Overview
Definition:
Autoimmune encephalitis (AE) is a group of inflammatory brain disorders characterized by inflammation of the brain parenchyma, often triggered by autoantibodies against neuronal surface antigens
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common form of autoimmune encephalitis, frequently affecting young adults and children, and characterized by a distinct clinical syndrome involving neuropsychiatric and neurological symptoms.
Epidemiology:
Anti-NMDA receptor encephalitis accounts for approximately 4% of first-episode psychoses
It can occur at any age but has a bimodal age distribution, with a peak in adolescents and young adults (15-30 years) and a smaller peak in older adults
It is more common in females, particularly in the younger age group, often associated with ovarian teratomas
The incidence is estimated to be around 1.0 per 100,000 person-years.
Clinical Significance:
This condition is crucial for pediatric residents and DNB/NEET SS aspirants to recognize due to its potentially devastating neurological and psychiatric consequences
Early diagnosis and prompt immunosuppressive treatment can significantly improve outcomes, preventing severe disability or death
The complex presentation can mimic primary psychiatric disorders, leading to delayed diagnosis and management.
Clinical Presentation
Symptoms:
Prodromal phase with flu-like symptoms or viral illness lasting about two weeks
Psychiatric symptoms: delusion, hallucinations, paranoia, confusion, agitation, anxiety, depression, insomnia
Seizures: focal or generalized, often refractory to standard antiepileptic drugs
Movement disorders: dyskinesias, choreoathetosis, stereotypies, parkinsonism
Autonomic dysfunction: tachycardia, hypertension, hypothermia, urinary retention
Language dysfunction: mutism, echolalia, neologisms
Cognitive decline: memory impairment, disorientation.
Signs:
Fever may be present in the prodromal phase
Neurological examination may reveal signs of psychosis or catatonia
Seizures are common
Movement disorders such as choreoathetoid movements, dystonia, or parkinsonism are characteristic
Cerebellar ataxia and cranial nerve palsies can occur
Autonomic instability is frequent, with fluctuations in heart rate, blood pressure, and temperature
Altered consciousness ranging from confusion to coma.
Diagnostic Criteria:
No universally agreed-upon diagnostic criteria exist, but a combination of clinical presentation, CSF analysis, and serological testing is used
Key elements include a subacute onset of neurological and psychiatric symptoms, exclusion of other causes of encephalitis, detection of anti-NMDA receptor antibodies in serum or CSF, and characteristic MRI findings or EEG abnormalities
The presence of anti-NMDA antibodies along with a compatible clinical syndrome is highly suggestive.
Diagnostic Approach
History Taking:
Detailed history of recent illness, including any preceding infections
Thorough psychiatric history focusing on new-onset behavioral changes, delusions, hallucinations, or mood disturbances
Detailed seizure history, including type, frequency, and response to medications
Family history of autoimmune diseases or psychiatric disorders
For adolescent females, inquiry about menstrual irregularities or history suggestive of ovarian teratoma.
Physical Examination:
Comprehensive neurological examination to assess for seizures, movement disorders, cranial nerve deficits, and signs of autonomic instability
Psychiatric evaluation to assess for psychosis, mood disorders, and cognitive impairment
Full systemic examination to rule out other causes of illness and identify any potential associated conditions.
Investigations:
Cerebrospinal fluid (CSF) analysis: typically shows pleocytosis (lymphocytic predominance) and elevated protein levels, with the presence of oligoclonal bands in some cases
Anti-NMDA receptor antibodies in CSF and serum (using indirect immunofluorescence or cell-based assays) are the hallmark
Electroencephalogram (EEG): often shows diffuse slowing, epileptiform discharges, or a characteristic extreme delta brush pattern in some cases
Magnetic Resonance Imaging (MRI) brain: may show T2-weighted hyperintensities in the medial temporal lobes, basal ganglia, thalamus, brainstem, and cerebellum, although it can be normal in the early stages
Tumor screening: in adolescent and adult females, pelvic ultrasound and CT/MRI of the thorax, abdomen, and pelvis to rule out ovarian teratoma or other tumors
in males, similar screening for testicular tumors.
Differential Diagnosis:
Other forms of autoimmune encephalitis (e.g., anti-LGI1, anti-CASPR2, anti-GABAAR encephalitis)
Viral encephalitis (e.g., HSV, enterovirus)
Paraneoplastic syndromes
Primary psychiatric disorders (e.g., schizophrenia, bipolar disorder)
Metabolic encephalopathies
Drug-induced encephalopathy
Infectious meningoencephalitis.
