A 21-year-old Indigenous woman was admitted to hospital with an acute change in mental state over the preceding 24 hours. She had become agitated, was pressured in speech and singing constantly. In the weeks before presentation, family members had noted increasingly disorganised behaviour and altered sleep patterns.

The patient’s family history included schizophrenia in a second-degree relative. The patient had used marijuana at least weekly for several years, but had no history of alcohol misuse. She had completed tertiary studies in the previous 18 months.

On psychiatric evaluation, the patient was markedly manic, with pressure of speech, elevation of mood, disinhibited behaviour, insomnia and constant loud singing. She showed delusions of special powers, such as the ability to predict the future. There were no features of delirium at this time.

A provisional diagnosis of psychotic mania was made, and treatment commenced with olanzapine and sodium valproate. Olanzapine was titrated to 10 mg twice daily and sodium valproate to 1 g twice daily over several days. Persistent profound disinhibition was partly alleviated with low doses of chlorpromazine. Intramuscular midazolam was used in the early stages for agitation but later withdrawn. A low-grade fever was noted, and treatment was begun for a microbiologically proven urinary tract infection.

Ten days after admission, a 2-minute generalised tonic–clonic seizure was witnessed. This was thought most likely to be a consequence of withdrawal of midazolam and concurrent urinary tract infection. A computed tomography (CT) scan of the brain appeared normal. An electroencephalogram (EEG) was not performed because of the patient’s inability to comply with the procedure. Over the subsequent 2 weeks, she was noted to have features of delirium with agitation. A further seizure was witnessed on Day 28 of admission, with subsequent fluctuation between delirium with aggressive outbursts and signs consistent with catatonic stupor, including waxy flexibility, posturing, staring, mutism and stereotyped behaviour. The patient lost considerable weight.

Magnetic resonance imaging (MRI) of the brain revealed two small foci of T2 hyperintensity in the right frontal lobe of uncertain significance. Cerebrospinal fluid (CSF) protein and glucose levels were within reference ranges, as were CSF cell counts. CSF culture showed no growth, and polymerase chain reaction tests of CSF for herpes simplex virus were negative. Oligoclonal bands were detected in both CSF and serum. The full blood count showed macrocytosis. Serum levels of vitamin B12, folate and thyroid antibodies, results of thyroid function tests and biochemical parameters were within reference limits, and the autoimmune profile was normal (including antinuclear, extractable nuclear antigen, antineutrophil cytoplasmic, double-stranded DNA, lupus anticoagulant and cardiolipin antibodies, and complement levels). Serological tests gave negative results for syphilis, HIV and hepatitis.

On Day 44 of admission, the patient developed a low-grade fever, increased rigidity and an elevated serum level of creatine kinase (1459 U/L; reference range, 0–175 U/L), suggestive of neuroleptic malignant syndrome. Olanzapine was withdrawn, and a course of electroconvulsive therapy (ECT) commenced. After the first and only ECT treatment, fever recurred and the patient continued to display features of catatonic stupor. Four days later, she had a right-sided focal motor seizure with secondary generalisation. Endotracheal intubation and artificial ventilation were required for safe management; brain imaging repeated at this time was unchanged.

An EEG showed diffuse 3 Hz delta slowing, indicative of diffuse cerebral dysfunction. Anti-epileptic therapy was escalated over several days, with the addition of levetiracetam (1500 mg twice daily), topiramate (50 mg twice daily) and phenobarbitone (30 mg three times daily). On Day 45, paroxysms of rigidity with arching of the back associated with orobuccal stereotypies and rapid eye movements were noted. Fever persisted and continuous buccolingual dyskinesia evolved, with “rabbit-like” movements of the lips and nose and involuntary stereotyped repetitive rolling movements of the tongue. The abnormal movements did not occur, or appear consistent, with seizure activity.

Over the next 5 days, the clinical picture alternated between rigidity, with buccolingual dyskinesia and posturing, and periods of profound agitation, when the patient would scream uncontrollably and climb out of bed. Two further generalised tonic–clonic seizures occurred, and the score on the Glasgow Coma Scale fluctuated between 4 and 6.

Infectious or autoimmune encephalitis had been considered as possible diagnoses, along with non-convulsive status epilepticus and inherited or acquired metabolic disorders. Paraneoplastic immune-mediated encephalitis was postulated and, while serum and CSF samples were sent for analysis, empirical treatment with intravenous immunoglobulin was commenced on Day 53 of admission. An intravenous dose of immunoglobulin 0.4 g/kg daily was given for 5 days. It was chosen as the first-line immunotherapy to avoid the possible psychiatric side effects of high-dose corticosteroids confusing the clinical response. Blood samples were analysed for antibodies, including anti-Hu, anti-Yo, anti-Ri, anti-CV2, anti-Ma and amphiphysin, all of which were negative.

The search for an underlying malignancy ensued, particularly ovarian teratoma because of its association with anti-N-methyl-d-aspartate (NMDA)-receptor encephalitis. No malignancy was found despite extensive investigations, including CT, transabdominal and transvaginal ultrasonic scanning, MRI of the pelvis and whole-body fluorodeoxyglucose positron emission tomography.

Despite modest improvements after the initiation of intravenous immunoglobulin, the patient’s condition further deteriorated, and a trial of intravenous methylprednisolone 1 g daily for 5 days was given. Over the following 2 weeks, the patient’s body was less rigid, she began using single words to express needs and was able to follow simple commands. However, her behaviour remained markedly abnormal, with singing and mumbling to herself and persistent buccolingual dyskinesia.

