-Yo, anti-Ri, anti-Ma2/Ta, anti-CV2, anti-amphiphysin) |
| HSV encephalitis | Post-infectious immune trigger; new deterioration after HSV warrants evaluation for viral relapse and secondary AE | Post-HSV anti-NMDAR encephalitis (important in children) |
| Female sex | Higher autoimmune predisposition; ovarian teratoma association | Anti-NMDAR |
| Young age | Higher incidence of anti-NMDAR; children more prone to post-infectious AE | Anti-NMDAR |
| Autoimmune comorbidity | Hashimoto's thyroiditis, type 1 DM, other autoimmune conditions | Anti-GAD65, anti-LGI1 |
| Malignancy | "May be associated with underlying malignancies and infections that have triggered an immune response against the brain parenchyma" [1] | All paraneoplastic subtypes |
High Yield
Always screen for ovarian teratoma in young women with anti-NMDAR encephalitis (pelvic ultrasound or CT/MRI abdomen-pelvis). Tumour removal is part of the treatment and dramatically improves prognosis.
4. Anatomy and Function: Relevant Neuroanatomy
"Limbic encephalitis" (LE) is the classic presentation because many AE antibodies target structures in the limbic system:
- Hippocampus: memory formation → memory deficits, amnesia
- Amygdala: emotion and fear processing → psychiatric symptoms, anxiety, emotional lability
- Medial temporal lobes: learning and memory → anterograde amnesia
- Hypothalamus: autonomic regulation, temperature, sleep-wake → autonomic dysfunction, hyperthermia, sleep disturbances
- Cingulate gyrus: motivation, emotional regulation → apathy, behavioural change
- Orbitofrontal cortex: personality, social behaviour → personality change, disinhibition
Understanding the antibody target explains the clinical features:
| Target | Normal Function | Effect When Blocked/Attacked |
|---|---|---|
| NMDA receptor | Glutamate receptor essential for synaptic plasticity, memory, learning; also regulates dopamine release | Loss of GABAergic inhibition → seizures; dopamine dysregulation → psychosis, movement disorders; glutamate pathway disruption → memory loss, catatonia |
| LGI1 (Leucine-rich Glioma Inactivated 1) | Organises the VGKC complex at the synapse, modulates AMPA receptor trafficking | Seizures (especially faciobrachial dystonic seizures), memory loss, hyponatraemia (LGI1 is expressed in hypothalamus affecting ADH) |
| CASPR2 (Contactin-Associated Protein-like 2) | Part of the VGKC complex at the juxtaparanodal region of the node of Ranvier; modulates K⁺ channel clustering | Peripheral nerve hyperexcitability (neuromyotonia/Morvan syndrome), encephalitis, neuropathic pain |
| GABA-B receptor | Major inhibitory neurotransmitter receptor | Seizures (often prominent, early, refractory), cognitive decline |
| GABA-A receptor | Major inhibitory neurotransmitter receptor (ionotropic) | Severe seizures, refractory status epilepticus |
| AMPA receptor | Fast excitatory glutamate receptor | Limbic encephalitis, seizures |
| DPPX (Dipeptidyl-peptidase-like protein 6) | Modulates Kv4.2 potassium channels; expressed in myenteric plexus and CNS | Encephalitis with prominent GI symptoms (diarrhoea, weight loss), hyperexcitability, myoclonus |
| GAD65 (Glutamic Acid Decarboxylase) | Enzyme converting glutamate → GABA (intracellular) | Stiff-person syndrome, cerebellar ataxia, limbic encephalitis, epilepsy |
| Intracellular antigens (Hu, Yo, Ri, Ma2, CV2, amphiphysin) | Various intracellular neuronal proteins | T-cell mediated neuronal destruction → poor prognosis, irreversible damage |
Why Does Blocking NMDA Receptors Cause Psychosis?
NMDA receptors are found on GABAergic interneurons. When antibodies block NMDA receptors on these interneurons, the interneurons become hypoactive → loss of inhibitory control → downstream dopaminergic hyperactivity → psychosis and agitation. This is the same mechanism by which ketamine and PCP (NMDA antagonists) cause psychosis — the "NMDA hypofunction model of schizophrenia."
5. Aetiology (with Focus on Hong Kong)
"Increasing number of antibodies being recognised — most common being anti-NMDA (N-methyl-D-aspartate) receptor encephalitis" [1].
5A. Classification by Antibody Target
This is the most clinically useful classification and directly from lecture material [2]:
Classical paraneoplastic encephalitis includes Hu- and Ma2-associated disease. Related antibodies such as Yo and Ri more often cause other paraneoplastic neurological syndromes, not limbic encephalitis.
| Feature | Detail |
|---|---|
| Target | Intracellular antigens [2] |
| Association with malignancy | +++ (very strong) [2] |
| Course | Monophasic and progressive [2] |
| Prognosis | Poor [2] — because the damage is T-cell mediated neuronal destruction, which is irreversible |
| Treatment | Treat underlying malignancy [2] — immunotherapy has limited benefit because the damage is cytotoxic T-cell driven, not purely antibody-mediated |
Why is prognosis poor? The antibodies themselves are markers of the disease, not the cause. The actual damage is done by cytotoxic T cells that infiltrate the brain and directly kill neurons expressing the target antigen. You can remove antibodies with plasma exchange, but the T cells have already caused irreversible neuronal death.
Common intracellular antibodies:
- Anti-Hu (ANNA-1): SCLC → sensory neuropathy, encephalomyelitis, cerebellar degeneration
- Anti-Yo (PCA-1): Ovarian/breast cancer → cerebellar degeneration
- Anti-Ri (ANNA-2): Breast cancer → opsoclonus-myoclonus
- Anti-Ma2/Ta: Testicular germ cell tumour → limbic/brainstem encephalitis
- Anti-CV2/CRMP5: SCLC, thymoma → chorea, peripheral neuropathy, optic neuritis
- Anti-amphiphysin: Breast cancer, SCLC → stiff-person syndrome
"Neuronal surface antibody syndrome (NSAS): e.g. NMDA-R, LGI-1, CaspR" [2]
| Feature | Detail |
|---|---|
| Target | Extracellular (cell-surface) antigens [2] |
| Association with malignancy | + (variable, less than classical) [2] |
| Course | May be monophasic or relapsing |
| Prognosis | Better [2] — because antibodies cause reversible receptor internalisation/blockade, not permanent neuronal death |
| Treatment | Immunosuppressants [2] |
Why is prognosis better? The antibodies directly cause dysfunction by cross-linking and internalising surface receptors (like NMDA receptors) from the synaptic membrane. When you remove the antibodies (via immunotherapy), the receptors can be re-expressed and function can recover. This is fundamentally different from T-cell-mediated neuronal killing.
GAD65 is intracellular. High-titre, clinically concordant antibodies and intrathecal synthesis may support a neurological syndrome, but low serum titres are common in diabetes. Direct antibody pathogenicity is uncertain; T-cell mechanisms are important. Epilepsy, stiff-person spectrum and ataxia have different treatment responses, and GAD65-associated epilepsy is often resistant. A blanket “better prognosis” label is misleading. [21]
5B. Specific Antibody Subtypes — Detailed
"Associated with ovarian teratomas" [1][2]
- Demographics: Young women and children; F:M ≈ 4:1
- Tumour association: ~40% of adult women have ovarian teratoma; rare in children and males; other tumours rarely associated
- Pathophysiology:
- Ovarian teratoma contains ectodermal tissue including neurons expressing NMDA receptors
- The immune system recognises these NMDA receptors as foreign → produces IgG antibodies
- These antibodies cross the blood-brain barrier → bind to the NR1 subunit of NMDA receptors on neurons
- Antibody binding causes cross-linking and internalisation (removal) of NMDA receptors from the post-synaptic membrane
- This reduces NMDA receptor density → functional NMDA receptor hypofunction
- On GABAergic interneurons: loss of NMDA input → disinhibition → excitotoxicity, seizures
- Frontostriatal dopamine pathway dysregulation → psychosis, catatonia, movement disorders
- Hippocampal NMDA receptor loss → memory deficits
- Brainstem/autonomic centres → autonomic instability, central hypoventilation
- Demographics: Older adults (median ~60 years), male predominance
- Tumour association: Usually non-paraneoplastic; malignancy is uncommon
- Pathophysiology:
- LGI1 is a secreted protein that bridges presynaptic ADAM23 and postsynaptic ADAM22 at excitatory synapses
- LGI1 modulates AMPA receptor-mediated synaptic transmission and Kv1.1 potassium channel function
- Anti-LGI1 antibodies disrupt LGI1-ADAM22/23 interaction → hyperexcitability → seizures
- LGI1 expressed in hypothalamus → disruption of vasopressin regulation → SIADH → hyponatraemia (classic clue)
- Hallmark: Faciobrachial dystonic seizures (FBDS) — brief (~3 seconds), frequent (up to 100/day), stereotyped seizures with arm posturing ± ipsilateral facial grimace. These are highly characteristic and often precede full-blown limbic encephalitis. Recognising FBDS early and starting immunotherapy can prevent progression.
