Presentations

Abstract

Introduction: NMDA receptors play pivotal roles in the central nervous system (CNS) with processes of learning and memory [1,3]. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune and paraneoplastic process that presents with prominent neuropsychiatric symptoms. Literature on this form of encephalitis is lacking, however, prevalence seems to be increasing[9]. While published case reports have a wide demographic, most patients are females with median age of presentation in the early to mid 20s [1, 4]. Anti-NMDA receptor encephalitis has a close link with ovarian teratomas (as it was first described in 1997) [1,3,4], though the mechanism of that association remains unclear. Patient presentation often begins with viral-like prodrome, which then progresses to severe psychiatric manifestations [4]. Symptom onset to psychosis is about one week [4], and typically affects patients with no prior psychiatric history. Early recognition and diagnosis of NMDA receptor encephalitis is difficult, but is key in attaining positive outcomes for these patients. Diagnosis requires the presence of anti-NMDA receptor antibodies in serum and/or cerebrospinal fluid (CSF) [3,4]. Screening for ovarian teratoma in female patients is also recommended, as early surgical excision is associated with improved outcomes [1,3]. Brain imaging and electroencephalogram (EEG) are often utilized as adjunct studies, with EEG showing focal or diffuse abnormal activity [3]. In addition to removal of ovarian teratoma if present, first line treatment guidelines recommend corticosteroids, intravenous immunoglobulins, and plasmapheresis [1,3,4]. The majority of patients who present to the Emergency Department (ED) with NMDA receptor encephalitis are misdiagnosed on initial evaluation, with their symptoms being attributed to a psychiatric disorder or other etiology[1]. Here, we present the case of a previously healthy 21 y.o. female who presented to the ED accompanied by police with psychotic symptoms. She quickly progressed to catatonia, and then subsequent seizure activity.. Further workup revealed an ovarian mass on abdominal imaging along with positive serum and CSF anti-NMDA receptor antibodies.

Case Information: A 21-year-old woman with no past medical or psychiatric history presented to the ED early in the morning in police custody. She would not answer questions other than stating "let me go," and required frequent redirection to return to her seat. Police from the scene reported that there was concern for drug use, and that the patient was found on top of her grandmother in the midst of a physical attack. She was noted to be tachycardic with a heart rate in the 100-110s range. Other vital signs were within normal limits. On exam she was alert, handcuffed, and seated in a chair. She had no signs of trauma. Her initial evaluation included a complete blood count (CBC), basic metabolic panel (BMP), blood alcohol level, urine drug screen (UDS), and a computed tomography (CT) scan of her head. All studies were normal. She was referred for evaluation by our psychiatric social work service, and was awaiting inpatient psychiatric placement. By her third day in the ED the patient had stopped communicating, and was no longer eating or drinking. She showed no improvement in her presumed catatonia with benzodiazepines, and no change in psychotic symptoms with olanzapine. She began to show clinical signs of dehydration, including dry mucous membranes, as well as ketonuria and an elevated urine specific gravity. Given concern about her volume status and cessation of oral intake, and possible organic cause of her symptoms, she was admitted to the hospitalist service. That evening the patient had seizure activity. A lumbar puncture was performed and CSF studies were positive for NMDA-receptor antibodies. Further evaluation with pelvic ultrasound CT of the abdomen and pelvis demonstrated an ovarian mass. She was diagnosed with anti-NMDA Receptor encephalitis. Her course was protracted, requiring intubation, tracheostomy, and PEG tube. She underwent a laparoscopy by gynecology for removal of an ovarian teratoma. She slowly had recovery and improvement of her encephalopathy and was transitioned to an inpatient rehabilitation center.

Discussion/Clinical Findings: Anti-NMDA receptor encephalitis is a life threatening condition which was first discovered in 1997 [1] with an incidence of nearly 1.5 million people per year suffering from the disease [6]. The NMDA receptor is an ionotropic glutamate receptor which regulates excitatory synaptic transmission in the CNS. This receptor plays a critical role in the brain's neuronal development and function [3]. Patients who develop anti-NMDA receptor encephalitis often present with viral-like prodrome symptoms including but not limited to fever, vomiting, nausea, fatigue which later progresses to psychiatric manifestions of confusion, hallucinations, mood disturbances, homicidal or suicidal behaviours within a week[1]. Although the vast majority of cases have been associated with ovarian teratomas in female patients, a significant number of cases have been linked to infections including herpes simplex encephalitis and other CNS infections [7]. Due to the atypical presentation of anti-NMDA receptor encephalitis, the majority of patients who present are initially misdiagnosed, and their symptoms attributed to new onset psychiatric disorders [1]. These patients are often referred to psychiatric departments, or treated with antipsychotic drugs, without benefit hence delaying treatment. Delayed diagnosis and intervention is associated with complications including autonomic instability, hypoventilation requiring ventilatory support, intensive care unit (ICU) admission, and death[1,8]. When anti-NMDA receptor encephalitis is appropriately diagnosed, outcomes may be favorable. Diagnosis involves identifying the presence of anti-NMDA receptor antibodies in the serum or CSF, EEG, and brain MRI [1,3,4]. MRI can be normal, but may show FLAIR signal hyperintensity in the brainstem, basal ganglia, hippocampus [9]. EEG may show focal or diffuse abnormalities in the setting of seizures [3]. Once anti-NMDA receptor encephalitis has been diagnosed, it is important to identify the underlying etiology such as a teratoma which can be further evaluated by pelvic ultrasound, CT or MRI [1]. Following the identification of a teratoma, early surgical excision will result in improved outcomes. First line immunosuppressive therapies include intravenous steroids, immunoglobulins and plasmapheresis, with rituximab and cyclophosphamide as second line therapy [1]. Although cases of Anti-NMDA receptor encephalitis have been reported in patients ranging from 8 months to 85 years old [1] , a review by Dalmau et al report the median age of presentation is 21 years old with a total of 74% of cases constituting of females and 26% males[9]. This female predominance was also demonstrated in a large study in India by Chowdhury et al [7]. Presentations in pediatric populations are similar to the adult populations, but with fewer MRI abnormalities compared to adult groups [7]. Our case of a 21-year-old woman who was initially misdiagnosed as having new onset psychosis, highlights the difficulty of diagnosis of anti-NMDA receptor encephalitis. Current data shows that about 75% of patients recover fully with appropriate treatment, while the remaining percentage die or are severely disabled [9]. Our patient had a protracted course, but ultimately made a full neuropsychiatric recovery after her teratoma resection, IV immunoglobulin, methylprednisolone, and plasma exchange.

Conclusion: Anti-NMDA receptor encephalitis remains a life threatening condition which is difficult to diagnose and treat due to its vague clinical presentation and the absence of clinical guidelines on the treatment and prevention of the disease. It is most prevalent in young females, and associated with ovarian teratomas [1]. Current data on the pathophysiology of anti-NMDA receptor encephalitis is limited and the disease is often misdiagnosed leading to fatal outcomes. Awareness, leading to early detection and intervention by healthcare providers is essential. Future research detailing prevalence, incidence, symptomatology, treatment practice patterns, and patient outcomes worldwide, would be a tremendous resource.