Symptoms: Altered & Nonverbal

A 16-year-old male was brought into the emergency department (ED) by his brother and family friend after a week of odd behaviors including not recognizing family members, not following commands, and intermittent self-injurious behaviors. They report that the patient complained of a headache around the time of onset of symptoms but has been otherwise nonverbal. The patient had two prior ED visits over the past week for the same symptoms. His lab evaluations at those visits were negative, including negative urine drug screens (UDS). He was discharged on the first visit, and the family left against medical advice (AMA) during the second visit. The patient has no past medical problems and lived in Guatemala until he moved to the United States 1.5 years ago. In the ED, initial physical exam was pertinent for a nonverbal patient who would track but not follow commands, had dilated and reactive pupils. He was noted to be intermittently clenching his jaw and left hand and had odd lip-smacking movements. A decision was made to treat for potential seizure versus catatonia with 2 mg of Ativan, after which the patient responded with mild improvement. Diagnostic Workup Initial workup in the ED included CBC, CMP, TSH, CK, and UA, which showed mild leukocytosis and elevated CK. UDS was only positive for marijuana. HIV-1 and HIV-2 antibodies were nonreactive. A Computed Tomography Angiography (CTA) head and neck was unremarkable. A lumbar puncture was performed in the ED, and initial CSF results are shown in Table 1. Neurology, toxicology, and psychiatry were consulted alongside a pending MRI. Table 1 - Initial CSF Results. Color, fluid Colorless Appearance, fluid Clear WBC, fluid 25^ RBC, fluid 501^ Segmented neutrophils, fluid 5 Lymphs, fluid 88 Mono/macro, fluid 7 Protein, CSF 29.5∗ Glucose, CSF 68 The patient was initially admitted to the pediatric floor but was transferred to the pediatric ICU, where he was intubated and sedated for persistent agitation and the inability to follow commands. EEG was done and was unremarkable. What diagnosis should be considered? ANSWER: Anti-NMDAR Encephalitis Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most recognized form of autoimmune encephalitis. It was first described in 2005 by Dr Josep Dalmau and colleagues in a case series involving young women with psychiatric symptoms, seizures, and autonomic instabilities.1 Most of those patients had ovarian teratomas containing tissue expressing NMDAR. In fall 2007, the California Encephalitis Project began identifying cases of anti-NMDAR encephalitis and found that anti-NMDAR encephalitis was the leading form of encephalitis at that time and occurred about 4 times as frequently as herpes simplex virus 1 (HSV-1) and about 6 times as frequently as West Nile virus or varicella-zoster virus.2 Female sex (4:1) and younger age (<20 years) are associated with higher rates of NMDAR detection, according to a recent study involving over 40,000 patients tested at the Mayo Clinic Neuroimmunology Laboratory.3 HSV-1 encephalitis cases have shown antibody development and relapse with anti-NMDAR encephalitis after apparent recovery.4 NMDA receptors are glutamate-activated ion channels that play a significant role in excitatory neurotransmission within the central nervous system. Anti-NMDAR encephalitis is an autoimmune disease characterized by autoantibodies binding to the NMDAR GluN1 subunit. This binding disrupts the interaction of NMDARs with receptor tyrosine kinase EphB2, leading to internalization and reduced function of NMDARs. As a result, glutamatergic signaling in cortical, hippocampal, and subcortical circuits is affected, which underlies the psychiatric, cognitive, motor, and autonomic manifestations of the disease. Furthermore, reduced NMDAR activity on inhibitory interneurons can disinhibit excitatory networks, lowering seizure threshold.5 Seizures and movement disorders are more prominent in children, while psychiatric symptoms dominate early in adults. Orofacial dyskinesias, such as lip smacking, chewing, and grimacing, are highly suggestive of anti-NMDAR encephalitis.6 CSF anti-GluN1 IgG is the definitive diagnostic marker and is more sensitive than testing in serum. However, false-positive and false-negative results have been reported in both CSF and serum. Therefore, the current recommendation is combined testing in both CSF and serum.6 During the acute phase, first-line immunotherapy—typically a combination of high-dose corticosteroids, intravenous immunoglobulin, and/or plasma exchange—is the gold standard. If patients do not respond adequately, the second-line therapy is rituximab, which helps enhance recovery and reduce the risk of relapse. In refractory cases, additional immunomodulatory agents, such as cyclophosphamide, bortezomib, or tocilizumab may be considered. Relapses occur in approximately 10% to 30% of patients, usually within the first 2 years after onset, emphasizing the need for ongoing follow-up to assess whether long-term maintenance therapy is necessary.6 Our patient was started on 7 days of high-dose methylprednisolone followed by a 10-week steroid taper. He received a 5-day course of IVIG. He experienced both overt and subclinical seizures, which were managed with levetiracetam (Keppra) and valproic acid. He had a negative workup for neoplasm. CSF returned positive for NMDA IgG after 2 weeks of initial presentation, and he was started on rituximab. Treatment with physical therapy and occupational therapy helped the patient regain functionality, and he was discharged after 47 days in the hospital. Take-Home Message Recognition of age-specific patterns aids early diagnosis and management of NMDAR encephalitis. In children, seizures and movement disorders may be the first clues, whereas in adults, acute psychiatric symptoms often precede neurologic signs. Teratoma workup is necessary in patients diagnosed with anti-NMDAR encephalitis. Treatment with steroids should not be postponed until definite diagnosis is made, as CSF antibodies can take weeks to result. To avoid false-negative or false-positive results, it is recommended to test NMDAR antibodies in both CSF and serum. Relapses are not uncommon. Patients should be followed up to determine if chronic maintenance therapy is required.