Management
Initial Management:
Prompt initiation of immunotherapy is crucial
Supportive care includes airway management, mechanical ventilation if needed, seizure control with antiepileptic drugs (e.g., levetiracetam, valproate, lacosamide), and management of autonomic instability
Fluid and electrolyte balance must be carefully monitored.
Medical Management:
First-line immunotherapy: Intravenous immunoglobulin (IVIg) 2g/kg over 5 days, or plasma exchange (PLEX) to remove autoantibodies
Second-line therapy: Corticosteroids (e.g., methylprednisolone 1g/day IV for 3-5 days followed by oral prednisone) if IVIg or PLEX is insufficient or not available
Rituximab (e.g., 1000 mg IV every 2 weeks for two doses) or cyclophosphamide are used as third-line agents for refractory cases
Treatment of seizures with appropriate AEDs is essential
refractory epilepsy may require ketogenic diet or further immunosuppression.
Surgical Management:
Surgical removal of a teratoma or other associated tumor, particularly in cases of ovarian teratoma, is a critical component of management if identified
This can lead to significant clinical improvement
Oophorectomy is indicated if a teratoma is confirmed.
Supportive Care:
Intensive care unit (ICU) monitoring is often required for patients with severe disease, respiratory compromise, or autonomic instability
Nutritional support via nasogastric tube or gastrostomy if oral intake is compromised
Physical and occupational therapy to address movement disorders and functional deficits
Psychological support for the patient and family is essential throughout the illness and recovery phase.
Complications
Early Complications:
Status epilepticus refractory to treatment
Severe autonomic dysfunction leading to hemodynamic instability
Respiratory failure requiring mechanical ventilation
Deep vein thrombosis (DVT) and pulmonary embolism (PE) due to immobility
Hyponatremia
Increased intracranial pressure.
Late Complications:
Cognitive deficits: memory impairment, attention deficits, executive dysfunction
Psychiatric sequelae: persistent mood disorders, anxiety, or psychosis
Motor deficits: persistent dyskinesias or parkinsonism
Epilepsy: chronic seizures despite immunosuppression
Behavioral changes and social reintegration challenges
Relapse can occur, sometimes years after initial recovery.
Prevention Strategies:
Early recognition and prompt initiation of immunosuppressive therapy are key to preventing severe early complications
Aggressive seizure control reduces the risk of neurological damage and status epilepticus
Prophylaxis for DVT in immobilized patients
Careful monitoring of fluid and electrolytes prevents hyponatremia
Thorough tumor screening in affected individuals helps identify and remove potential triggers.
Prognosis
Factors Affecting Prognosis:
Timeliness of diagnosis and treatment initiation are paramount
Age at onset (younger children may have poorer outcomes)
Presence of teratoma (removal can improve prognosis)
Severity of initial presentation and presence of refractory status epilepticus or severe autonomic dysfunction
Response to immunotherapy
Underlying genetic predispositions.
Outcomes:
With timely and aggressive treatment, approximately 75% of patients recover, with half achieving full recovery and the other half experiencing significant residual deficits
About 10% may die from the condition
Relapses can occur in about 10-20% of patients, necessitating long-term monitoring and sometimes re-treatment
Improvement can be gradual, taking months to years.
Follow Up:
Long-term follow-up is essential, typically with neurology and psychiatry specialists
Regular clinical assessments, including neurological and psychiatric evaluations, cognitive testing, and EEG
Repeat MRI may be performed to monitor for residual changes
Continued immunotherapy may be considered for patients with relapsing disease
Education and support for patients and families regarding potential long-term challenges and relapse signs are crucial.
Key Points
Exam Focus:
Anti-NMDA receptor encephalitis is the most common form of autoimmune encephalitis
Distinctive psychiatric and neurological features
Bimodal age distribution, more in females
Association with ovarian teratomas
CSF analysis: pleocytosis, elevated protein, oligoclonal bands
Characteristic EEG finding: extreme delta brush
Treatment involves immunotherapy: IVIg, PLEX, steroids, rituximab
Tumor screening is mandatory.
Clinical Pearls:
Suspect autoimmune encephalitis in adolescents with new-onset psychosis or refractory seizures, especially with a preceding febrile illness
The presence of movement disorders and autonomic dysfunction should raise suspicion
A normal initial MRI does not exclude the diagnosis
Consider anti-NMDA antibodies in any young patient with a complex neurological and psychiatric presentation
Early aggressive immunotherapy can dramatically alter the prognosis.
Common Mistakes:
Misdiagnosing the initial presentation as a primary psychiatric disorder, delaying crucial immunotherapy
Failing to perform thorough tumor screening in affected females
Underestimating the severity of autonomic instability or seizures
Inadequate or delayed immunosuppressive treatment
Discontinuing immunotherapy too early, leading to relapse.