- Demographics: Older males
- Tumour association: Thymoma, particularly with Morvan syndrome; frequency varies by cohort
- Pathophysiology: CASPR2 is in the juxtaparanodal region of peripheral and central neurons → antibodies cause both peripheral and central hyperexcitability
- Clinical spectrum: Neuromyotonia (peripheral nerve hyperexcitability → muscle cramps, fasciculations, myokymia) + encephalitis + autonomic dysfunction + insomnia (= Morvan syndrome)
- Demographics: Older adults
- Tumour association: ~50% have SCLC
- Clinical features: Prominent early seizures (often the presenting feature), limbic encephalitis
- Demographics: Young adults and children
- Tumour association: Variable; thymoma is an association
- Clinical features: Severe refractory seizures, status epilepticus, often fulminant course
- Demographics: Middle-aged women
- Tumour association: ~65% (lung, breast, thymoma)
- Clinical features: Limbic encephalitis with prominent psychiatric features; tends to relapse
- Demographics: Middle-aged adults
- Tumour association: Rare
- Clinical features: Prominent prodromal diarrhoea and weight loss (DPPX expressed in myenteric plexus), followed by encephalitis with hyperexcitability, myoclonus, tremor
- Demographics: Older adults
- Clinical features: Sleep disorder (parasomnia, sleep apnoea), bulbar dysfunction, gait instability, chorea
- Unique: Associated with tauopathy on neuropathology; may bridge autoimmune and neurodegenerative disease
6. Pathophysiology — Unified Framework
- Receptor internalisation: Antibodies cross-link surface receptors → endocytosis → reduced receptor density (e.g., anti-NMDAR reducing NMDA receptor surface expression)
- Direct functional blockade: Antibodies directly block ligand binding or channel function
- Complement activation: Some antibodies (e.g., anti-LGI1 IgG4 does NOT fix complement, but anti-LGI1 IgG1 may) → local inflammation
- Disruption of protein-protein interactions: e.g., anti-LGI1 disrupting LGI1-ADAM22/23 complex
In non-paraneoplastic AE, the trigger for immune tolerance breakdown is unclear. Possible mechanisms include:
- Molecular mimicry: Cross-reactivity between infectious antigens and neuronal proteins
- Post-infectious: HSV encephalitis → neuronal damage → release of sequestered NMDA receptor antigens → immune sensitisation → anti-NMDAR antibodies (this is well-documented)
- Idiopathic autoimmunity: Genetic predisposition (HLA associations) + environmental triggers
7. Classification
| Category | Examples | Target | Malignancy | Prognosis | Treatment |
|---|---|---|---|---|---|
| Classical paraneoplastic | Anti-Hu, Yo, Ri, Ma, CV2, amphiphysin | Intracellular | +++ | Poor | Treat underlying malignancy |
| Neuronal surface antibody syndrome (NSAS) | Anti-NMDAR, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX | Extracellular | + | Better | Immunosuppressants |
| GAD65-associated disease | GAD65 | Intracellular | Usually non-paraneoplastic | Variable; epilepsy often resistant | Syndrome-specific immunotherapy and symptomatic care |
| Syndrome | Common Antibodies | Key Features |
|---|---|---|
| Limbic encephalitis | LGI1, CASPR2, GABA-B, AMPA, Hu, Ma2 | Memory loss, seizures, psychiatric symptoms |
| Anti-NMDAR encephalitis | NMDAR | Psychiatric → movement disorders → autonomic → decreased consciousness |
| Faciobrachial dystonic seizures | LGI1 | Brief, frequent dystonic seizures of face and ipsilateral arm |
| Morvan syndrome | CASPR2 | Neuromyotonia + encephalitis + autonomic + insomnia |
| Stiff-person syndrome | GAD65, amphiphysin, glycine receptor | Axial rigidity, spasms |
| Cerebellar degeneration | Yo, Tr (DNER), mGluR1 | Progressive cerebellar ataxia |
| Encephalomyelitis | Hu, CV2 | Multifocal CNS involvement |
| Opsoclonus-myoclonus | Ri, neuroblastoma (children) | Chaotic eye movements + myoclonus + ataxia |
- Paraneoplastic (tumour-associated): Always search for underlying tumour. "May be associated with underlying malignancies and infections that have triggered an immune response against the brain parenchyma" [1].
- Non-paraneoplastic (idiopathic autoimmune): No tumour found despite comprehensive screening.
8. Clinical Features
8A. Symptoms (with Pathophysiological Basis)
- "Viral-like prodrome" [1] — fever, headache, upper respiratory symptoms, GI symptoms
- Why? In many cases (especially anti-NMDAR), the prodrome may represent the initial immune activation or a preceding viral infection that triggered the autoimmune response. ~70% of anti-NMDAR encephalitis patients have a prodromal phase.
"Neuropsychiatric symptoms (altered cognition, behavioural changes – psychosis, aggression, catatonia..)" [1] "Memory deficits" [2]
- Psychosis (hallucinations, delusions, paranoia): NMDA receptor hypofunction on GABAergic interneurons → disinhibition of mesolimbic dopamine pathway → psychotic symptoms (same mechanism as ketamine/PCP psychosis)
- Agitation, aggression, behavioural change: Frontal and temporal lobe dysfunction due to antibody-mediated receptor loss
- Catatonia: NMDA receptor hypofunction in frontostriatal circuits → motor and behavioural arrest; also GABA-glutamate imbalance
- Anxiety, fear, emotional lability: Amygdala and limbic system involvement
- Cognitive decline, confusion: Widespread cortical NMDA receptor loss → global cognitive impairment
Common Exam Pitfall
Many AE patients are initially misdiagnosed as having a primary psychiatric disorder (acute psychosis, mania, catatonic schizophrenia). Key red flags that distinguish AE from primary psychiatry: (1) rapid progression over days-weeks, (2) neurological signs (seizures, movement disorders, focal deficits), (3) autonomic instability, (4) decreased consciousness, (5) CSF pleocytosis. If a young patient with "first-episode psychosis" develops seizures or movement disorders, think AE.
- Seizures are common, with frequency varying markedly by antibody subtype
- Why? Loss of inhibitory tone from GABAergic interneuron dysfunction (anti-NMDAR) or direct hyperexcitability (anti-LGI1, anti-GABA-B/A)
- Anti-LGI1: Faciobrachial dystonic seizures (FBDS) — highly characteristic, brief (1–3 sec), up to 100/day, unilateral arm dystonic posturing ± ipsilateral facial contraction. These are often resistant to AEDs but respond to immunotherapy.
- Anti-GABA-A: May present with refractory status epilepticus
"Abnormal movements (orofacial, limb or trunk dyskinesias)" [1] "Movement disorders" [2]
- Orofacial dyskinesias: Repetitive chewing, lip-smacking, tongue protrusions — very characteristic of anti-NMDAR encephalitis
- Why? Basal ganglia NMDA receptor loss → dopamine-GABA imbalance → involuntary movements (similar mechanism to tardive dyskinesia)
- Limb and trunk dyskinesias: Choreiform or dystonic movements
- Catatonia: Alternating between immobility and agitation
- Tremor, myoclonus: Cortical and subcortical hyperexcitability
"Language dysfunction" [2]
- Progressive speech reduction → mutism (common in anti-NMDAR encephalitis)
- Why? Left temporal and frontal cortex NMDA receptor involvement + catatonic features
"Autonomic dysfunction" [1][2]
- Tachycardia, bradycardia, blood pressure instability
- Central hypoventilation (may require ICU ventilation)
- Hyperthermia
- Urinary dysfunction
- Excessive salivation
- Why? Brainstem and hypothalamic NMDA receptor involvement; also direct autonomic centre dysfunction
- "Cardiac arrhythmias, postural hypotension, or central hypoventilation are frequent causes of death in patients with encephalomyelitis" [8]
"Sleep disturbances" [2]
- Insomnia (especially in anti-CASPR2 / Morvan syndrome)
- Hypersomnia
- Why? Hypothalamic and brainstem sleep-wake centres involvement
- ~60% of anti-LGI1 encephalitis patients have hyponatraemia
- Why? LGI1 is expressed in the hypothalamus → antibody disruption → inappropriate ADH secretion (SIADH)
- This is a useful clinical clue: encephalitis + hyponatraemia + older male → think anti-LGI1
- Severe diarrhoea and weight loss preceding encephalitis by weeks-months
- Why? DPPX expressed in myenteric plexus neurons → autoimmune GI dysmotility
8B. Signs (with Pathophysiological Basis)
| Sign | Basis |
|---|---|
| Decreased GCS / obtundation | Global cortical dysfunction from widespread receptor loss |
| Seizures (focal or generalised) | Cortical hyperexcitability from loss of inhibitory interneuron function |
| Orofacial dyskinesias | Basal ganglia dopamine-GABA imbalance from NMDA receptor loss |
| Choreoathetosis, dystonia | Extrapyramidal circuit disruption |
| Catatonia (waxy flexibility, posturing, mutism, negativism) | Frontostriatal NMDA receptor hypofunction |
| Opisthotonos | Severe axial dystonia (anti-NMDAR) |
| Myoclonus | Cortical hyperexcitability (anti-DPPX, anti-CASPR2) |
| Ataxia | Cerebellar involvement (anti-Yo, anti-Tr, anti-mGluR1, anti-GAD) |
| Hyperreflexia, extensor plantar responses | UMN dysfunction from cortical/corticospinal tract involvement |
- Neck stiffness and meningism are typically absent in pure AE (unlike infectious meningitis)
- May be present if there is concurrent meningoencephalitis
| Sign | Basis |
|---|---|
| Tachycardia / bradycardia | Brainstem autonomic centre dysfunction |
| Blood pressure lability | Hypothalamic-brainstem cardiovascular regulation disruption |
| Central hypoventilation | Medullary respiratory centre dysfunction |
| Hyperthermia | Hypothalamic thermoregulatory centre dysfunction |
| Excessive salivation / diaphoresis | Parasympathetic/sympathetic imbalance |
| Urinary retention / incontinence | Autonomic bladder centre dysfunction |
| Sign | Basis |
|---|---|
| Agitation, aggression | Amygdala and frontal lobe dysfunction |
| Psychotic features (hallucinations, delusions) | Mesolimbic dopamine disinhibition from NMDA receptor hypofunction |
| Flat affect / emotional blunting | Prefrontal cortex dysfunction |
| Echolalia, perseveration | Frontal lobe dysfunction |
| Catatonic features | Frontostriatal circuit dysfunction |
This is a useful teaching sequence, but phases overlap, timing varies and not every patient follows it:
- Prodromal phase (days 1–14): Viral-like prodrome — fever, headache, URTI symptoms
- Psychiatric phase (weeks 1–2): Neuropsychiatric symptoms — psychosis, agitation, bizarre behaviour, insomnia, anxiety. Often admitted to psychiatry at this stage.
