Autoimmune encephalitis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Antibodies against neuronal cell-surface or synaptic proteins can alter receptor function and provoke potentially reversible network dysfunction. NMDAR, LGI1, CASPR2, GABA-B and AMPA receptor syndromes are important examples. Antibodies against intracellular antigens more often mark a cytotoxic T-cell and paraneoplastic process, which may respond less completely to immunotherapy and increases the urgency of cancer treatment. Seronegative autoimmune encephalitis remains possible when the clinicoradiological syndrome is strong and alternatives have been rigorously excluded.

Presentation is shaped by the neural circuit involved. Limbic inflammation causes short-term memory failure, temporal seizures, anxiety and behavioural change. Diffuse receptor dysfunction produces psychosis, catatonia, movement disorder, dysautonomia and reduced consciousness. Brainstem or peripheral hyperexcitability may accompany CASPR2 disease. Fever and headache can occur in both infection and autoimmunity, so apparent inflammatory clues do not remove the need for microbiological testing and empiric aciclovir.

Management crosses traditional boundaries. Neurology leads syndrome classification and immune treatment; infectious diseases supports antimicrobial decisions; intensive care manages refractory seizures, dysautonomia and ventilation; psychiatry helps behavioural care without diagnostic overshadowing; oncology or gynaecology addresses a tumour; and rehabilitation treats cognitive, communication, swallowing and motor consequences. Early gains may be subtle, and treatment should not be abandoned because consciousness or behaviour fails to normalise immediately.

Key points

Autoimmune encephalitis typically evolves over days to fewer than three months with impaired memory, altered mental state or psychiatric change plus seizures, focal findings, CSF inflammation, EEG abnormalities or compatible MRI features.
A first psychotic presentation with catatonia, seizures, dyskinesia, fluctuating consciousness or autonomic disturbance needs an organic assessment; age alone must not divert the patient exclusively into a psychiatric pathway.
Anti-NMDA-receptor encephalitis often progresses from psychiatric and cognitive symptoms to seizures, oro-facial dyskinesia, autonomic instability and hypoventilation, especially in younger people.
LGI1 encephalitis is suggested by very brief frequent faciobrachial dystonic seizures, memory loss, temporal-lobe seizures and hyponatraemia, often before routine MRI or CSF becomes striking.
Send both CSF and serum neuronal-antibody panels through an accredited laboratory because sensitivity and specificity differ by antibody; a serum-only low-positive result can mislead.
Do not wait for an antibody result to give intravenous aciclovir when herpes simplex encephalitis remains possible, or to treat a compelling severe autoimmune syndrome after appropriate samples and specialist review.
MRI may be normal, particularly in NMDAR disease; EEG can reveal non-convulsive seizures or characteristic slowing but is rarely antibody-specific.
Search for a phenotype-linked tumour, such as ovarian teratoma with NMDAR antibodies or small-cell lung cancer with certain intracellular antibodies, and repeat screening when specialist guidance indicates.
First-line immunotherapy usually combines high-dose corticosteroid with intravenous immunoglobulin or plasma exchange; rituximab or cyclophosphamide is considered when response is inadequate.
Recovery is often slow and uneven, requiring neurorehabilitation, neuropsychology, speech and language therapy, epilepsy review and support for families long after inflammation is controlled.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Neuronal surface antibodies

Antibodies targeting NMDAR, LGI1, CASPR2 and other surface or synaptic proteins can disrupt receptor function and produce potentially reversible network dysfunction.

Paraneoplastic intracellular immunity

Antibodies to intracellular antigens often mark a tumour-driven cytotoxic T-cell response, making cancer identification central and neurological recovery less predictably responsive to immunotherapy.

