In this present case, it was clear that we were not facing a common psychiatric condition. A diagnosis of an organic psychiatric disorder was considered because of the presence of atypical psychiatric symptoms such as visual hallucination and also by the uncommon sequence and mixture of psychiatric and neurologic symptoms. A diagnosis of anti-NMDA receptor encephalitis was hypothesized because of the following course of the illness: 1 week before symptoms onset the patient experienced common cold-like symptoms; day 1 of symptoms onset, she experienced incoherent speech, restlessness and expressed the feeling that “something was happening”; day 2, she presented with visual hallucinations and agitation; day 3, she was agitated, had speech blockade, had difficulty swallowing and refused to eat; day 5, she displayed panic attack; day 8, she experienced psychomotor retardation, speech changes, and regressive posture; day 10, she displayed agitation, tremor in her upper limbs, mood elation, and persecutory and grandiose delusions; day 18, she had episodes of negativism, mutism, tremor, echopraxia, prostration, and neglected her hygiene. At that moment she was admitted into a psychiatry ward. Blood workup and brain CT scan were normal. At day 23 of the disease (5 days after her admission in the psychiatry ward), a lumbar puncture was performed to test for auto-antibodies against NMDA receptors, and owing to decreased consciousness and catatonia she was admitted to an ICU. This clinical picture is consistent with the several cases of anti-NMDA receptor encephalitis that have been reported in literature [10, 15–21]. Anti-NMDA receptor encephalitis is an autoimmune disease that was first identified as a paraneoplastic syndrome in young women with ovarian teratomas, and can also occur as a rare manifestation of teratoma of the mediastinum, or due to testicular cancer or small-cell lung carcinoma [7, 10]; however it can also be non-paraneoplastic [3, 22]. The clinical presentation usually consists of three stages: a prodromal period that lasts up to 1 week with common cold-like symptoms, fever, headache, malaise or gastroenteritis; an intermediate period, lasting 1–3 weeks, with behavioral changes, psychiatric symptoms or mood changes. The most common clinical presentation resembles acute psychosis (anxiety, agitation, paranoia, auditory or visual hallucinations) [7, 23], meaning that psychiatrists are usually the first physicians to observe these patients. The third stage can last from weeks to months, and consist of neurological and autonomic symptoms, including alteration in speech, catatonia, and seizures. The common autonomic symptoms include urinary incontinence or sleep dysfunction. The more severe autonomic symptoms, such as hypoventilation, dysrhythmia, tachycardia, and hyperthermia, are not frequent in children . It has been shown that this condition is more frequent in children than was previously thought and that its clinical manifestations in the pediatric population are similar to those of adults .
The exact pathophysiology of anti-NMDA receptor encephalitis is not fully understood. It is believed that NR1 subunits expressed by tumoral neural tissues may break the immune tolerance . However, anti-NMDA receptor encephalitis is not always related to teratoma or other malignancies, and hence, other immunologic mechanisms might be involved. Hypotheses thus far proposed include the concept that there is an immunological response to a flu-like prodromal phase possibly related to a viral infection, and genetic susceptibility . It is well known that NMDA plays an important role in the mechanism of psychosis, which is supported by association studies on hypofunction of glutamate and psychosis symptoms . Also, immunoglobulin against NR1 can induce a reversible hypofunction of the glutamate receptors by triggering internalization of the receptors . In our patient, the underlying etiology was unknown, but we cannot rule out a possible viral mechanism, since she had a short period of common cold-like symptoms before symptoms onset, and no tumor was detected.
