Elsevier

The Lancet Neurology

Volume 10, Issue 1, January 2011, Pages 63-74
The Lancet Neurology

Review
Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis

https://doi.org/10.1016/S1474-4422(10)70253-2Get rights and content

Summary

Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. The disorder predominantly affects children and young adults, occurs with or without tumour association, and responds to treatment but can relapse. The presence of a tumour (usually an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older than 18 years, and slightly more predominant in black women than it is in white women. Patients treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) respond faster to treatment and less frequently need second-line immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who receive similar initial immunotherapy. More than 75% of all patients have substantial recovery that occurs in inverse order of symptom development and is associated with a decline of antibody titres. Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation. On the basis of models of pharmacological or genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.

Introduction

In 2005, a syndrome of memory deficits, psychiatric symptoms, decreased consciousness, and hypoventilation was reported in four young women with ovarian teratomas.1 Specific autoantibodies to the N-methyl D-aspartate receptor (NMDAR) were soon detected in these and eight other patients with similar neurological symptoms, seven of whom also had ovarian teratomas.2 During the following 3 years we identified 419 other patients with this syndrome, many of them children and young adults with or without an associated tumour. The discovery of this disorder, termed anti-NMDAR encephalitis, has changed the diagnostic approach to clinical problems as diverse as catatonia, subacute memory disturbance, seizures, abnormal movements, and limbic encephalitis.3 It has also led to the discovery of other autoimmune synaptic encephalitides mediated by antibodies against the AMPA receptor (AMPAR);4 the γ-amino-butyric acid-B receptor (GABAB-R);5 and leucine-rich, glioma-inactivated 1 (LGI1), which is the main autoantigen of limbic encephalitis previously attributed to voltage-gated potassium channels.6 In addition to their clinical significance, these immune responses provide insights into the function of the neurotransmitter receptor targeted by the antibodies.7

In this Review we present our clinical experience in the diagnosis and management of hundreds of patients with anti-NMDAR encephalitis and also discuss reports from other investigators. We address the clinical presentation, differential diagnosis, frequency of tumour association, the cellular and synaptic mechanisms of the disease, and the process of recovery. We also discuss several confounding factors that often delay the recognition of this disorder, and propose an algorithmic strategy to guide treatment.

Section snippets

Frequency

The exact incidence of anti-NMDAR encephalitis is unknown, but on the basis of the rapid accrual of patients and increasing number of case reports, it seems to be more frequent than any other known paraneoplastic encephalitis. Evidence from intensive care,9, 10, 11 paediatric,12, 13 and neurology departments8 lend support to this idea. In one retrospective analysis of encephalitis of unknown origin,10 NMDAR antibodies were identified in 1% of patients (aged between 18 and 35 years) admitted to

The syndrome

Antibodies against the NR1 subunit of the NMDAR (NMDAR antibodies) are associated with a characteristic syndrome that develops in several stages of illness and recovery, as first reported by Iizuka and colleagues17 and Sansing and colleagues.18 About 70% of patients have prodomal symptoms consisting of headache, fever, nausea, vomiting, diarrhoea, or upper respiratory-tract symptoms. Within a few days, usually less than 2 weeks, patients develop psychiatric symptoms and many are seen initially

Diagnostic tests

Brain MRI is unremarkable in 50% of patients, and in the other 50%, T2 or FLAIR signal hyperintensity might be seen in the hippocampi, cerebellar or cerebral cortex, frontobasal and insular regions, basal ganglia, brainstem, and, infrequently, the spinal cord.2 The findings are usually mild or transient and can be accompanied by subtle contrast enhancement in the affected areas or the meninges.8 Follow-up MRIs either remain normal or show minimum change despite the severity and duration of

Sex, tumour association, and potential triggers of the immune response

About 80% of patients with anti-NMDAR encephalitis are women. The detection of an underlying tumour is dependent of age, sex, and ethnic background.8, 12 Figure 2 shows the distribution of 400 patients grouped by age and the presence or absence of a tumour. When compared with a previous series,8 these data show that, with increased awareness of this disorder, the disease is being more frequently recognised in younger teenagers and children. Analysis of these 400 patients confirms that the

Treatment, outcome, and relapses

About 75% of patients with NMDAR antibodies recover or have mild sequelae; all other patients remain severely disabled or die.8 Management of anti-NMDAR encephalitis should initially focus on immunotherapy and the detection and removal of a teratoma. Most patients receive corticosteroids, intravenous immuno-globulins (IVIg) or plasma exchange as first-line of immunotherapy. These treatments have enhanced effectiveness and speed of action when patients have an underlying tumour that is removed.8

The process of recovery

Recovery from anti-NMDAR encephalitis occurs as a multistage process that happens in the reverse order of symptom presentation. Patients slowly wake from coma as their autonomic functions stabilise, respiration recovers, and dyskinesias subside; they are able to follow simple commands and can have appropriate interactions before they recover verbal functions. During this period patients can become psychotic and agitated again, calming as they recover further (JD, unpublished observations).