During this period of modest improvement, the results of paraneoplastic antibody testing confirmed the presence of antibodies to NMDA NR1–NR2 receptors in both serum and CSF. (This testing was performed by J D at the University of Pennsylvania, Philadelphia.) Given the limited response to intravenous immunoglobulin and methylprednisolone, plasmapheresis was commenced but failed to have a significant effect on recovery. The patient remained significantly disabled after 9 weeks of immunotherapy, including a repeat pulse of 5 days of intravenous methylprednisolone given 6 weeks after the first dose. In view of the known strong association of anti-NMDA-receptor encephalitis with ovarian teratoma, and evidence that tumour removal expedites recovery, the possibility of oophorectomy was discussed in detail by members of the neurology, psychiatry, intensive care and gynaecology teams, together with the patient’s legal guardian. Although investigations did not yield evidence of a tumour, the strong association coupled with the possibility of microscopic disease led to the decision to perform a laparotomy and bilateral oophorectomy on Day 120 of admission. No ovarian tumour was identified microscopically. There was no evidence of mediastinal teratoma on imaging.

Immunomodulation was maintained with the introduction of rituximab. These interventions were accompanied by rapid improvements in the patient’s rigidity and buccolingual dyskinesia. Given concurrent management with surgery and immunotherapy, it is not possible to determine the relative effect of each intervention on the patient’s recovery. The patient’s behaviour and communication improved gradually over a period of 9 months, and neuropsychological testing 14 months after her initial presentation showed her cognitive performance to be in the high–average range across domains.

Anti-NMDA-receptor encephalitis is an immune-mediated encephalitis that predominantly affects young women and has a strong association with underlying ovarian teratoma. It usually presents in the second to fifth decade of life,1 with a median age of onset of 23 years.2 Cases occurring in children and male patients have been identified.2-5 The incidence is unknown. Before the detailed description of four cases in 2005, only five cases had been reported in the English literature.6 A hundred cases have now been clinically characterised, suggesting that this disorder has been under-recognised in the past.2

The clinical syndrome (Box) begins with a prodromal illness of fever, headache or viral-like symptoms,3 followed by an acute- to subacute-onset psychiatric illness.1 Our patient presented with all the criteria, as listed by the Diagnostic and statistical manual of mental disorders, fourth edition, of a manic phase of bipolar illness,7 illustrating how difficult it may be to diagnose this illness at presentation. Short-term memory loss or seizures, alone or in combination with psychiatric manifestations, occur less commonly.2 The psychiatric presentation is typically followed by seizures. A state of unresponsiveness evolves with the patient appearing mute and akinetic. Akinesia may alternate with agitation.2 Autonomic instability is common at this stage,1 and mechanical ventilation is often required.2,3 Hyperkinetic movement disorder is characteristic, specifically orobuccal dyskinesia,2 as seen in our patient.

About 60% of patients have an underlying tumour, usually a cystic ovarian teratoma.2,3 The teratoma can be benign or malignant. The neurological syndrome precedes the diagnosis of tumour in most cases.1,2 CSF lymphocytic pleocytosis is characteristic,1,2 with elevated CSF protein levels and oligoclonal bands seen in some cases. MRI findings often lack changes localised to the mesial temporal lobes as seen in other forms of paraneoplastic limbic encephalitis. Small punctate T2 hyperintensities in the frontal and parietal cortex, meningeal enhancement or a normal appearance on imaging have all been reported. Only 55% of patients in the recent case series had MRI abnormalities in one or several brain regions.2 An EEG classically shows diffuse delta activity. Investigations for viral, bacteriological and fungal pathogens, and for systemic autoimmunity, thyroid autoimmunity and classic antineuronal antibodies are negative.

All cases show antibodies to the NMDA receptor.1 This receptor is made up of a heteromer containing two of each of the NR1 and NR2 subunits. The main epitope targeted by antibodies is the extracellular domain of the NR1 subunit.2 Antibodies reduce the number of cell surface NMDA receptors in cell cultures, and this effect can be reversed by antibody removal.2 In the clinical context, improvement is associated with a decrease in serum antibody levels.2

Recommended management is removal of the tumour and aggressive immunotherapy. Options include corticosteroids, plasma exchange, intravenous immunoglobulin, rituximab, cyclophosphamide and azathioprine. If one type of immunotherapy is ineffective, the condition may respond to another type. Tumour removal expedites recovery and reduces relapses.2,3,8,9 The relative effect of tumour removal versus immunotherapy is difficult to discern as these interventions are usually carried out simultaneously.

Recovery is typically slow and may take many months. In the case series of 100 patients, 75% recovered or had mild deficits, the most common being signs of frontal lobe dysfunction and sleep disturbance.2 A characteristic feature of patients who recover from anti-NMDA-receptor encephalitis is persisting amnesia for the entire period of illness.2 Interestingly, detection of an ovarian teratoma is a good prognostic factor as the tumour is most often curable. Relapse is more common in patients with undetected or recurrent tumour.2

Anti-NMDA-receptor encephalitis is a severe, potentially lethal but treatment-responsive encephalitis, often associated with benign tumour. It provides an autoimmune model of movement, psychiatric and cognitive disorders. Practitioners across the disciplines need to be aware of this recently recognised entity to ensure effective treatment and favourable outcomes.