Seronegative immune encephalitis

A convincing clinicoradiological inflammatory syndrome may lack an identified antibody after rigorous testing; infection, malignancy, toxic and primary psychiatric alternatives should then be excluded carefully.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Loss of immune tolerance
Tumour antigens, infection or unexplained immune dysregulation activates B-cell, antibody or cytotoxic T-cell responses against neuronal targets.
2
Limbic and network dysfunction
Immune effectors enter the central nervous system and alter synaptic receptors or injure neurons, particularly within memory, seizure, behavioural and autonomic networks.
3
Escalating cerebral instability
Continuing inflammation produces seizures, psychosis, catatonia, dyskinesia, impaired consciousness and dysautonomia; receptor dysfunction may be reversible even when early recovery appears slow.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

NMDAR phenotypeRed flag

A younger patient develops anxiety, insomnia, psychosis or cognitive change, then seizures, catatonia, oro-lingual or limb dyskinesia, autonomic swings and central hypoventilation. An ovarian teratoma is an important association.

LGI1 patternRed flag

An older adult has dozens of brief unilateral face-and-arm dystonic episodes, new memory impairment and hyponatraemia. These seizures may precede full limbic encephalitis and warrant urgent specialist recognition.

Limbic syndromeRed flag

Subacute anterograde amnesia, confusion, mood or behavioural change and focal temporal seizures accompany mesial-temporal MRI signal or EEG abnormalities. HSV and tumour-associated causes remain key alternatives.

Critical deteriorationRed flag

Status epilepticus, reduced consciousness, temperature or blood-pressure instability, arrhythmia, hypersalivation and hypoventilation indicate severe network and autonomic involvement requiring intensive monitoring.

Red flags against autoimmunity

A toxic exposure, metabolic derangement, medication effect, primary infection, rapidly growing tumour, prion-like progression or isolated chronic psychiatric symptoms without neurological evolution should redirect or broaden investigation.

Relapse or aftermath

New objective seizures, behavioural change or cognitive decline after recovery may be relapse, while fatigue, executive difficulty, mood symptoms and sleep disruption can persist without fresh inflammation; specialist reassessment distinguishes them.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
MRI brain with contrastFirst step
Why
Identify limbic or extra-limbic inflammation and exclude stroke, tumour, abscess, demyelination and other structural causes.
Interpretation and limitations
Mesial-temporal T2 or FLAIR signal supports limbic encephalitis but may be unilateral or absent. A normal MRI, especially in NMDAR disease, does not override a convincing evolving syndrome.
02
CSF analysis and paired neuronal antibodies
Why
Investigate infection, demonstrate inflammation and improve the specificity of immune testing.
Interpretation and limitations
Send cell count, protein, glucose, cultures or PCR including HSV/VZV as indicated, oligoclonal bands, cytology when relevant and a phenotype-led antibody panel. Interpret serum and CSF together through the specialist laboratory.
03
EEG with prolonged monitoring when required
Why
Detect focal or non-convulsive seizures, status epilepticus and diffuse cerebral dysfunction during fluctuating behaviour or consciousness.
Interpretation and limitations
Temporal discharges, slowing or an extreme-delta-brush pattern may support the syndrome, but no finding is sufficiently specific to replace clinical and antibody assessment. Repeated events need video-EEG correlation.
04
Metabolic, toxic and infectious work-up
Why
Identify common reversible encephalopathies and safely determine how long empiric antimicrobial treatment is required.
Interpretation and limitations
Check glucose, electrolytes including sodium, calcium, liver and renal function, inflammatory markers, cultures, HIV and toxicology according to context; repeat HSV PCR if early sampling and suspicion remain high.
05
Phenotype-directed tumour screening
Why
Find an associated malignancy whose removal or treatment is part of neurological disease control.
Interpretation and limitations
Choose pelvic imaging, CT chest-abdomen-pelvis, testicular ultrasound, mammography or whole-body metabolic imaging based on sex, age, antibody and risk; surveillance intervals need specialist agreement.
06
Pretreatment and complication baseline
Why
Prepare safely for immunosuppression and quantify organ support, rehabilitation and safeguarding needs.
Interpretation and limitations
Use blood count, immunoglobulins, hepatitis, HIV and TB screening, pregnancy testing, ECG, swallow and respiratory assessment, pressure-risk review and a documented cognitive or functional baseline as clinically appropriate.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

HSV or other infectious encephalitis

Fever, temporal seizures and cerebrospinal-fluid inflammation overlap substantially. Viral PCR, microbiology and MRI guide distinction while empirical aciclovir continues until infection is sufficiently excluded.