- Unresponsive/hyperkinetic phase (weeks 2–4): Decreased consciousness + movement disorders — catatonia, orofacial dyskinesias, limb dyskinesias, seizures. Patient becomes progressively obtunded.
- Autonomic/hypoventilation phase (weeks 3–6+): Autonomic dysfunction — blood pressure instability, tachycardia/bradycardia, central hypoventilation requiring intubation and ICU care, hyperthermia.
- Recovery phase (months): Gradual, variable improvement; cognitive symptoms can outlast other deficits. Recovery can take months to years.
High Yield — Anti-NMDAR vs Anti-LGI1 Comparison
| Feature | Anti-NMDAR | Anti-LGI1 |
|---|---|---|
| Age | Young (20s) | Older (60s) |
| Sex | Female | Male |
| Tumour | Ovarian teratoma (~40%) | Usually no tumour |
| Key feature | Psychosis → dyskinesias → autonomic | FBDS → limbic encephalitis → hyponatraemia |
| Seizure type | Generalised; may have status | Faciobrachial dystonic seizures |
| Na⁺ | Usually normal | Hyponatraemia (SIADH) |
| MRI | Often normal or non-specific | Medial temporal lobe T2/FLAIR hyperintensity |
| Prognosis | Good if treated (75-80% good outcome) | Good if treated early |
From the Cancer Block lecture [8]:
- "Cerebellar gait and limb ataxia" [8]
- "Myelitis: Lower or upper motor neuron symptoms, myoclonus, muscle rigidity, and spasms" [8]
- "Autonomic dysfunction as a result of involvement of the neuraxis at multiple levels, including hypothalamus, brainstem, and autonomic nerves" [8]
- "Cardiac arrhythmias, postural hypotension, or central hypoventilation are frequent causes of death in patients with encephalomyelitis" [8]
All three are needed: onset within 3 months of working-memory impairment, altered mental status or psychiatric symptoms; at least one of new focal CNS findings, seizures unexplained by a known seizure disorder, CSF white cells >5/mm³ or MRI suggesting encephalitis; and reasonable exclusion of alternatives. EEG slowing alone is not a possible-AE criterion. See the Ix tab for definite limbic and NMDAR frameworks. [20]
| Antibody | Peak Age | Sex | Tumour | Hallmark Feature | MRI Pattern | Na⁺ | Prognosis |
|---|---|---|---|---|---|---|---|
| NMDAR | 20s | F >>> M | Ovarian teratoma | Psychosis → dyskinesia → autonomic | Often normal; may show cortical/subcortical FLAIR | Normal | Good if treated |
| LGI1 | 60s | M > F | Usually no tumour | FBDS, amnesia | Medial temporal T2/FLAIR ↑ | Low (SIADH) | Good |
| CASPR2 | 60-70s | M >> F | Thymoma | Morvan syndrome (neuromyotonia + encephalitis) | Variable | Variable | Moderate |
| GABA-B | 60s | M = F | SCLC (~50%) | Prominent early seizures | Medial temporal T2/FLAIR ↑ | Normal | Moderate |
| GABA-A | Young | Variable | Thymoma in some cases | Refractory status epilepticus | Multifocal cortical/subcortical FLAIR | Normal | Variable |
| AMPA | 50-60s | F > M | Lung/breast/thymoma | Relapsing limbic encephalitis | Medial temporal T2/FLAIR ↑ | Normal | Moderate; relapses |
| GAD65 | 30-60s | F > M | Low | Stiff-person, cerebellar ataxia, LE | Variable | Normal | Moderate |
| Hu | 50-60s | Any | SCLC | Encephalomyelitis, sensory neuropathy | Variable | Normal | Poor |
| Yo | 50-60s | F | Ovary/breast | Cerebellar degeneration | Cerebellar atrophy | Normal | Poor |
High Yield Summary — Overview
NMDAR: psychiatric/cognitive change, speech reduction, seizures, dyskinesias and autonomic dysfunction; assess for ovarian teratoma when relevant. LGI1: amnesia, brief faciobrachial dystonic seizures and hyponatraemia, usually without a tumour. Surface-antibody dysfunction may be reversible, whereas classical intracellular-antigen syndromes often involve irreversible T-cell injury. GAD65 epilepsy can be resistant. Normal MRI does not exclude AE.
Active Recall — Overview
[1] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (Autoimmune Encephalitis section) [2] Senior notes: Maksim Medicine Notes.pdf (Section 11.9, p.264) [3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Neurological Diseases - Meningitis and Encephalitis sections, p.500-519) [4] Senior notes: Ryan Ho Neurology.pdf (Section 7.2 Encephalitis, p.147-148) [5] Lecture slides: GC 225. Neuroimmunological disorders of the central nervous system.pdf (Diagnostic criteria for possible autoimmune encephalitis, p.28) [6] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Diagnosis section, p.1184-1186) [7] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (Pathological differentials, p.18) [8] Lecture slides: Cancer Block - Paraneoplastic Syndrome.pdf (Paraneoplastic Encephalomyelitis, p.23) [9] Senior notes: Ryan Ho Psychiatry.pdf (Dementia - autoimmune causes, p.77)
[20] Graus et al. Diagnostic framework (2016). [21] GAD65 neurological autoimmunity: clinical spectrum and outcomes.
Differential Diagnosis of Autoimmune Encephalitis
A patient with autoimmune encephalitis (AE) typically presents with subacute onset of altered mental status, psychiatric symptoms, seizures, and/or movement disorders — a constellation that overlaps with many other conditions. The challenge is that AE is a diagnosis of exclusion at the bedside initially; you must rule out life-threatening mimics (especially infections and metabolic crises) before confidently attributing the presentation to AE. Equally, you must think of AE early, because delayed immunotherapy worsens outcomes.
The GC 051 lecture slide frames the starting point perfectly:
"Differential Diagnosis of Patient with Fever and Confusion:
- CNS infections
- Other non-CNS infections (+/- systemic involvement) with encephalopathy (septic, metabolic, toxic)
- Sepsis in patients with primary psychiatric disorder
- Autoimmune encephalitis (e.g. anti-NMDA receptor encephalitis)
- Inflammatory disorders affecting the brain (e.g. vasculitis, cerebral lupus)
- Sepsis with nonconvulsive status epilepticus
- Thyroid storm" [1]
This is the high-yield exam list. Let's now systematically dissect each differential.
The clinical syndrome of AE can be framed as subacute encephalopathy (altered cognition/consciousness developing over days to weeks, often with seizures, psychiatric features, and/or movement disorders). The differentials therefore include anything that causes subacute-to-acute encephalopathy with or without seizures.
A useful organising framework is the pathological sieve tailored to encephalopathy, as highlighted in the CFB Neuro and Neurology lecture slides [7][10]:
Detailed Differential Diagnosis
1. Infectious Encephalitis / Meningoencephalitis
This is the single most important differential to exclude urgently because it requires completely different treatment (antivirals/antibiotics) and delay kills.
| Feature | HSV Encephalitis | Anti-NMDAR Encephalitis |
|---|---|---|
| Onset | Acute (days) | Subacute (weeks) |
| Prodrome | Headache, fever, malaise | Viral-like prodrome [1] then psychiatric |
| Key features | Temporal lobe signs: aphasia, olfactory hallucinations, personality change, seizures | Neuropsychiatric symptoms, orofacial dyskinesias, catatonia [1] |
| MRI | T2/FLAIR hyperintensity in medial temporal lobes (often unilateral, with haemorrhagic component) | Often normal; if abnormal, cortical/subcortical FLAIR — bilateral medial temporal in anti-LGI1 |
| EEG | Periodic lateralised epileptiform discharges (PLEDs) over temporal lobes | Diffuse slowing; "extreme delta brush" pattern in anti-NMDAR |
| CSF | Lymphocytic pleocytosis, ↑protein, HSV PCR +ve, may have RBCs | May show pleocytosis/oligoclonal bands or be normal; interpret neuronal antibodies with phenotype and infectious testing |
| Treatment | IV acyclovir 10 mg/kg Q8H | Immunosuppressants |
Why must you always cover HSV first? HSV encephalitis has ~70% mortality untreated, and empirical acyclovir is started before any result comes back. Additionally, HSV encephalitis itself can trigger secondary anti-NMDAR encephalitis (post-infectious autoimmunity) — post-infectious AE can develop weeks after the initial infection. So a patient who initially improves on acyclovir but then deteriorates should prompt re-investigation for AE.
Critical Clinical Pearl
Never stop acyclovir prematurely just because you suspect AE. Start acyclovir AND investigate for AE simultaneously. Many patients have overlapping or sequential pathologies (HSV → post-HSV anti-NMDAR).
