Anti-NMDA receptor encephalitis

What it is

Anti-NMDA receptor encephalitis is an antibody-mediated brain disease in which the immune system makes IgG antibodies against the GluN1 subunit of the NMDA receptor. The antibodies cross-link and internalise NMDA receptors at the synapse, producing a reversible hypofunction of NMDA-mediated transmission. This neurobiological substrate explains the striking psychiatric, motor and autonomic features — broadly similar to ketamine-induced symptoms — and crucially explains why the disease is reversible if the antibody-producing B and plasma cells are removed and the NMDA receptors can be re-expressed.

The condition was first described by Josep Dalmau and colleagues in 2007 in young women with ovarian teratoma; subsequent recognition has extended the picture to all ages, both sexes, and increasingly to post-infectious presentations.

How it presents

The clinical course is characteristic enough that, once seen, it is recognisable in subsequent cases:

• Prodromal flu-like illness — fever, headache, malaise — in days to weeks before symptoms (about 70%)
• Behavioural and psychiatric — sudden personality change, agitation, insomnia, paranoia, hallucinations. Often misdiagnosed as primary psychiatric illness, especially in adolescents
• Seizures — focal or generalised; can be the presenting feature in younger children
• Movement disorder — orofacial dyskinesias (lip-smacking, chewing, tongue protrusion), choreoathetosis, dystonia. Especially prominent in children
• Reduced consciousness — progresses from somnolence to mutism to a 'catatonic-like' state
• Autonomic instability — fluctuating blood pressure, tachycardia, hyperthermia, urinary retention, central hypoventilation requiring ventilation
• Speech regression — often the earliest symptom in young children (sudden mutism after a prodromal illness)

Diagnosis

The diagnostic gold standard is detection of IgG anti-NMDA receptor antibodies in cerebrospinal fluid (more specific than serum, which can be falsely positive or negative). The Graus et al. (2016) consensus criteria allow a clinical diagnosis on the basis of the typical syndrome plus exclusion of alternatives, with antibody confirmation moving the diagnosis to 'definite'.

Supportive investigations: CSF often shows mild lymphocytic pleocytosis and oligoclonal bands; EEG may show 'extreme delta brush' — a highly characteristic pattern of high-amplitude beta superimposed on slow delta activity; MRI is often normal or shows non-specific abnormalities in mesial temporal lobes or basal ganglia.

Once the diagnosis is made, search for an underlying tumour: pelvic and abdominal ultrasound / MRI in girls and women for ovarian teratoma; whole-body PET/CT in adults; testicular ultrasound in young men; less often whole-body imaging in younger children.

Treatment

Treatment has three goals: remove any underlying tumour, suppress the antibody-producing immune cells, and support the patient through the often prolonged recovery. Aggressive early treatment correlates strongly with good outcome.

• First-line — IV methylprednisolone 30 mg/kg/day for 5 days + IVIG 0.4 g/kg/day for 5 days + plasma exchange (5–7 sessions) — typically used in combination rather than sequentially in severe disease
• Tumour resection where present — this is itself disease-modifying
• Second-line — when first-line therapy fails or relapse occurs: rituximab (375 mg/m² weekly × 4 or 1000 mg × 2) plus cyclophosphamide (750 mg/m² IV monthly). The 2013 Titulaer cohort and the 2018 GENERATE network analyses both confirmed substantially better outcomes with early second-line treatment when first-line fails
• Maintenance — long-term immunosuppression with rituximab every 6 months and/or mycophenolate mofetil for the first 1–2 years to prevent relapse, particularly in tumour-negative cases
• Symptomatic — atypical antipsychotics for psychiatric symptoms (with care as NMDA-antagonism overlap can worsen movements); benzodiazepines for catatonia and agitation; antiseizure medicines; ITU support for autonomic instability and central hypoventilation
• Rehabilitation — speech and language therapy, occupational therapy, physiotherapy and neuropsychological support over many months

Recovery

Recovery occurs in roughly the reverse order of symptom onset: first the autonomic instability and consciousness, then the movement disorder and seizures, then the psychiatric features and finally cognition and personality. It is typically slow — 6–24 months for major recovery, with some residual cognitive and fatigue symptoms in many. Children generally recover better than adults.

Relapse occurs in 12–25%, more common in tumour-negative cases. Long-term immunosuppression reduces relapse risk.

Prognosis

With prompt diagnosis and aggressive treatment, around 75–85% of children achieve a good functional outcome (modified Rankin Scale 0–2). Mortality is around 5%. The strongest predictors of good outcome are early treatment, removal of any underlying tumour, and use of second-line immunotherapy when first-line fails.

How an educational review can help

Families navigating anti-NMDA receptor encephalitis often face a long ITU stay, multiple immunotherapies, slow rehabilitation, and the difficult question of how long maintenance treatment should continue. An educational review can pull together where the evidence stands today, place the trajectory against published cohorts, and help prepare focused questions for the treating team — particularly around second-line therapy, tumour screening and rehabilitation planning.

It is an educational second opinion — not a diagnosis, treatment or prescription — and it does not replace the care of your child's own clinicians.