Primary psychiatric illness or catatonia

Isolated psychiatric symptoms may be primary, but new seizures, dyskinesia, fluctuating consciousness, memory loss or autonomic instability strongly support an organic neurological assessment.

Non-convulsive status epilepticus

Persistent altered behaviour or responsiveness may reflect ongoing electrical seizure activity; urgent EEG can distinguish a treatable ictal state from encephalitic dysfunction.

Toxic, metabolic or neoplastic disease

Medicine exposure, electrolyte or organ failure, lymphoma and infiltrative disease can mimic subacute encephalopathy and require history-led laboratory, imaging and sometimes tissue investigation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Unstable presentationStabilise without diagnostic delayFirst stepEncephalopathy is accompanied by seizure, autonomic instability, hypoventilation or falling consciousness.

1Use ABCDE, check bedside glucose, protect the airway, treat status epilepticus through the emergency protocol and obtain critical-care input for hypoventilation, dysrhythmia or severe autonomic fluctuation.
2After blood cultures and prompt lumbar puncture when safe, start intravenous aciclovir at the locally adjusted encephalitis dose while HSV remains plausible; add antibacterial therapy if meningitis cannot be excluded.
3Arrange urgent MRI and EEG, send paired serum and CSF antibodies, and involve neurology before sedating behavioural symptoms in ways that could conceal seizures or worsen autonomic instability.
4Use careful low-stimulus nursing, venous-thromboembolism prevention, nutrition, bladder, bowel, pressure and family-support plans during prolonged reduced consciousness.

02Immune treatmentAct on a compelling syndromeInfection has been reasonably covered or excluded and clinical, CSF, EEG or MRI evidence strongly supports autoimmune encephalitis.

1Secure pretreatment samples and infection screening without waiting passively for antibody completion when neurological decline is continuing.
2Under specialist direction, use high-dose intravenous corticosteroid with IV immunoglobulin or plasma exchange according to severity, access, thrombotic risk, autonomic stability and likely antibody biology.
3EscalationAssess objective change in seizure burden, arousal, movement disorder, autonomic support and cognition over an appropriate interval, then escalate to rituximab or cyclophosphamide for inadequate response.
4Identify and treat an associated tumour promptly because immune treatment without tumour control may produce an incomplete or short-lived response.

03Recovery phaseRehabilitate the whole syndromeSeizures and autonomic instability are controlled but cognitive, behavioural or physical disability remains.

1Review antiseizure and psychoactive medicines frequently, reducing unnecessary burden cautiously while avoiding abrupt withdrawal or recurrence of status.
2Provide neuropsychology, occupational, physiotherapy and speech-and-language input for memory, executive function, communication, swallowing, mobility, fatigue and graded return to education or work.
3Agree relapse warning signs, tumour-surveillance and immunotherapy monitoring with a named specialist, and support carers who may be managing striking personality or dependency changes.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Treats possible herpes simplex or varicella-zoster encephalitis while microbiological evidence is pending.

Intravenous aciclovir

Use the local encephalitis regimen, commonly 10 mg/kg intravenously every eight hours with renal adjustment.

Dose by the locally specified weight and renal function, ensure appropriate hydration, monitor creatinine and neurological toxicity, and do not stop solely because the first early HSV PCR is negative.

Provides rapid first-line immunosuppression when autoimmune encephalitis is sufficiently likely.

Intravenous methylprednisolone

A common specialist immune regimen is 1 g once daily for three to five days.

Balance active infection risk and monitor glucose, blood pressure, potassium, sleep, mood and gastrointestinal complications; severe agitation may transiently worsen.

Modulates pathogenic immune activity and may accompany or follow corticosteroid in first-line treatment.

Intravenous immunoglobulin

A frequently used total course is 2 g/kg divided over two to five days by protocol.