- VZV encephalitis: Subacute onset ~1 week after vesicular rash; MRI shows subcortical white matter lesions; VZV PCR in CSF [4]
- Japanese B encephalitis: Endemic in Asia but rare in HK; rapid onset psychosis + extrapyramidal signs; predilection for bilateral thalamus on MRI; anti-JEV IgM in CSF [4]
- Enteroviral encephalitis: More common in children; hand-foot-and-mouth disease may precede
- HIV encephalitis / AIDS-dementia complex: Check HIV serology in all encephalitis patients
- Rabies: Travel history and animal bite; hydrophobia, aerophobia
"Meningitis (bacterial / viral / TB / fungal) complicated with cerebral oedema or cerebral venous thrombosis" [3][6]
- Key distinction from AE: Bacterial meningitis is typically hyperacute (hours), with prominent fever, neck stiffness, and meningism. AE is more subacute (weeks) with psychiatric features predominating.
- However, partially treated bacterial meningitis can smoulder and mimic AE.
- CSF in bacterial meningitis: neutrophilic pleocytosis, ↓glucose (< 50% of serum), ↑↑protein, +ve Gram stain/culture.
- Subacute onset over weeks — this tempo can overlap with AE [12]
- Classically triphasic: prodromal (malaise, personality change) → meningitic → paralytic
- CN palsies (especially VI), basal meningeal enhancement, hydrocephalus on imaging
- CSF: lymphocytic pleocytosis, ↓↓glucose, ↑↑protein, AFB smear/culture/PCR
- Key distinguisher from AE: CSF glucose is characteristically very low in TB meningitis but normal in AE
2. Autoimmune and Inflammatory Disorders
When you suspect one type of AE, remember the differential includes other AE subtypes. The clinical and laboratory phenotype helps distinguish them:
| Feature | Anti-NMDAR | Anti-LGI1 | Anti-CASPR2 | Anti-GABA-B |
|---|---|---|---|---|
| Age | Young | Elderly | Elderly | Elderly |
| Sex | F | M | M | Either |
| Hallmark | Psychosis → dyskinesias → autonomic | FBDS, hyponatraemia | Morvan syndrome | Early prominent seizures |
| Tumour | Ovarian teratoma | Usually no tumour | Thymoma | SCLC (~50%) |
The GC 225 teaching framework highlights older age, memory impairment, seizures including FBDS, hyponatraemia and steroid responsiveness in LGI1 disease [5]. Malignancy is uncommon; thymoma is a more characteristic association of CASPR2 disease.
High Yield Exam Point
The GC 225 slide explicitly states that the differential diagnosis of anti-LGI1 encephalitis includes CJD [5]. Both can present with rapidly progressive dementia, myoclonus, and EEG abnormalities. The crucial difference: CJD has no effective treatment and is invariably fatal; anti-LGI1 has a good response to steroid [5]. Missing AE masquerading as CJD is a catastrophic error.
"Inflammatory disorders affecting the brain (e.g. vasculitis, cerebral lupus)" [1]
- SLE can cause neuropsychiatric lupus (NPSLE) with psychosis, seizures, cognitive decline, movement disorders — very similar to AE
- Key distinguishers: systemic lupus features (malar rash, arthritis, serositis, nephritis), positive ANA/anti-dsDNA, low complement
- CNS vasculitis (primary or secondary): subacute encephalopathy with multifocal strokes; angiography or brain biopsy needed
- "SLE may present as a recurrent neurologic syndrome before systemic manifestation occurs" [9] — so always check ANA and complement
"Autoimmune demyelinating disease of CNS that typically follows an immunization or vaccination (post-vaccination encephalomyelitis) or systemic viral infection (parainfectious encephalomyelitis)" [9]
- More common in children
- Monophasic course (unlike MS)
- MRI: widespread multifocal white matter lesions (more diffuse than MS)
- Distinguished from AE by predominant white matter involvement and preceding vaccination/infection history
- Histology: perivascular inflammation and demyelination, no neuronal destruction or viral particles [6]
- MS: relapsing-remitting course, white matter plaques disseminated in time and space, oligoclonal bands in CSF
- NMOSD: anti-AQP4 antibodies; severe optic neuritis + longitudinally extensive transverse myelitis (LETM ≥ 3 segments); area postrema syndrome [10]
- Both can occasionally present with encephalopathic features but white matter/optic nerve/spinal cord involvement predominates
- Subacute meningoencephalitis, cranial neuropathies (especially VII), hypothalamic involvement
- Systemic sarcoid features: bilateral hilar lymphadenopathy, erythema nodosum, uveitis
- CSF: lymphocytic pleocytosis, ↑ACE level
- Non-caseating granulomas on biopsy
- Subacute encephalopathy + seizures + myoclonus + high anti-TPO/anti-Tg antibodies
- A diagnosis of exclusion — the relationship between thyroid antibodies and encephalopathy is controversial (the antibodies may be an epiphenomenon)
- Steroid responsiveness is variable and nonspecific; thyroid antibodies are common and do not establish causation
- Must rule out other AE subtypes before settling on this diagnosis
3. Metabolic and Toxic Encephalopathy
"Other non-CNS infections (+/- systemic involvement) with encephalopathy (septic, metabolic, toxic)" [1]
- Diffuse brain dysfunction secondary to systemic infection/sepsis WITHOUT direct CNS infection
- Why it mimics AE: Confusion, agitation, reduced consciousness, occasionally seizures
- Key distinguisher: Identified systemic infection source, positive blood cultures, multi-organ dysfunction; CSF is typically normal (no pleocytosis)
"Metabolic encephalopathy: Hypoglycemia, Electrolyte disturbance" [3][6]
- Hyponatraemia: Particularly relevant because anti-LGI1 encephalitis itself causes SIADH → hyponatraemia [5][11]. You must determine whether hyponatraemia is the cause of encephalopathy or a feature of AE.
- CNS causes of SIADH include: meningitis, encephalitis, brain abscess, head trauma, SAH, CVA, raised ICP [11]
- If you correct sodium but encephalopathy persists → think AE
- Hypoglycaemia: Can cause acute confusion, seizures, focal deficits. Always check bedside glucose.
- Hepatic encephalopathy: Chronic liver disease, asterixis, elevated ammonia
- Uraemic encephalopathy: Elevated creatinine/urea, myoclonus, asterixis
- Neuroleptic malignant syndrome (NMS): Fever + rigidity + altered consciousness + autonomic instability after starting antipsychotics — can be triggered when a patient with anti-NMDAR encephalitis is misdiagnosed as primary psychosis and given antipsychotics
- Serotonin syndrome: Similar features after serotonergic drugs; myoclonus, hyperreflexia, diarrhoea
- Wernicke encephalopathy: Thiamine deficiency → confusion + ophthalmoplegia + ataxia triad. Consider in alcoholics and malnourished patients
- Drug intoxication / withdrawal: Benzodiazepine withdrawal, alcohol withdrawal, recreational drugs
Common Exam Trap
A young woman with "first-episode psychosis" is started on haloperidol. She develops fever, rigidity, autonomic instability, and elevated CK. The question asks: NMS or anti-NMDAR encephalitis? Both can look identical. The key is the timeline: if psychiatric symptoms preceded antipsychotic use by days-weeks and there were prodromal features, consider underlying anti-NMDAR, especially with seizures, dyskinesias or reduced consciousness; timing and a viral-like prodrome alone cannot distinguish it from primary psychosis with NMS. Check anti-NMDAR antibodies and do pelvic imaging for teratoma.
"Viral encephalitis, Hypertensive encephalopathy, Wernicke encephalitis" — listed as differential of encephalitis [3][8]
- Classic triad: confusion, ophthalmoplegia, ataxia
- Due to thiamine (B1) deficiency — alcoholism, malnutrition, hyperemesis
- MRI: symmetric signal changes in medial thalami, mammillary bodies, periaqueductal grey
- Treatment: Give IV thiamine promptly before or alongside glucose when feasible, but never delay emergency glucose for hypoglycaemia
"Brain tumours (primary / metastatic)" [3][6]
- Primary CNS lymphoma, gliomatosis cerebri, and leptomeningeal carcinomatosis can present subacutely with encephalopathy, personality change, and seizures
- Distinguished by MRI showing mass lesion(s) or diffuse leptomeningeal enhancement
- CSF cytology may show malignant cells
Paraneoplastic encephalitis is both a differential and a subtype of AE:
Paraneoplastic encephalomyelitis — "usually associated with SCLC. Patients with SCLC — anti-Hu antibodies in serum and CSF. Anti-CV2/CRMP5 antibodies occur less frequently" [13]
"Inflammatory involvement of multiple CNS areas including brain, brainstem, cerebellum, and spinal cord" [14]
- Limbic encephalitis: "confusion, depression, agitation, anxiety, severe short-term memory deficits, partial complex seizures, and dementia; MRI usually shows unilateral or bilateral medial temporal lobe abnormalities" [14]
- Brainstem encephalitis: "eye movement disorders (nystagmus, supranuclear or nuclear paresis), cranial nerve paresis, dysarthria, dysphagia" [14]
- Cortical encephalitis: "may present as epilepsia partialis continua" [14]
"Sepsis in patients with primary psychiatric disorder" [1]
This is a bidirectional problem:
- AE misdiagnosed as primary psychiatry: Many anti-NMDAR patients are initially admitted to psychiatry with "acute psychosis," "mania," or "catatonic schizophrenia." Red flags for AE over primary psychiatry are detailed below.