Regarding the diagnosis, brain imaging is not helpful because there are no specific imaging biomarkers associated with this syndrome, though most patients may show minor nonspecific abnormalities during brain imaging . For example, an MRI may show cerebral, cerebellar or brainstem hyperintensities . Transient contrast enhancements of the cerebral cortex, meninges, and basal ganglia have also been noted . Furthermore, though not specific, EEG may show epileptiform activity or diffuse slow waves . The cerebrospinal fluid may have pleocytosis, high protein levels, and oligoclonal bands. Diagnosis is made on the presence of anti-NMDA receptor antibodies in the spinal fluid and/or in the blood . Underlying neoplasm should be ruled. Since ovarian teratomas are the most frequent tumors associated with anti-NMDA receptor encephalitis, at least an ultrasound or MRI of the abdomen and pelvis must be considered in the initial diagnosis, and periodically for at least 2 years after the episode. However, attention should be paid to other tumors such as the more frequently associated with this autoimmune disorder (e.g. extraovarian teratomas, testicular, lung and breast tumors, ovarian carcinoma, thymic carcinoma or pancreatic cancer) . Since virtually all tumor may trigger the production of autoantibodies against NMDA receptors, clinicians should consider the assessment of a possible underlying tumor according to the signs and symptoms of each clinical case. In our patient, the blood chemistry was normal and she had no alterations on brain CT. Since she was a 15 year-old adolescent, a pelvic ultrasound was performed to rule out tumor or teratomas, but no changes were found. Lumbar puncture was performed 5 days after her admission (23 days after disease onset) and was found to be positive for anti-NMDA receptor auto-antibody. At that time the patient also experienced autonomic instability, namely tachycardia, and also more severe neurological symptoms, such as decreased consciousness that justified her admission to the ICU. These findings in our patient were also consistent with the third stage of the course of the disease that can culminate in admission to the ICU. We further highlight the fact that diagnosis was made 23 days after symptoms onset. The delay was mainly due to the fact that the disease was reported for the first time only 10 years ago as of this report, which means that the clinicians were not yet aware of this syndrome. Since the course of the disease usually presents with psychiatric symptoms, and adult psychiatrists or child psychiatrists are the first physicians to see the patients, usually a preliminary diagnosis of a functional psychosis is made and psychopharmacology treatment is started. Indeed, a similar scenario happened with our patient, since she was admitted to the psychiatric ward after failure to respond to antipsychotics and benzodiazepines. However, we emphasize the fact that the pleomorphic presentation of the disease raised the hypothesis of possible atypical psychiatric conditions.
In terms of treatment for anti-NMDA receptor encephalitis, if a neoplasm is detected, tumor removal and immunotherapy (corticosteroids, intravenous immunoglobulin or plasma exchange) are the first-line treatments. In such cases, second-line immunotherapy (cyclophosphamide and/or rituximab) is seldom needed. However, in cases unrelated to tumors, first-line therapy tends to be less efficient, and escalation to second-line immunotherapy is frequently necessary . Significant improvement occurs in more than two-third of patients after 2–3 months of therapy, which correlates with decreasing antibody titers. Symptoms resolution is inversely proportional to the order of symptom development . Our patient was treated with immunoglobulin (2 mg/kg/day) and methylprednisolone (30 mg/kg/day), plasmapheresis, rituximab (375 mg/m2/week) and risperidone (1 mg two times a day) and lorazepam (2.5 mg if needed). Since she had no tumor, her prognosis was worse than if she had a neoplasm. Relapses have been documented in literature . Ten months after symptoms onset, our patient had a seizure episode and a new treatment cycle was started. These findings are also consistent with the literature since the long course of the disease is characterized by slow recovery that can take years, and may be associated with prolonged neuropsychiatric deficits . Presently (almost 3 years after the disease onset), the psychiatric symptoms have improved, but she still experiences verbal memory impairment, attention and concentration difficulties. According to the literature, long-lasting cognitive deficits, mainly memory impairment and executive dysfunction may occur in about 88.8 % of the patients . Although a recent study (using MRI of patients after anti-NMDA receptor encephalitis), reported that hippocampal volumetric and microstructural impairments correlate with memory performance , in our patient, we did not perform any further imaging study such as MRI.
Regarding the outcome, the main good prognostic factors are: early detection and intervention, presence and subsequent removal of an underlying tumor, good response to first line immunotherapy, no need for intensive care unit admission, and the absence of relapses [10, 15]. Our patient had more bad than good prognostic factors since she had no tumor, the diagnostic was made 23 days after symptoms onset, she experienced autonomic symptoms, she was subsequently admitted to an intensive care unit and had a relapse 10 months after the symptoms onset.
Finally, we would like to highlight that even though anti-NMDA receptor encephalitis is classically described as having a step-wise presentation with a prodromal flu-like phase followed by periods of psychiatric, neurological and autonomic symptoms, these phases and symptoms (mainly the psychiatric and neurological ones) can occur in a mixed form as in the case of our patient. Such an uncommon presentation of psychiatric and neurological symptoms before the autonomic instability should raise the clinician awareness to consider a diagnosis of an organic psychiatry disorder.