Check product guidance and immunoglobulin A history; monitor thrombosis, renal injury, haemolysis, headache and fluid load, especially in immobile or critically ill patients.

Removes circulating antibody in severe disease or when steroid and IV immunoglobulin response is inadequate.

Therapeutic plasma exchange

Specialist teams often plan five to seven exchanges with timing adapted to clinical response.

Consider vascular access, hypotension, citrate reactions, coagulopathy, infection and removal of concomitant medicines or recently administered immunoglobulin.

Common second-line B-cell therapy for severe, refractory or relapsing cell-surface-antibody encephalitis.

Rituximab

Use a specialist induction and redosing schedule after infection screening and multidisciplinary review.

Screen hepatitis B and tuberculosis as indicated, review vaccination, blood counts and immunoglobulins, and monitor infusion reactions and prolonged infection susceptibility.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Refractory seizures and brain injury

Frequent clinical or electrographic seizures can progress to status epilepticus, causing metabolic stress, aspiration and prolonged critical-care dependence.

Dysautonomia and hypoventilation

Severe receptor-mediated disease can destabilise heart rate, blood pressure, temperature and breathing, requiring continuous monitoring, airway protection or mechanical ventilation.

Persistent cognitive and psychiatric disability

Memory, executive function, mood, behaviour, communication and fatigue may recover slowly and unevenly, necessitating neuropsychology, rehabilitation and sustained family support.

Tumour or relapse risk

An associated neoplasm may progress unless identified and treated, while some antibody syndromes relapse and require surveillance or longer-term immune management.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Use continuous or repeated EEG when consciousness fluctuates, abnormal movements are ambiguous or non-convulsive status remains possible despite apparent sedation.
Chart respiratory rate, blood gases when indicated, temperature, blood pressure, rhythm, urine output and autonomic episodes; NMDAR disease may require prolonged critical-care support.
Record seizure frequency, sedative exposure, movement phenotype, communication, swallowing and structured cognitive or functional milestones to detect slow improvement.
Follow blood count, renal and liver function, immunoglobulins, glucose and infection markers according to aciclovir, antiseizure and immunotherapy protocols.
Maintain the antibody-specific tumour search and repeat surveillance schedule agreed by neurology and oncology, rather than treating one negative scan as permanent exclusion.
After discharge, assess relapse features separately from depression, trauma, fatigue, sleep disorder and residual executive impairment, with rapid re-access for objective deterioration.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Normal MRI is compatible

NMDAR encephalitis may have severe clinical dysfunction despite an unremarkable scan, making serial examination, EEG and paired antibody testing crucial.

CSF prevents false labels

Some serum neuronal antibodies are nonspecific at low titres; a compatible syndrome and CSF result markedly improve diagnostic confidence.

FBDS is a treatment clue

Faciobrachial dystonic seizures can be extremely brief and frequent, and immune treatment may prevent evolution into disabling LGI1 limbic encephalitis.

Tumour links are patterned

The relevant search is guided by antibody, age and sex; indiscriminate investigations may still miss the anatomical site most associated with that syndrome.

Behaviour is neurology

Agitation, psychosis or catatonia can be the leading expression of receptor dysfunction and should be co-managed with psychiatry without surrendering medical ownership.

Recovery needs patience

A patient may show little early change yet later make substantial gains over months; objective trends and complication prevention are more reliable than a single bedside impression.

11Common pitfallsFrequent interpretation and management errors.

01
Attributing new psychosis to a primary psychiatric disorder despite seizures, dyskinesia, catatonia or autonomic instability.
02
Stopping aciclovir after one very early negative HSV PCR when the infectious phenotype remains convincing.
03
Diagnosing autoimmune encephalitis from an isolated low-positive serum antibody with no compatible syndrome or CSF support.
04
Waiting for the complete antibody panel while status epilepticus, hypoventilation or cognitive decline continues untreated.
05
Failing to search for and treat a phenotype-linked tumour as part of immune control.
06
Assuming abnormal movements are all seizures, or conversely that unusual motor activity cannot conceal electrographic status.