- Concurrent sepsis in a psychiatric patient: A patient with known schizophrenia who develops fever and confusion may have a systemic infection causing delirium rather than AE.
| Feature | AE (Anti-NMDAR) | Primary Psychosis (Schizophrenia) |
|---|---|---|
| Onset | Subacute (days-weeks) | Variable (may be insidious) |
| Age | Young woman | Variable |
| Prodrome | Viral-like illness | Often insidious social withdrawal |
| Movement disorders | Orofacial dyskinesias, limb dyskinesias — present early, NOT drug-related | Absent (unless drug-induced EPS) |
| Seizures | Common (~70-80%) | Uncommon in primary psychosis |
| Autonomic dysfunction | Present (tachycardia, BP lability, hypoventilation) | Absent |
| Decreased consciousness | Progressive obtundation | Consciousness preserved |
| Response to antipsychotics | Poor; may precipitate NMS | Usually responds |
| CSF | May show pleocytosis/antibodies or be normal | Usually normal |
| MRI/EEG | MRI often normal in NMDAR; EEG may be abnormal | Usually normal |
6. Vascular
- Subacute headache, seizures, confusion, focal deficits
- Risk factors: OCP, pregnancy, prothrombotic states, dehydration
- Diagnosed by CT/MR venography
- Distinguished from AE by prominent headache and venographic findings
- Acute/subacute encephalopathy + seizures + visual disturbance + headache
- Associated with hypertensive crisis, eclampsia, immunosuppressants (ciclosporin, tacrolimus)
- MRI: bilateral posterior white matter vasogenic oedema
- Distinguished from AE by posterior-predominant MRI changes and association with hypertension/drugs
"Sepsis with nonconvulsive status epilepticus" [1]
a. Non-Convulsive Status Epilepticus (NCSE)
- Prolonged altered consciousness with subtle or no motor manifestations
- "Requires EEG for detection" [3]
- Can mimic AE because the patient appears confused/obtunded with no obvious seizure
- Key: EEG shows continuous or near-continuous epileptiform activity
- Can be a complication of AE (AE causes seizures, which can become non-convulsive status)
8. Endocrine
"Thyroid storm" [1]
- Severe thyrotoxicosis → agitation, confusion, psychosis, seizures, fever, tachycardia, autonomic instability
- Can closely mimic the autonomic and psychiatric features of anti-NMDAR encephalitis
- Check TFTs (↓↓TSH, ↑↑fT4/fT3) and look for goitre, lid retraction, tremor
- Severe hypothyroidism → progressive encephalopathy, hypothermia, hyponatraemia, hypoventilation
- TFTs diagnostic
- Discussed under autoimmune/inflammatory above
- Encephalopathy + elevated anti-TPO antibodies + steroid-responsive
a. Creutzfeldt-Jakob Disease (CJD)
"Differential diagnosis: CJD" — explicitly stated for anti-LGI1 encephalitis [5]
- Rapidly progressive dementia (weeks-months) + myoclonus + ataxia + visual disturbance
- EEG: periodic sharp wave complexes
- MRI: cortical ribboning and caudate/putamen high signal on DWI
- CSF RT-QuIC supports prion disease; 14-3-3 is a nonspecific neuronal injury marker
- Why it mimics AE: Both have rapidly progressive cognitive decline + seizures/myoclonus + EEG abnormalities. The critical difference is that CJD is invariably fatal with no treatment, while anti-LGI1 has a "good response to steroid" [5]. Missing treatable AE in a "CJD-like" patient is devastating.
High Yield
Any patient with suspected CJD should have AE antibodies checked. CJD is a diagnosis of exclusion — you must rule out treatable mimics, of which AE is the most important.
| Differential | Tempo | Key Feature Distinguishing from AE | Key Investigation |
|---|---|---|---|
| HSV encephalitis | Acute (days) | Temporal lobe necrosis, PLEDs on EEG | CSF HSV PCR, MRI |
| Bacterial meningitis | Hyperacute (hours) | Meningism, purulent CSF, ↓glucose | CSF Gram stain, culture |
| TB meningitis | Subacute (weeks) | CN palsies, basal enhancement, ↓↓CSF glucose | CSF AFB, TB PCR |
| Brain abscess | Subacute | Ring-enhancing lesion on MRI | MRI with contrast |
| CNS vasculitis / Cerebral lupus | Subacute | Systemic lupus features, multifocal strokes | ANA, anti-dsDNA, complement, angiography |
| ADEM | Acute/subacute | Post-infectious, widespread white matter lesions | MRI, preceding infection/vaccination |
| Primary psychosis | Variable | No seizures/dyskinesias/autonomic Sx, consciousness preserved | Clinical; CSF and MRI normal |
| Septic encephalopathy | Acute | Systemic infection source, normal CSF | Blood cultures, sepsis workup |
| Metabolic encephalopathy | Acute/subacute | Identifiable metabolic cause (glucose, Na⁺, liver, kidney) | Metabolic panel |
| NMS | Acute | After antipsychotic, rigidity, ↑CK | Drug history, CK |
| NCSE | Acute/subacute | Continuous epileptiform activity on EEG | EEG |
| Thyroid storm | Acute | Goitre, thyrotoxic features, ↓↓TSH, ↑↑fT4 | TFTs |
| CJD | Subacute (weeks) | Relentless progression, periodic sharp waves, 14-3-3 protein, no treatment response | MRI DWI, CSF RT-QuIC |
| CNS lymphoma | Subacute | Mass lesion, periventricular location | MRI, CSF cytology |
| PRES | Acute/subacute | Posterior white matter oedema, hypertension | MRI, BP |
| CVST | Subacute | Prominent headache, haemorrhagic venous infarcts | CT/MR venography |
| Wernicke encephalopathy | Acute/subacute | Triad: confusion + ophthalmoplegia + ataxia; alcoholism | Clinical, MRI, thiamine trial |
The practical bedside approach follows three steps:
Step 1 — Is this AE or something else?
- Apply the Graus 2016 criteria for possible AE [5]: subacute memory/mental-status/psychiatric change, a qualifying focal/seizure/CSF/MRI finding, and exclusion of alternatives (see Ix tab)
- Simultaneously start empirical acyclovir (to cover HSV) and broad-spectrum antibiotics (if bacterial meningitis cannot be excluded) while awaiting results
Step 2 — Exclude urgent life-threatening mimics:
- Bedside glucose (hypoglycaemia), metabolic panel (Na⁺, Ca²⁺, glucose, LFT, RFT, ammonia)
- TFTs (thyroid storm)
- Blood cultures (sepsis)
- Brain imaging: CT for urgent structural exclusion when indicated; MRI is more sensitive for encephalitis, PRES and other mimics
- Lumbar puncture with opening pressure, cell count, glucose, protein, Gram stain, culture, HSV/VZV PCR
- EEG (NCSE)
Step 3 — If initial workup supports AE, refine the diagnosis:
- Send serum AND CSF for AE antibody panel (NMDAR, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX, GAD65)
- Send paraneoplastic antibody panel if indicated (Hu, Yo, Ri, Ma2, CV2, amphiphysin)
- MRI brain with contrast
- Screen for underlying tumour: CT chest/abdomen/pelvis, pelvic ultrasound (ovarian teratoma in young women), testicular ultrasound (young men), whole-body PET-CT if high suspicion
High Yield Summary — Differential Diagnosis of Autoimmune Encephalitis
Must-exclude emergencies (treat first, investigate in parallel):
- HSV encephalitis → empirical acyclovir
- Bacterial meningitis → empirical antibiotics
- Hypoglycaemia → bedside glucose
- NCSE → EEG
Key AE mimics on exams:
- Primary psychiatric disorder — no seizures/movement disorder/autonomic instability; consciousness preserved
- CJD — relentless, no treatment response; explicitly listed as DDx of anti-LGI1 [5]
- Thyroid storm — check TFTs in all encephalopathy
- NMS — may be superimposed on AE after inappropriate antipsychotic use
- Cerebral lupus / CNS vasculitis — check ANA, complement
Red flags suggesting AE over primary psychiatry:
- Viral prodrome preceding psychiatric symptoms
- Seizures (especially FBDS)
- Movement disorders (orofacial dyskinesias)
- Autonomic dysfunction
- Progressive decrease in consciousness
- CSF pleocytosis
- Poor response to antipsychotics
Active Recall - Differential Diagnosis of Autoimmune Encephalitis
References
[1] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (Differential Diagnosis slide, p.3; Autoimmune Encephalitis slide, p.45) [2] Senior notes: Maksim Medicine Notes.pdf (Section 11.9, p.264) [3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Encephalitis differential diagnosis, p.1199; Delirium DDx, p.1132-1134; Headache DDx, p.1144-1146) [4] Senior notes: Ryan Ho Neurology.pdf (Section 7.2 Encephalitis, p.147-148) [5] Lecture slides: GC 225. Neuroimmunological disorders of the central nervous system.pdf (Anti-LGI1 clinical features, p.42; Diagnostic criteria, p.28) [6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Encephalitis DDx, p.520; Meningitis vs Encephalitis, p.500) [7] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (Pathological differentials, p.18) [8] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Differential diagnosis, p.1148) [9] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (MS/NMO/ADEM DDx, p.1273) [10] Lecture slides: CFB_Neuro clinical skills demonstration_01.08.22_file to students.pdf (Pathological differentials, p.8) [11] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (SIADH causes, p.21) [12] Senior notes: Ryan Ho Respiratory.pdf (TB meningitis, p.79) [13] Lecture slides: Cancer Block - Paraneoplastic Syndrome.pdf (Paraneoplastic encephalitis, p.24) [14] Lecture slides: Cancer Block - Paraneoplastic Syndrome.pdf (Focal encephalitis types, p.22-23)
Diagnosis and investigations
All three are needed: onset within 3 months of working-memory impairment, altered mental status or psychiatric symptoms; at least one of new focal CNS findings, seizures unexplained by a known seizure disorder, CSF white cells >5/mm³ or MRI suggesting encephalitis; and reasonable exclusion of alternatives. EEG slowing alone is not a possible-AE criterion. [20]
These criteria identify a syndrome requiring further assessment; they do not prove an autoimmune cause. Normal MRI or routine CSF does not exclude AE. An isolated positive serum antibody also does not establish the diagnosis.
