The patient was a previously healthy, 16-year-old, bilingual (Spanish-English speaking) Hispanic female living in the United States (U.S.), with no prior concerns regarding her functioning. The primary language spoken at home was Spanish, although the patient had been exposed to English since pre-school, and participated in English only classes in school since the second grade. She was enrolled in an advanced 10^th grade curriculum in a public high school in the U.S. at the time of symptom onset and was considered an excellent student, with good social functioning and involvement in several honor societies and volunteer groups. Eleven days prior to hospital admission she requested assistance to change her clothes because she was unable to use her right hand. She was promptly evaluated by her primary care physician who attributed this symptom to stress. Three days later she was referred to a psychologist by school personnel, to whom she reported auditory hallucinations (hearing voices), insomnia, and extreme forgetfulness. She was observed to have paucity of speech, saying only “yes”, “no”, and “I don’t know” during the session. She was then sent to an emergency room, where MRI and blood tests were normal except for elevated thyroid stimulating hormone (TSH) and a urinary tract infection. Psychiatric admission was recommended, but no beds were available. The patient returned to her primary care physician who reportedly prescribed an unspecified “relaxant.” Ten days after symptom onset she presented with severe disorientation in school. She was confused and unable to locate her classes even when a printed schedule was provided. The school nurse contacted the patients’ primary care physician, who referred her to a tertiary pediatric hospital for a full evaluation due to severe cognitive impairment and concern for encephalopathy.

The patient was admitted to the hospital eleven days after symptom onset, where an extensive medical work-up revealed high titer NMDAR antibodies in both serum and CSF. MRI findings revealed no atrophy or lesions, and electroencephalogram (EEG) studies found continuous generalized slowing, more prominent in left frontal, left temporal and left temporo-central regions initially. In addition to psychiatric symptoms (auditory and visual hallucinations,), the patient demonstrated the following symptoms: right hemiparesis, waxing and waning mental status consisting of confusion and disorientation, sleep disturbance, memory problems, and aphasia characterized by reduced verbal expression and perseverative language. Symptoms later progressed to autonomic instability, dysphagia requiring nasogastric tube placement, choreiform movements, and amenorrhea.

Starting 13 days after symptom onset the patient was treated with first line-immunosuppression per institutional best care practices. This included high dose pulse methylprednisolone (8 doses total of 1 gram each during the first 3 weeks), IVIG (2 g/kg split over a five-day course), as well as six cycles of plasma exchange due to limited response to initial medical management. Second line therapy of rituximab (500 mg/2 at 1 gram for 2 doses) was initiated to deplete autoantibody producing lymphocytes (B cells) due to lack of initial response and worsening encephalopathy. Clinical focal seizures consisting of twitching of the right hand and face, aphasia, and confusion, were associated with activity arising from left temporo-central region. These were initially treated with lorazepam and levetiracetam, and later with oxcarbazepine. Her psychiatric symptoms were treated with an atypical antipsychotic (quetiapine). She initially required propranolol for blood pressure control and management of dysautonomia but was later titrated off this medication without complication. She spent 6 weeks on the general neurology floor, requiring transfer to the PICU for management of worsening symptoms for 2 days out of her total length of stay. She was then transferred to the hospital’s inpatient rehabilitation unit (IRU), where she received physical, occupational and speech/language therapy for four weeks. In the IRU, her neurobehavioral status was monitored by neuropsychology, but significant, persistent altered mental status rendered her untestable. She demonstrated improvements in alertness, orientation, ability to follow commands, mobility and activities of daily living. She was discharged home 11 weeks after symptom onset under continued treatment with monthly IVIG, quetiapine and methylphenidate. [See Figure 1 for clinical course and treatment.]

Initial Neuropsychological Evaluation

Approximately 5 months after initial symptoms the patient was receiving homebound school instruction but expressed a desire to return to school. Her clinical presentation during a follow-up with pediatric neurology suggested that she might be able to return to school, so she was referred for a comprehensive outpatient neuropsychological evaluation to identify accommodations that would facilitate her return to school. She took her prescribed quetiapine for the first testing session, and both methylphenidate and quetiapine for her second session. She demonstrated some awareness of her persistent cognitive and psychiatric symptoms and appeared social. Her presentation was remarkable for blunted affect, slow processing speed and significant word finding problems. She was unable to simultaneously eat a snack and participate in a conversation. The content of her spontaneous language was limited, vague, and perseverative, particularly on the subject of returning to school. She was noted to have more difficulties expressing facts in Spanish than in English, and could not correctly identify her year of birth in Spanish, although she did identify it correctly in English. The neuropsychological evaluation was carried out by a bilingual clinician and included both English and Spanish measures. The majority of the measures were administered in English given her apparent difficulties communicating facts in Spanish. However, Spanish instruments were administered in Spanish using standardized Spanish procedures. Her premorbid level of intellectual functioning was estimated to be at least average, based on her excellent performance within an advanced academic curriculum, as evidenced in school documents provided by her parents. The neuropsychological evaluation, however, revealed profound global impairments, most notably in processing speed, memory, expressive language, and fine-motor coordination with right hand more impaired than left hand. [See Figures 2-5 for test results]