Anti-NMDAR encephalitis during pregnancy

Three patients were diagnosed with anti-NMDAR encephalitis while pregnant, and two of them had ovarian teratomas.54 The pregnancy was terminated in one patient who had recurrent bilateral ovarian teratomas. The two other patients carried the pregnancy to term and delivered healthy babies. One baby was thoroughly tested for antibodies in serum, cord blood, and CSF, and was shown to be negative; at diagnosis the mother had antibodies detectable only in CSF, which probably explained the absence of

Milder or incomplete forms of the disorder (formes frustes)

Milder or incomplete forms of the disorder in which patients develop predominant or apparently isolated psychiatric symptoms, seizures,55 or dystonia56 can occur. Some of these forms represent a referral bias—eg, 5 of 6 patients with new onset epilepsy55 also had other neurological or psychiatric symptoms. In our experience, pure monosymptomatic syndromes are uncommon and arise in less than 5% of patients.8 The most common scenario is that of patients with a predominant symptom and milder

Mortality and causes of death

On the basis of data for 360 patients with clinical follow-up longer than 6 months, the estimated mortality for anti-NMDAR encephalitis is 4% (15 patients died; seven of them previously reported8). The median time from disease onset until death was 3·5 months (ranging from 1 to 8 months). 14 patients died in intensive care units: three died of sepsis, two of sudden cardiac arrest, two of acute respiratory distress (one associated with renal failure, and one with atrial fibrillation and

Differential diagnosis

The constellation of symptoms in anti-NMDAR encephalitis results in a characteristic syndrome that can suggest alternative diagnoses at different stages. Patients, particularly adults, are often diagnosed with new onset psychosis. Many patients are treated with antipsychotic medication, such as haloperidol, and then when they develop rigidity, autonomic instability, increased concentrations of muscle enzymes, or rhadomyolysis are thought to have neuroleptic malignant syndrome.18 However, these

Pathogenic mechanisms and effects of antibodies

Compelling clinical and laboratory evidence exists that anti-NMDAR antibodies are pathogenic. As previously discussed, antibody titres in CSF and, less often, in serum relate with clinical outcome. Furthermore, the reversibility of the disorder, irrespective of the duration of symptoms, suggests an immune-mediated neuronal dysfunction rather than irreversible degeneration. These features, coupled with the paucity of brain T-cell infiltrates, places this disorder in a category distinct from

Patients phenotype resembles those of genetic or pharmacological disruption of NMDAR

Studies investigating the effects of phencyclidine and ketamine (non-competitive antagonists of NMDARs) in human beings show that these drugs induce behaviours that are much the same as the positive and negative symptoms of schizophrenia, along with repetitive orofacial and limb movements, autonomic instability, and seizures.25, 72, 73, 74, 75 In rodents, drugs that antagonise NMDAR function induce cataleptic freeze and locomotor and stereotypical behaviours.76, 77, 78, 79 Mice with decreased

Approach to diagnosis and proposal of a treatment strategy

Anti-NMDAR encephalitis should be suspected in any individual, usually younger than 50 years and especially a child or a teenager, who develops a rapid change of behaviour or psychosis, abnormal postures or movements (mostly orofacial and limb dyskinesias), seizures, and variable signs of autonomic instability, hypoventilation, or both. Supportive findings include CSF lymphocytic pleocytosis or oligoclonal bands; electroencephalogram with infrequent spikes, but frequent, slow, disorganised,

Future studies

In this Review we have shown that anti-NMDAR encephalitis defines a new syndrome, reclassifies poorly defined disorders, and strengthens previous hypotheses, such as hypofunction of NMDAR in schizophrenia. Future studies should clarify the mechanism and timing of how the immune response is expanded in the CNS, the best treatment approach, and strategies to accelerate the process of recovery. The frequency of the disorder suggests that multicenter clinical trials are feasible. The idea that

Search strategy and selection criteria

References for this Review were identified by searches of PubMed from 1966 to October, 2010, with the search terms “NMDA receptor encephalitis”, “anti-NMDAR encephalitis”, and “N-methyl-D-aspartate receptor encephalitis”. Articles were also identified through searches of the authors' own files. Papers published in English, German, and Spanish were reviewed. Data from 400 patients were obtained from clinical examination (72 cases seen by JD) and information provided by patients, their families,

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