The antibody-independent framework requires subacute limbic symptoms, bilateral medial temporal T2/FLAIR abnormalities, CSF pleocytosis or temporal EEG epileptic/slow activity, and exclusion of alternatives. A clinically relevant antibody can establish an autoimmune subtype when this complete imaging-based pattern is absent. [20]
Probable: rapid onset of at least four of six groups (behaviour/cognition, speech, seizures, movement/rigidity/posturing, reduced consciousness, autonomic dysfunction/hypoventilation), abnormal EEG or inflammatory CSF/oligoclonal bands, and exclusion of alternatives. Three symptom groups with a systemic teratoma can also qualify. Definite: at least one group with IgG anti-GluN1 and exclusion of alternatives; include CSF testing. [20]
- Bedside glucose, FBC, electrolytes including sodium/calcium, renal and liver function; CRP and blood cultures when infection is possible.
- Directed tests: thyroid function, toxicology, ammonia, HIV/syphilis testing, autoimmune markers and nutritional investigations according to the presentation. A positive ANA or thyroid antibody is not proof of an autoimmune brain disorder.
- Baseline FBC, renal/liver function, immunoglobulins and infection screening before immunosuppression; HBsAg and anti-HBc before rituximab.
- Obtain neuronal antibody samples before IVIG or plasma exchange when feasible, without delaying urgent treatment.
Assess clinical contraindications and stabilise the patient first. Neuroimaging is needed before LP when there is concern for a mass lesion, herniation or other contraindication; a normal CT does not itself establish LP safety. Do not delay empirical antimicrobials for imaging or LP.
| Test | Interpretation |
|---|---|
| Opening pressure, cell count/differential | AE may show mild lymphocytic pleocytosis or entirely normal results |
| Protein and paired CSF/blood glucose | Protein may be normal or raised; glucose usually preserved. Low glucose should prompt infection, malignancy and other alternatives |
| Gram stain/culture, HSV/VZV PCR | Exclude infectious mimics; add TB, fungal and other tests based on exposure and immune status |
| Oligoclonal bands and IgG index | Support intrathecal inflammation but are not specific for AE |
| Neuronal antibodies | Send paired CSF and serum; CSF is especially important for NMDAR, whereas serum is often more sensitive for LGI1 [21] |
| Cytology/flow cytometry or RT-QuIC | Selected cases where malignancy or prion disease is plausible |
Bacterial meningitis usually produces substantial neutrophilic pleocytosis, raised protein and reduced glucose, but early or partially treated cases can be atypical. No single CSF value safely excludes infection. Repeat HSV PCR after 3–7 days if an early result is negative but clinical suspicion persists, continuing acyclovir meanwhile.
| Investigation | Findings and limitations |
|---|---|
| MRI brain | Often normal in anti-NMDAR; medial temporal changes in limbic encephalitis; multifocal cortical/subcortical lesions in GABA-A disease. MRI patterns overlap with infection, seizure-related changes and malignancy |
| EEG | Detects seizures/NCSE and focal or diffuse dysfunction; slowing is nonspecific |
| Extreme delta brush | Suggests anti-NMDAR in the right syndrome but is neither required nor independently diagnostic |
| Temporal periodic discharges | Can occur with HSV and other disorders, including AE; not a reliable stand-alone discriminator |
| FBDS | May lack a scalp EEG correlate; a normal ictal EEG does not exclude them |
Use validated antigen-specific assays and the clinical phenotype. Prefer LGI1/CASPR2-specific tests over nonspecific “VGKC-complex” results. Low-titre serum GAD65 is common in diabetes and does not establish neurological autoimmunity; assay, titre, CSF findings and syndrome all matter. There is no universal numerical cutoff across assays. Seronegative AE requires careful application of clinical criteria and exclusion of mimics, not simply a negative panel followed by a steroid trial.
| Syndrome/antibody | Important association and directed investigation |
|---|---|
| NMDAR in a postpubertal female | Ovarian teratoma: pelvic ultrasound and/or MRI; a nondiagnostic ultrasound may need MRI |
| CASPR2 | Thymoma: chest imaging |
| GABA-B or Hu | Small-cell lung cancer: chest imaging; further evaluation if suspicion remains high |
| AMPAR | Lung/breast/thymic tumours: directed screening |
| Ma2 | Testicular germ-cell tumour: examination and ultrasound when appropriate |
| LGI1 | Usually non-paraneoplastic; initial screening based on age and risk |
Adults often have baseline CT chest/abdomen/pelvis, supplemented by sex-, antibody- and risk-directed testing. Children require age-appropriate screening with attention to radiation exposure. FDG-PET is a selected second-line investigation, not an automatic test after every negative pelvic ultrasound. Repeat surveillance depends on the antibody, cancer risk and initial results; a six-monthly whole-body scan for every AE patient is not warranted. [22]
High Yield Summary — Diagnosis
Clinical syndrome + objective support + exclusion of mimics precede interpretation of antibody tests. Send paired serum/CSF, MRI and EEG. Normal MRI/CSF and negative serum NMDAR do not exclude AE. EEG slowing alone cannot satisfy possible-AE criteria. Screen for tumours according to subtype and patient risk.
Active Recall — Diagnosis
References
[20] Graus et al. A clinical approach to diagnosis of autoimmune encephalitis (2016). [21] Abboud et al. Best-practice recommendations for diagnosis and acute management (2021). [22] Abboud et al. Symptomatic and long-term management (2021).
Management of autoimmune encephalitis
Stabilisation, investigation, seizure treatment and planning immunotherapy proceed together. Involve neurology early; severe dysautonomia, hypoventilation or refractory status epilepticus requires critical care.
| Priority | Action |
|---|---|
| Airway and breathing | Assess airway protection and ventilation; intubate when needed. Oxygen saturation alone can miss hypoventilation |
| Seizures | Treat status epilepticus urgently under the local protocol; use EEG to detect nonconvulsive seizures and distinguish dyskinesias |
| Circulation | Telemetry, blood pressure and temperature monitoring; treat dysautonomia and assess for infection |
| Infectious mimics | Start IV acyclovir promptly while investigating HSV/VZV; add bacterial meningitis coverage when indicated |
| Supportive care | Swallow assessment, nutrition, pressure care, thromboprophylaxis when appropriate, early rehabilitation and family support |
A usual adult acyclovir regimen is 10 mg/kg IV every eight hours, adjusted for renal function with hydration and renal monitoring. Stop only when infection has been adequately excluded in clinical context. A single early negative HSV PCR is insufficient when suspicion remains high; repeat after 3–7 days. Confirmed HSV encephalitis generally needs 14–21 days of treatment. Paediatric dosing follows age-specific protocols. [23]
Start when AE is strongly supported and infectious causes have been reasonably excluded; do not await antibody results. If infection remains plausible, decisions about concurrent immunotherapy require specialist assessment. Acyclovir does not make all immunosuppression risk-free. Obtain planned lymphoma biopsy before steroids when feasible because steroids can obscure histology. [21]
Typical adult options are:
| Treatment | Regimen and role | Main precautions |
|---|---|---|
| IV methylprednisolone | Often 1 g daily for 3–5 days, followed by an individualised oral taper | Infection, glucose, blood pressure, mood/psychosis, gastrointestinal and bone risks with prolonged therapy |
| IVIG | Total 2 g/kg over 2–5 days | Infusion reactions, thrombosis, renal injury, aseptic meningitis; assess prior reactions and product suitability |
| Plasma exchange | Often 5–7 exchanges; selected alone or combined with steroids | Vascular access, haemodynamic tolerance, calcium, coagulation and line infection |
Combination therapy may be appropriate for severe disease. Choice depends on syndrome, contraindications and local expertise; no option is universally superior. [21]
IVIG and plasma exchange sequencing: subsequent exchanges remove administered immunoglobulin. When both are planned, give IVIG after the final planned exchange where feasible. Selective IgA deficiency alone is not an automatic IVIG contraindication; previous severe reactions, anti-IgA status where relevant, and the product require specialist assessment. [24]
Remove an associated ovarian teratoma promptly when clinically feasible and treat other associated tumours with the appropriate team. This removes an antigenic stimulus but does not instantly stop all antibody production or replace immunotherapy. Use fertility-preserving surgery when oncologically appropriate.
- LGI1 faciobrachial dystonic seizures: ASMs alone are often inadequate; prompt immunotherapy is crucial. Adjunctive ASMs still have a role.
- Select ASMs around psychiatric symptoms, interactions, pregnancy potential and organ function. Levetiracetam can worsen behavioural symptoms; valproate has major reproductive risks.
- Carbamazepine/oxcarbazepine can worsen hyponatraemia and are poor choices in a patient with low sodium.
- Severe symptomatic hyponatraemia needs urgent monitored hypertonic saline under a sodium-correction protocol. Fluid restriction may suit stable SIADH; it is inadequate for hyponatraemic seizures. Avoid overcorrection and osmotic demyelination.
- Agitation and catatonia need specialist psychiatric/neurological input. Minimise antipsychotic exposure and monitor for rigidity, fever, autonomic changes and CK elevation; anti-NMDAR patients may be unusually sensitive. Do not mistake all abnormal movements for seizures.