Neurocognitive findings, coupled with the return of intermittent visual hallucinations and paranoid ideation, prompted the following adjustments in her treatment: increased IVIG schedule (from monthly to every three weeks), repeat rituximab (2 additional doses once it was apparent that B cells were depleted), added methylprednisolone pulse dosing (2x), and increased quetiapine dosage. The family reported a decrease in psychotic symptoms and an increase in social and academic functioning following these adjustments. Given the severity of her cognitive and academic deficits, homebound special education instruction was recommended to re-teach academic skills that had been lost and to allow time for further recovery prior to returning to campus. Speech/language therapy and occupational therapy were recommended to address her persistent language and motor deficits. Care was taken to provide the parents with information about NMDAR encephalitis and the recovery process in Spanish, their native language, and to support them in the process of obtaining services for the patient.

Second Neuropsychological Evaluation

The patient underwent a second neuropsychological evaluation approximately 9 months after symptom onset, having taken her prescribed methylphenidate and quetiapine. Notable improvements in affect, alertness and reciprocal conversation were observed. Although she was relatively faster and more flexible when responding to questions, her presentation continued to be remarkable for slow processing speed and word finding problems in English and Spanish. She required frequent repetition of instructions. Test results revealed persistent, global cognitive deficits. Slightly higher scores were obtained on measures of memory, expressive English vocabulary, verbal reasoning, processing speed, fine motor coordination (although marked right hand incoordination persisted), and academic skills [See Figures 2-5 for test results].

Given her estimated premorbid level of functioning (based on a documented excellent academic performance in an advanced school curriculum), some improvement was noted but she had not returned to the estimated baseline. Spanish receptive vocabulary did not appear to show improvement on standardized testing. Recommendations for school included ongoing special education supports and consideration of an additional year of school. She was again referred for outpatient speech/language therapy, which she received weekly for the next four months. She also received outpatient physical therapy (PT). Approximately 10½ months after symptom onset (April, 2015), she returned to school half-time to complete her senior year. She had significant difficulties adjusting to the classroom setting and keeping up with classes, but was allowed to graduate due to her pre-illness academic accomplishments.

Treatment with IVIG ended 13 months after symptom onset, but treatment continued with maintenance phase immunotherapy (mycophenolate), due to the continued presence of high titer serum antibodies and the protracted course of her initial disease presentation. Both oxcarbazepine and quetiapine were discontinued 16 months after symptom onset; treatment with methylphenidate was maintained.

The patient enrolled at a state college near her home but struggled to sustain her attention and keep up with her course work. After one month, she decided to postpone college due to her cognitive difficulties. She applied for several jobs but significant anxiety interfered with her performance during interviews. Nonetheless, continued gradual improvement was noted. By 19 months after symptom onset, she became fully independent with activities of daily living, driving, and managing her appointments and medications. She began a pharmacy technician course at an institute of technology. At the time of her third evaluation, she was obtaining all A’s in her classes. Treatment with methylphenidate and mycophenolate continued.

Third Neuropsychological Evaluation

A follow-up evaluation was conducted 22 months after symptom onset. The patient took methylphenidate prior to the assessment. Serum antibodies remained elevated per blood tests completed at the time of the evaluation. Significant improvements were noted in alertness, attention, mental flexibility, and interpersonal engagement. Persistent word finding problems were noted but she more easily followed conversations and responded to questions. Objective test results showed significant, global improvements in cognitive functioning. Overall intelligence, memory, mental flexibility, and fine motor skills improved to the Average range. Persistent, subtle weaknesses were noted in working memory and processing speed, although considerable improvement was noted. Academic functioning improved to the Average range, with the exception of her performance on academic fluency measures, reflecting the subtle, persistent difficulties processing speed and sustained attention. Spanish receptive vocabulary could not be evaluated because the patient had aged out of the established age range for the test that we had available. Recommendations included school accommodations to reduce the impact of inattention and slower processing on academic performance and follow-up with the state department of rehabilitation. [See Figures 2-5 and Table 1 for test results]