Case 1: A 16-year-old girl with strange behaviour

A previously healthy 16-year-old girl presented with a generalized tonic-clonic seizure after one week of insomnia and decreased appetite. A partial septic work-up, metabolic and drug screen, electroencephalography (EEG), computed tomography scan of the head and magnetic resonance imaging (MRI) of the brain were normal. She was discharged home with presumed pseudoseizures. The next day, she presented with repetitive hand rolling, agitation, incontinence and hallucinations. On examination, she was incoherent, disoriented, hypertensive and tachycardic. Symptoms were managed with antipsychotics and benzodiazepines. Over the next week, she developed dystonias, orofacial dyskinesias, lead-pipe rigidity, hyper-reflexia and clonus. Her mental status varied from severe agitation to catatonia, mutism and refusal to eat. She had autonomic instability with fluctuating vital signs and episodes of hypoventilation with desaturation, repetitive rhythmic limb movements and intermittent unresponsiveness, with a Glasgow Coma Scale score of 3 to 6. Investigations revealed mildly elevated C-reactive protein level, white blood cell (WBC) count, transaminase level and creatine kinase level, which all rapidly resolved. Cerebrospinal fluid (CSF) protein level and WBC count were mildly elevated, but all cultures and viral studies were negative. A brain MRI was normal. Repeat EEG showed diffuse nonspecific slowing, but no epileptic events. Vitamin B12, folate, ceruloplasmin, thyroid-stimulating hormone and complement levels, and antistreptolysin O, antinuclear, antiphospholipid, antineutrophil cytoplasmic and thyroid peroxidase antibodies were normal. The initial working diagnosis was an extrapyramidal reaction complicating an acute conversion disorder because the patient had received multiple antipsychotics early in her second presentation and there was also a background of preceding psychosocial stressors. However, nine days after discontinuation of antipsychotics, her symptoms had worsened. At this time, a diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was considered. While awaiting confirmation, empirical treatment was started with methylprednisolone, intravenous immunoglobulin G and plasmapheresis. Eleven days into treatment, anti-NMDAR antibodies were reported as being highly positive in cerebrospinal fluid and weakly positive in serum. A repeat MRI showed a small region of increased cortical fluid-attenuated inversion recovery signal in the left superior temporal gyrus. Anti-NMDAR encephalitis is the most common cause of autoimmune encephalitis in children, with 40% of all cases occurring in the paediatric population (1). Since this disorder was first described in 2005 in young women with ovarian teratomas (2), an increasing number of cases are being identified, including patients previously classified as having idiopathic encephalitis (1). The clinical progression is highly predictable, starting with a prodrome of fever, headache and nonspecific flu-like symptoms (1). Neurological and behavioural symptoms follow within one month and include psychiatric symptoms such as agitation, anxiety, hallucinations, bizarre behaviour and paranoia; movement disorders including orofacial dyskinesias, complex stereotyped movements and dystonic posturing such as opisthotonus and oculogyric crises; speech disturbances, ranging from echolalia to mutism; seizures, which can be convulsive or nonconvulsive; and insomnia, autonomic dysfunction and central hypoventilation (2). Due to the prominent psychiatric features, patients are often first managed by psychiatry (2). The differential diagnosis includes: primary psychiatric disorders such as acute psychosis, schizophrenia and catatonia; neuroleptic malignant syndrome; infectious or postinfectious encephalitis secondary to viruses, mycoplasma or streptococci; and other types of autoimmune encephalitis including Hashimoto’s and the presence of autoantibodies to other neuronal proteins such as Hu, Ma2, LGI1 and CASPR-2 (1,2). The majority of cases of anti-NMDAR encephalitis are due to a paraneoplastic phenomenon, but this is age-dependent, with 56% of adult women and only 9% of girls <14 years of age identified as having an ovarian teratoma (1). Testicular teratomas are rare (1). In most nonparaneoplastic cases, the immunological trigger is not identified, although a preceding viral or mycoplasma infection may play a role (2). In our patient’s case, the pelvic MRI and infectious studies were negative. The diagnosis is confirmed by identifying antibodies to the NR1 subunit of the NMDAR in the serum or CSF, with CSF levels correlating best with disease activity (1). Other diagnostic clues include CSF pleocytosis and oligoclonal bands (2). EEGs often show nonspecific slowing with disorganized activity and occasional epileptic events (2). In one-half of patients, MRIs show transient fluid-attenuated inversion recovery or contrast enhancing abnormalities (2). Although an ultrasound can be used as an initial screen for a teratoma, an MRI must also be performed (2). First-line treatment consists of methylprednisolone, intravenous immunoglobulin G or plasmapheresis, along with possible tumour resection (2). Two weeks into treatment, our patient had not substantially improved, at which time rituximab was initiated. Cyclophosphamide can also be considered as a second-line agent. Four months into treatment, she was less agitated, more communicative and aware of her surroundings. A repeat MRI was normal and she was discharged home. One year after diagnosis, the patient has dramatically improved and is socially functioning as a normal teenager, although school continues to be a challenge. The typical prognosis is that 80% of patients make a significant recovery (1). Residual symptoms are consistent with frontal lobe dysfunction and may include poor attention, planning and impulsivity. Relapse occurs in 20% of children (1). Consider autoimmune encephalitis, particularly anti-NMDAR, as part of the differential diagnosis for encephalitis, acute behavioural change, seizures, dystonia and dyskinesia. Anti-NMDAR encephalitis has a characteristic presentation with a nonspecific flu-like prodrome followed by behavioural and psychiatric manifestations. Follow-up entails yearly pelvic MRIs to uncover a paraneoplastic phenomenon, especially the presence of an ovarian teratoma, and to monitor for recurrence of a tumour postresection.

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