Consider rituximab, or selected use of cyclophosphamide, after inadequate first-line response (often assessed over 2–4 weeks; earlier escalation may be needed in severe disease). Rituximab is commonly preferred for cell-surface antibody disease; cyclophosphamide has broader toxicity and may be considered in selected T-cell-mediated or refractory syndromes. Refractory disease merits reassessment of the diagnosis before experimental escalation. [21]
| Agent | Important safety checks |
|---|---|
| Rituximab | HBsAg, anti-HBc, immunoglobulins, FBC and infection assessment. Current infection and HBsAg-negative/anti-HBc-positive resolved infection require antiviral prophylaxis with anti-CD20 therapy under the relevant protocol. [25] Pregnancy decisions require individual specialist risk assessment |
| Cyclophosphamide | Cytopenias, infection, haemorrhagic cystitis, infertility and malignancy risk; hydration/mesna according to regimen and fertility counselling |
| Azathioprine | TPMT and, where relevant, NUDT15 assessment; ongoing FBC/liver monitoring |
| Mycophenolate | Pregnancy prevention, cytopenia, infection and renal/liver monitoring |
A bridging steroid taper or other treatment may follow acute therapy. Long-term immunosuppression is individualised, especially for relapsing disease; every first episode does not require indefinite maintenance. Specialist options for refractory cases include tocilizumab or bortezomib, supported by limited evidence. [22]
Assess clinical recovery, cognition, function, seizures, mood and rehabilitation needs. Repeat EEG/MRI or LP for a clinical indication, not a compulsory timetable. Antibody titres may remain positive after recovery and must not alone drive escalation. Tumour surveillance depends on antibody and patient risk. [22]
Recovery can take months to years. Early treatment and lower initial severity generally favour recovery; absence of a tumour is not a universal poor-prognosis marker. Persistent cognitive problems can occur despite a good motor/functional score. Classical intracellular-antigen syndromes often respond less well because neuronal injury can be irreversible. GAD65-associated epilepsy can be particularly treatment-resistant.
High Yield Summary — Management
Stabilise and treat infectious mimics, then start justified immunotherapy without waiting for antibodies. First-line options are IV methylprednisolone, IVIG and plasma exchange; remove an associated tumour. Escalate under specialist care, monitor treatment risks, and individualise maintenance and cancer surveillance.
Active Recall — Management
References
[21] Abboud et al. Diagnosis and acute management recommendations (2021). [22] Abboud et al. Symptomatic and long-term management recommendations (2021).
[23] IDSA encephalitis guideline. [24] AAAAI primary immunodeficiency practice parameter: immunoglobulin safety. [25] AASLD guidance: HBV reactivation during immunosuppression.
Complications of Autoimmune Encephalitis
Complications of autoimmune encephalitis can be divided into disease-related (direct consequences of the autoimmune process and its neurological effects) and treatment-related (iatrogenic complications from immunotherapy and prolonged hospitalisation). Understanding these is essential because many AE patients have a prolonged illness course — weeks to months in ICU — and it is the complications that often determine morbidity and mortality rather than the encephalitis itself.
1. Disease-Related Complications
"Close monitoring as patients may develop refractory seizures, autonomic instability" [1]
- Seizures are common in many AE subtypes and can escalate to status epilepticus (SE), both convulsive and non-convulsive
- Anti-GABA-A receptor encephalitis is particularly notorious for super-refractory SE — seizures that persist despite general anaesthesia for ≥ 24 hours [17]
- Anti-NMDAR encephalitis can also cause refractory SE, sometimes requiring weeks of ICU sedation
Why are AE seizures so difficult to control? Because anti-seizure medications (ASMs) act on downstream ion channels and receptors, but the upstream driver — ongoing antibody-mediated receptor dysfunction — continues unchecked. As long as pathogenic antibodies are present and internalising receptors (NMDA, GABA-A, GABA-B, LGI1-associated AMPA), the brain remains hyperexcitable. This is why the definitive treatment for AE seizures is immunotherapy, not escalating ASMs alone.
From GC 081 lecture (status epilepticus management): "Workup and treat possible underlying cause: … Autoimmune encephalitis" [19]. In the management of SE, autoimmune encephalitis is explicitly listed as a cause to investigate. At the supra-refractory stage, immunotherapy is a listed treatment option [17].
Consequences of prolonged SE:
- Excitotoxic neuronal injury: Sustained glutamate release during continuous seizure activity causes calcium influx → mitochondrial failure → neuronal death, particularly in the hippocampus → worsens memory outcomes
- Systemic sequelae: Rhabdomyolysis (↑CK), metabolic acidosis, hyperthermia, aspiration pneumonia, arrhythmias
- Prolonged ICU stay: With all its attendant complications (see Section 2 below)
"Autonomic dysfunction as a result of involvement of the neuraxis at multiple levels, including hypothalamus, brainstem, and autonomic nerves" [8]
"Cardiac arrhythmias, postural hypotension, or central hypoventilation are frequent causes of death in patients with encephalomyelitis" [8]
This is one of the most dangerous complications and a major cause of mortality in AE.
| Manifestation | Mechanism | Clinical Consequence |
|---|---|---|
| Central hypoventilation | Antibody-mediated dysfunction of medullary respiratory centres (nucleus tractus solitarius, pre-Bötzinger complex) | Apnoea, respiratory failure requiring intubation and mechanical ventilation; this can be the presentation that leads to ICU admission |
| Cardiac arrhythmias | Autonomic imbalance → sympathetic and parasympathetic instability affecting cardiac conduction | Tachyarrhythmias (SVT, VT) and bradyarrhythmias (asystole, heart block) → sudden cardiac death |
| Blood pressure lability | Hypothalamic and brainstem cardiovascular centre dysfunction | Hypertensive crises alternating with hypotension; complicates fluid management |
| Hyperthermia | Hypothalamic thermoregulatory centre dysfunction | Persistent high fever → must distinguish from concurrent infection and NMS; can worsen neuronal injury |
| Excessive secretions / diaphoresis | Parasympathetic/sympathetic imbalance | Aspiration risk; skin breakdown |
Why is central hypoventilation so dangerous? Unlike seizures or psychiatric symptoms, which are obvious and prompt attention, central hypoventilation can be insidious — the patient simply stops breathing adequately, often during sleep. If continuous SpO₂ and respiratory monitoring is not in place, it can be fatal. This is why GC 051 emphasises "close monitoring" [1].
"Memory deficits" [2]
"Severe short-term memory deficits" [14]
- Anterograde amnesia is one of the most persistent sequelae, particularly in limbic encephalitis (anti-LGI1, anti-NMDAR)
- Why? The hippocampus — the structure most vulnerable in limbic encephalitis — is essential for converting short-term memories into long-term memories (long-term potentiation via NMDA receptors). Prolonged inflammation causes hippocampal atrophy visible on follow-up MRI.
- In anti-NMDAR encephalitis, widespread cortical NMDA receptor loss impairs attention, executive function, processing speed, and working memory
- Recovery: Memory deficits can persist for months to years even after other symptoms resolve. Some patients never return to their premorbid cognitive baseline, especially if treatment was delayed
Hippocampal sclerosis: Chronic or recurrent limbic encephalitis (especially anti-LGI1) can lead to mesial temporal sclerosis — hippocampal neuronal loss and gliosis → this can become a secondary epileptic focus, resulting in chronic temporal lobe epilepsy even after the autoimmune process is controlled.
- Persistent psychiatric symptoms are common even after immunological remission
- Manifestations: Depression, anxiety, personality change, emotional lability, psychosis (residual), PTSD (from the illness experience and prolonged ICU stay)
- Why? (1) Residual neuronal dysfunction in frontal and limbic circuits; (2) psychological trauma from months of illness, ICU, and loss of independence; (3) some patients have partial or no memory of their acute illness, creating dissociative experiences
- In anti-NMDAR encephalitis specifically, frontal lobe dysfunction may persist → executive dysfunction, disinhibition, impulsivity
- Residual dyskinesias, dystonia, or tremor may persist after acute anti-NMDAR encephalitis
- Catatonia may be prolonged and difficult to manage
- In classical paraneoplastic cerebellar degeneration (anti-Yo), irreversible cerebellar ataxia develops because the Purkinje cells are permanently destroyed by cytotoxic T cells → cerebellar gait and limb ataxia [8]
Surface-antibody syndromes may be monophasic or relapsing.
- Relapse rate varies by antibody:
- Anti-NMDAR: ~12–25% relapse rate, lower with early and adequate immunotherapy
- Anti-LGI1: ~10–20% relapse, often milder than initial episode
- Anti-CASPR2: can relapse
- Classical paraneoplastic: typically monophasic and progressive (often continued deterioration, though course varies) [2]
- Triggers for relapse: Persistent immune activity or an untreated/recurrent tumour in relevant cases; relapse does not prove inadequate treatment
- Clinical pattern: Relapses often recapitulate the initial presentation but may be milder or present with different symptom combinations
- Relapse risk varies by subtype and prior treatment. Absence of a tumour is not a general marker of poor outcome.
