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Anti-NMDAR encephalitis phase, patients are often referred to psychiatric
Anti‑NMDAR encephalitis, among all the autoimmune assessment and may receive treatment with psychoactive
encephalitis, is the best‑understood variant and the agents or admission to psychiatric facilities.
most frequently associated with almost exclusively
psychiatric presentation. The illness was first described This psychotic phase can be followed by physical
as a distinct clinical entity in an observational study decompensation involving autonomic instability (less
in 2005 by Vitaliani et al. [11] in four young women common in children), with hypo‑ or hypertension,
who developed acute psychiatric symptoms, seizures, hypo‑ or hyperthermia, hypoventilation, cardiac
memory deficits, decreased level of consciousness, arrhythmia, decreased responsiveness, and occasionally
autonomic instability, and hypoventilation in short‑term memory loss. Some patients may also have
association with the presence of an ovarian teratoma. seizures, most commonly generalized tonic‑clonic, but
Two years later, a paper by this group described the also partial and/or complex type. In some patients, early
underlying pathology, mediated by auto‑antibodies treatment with antiepileptic drugs may mask seizures.
directed against the NR1 subunit of the NMDAR. [12] Dyskinesias, extrapyramidal signs, and stereotyped
These antibodies cause a decrease in the number of motor automatisms may also be observed. [38] During
NMDARs in target cells by inducing cross‑linking and this phase, patients not already admitted to the hospital
internalization of NMDARs by autophagy. Therefore, often present to the emergency department because
[32]
anti‑NMDAR encephalitis represents a state of NMDA‑R they no longer follow verbal commands and may appear
hypofunction, associated to glutamate dysregulation. [33] mute (with language disintegration) and akinetic.
Initially, it was classified as a paraneoplastic syndrome Patients may maintain gaze as if in a catatonic state,
[12]
due to the strong association (upwards of 60%) with a smile inappropriately, or demonstrate stereotyped
teratoma or other tumor types. athetosic movements. [34,39]

Although many patients have been diagnosed with Since the initial descriptions, further studies have
anti‑NMDAR encephalitis to date, the exact prevalence expanded the clinical phenotype of this syndrome.
of this disorder is unknown. A study of 100 patients Some patients with anti‑NMDAR antibodies have
revealed that although most patients are young women, predominant or isolated psychiatric features, dystonia,
the disorder can occur in men and children. [34] In fact, or epilepsy, without the classic multistage presentation,
with increasing awareness of the syndrome, the number potentially representing a forme fruste of anti‑NMDAR
of pediatric cases has steadily grown and appears to encephalitis, mimicking a psychiatric disorder. [3,40]
represent about 40% of all cases. [28] The younger the
patient, the less likely an underlying tumor will be The diagnosis of anti‑NMDAR encephalitis is confirmed
detected at the time of presentation. [34] by the detection in serum or CSF of antibodies to the
NR1 subunit of the NMDA receptor. After treatment or in
A stereotypical clinical course with different phases is advanced stages of the disease, the CSF antibodies usually
noted for patients with anti‑NMDAR encephalitis. [35] In remain elevated if there is no clinical improvement,
70% of patients, the illness begins with a prodromal whereas serum antibodies may be substantially decreased
phase lasting 5‑14 days. [3,36] This nonspecific flu‑like by treatments. The titer of CSF antibodies appears to
prodrome is characterized by subfebrile temperature, correlate more closely with the clinical outcome. Patients
fatigue, malaise, headache, nausea, diarrhea, vomiting. with anti‑NMDAR encephalitis may have abnormalities
This is followed by other clinical phases, which may of both CSF and MRI. 80% of patients with confirmed
vary in sequence, presentation and severity. anti‑NMDAR encephalitis have abnormal CSF with the
majority of them exhibiting a lymphocytic pleocytosis,
After the initial phase, psychiatric manifestations go but over a half also show raised proteins. There may
on to develop, including emotional and behavioral also be the presence of isolated oligoclonal bands in the
disturbances such as apathy, anxiety, panic attacks, CSF of patients with autoimmune encephalitis (around
fear, depression, decreased cognitive skills, sleep 60%). In contrast to the consistency of the clinical
[3]
disorders. In most cases, an excited manic or mixed picture, MRI findings are less predictable; only 55%
manic symptomatology develops in a variable of patients had increased fluid‑attenuated inversion
lapse of time, from hours to days; mood disorders recovery (FLAIR) or T2 signal in one or several brain
and agitation are almost invariably associated with regions, without significant correlation with patients’
psychotic features such as grandiose delusions, Capgras symptoms. MRI can be normal or demonstrate medial
syndrome, paranoid interpretation, and different types temporal involvement or focal areas of hyperintensity in
of hallucinations. From mild to moderate cognitive the frontal or parietal cortex. Other studies demonstrated
disorders are frequently presented. [18,37] During this that [18F]‑fluorodeoxyglucose positron emission

230 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015