Anti-N-methyl-D-aspartate Receptor Encephalitis in Children and Adolescents

Abstract & Commentary

By Shefali Karkare, MD, and Steven Weinstein, MD. Dr. Karkare is a Fellow in the Division of Pediatric Neurology, Weill Medical College of Cornell University. Dr. Weinstein is Director of the Pediatric Comprehensive Epilepsy Program, Weill Cornell Medical School, New York Presbyterian Hospital. Neither Dr. Karkare nor Dr. Weinstein report financial relationships relevant to this field of study.

Synopsis: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been recognized in children as young as 23 months as well as adolescents.

Source: Florance NR, Davis RL, Lam Christopher et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009;66:11-18.

Immune mediated disorders of the nervous system are increasingly recognized as a primary cause of neurologic symptoms and injury. This list now includes antibodies to NR-1 subunits of anti-N-methyl-D-aspartate receptors (NMDAR) , initially described in association with ovarian teratomas, presenting with an early encephalitis picture that included neuropsychiatric symptoms and autonomic instability. The entity has been identified in women without neoplasm, men, and now in 32 children.

The incidence of NMDAR encephalitis is unknown but must be relatively common, with 81 patients in an eight-month period having identifiable antibodies. The group included 32 children <18 years old, eight followed at Children's Hospital of Philadelphia and the remainder from outside institutions using serum and cerebrospinal fluid (CSF) assays. The majority were female (24/32), and the frequency of ovarian teratomas was lower than the adult figure of 56%: 31% (8/26) in girls ≤ 18 years old (p = 0.05), and 9% (1/11) in girls ≤ 14 years old (p = 0.008). None of the males had a tumor.

A viral-like prodrome preceded neurologic symptoms in nearly half (48%). The majority presented with neuropsychiatric symptoms including mood, behavior or personality changes, and sleep disturbances, and progressed to severe agitation and combative or paranoid behavior. A range of severe speech problems was seen in two thirds. Early seizures were seen in six patients, though 77% had seizures later in the disease course. Movement disorders during the illness occurred in 84%, including orolinguofacial dyskinesia, choreoathetosis, and dystonic posturing. Autonomic instability in children was manifest mainly as tachycardia, hyperthermia, and hypertension, but hypoventilation and airway protection led to intubation in 23%.

CSF analysis was abnormal in 94 %, with a lymphocytic pleocytosis in 87%, occasional increased protein (13%), and oligoclonal bands found in 5/6 tested samples. All the patients had antibodies in CSF or serum that reacted with extracellular epitopes of NR1 subunit of the NMDA receptor. Twenty-one of 31 had paired CSF and serum samples, with CSF showing stronger antibody reactivity. Patients treated with plasma exchange or IVIG showed CSF positivity despite negative serum testing. The antibody titer was significantly higher in the 25% of the patients having a teratoma.

The MRI scans were abnormal in 31% (10) of the children demonstrating multifocal findings, half having only transient flair abnormalities. Seizures were observed in 77% of cases; however, the movement disorders were frequently difficult to distinguish, prompting continuous video EEG surveillance. Diffuse slowing was the most common finding during the movements.

Most of the patients were treated with immunotherapy (combination of corticosteroids, IVIG, or plasma exchange), with a few receiving rituximab and/or cyclophosphamide. Recovery began approximately six weeks after presentation, with 45% showing substantial clinical improvement, 29% having a full recovery, and 26% with limited improvement. The median time of follow-up was 4.5 months. Relapse of neurologic symptoms during tapering or completing immunotherapy occurred in 25%, and as late as one year later.

Commentary

An immunologic disorder previously described in adults, especially those with ovarian cancers, is now recognized in children as young as 23 months. These patients appear to have viral encephalitis, but cultures and titers are normal, consistent with "idiopathic" encephalitis. The clinical findings suggest a multifocal disease but with non-specific CSF, MRI, and EEG determinations. The disorder should be considered in any child with culture- and titer-negative CSF having the onset of behavioral and sleep changes, movement disorders, seizures, and autonomic instability, including hypoventilation. Other non-infectious etiologies of encephalitis such as systemic multiorgan disorders, including lupus erythematosus, specific disorders such as Bechets, or well-recognized post-infectious disorders, should also be considered. Tumors, ovarian or otherwise, need to be excluded, but the true incidence of their future development is unknown.

Recognition of this syndrome is important for diagnostic and therapeutic reasons, though questions remain as to exact mechanism of these antibodies, particularly in the absence of tumor, the role of early immunosuppression to improve outcome, or the utility of CSF antibody titers to predict relapses.