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 by psychiatrists. Anxiety, insomnia, fear, grandiose delusions, hyper-religiosity, mania, and paranoia are frequent manifestations; social withdrawal and stereotypical behaviour are sometimes seen. Short-term memory loss is common but underestimated because psychiatric symptoms and speech problems often interfere with the assessment of memory.8
A rapid disintegration of language, from reduction of verbal output and echolalia (usually with echopraxia) to frank mutism, is frequent and cannot be attributed to cortical aphasia.
In young children, the behavioural change can be difficult to detect because they often present with temper tantrums, hyperactivity, or irritability as opposed to frank psychosis. In children, the first symptom to be recognised is often non-psychiatric—eg, seizures, status epilepticus, dystonia, verbal reduction, or mutism. Some behaviours are hypersexual and violent (for instance, kicking and biting caregivers and parents). Because of anxiety and insomnia, some children need intense sedation.12
This initial phase of the illness is usually followed by decreased responsiveness that can alternate between periods of agitation and catatonia. At this stage, abnormal movements and autonomic instability are usual manifestations. Oro-lingual-facial dyskinesias are the most characteristic movements, but other types might occur simultaneously or alternate with limb and trunk choreoathetosis, elaborate motions of arms and legs, oculogyric crisis, dystonia, rigidity, and opisthotonic postures (see video recordings19–23
). The most frequent autonomic manifestations include hyperthermia, tachycardia, hypersalivation, hypertension, bradycardia, hypotension, urinary incontinence, and erectile dysfunction.8
Two women (aged 16 and 17 years) were thought to have Takotsubo cardiomyopathy (or stress cardiomyopathy) due to high blood pressure (JD, unpublished). Hypoventilation, requiring respiratory support, occurs as the patient becomes comatose but can occur earlier when the level of consciousness is relatively preserved. In some cases the central origin of hypoventilation is noted when patients cannot be weaned from mechanical ventilation. While recovering, one patient needed nocturnal ventilatory support for 3 months. Autonomic storms can fluctuate from tachycardia to bradycardia and longlasting cardiac pauses, which, in some patients, require a temporary pacemaker.18
A transient increase of intracranial pressure has been recorded in a few patients (JD, personal observation).
Motor or complex seizures develop at early stages of the disease. The overlap of abnormal movements and epileptic seizures can lead to under-recognition of the seizures or unnecessary escalation of antiepiletics for dyskinesias that are interpreted as seizures.24
In general, the frequency and intensity of the seizures decrease as the disease evolves. However, seizures and status epilepticus can resurface at any time during the illness. Attempts to wean patients from sedation can result in status epilepticus.2
During such stages, in which patients are usually managed in intensive care units, dissociative responses to stimuli are noted. For example, patients often resist eye opening but show little or no response to painful stimuli.17
This dissociative state is similar to that caused by NMDAR antagonists, such as phencyclidine or ketamine, which are called dissociative anesthetics.25,26
Oversimplification of the disease into cortical and subcortical stages and the suggestion that patients without a tumour have a less impaired level of consciousness than do patients with a tumour27
is (in our experience) highly inaccurate. Many symptoms with which a patient presents (such as anxiety, fear, bizarre or stereotypical behaviour, insomnia, and memory deficits) cannot be classified as cortical. Clinical examination of patients reveals a diffuse encephalopathy indicating dysfunction of subcortical structures, limbic regions, amygdalae, and frontostriatal circuitry. Patients without tumours have periods of unconsciousness and confusion that can be longer or worse than are those of patients with tumours.8,12,28