Robert B. Darnell

The neuronal nuclear antigen recognized by the human anti-Ri autoantibody is expressed in central but not peripheral nervous system neurons

Anti-Ri is a human autoantibody that recognizes a neuronal nuclear antigen (Ri). Biotinylated IgG from serum of two patients with high titers of anti-Ri antibodies was used to study the distribution of the Ri antigen in a panel of normal human tissues. the expression of the Ri antigen was evaluated by an avidin-biotin peroxidase technique and confirmed by immunoblotting. The Ri antigen was restricted to the neurons of the central nervous system (CNS) and some pituitary cells. Most neurons in dorsal root, Gasserian and sympathetic ganglia, and myenteric plexus were negative or, a few of them, very weakly positive. The functional implication of the different expression of the Ri antigen between neurons of the central and peripheral nervous system is presently unknown.

Autoimmune encephalopathy: the spectrum widens.

In 1997, Nokura and colleagues described a 19-yearold woman who developed memory loss, psychosis, seizures, central hypoventilation, and coma. An ovarian teratoma was discovered and removed, after which she made a partial recovery. Antineuronal antibodies were searched for, but not found. Other case reports appeared in the next few years, but no antibody was identified; for example, in 1999 Taylor and colleagues reported on a 24-year-old woman who presented with a 3-week history of memory loss, behavioral changes, auditory hallucinations, and hypersomnolence. She developed central respiratory failure and a flaccid paraplegia. An MRI initially showed no abnormalities, but a subsequent study, after the respiratory failure, revealed increased T2 signal in the medulla and spinal cord. There was a mild cerebrospinal fluid (CSF) pleocytosis. A pelvic mass that proved to be an ovarian teratoma was found and removed. The surgery along with immunosuppression by high-dose corticosteroids and intravenous immunoglobulin (IVIG) led to a full recovery. In 2005, reports from the laboratory of Josep Dalmau identified 4 young women with acute psychiatric symptoms, seizures, memory deficits, and hypoventilation, all of whom had ovarian teratomas. One of the patients died, but 3 made a good recovery. The serum and CSF of these patients contained antibodies that reacted at the cytoplasmic membrane of hippocampal neurons and its processes. The antibody reacted with N-methyl-D-aspartate receptors (NMDARs). The syndrome was considered a rare paraneoplastic disorder. Still, it was important to recognize the syndrome, because it affected young women who might not otherwise be thought to have a neoplasm, and because treatment of the tumor led to recovery of what otherwise could have been a fatal illness. The syndrome also turns out to be not so rare. Last year, Dalmau and colleagues described the clinical characteristics of 100 such patients, of whom only 60% had identifiable neoplasms. All of their patients were women, but other reports have identified the disorder in men associated with testicular tumors. Moreover, as the number of case reports increases, the percentage of patients with identifiable cancer decreases. In this issue of Annals of Neurology, Florance and colleagues, from the laboratory of Rosenfeld and Dalmau, have expanded the spectrum of the disorder to children and adolescents, many without neoplasms. This report describes the clinical and laboratory findings in 81 children and adolescents, 1 of whom was only 21 months old. Amazingly, these 81 patients were identified in 1 8-month period; 8 patients were seen at the University of Pennsylvania, where Dalmau and colleagues work; the other 73 were identified by examination of serum or CSF sent to their laboratory. Identifiable tumors were found in only about 1 2 of the patients. Most of the patients made a substantial recovery, but relapses occurred, particularly in those without identifiable tumor. The antibody present in patients with this syndrome reacts with the NR1 subunit of the NMDAR, a protein found on the surface of hippocampal and other neurons. The antibody is one of several antibodies against glutamate receptor proteins that have been implicated in neurologic diseases, including epilepsy and systemic lupus erythematosus. That an antibody was not identified in previous reports of what was undoubtedly the same syndrome is not surprising. As more careful searches are made and new techniques are developed, one can expect to find more antibodies in heretofore obscure neurologic syndromes. This and previous reports from this laboratory make several important points. For the clinician, the reports identify a relatively new syndrome that may be substantially more common than previously believed, and that may or may not be associated with an underlying neoplasm. The report is especially important for pediatric neurologists who may not be familiar with a disorder previously reported largely in adults. As the current report indicates, many patients with presumed viral encephalitis may have had this syndrome. Identification of the syndrome is extremely important, because unlike many of the other paraneoplastic syndromes, treatment seems to reverse what might otherwise be a fatal disease. Although many of the patients, particularly the youngest ones, may not have an identifiable cancer, it is important to consider the presence of a neoplasm and make an appropriate search, as outlined in the Florance report. It is possible that a tumor is present but unrecognized, either because it is too small to be identified by current laboratory testing or because it has been suppressed or eradicated by the immune response. A similar situation may occur in children with opsoclonus related to neuroblastoma. The presence of an occult neoplasm may explain why relapses are more common in those children in whom no tumor is identified. As more patients are described, the spectrum expands. This report includes infants, boys as well as girls, and many patients in whom the disorder is precipitated by an antigenic stimulus other than a neoplasm. The disorder now has to be suspected in patients previously believed to have viral encephalitis. Luckily, the clinical findings are relatively characteristic, even in children. A EDITORIALS