At least four recent papers, including one by Poloni et al.1 report on the clinical features of encephalitis in young children associated with the presence, in serum or cerebrospinal fluid, of antibodies recognizing the NR1 subunit of the N-Methyl-D-aspartate receptor (NMDAr) on the cell surface of neurons.1-4 The NMDAr is one of several types of excitatory glutamate receptors. The receptor serves as a Ca2+ channel to induce an increase in the intracellular free Ca2+ concentration. Excessive stimulation of the NMDAr leads to neurotoxicity. The association between acute neurological symptoms and antibodies directed against the NMDAr has been previously recognized as a likely paraneoplasic disorder manifesting with acute change of personality, reversible psychosis, and abnormal movements of the orofacial region and limbs, most often in young females with ovarian germinal tumor (teratoma). In young children, the main clinical characteristics of the entity associated with NMDAr antibodies, are personality change, seizures, epsiodic dyskinesia, sleep dysfunction, dystonia, and speech deficits. Importantly, cerebrospinal fluid (cell number and protein level) and initial brain magnetic resonance imaging can be normal. Of the reported 20 children with the disorder to date (<14-years-old), two had NMDAr antibodies in the presence of malignancy (teratoma,3 neuroblastoma4). However, the rarity of malignancy detection should be considered with caution. We know from another tumor-associated neurological condition in children, the opsoclonus-myoclonus syndrome (also known as ‘dancing eye syndrome’ [DES]) that the tumor can be very small and stable or even enter into spontaneous involution over time. With advances in whole body imaging technology, the vast majority of children with DES are found to harbor a small neuroblastoma, while this was considered relatively infrequent 10 years ago. In other children, DES is considered to be a post-viral immunological syndrome. Both malignancy and post-viral mechanisms for the induction of NMDAr antibodies remain a possibility for children with anti-NMDRr antibody-related encephalopathy. While the discovery of anti-NMDAr antibodies is recent, the clinical entity itself was recognized a long time ago. Probably some patients described by Gilles Lyon in his well recognized paper in 1961 discussing ‘The acute encephalopathies of obscure origin in infants and children’ were similar.5 The condition is, to me (and as suggested by Poloni et al.1), certainly identical to the acute condition our group described in 19926, and probably to encephalitis lethargica as proposed by Dale et al.2 Are these anti-NMDAr antibodies a mere marker of the condition or a major player in the pathophysiology of the disease? Any neuronal destruction, especially induced by seizures and hyperproduction of glutamate could conceptually induce the rise of such antibodies. Supporting the pathogenicity of these NMDAr antibodies are, in adult patients, the clinical response to treatments that reduce circulating antibodies titers and the clinical improvements noted post-surgical resection of tumor in patients with malignancies-related NMDAr antibodies. The direct role of NMDAr antibodies and their induction following expression on tumoral cells would support a new paraneoplasic syndrome in children, an entity previously considered very unusual in the pediatric age group. Determining the pathobiological relevance of NMDAr antibodies is important in guiding therapeutic strategies. Published case reports describe the use of IVIg, rituximab, plasma exchange, and cyclophosphamide but it is difficult to evaluate their respective benefit. Considering that the symptoms are very long-lasting, their severity, and the experience in DES, it would probably be wise to make an extensive search for occult malignancy followed by tumor removal if possible. Prompt initiation of immunosuppressive treatment, probably using rituximab initially followed by cyclophosphamide in case of resistance, may be of benefit. Duration of therapy remains to be determined.
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Feb 1, 2010
Julie E Reznicek + 1
Open Access