- SIADH occurs in ~60% of anti-LGI1 encephalitis
- Severe hyponatraemia (Na⁺ < 120 mmol/L) can itself cause seizures, cerebral oedema, and osmotic demyelination syndrome if corrected too rapidly
- Why this is a complication, not just a feature: Hyponatraemia can compound the seizure burden and worsen the encephalopathy, making it difficult to distinguish electrolyte-driven symptoms from the autoimmune process itself
- As discussed previously, HSV encephalitis can trigger post-infectious anti-NMDAR encephalitis in a subset of patients, particularly children
- This manifests as clinical deterioration weeks after the initial HSV encephalitis appeared to improve with acyclovir
- New-onset choreoathetosis, psychiatric symptoms, and seizures in a patient recovering from HSV encephalitis should prompt CSF anti-NMDAR testing
- This is both a complication of HSV encephalitis and a disease entity in its own right
Many AE patients (especially anti-NMDAR) spend weeks to months in ICU with decreased consciousness, mechanical ventilation, and immobility. The standard ICU complications apply:
| Complication | Mechanism | Prevention |
|---|---|---|
| Ventilator-associated pneumonia (VAP) | Prolonged intubation → colonisation of endotracheal tube → aspiration of contaminated secretions | VAP bundle: head-of-bed elevation, oral hygiene, sedation reduction when clinically safe, daily assessment for extubation readiness |
| Deep vein thrombosis / Pulmonary embolism | Immobility → venous stasis (Virchow's triad) | Pharmacological prophylaxis (LMWH), compression stockings/devices |
| Pressure injuries | Prolonged immobility → tissue ischaemia over bony prominences | Regular turning Q2H, pressure-relieving mattress, nutritional optimisation |
| Hospital-acquired infections | Invasive lines (CVC, urinary catheter), immunosuppression from treatment | Aseptic technique, minimise catheter duration, judicious immunosuppression dosing |
| ICU-acquired weakness (critical illness myopathy/neuropathy) | Prolonged immobility + systemic inflammation + corticosteroid use → muscle wasting and neuropathy | Early physiotherapy, minimise corticosteroid duration, nutritional support |
| Malnutrition | Decreased consciousness, orofacial dyskinesias impairing oral intake, prolonged illness | Early NG/PEG feeding, dietitian input, assess intake, weight and nutritional needs; albumin is affected by inflammation |
| Contractures | Prolonged immobility, catatonic posturing, dystonia | Physiotherapy, passive range of movement exercises |
| Psychological trauma / PTSD | Frightening ICU experiences, prolonged illness, partial awareness during catatonia | Psychological support, ICU diaries, psychiatric follow-up |
3. Treatment-Related Complications
| Treatment | Key Complications | Mechanism | Prevention/Monitoring |
|---|---|---|---|
| High-dose IV methylprednisolone | Hyperglycaemia, insomnia, steroid psychosis, hypertension, GI bleeding, avascular necrosis (long-term), osteoporosis (long-term), adrenal suppression, increased infection risk | Broad immunosuppression + metabolic effects of glucocorticoids | Monitor glucose; PPI for GI prophylaxis; calcium/vitamin D supplementation; gradual taper to avoid adrenal crisis |
| IVIG | Infusion reactions (headache, fever, chills), rare anaphylaxis, renal impairment, thromboembolic events, aseptic meningitis | Rare severe hypersensitivity; formulation-related renal injury and increased thrombosis risk | Assess previous reactions and IgA-related risks; IgA deficiency alone is not an absolute contraindication; adequate hydration; slow infusion rate; use sucrose-free preparation in renal impairment |
| Plasma exchange | Hypotension, hypocalcaemia, coagulopathy, line-related sepsis, allergic reactions | Citrate anticoagulant chelates calcium; removal of clotting factors; central venous catheter complications | Monitor calcium, coagulation profile; aseptic line care |
| Rituximab | Infusion reactions, hepatitis B reactivation, PML (rare), hypogammaglobulinaemia, late-onset neutropenia | B-cell depletion → reduced immunoglobulin production; loss of immune surveillance against JC virus | HBV screening mandatory (HBsAg, anti-HBc); antiviral prophylaxis for relevant current or resolved HBV infection; monitor immunoglobulin levels; PML awareness |
| Cyclophosphamide | Haemorrhagic cystitis, myelosuppression, gonadotoxicity (infertility), secondary malignancy, nausea | Acrolein metabolite damages bladder urothelium; DNA alkylation in gonads and bone marrow | Mesna + hydration for cystitis prevention; monitor FBC; discuss fertility preservation pre-treatment; antiemetics |
Exam-Relevant Iatrogenic Complication
A young woman with anti-NMDAR encephalitis is treated with cyclophosphamide. Months later, she develops amenorrhoea and infertility. This is a well-known complication of cyclophosphamide (gonadotoxicity). In current practice, rituximab is preferred over cyclophosphamide as second-line for this reason, especially in young women. If cyclophosphamide must be used, fertility preservation (oocyte/embryo cryopreservation) should be offered before treatment and GnRH agonist co-administration considered.
- Drug-resistant seizures may prompt ASM polytherapy → increased risk of drug interactions and side effects
- Carbamazepine/oxcarbazepine in anti-LGI1 patients → worsens hyponatraemia (these drugs cause SIADH themselves)
- Phenytoin → cardiac arrhythmias with IV loading, gingival hyperplasia, osteomalacia (long-term)
- Valproate → hepatotoxicity, pancreatitis, teratogenicity (avoid in women of childbearing age)
- Levetiracetam → psychiatric side effects (irritability, depression) — already difficult to assess in a patient with AE-related psychiatric symptoms
- Antipsychotic use in unrecognised anti-NMDAR → neuroleptic malignant syndrome (NMS): fever, rigidity, autonomic instability, ↑↑CK, rhabdomyolysis, renal failure, death
- Delayed immunotherapy due to misdiagnosis as primary psychiatry → worse neurological outcome, more prolonged ICU stay, higher relapse rate
Early appropriate immunotherapy is associated with better outcomes [5].
"Despite MRI findings suggesting widespread cortical damage and poor prognosis, tumor removal and immunotherapy may result in complete clinical recovery" [5]
Functional improvement can continue for months to years. A good modified Rankin score does not equal complete cognitive recovery. Memory, executive function, fatigue, mood and return to education/work need separate assessment. LGI1 can leave hippocampal damage; classical paraneoplastic syndromes often have greater irreversible injury. Recovery order and relapse rates vary across cohorts and individuals.
High Yield Summary — Complications
Monitor for status epilepticus, dysautonomia and hypoventilation. Persistent memory/cognitive, psychiatric and seizure problems may need prolonged rehabilitation. Immunotherapy can cause infection, HBV reactivation, cytopenias and drug-specific toxicity; cyclophosphamide can impair fertility. Relapse is possible but not inevitable.
Active Recall — Complications
References
[1] Lecture slides: GC 051. Fever and confusion_meningitis and encephalitis; suppurative brain infection.pdf (Autoimmune Encephalitis II — management slide, p.46) [2] Senior notes: Maksim Medicine Notes.pdf (Section 11.9 — Autoimmune encephalitis, p.264) [5] Lecture slides: GC 225. Neuroimmunological disorders of the central nervous system.pdf (Autoimmune encephalitis overview, p.26; MRI teaching points, p.31) [8] Lecture slides: Cancer Block - Paraneoplastic Syndrome.pdf (Paraneoplastic Encephalomyelitis — autonomic dysfunction, p.23) [14] Lecture slides: Cancer Block - Paraneoplastic Syndrome.pdf (Limbic encephalitis features, p.22) [17] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Status epilepticus management — immunotherapy at supra-refractory stage, p.1176-1178) [18] Lecture slides: Cancer Block - Paraneoplastic Syndrome.pdf (Treatment of paraneoplastic encephalitis, p.26) [19] Lecture slides: GC 081. Seizure and loss of consciousness Delirium and encephalopathy; epilepsy; coma and brain death; care of unconscious patients; electrophysiology I.pdf (Status epilepticus management — autoimmune encephalitis as underlying cause, p.69)
Revision summary
High Yield Summary — Overview
NMDAR: psychiatric/cognitive change, speech reduction, seizures, dyskinesias and autonomic dysfunction; assess for ovarian teratoma when relevant. LGI1: amnesia, brief faciobrachial dystonic seizures and hyponatraemia, usually without a tumour. Surface-antibody dysfunction may be reversible, whereas classical intracellular-antigen syndromes often involve irreversible T-cell injury. GAD65 epilepsy can be resistant. Normal MRI does not exclude AE.
High Yield Summary — Differential Diagnosis of Autoimmune Encephalitis
Must-exclude emergencies (treat first, investigate in parallel):
- HSV encephalitis → empirical acyclovir
- Bacterial meningitis → empirical antibiotics
- Hypoglycaemia → bedside glucose
- NCSE → EEG
Key AE mimics on exams:
- Primary psychiatric disorder — no seizures/movement disorder/autonomic instability; consciousness preserved
- CJD — relentless, no treatment response; explicitly listed as DDx of anti-LGI1
- Thyroid storm — check TFTs in all encephalopathy
- NMS — may be superimposed on AE after inappropriate antipsychotic use
- Cerebral lupus / CNS vasculitis — check ANA, complement
Red flags suggesting AE over primary psychiatry:
- Viral prodrome preceding psychiatric symptoms
- Seizures (especially FBDS)
- Movement disorders (orofacial dyskinesias)
- Autonomic dysfunction
- Progressive decrease in consciousness
- CSF pleocytosis
- Poor response to antipsychotics
High Yield Summary — Diagnosis
Clinical syndrome + objective support + exclusion of mimics precede interpretation of antibody tests. Send paired serum/CSF, MRI and EEG. Normal MRI/CSF and negative serum NMDAR do not exclude AE. EEG slowing alone cannot satisfy possible-AE criteria. Screen for tumours according to subtype and patient risk.
High Yield Summary — Management
Stabilise and treat infectious mimics, then start justified immunotherapy without waiting for antibodies. First-line options are IV methylprednisolone, IVIG and plasma exchange; remove an associated tumour. Escalate under specialist care, monitor treatment risks, and individualise maintenance and cancer surveillance.
High Yield Summary — Complications
Monitor for status epilepticus, dysautonomia and hypoventilation. Persistent memory/cognitive, psychiatric and seizure problems may need prolonged rehabilitation. Immunotherapy can cause infection, HBV reactivation, cytopenias and drug-specific toxicity; cyclophosphamide can impair fertility. Relapse is possible but not inevitable.
See the corresponding tabs for explanations, active-recall questions and references.
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