Four years ago, a five-year-old girl bumped the left side ofher forehead. She began having general convulsions andright-side seizures and paralysis. Her mental state andspeech deteriorated, and all of these neurological afflictionsworsened without let-up. They did not respond to standardpost-trauma epileptic therapy.Brain biopsy of her left-side cerebral cortex, in DukeUniversity's pediatric neurology clinic, revealed infiltratinglymphocytes "cuffing" around blood vessels, together withformations of microglial nodules. Both such aberrant cellssignify central nervous system infection, inflammation orautoimmune disease.They confirm a diagnosis of Rasmussen's encephalitis(RE), a progressive, relentless, though rare, variant ofepilepsy. When all else fails, the last-resort treatment forvery severe, intractable epilepsy, and RE, is surgicalremoval of the cortex on the injured side of the brain.The little girl, now nine years old, and known as "C K,"was spared this draconian surgery, thanks to two rabbitsstudied in Salt Lake City. There, geriatric neurologist ScottRogers of the Veterans Hospital and the University of Utahwondered whether such biopsy findings suggested that afactor in RE might be antibodies raised by the immunesystem against glutamate.Rabbits Bear WitnessThis amino acid (Glu) _ a chemical cousin of MSG,monosodium glutamate _ is the main excitatoryneurotransmitter in the mammalian central nervous system.To test their hypothesis, Rogers and his co-workersimmunized rabbits with bacterially expressed recombinantsubunits of the Glu receptor (GluR3).Two of the three animals given four shots of GluR3developed high blood levels of antibodies to that protein,and displayed muscle-twitching, food aversion and otherbehavior suggestive of seizure disorders. One even had aseverely bitten tongue, such as epileptics often inflict onthemselves during an attack.Rogers is first author of a paper in this week's Science,titled "Autoantibodies to Glutamate Receptor GluR3 inRasmussen's Encephalitis."Back in Durham, N.C., Duke University neurobiologistJames McNamara (the Science paper's principal author)biopsied the convulsive rabbits' brains, and found the sametelltale lymphocytic infiltrates and microglial nodules.As Rogers recalled, "Jim, having seen many in his career,said, `It looks just like Rasmussen's encephalitis,' _ andthat's what got us started."Which is why, instead of proceeding to surgery, little C Kbegan an 11-week course of daily plasmapheresis, designedto flush those GluR3 antibodies out of her white bloodcells.During the preceding 13 weeks, she had averaged 10 to 12seizures a day, did not speak spontaneously, and showeddwindling mental capacity.During the first seven weeks on plasmapheresis, as Sciencedepicts graphically, C K's seizures dropped well below fiveper day. She spoke spontaneously; her reading, writing anddrawing improved. "For the first time in two years, sheresumed playing with dolls, riding a bicycle" and helpingwith household chores.Then, from week eight daily seizure frequency climbedback to pre-plasmapheresis levels, and the child's mentalstate declined again. What went wrong?"We're working on that right now," Rogers told BioWorldToday. "We think we have multiple antibodies to theGluR3 receptors in her serum," he said. "So we'reexploring the possibility that one of these antibodies is oflow titer and high affinity. Thus it could escapeplasmapheresis cleansing, continue to build up, and theautoimmune response would recur."The Salt Lake City neurologist makes it clear that "thishypothesis, of course, assumes that the antibody is relatedto the disease. If it's some other component, then hopefullywe'll pick it up eventually here."C K was the only one of four RE patients to undergo GluR3antibody wash-out by plasmapheresis. The three others hadtheir serum tested for presence of the presumedautoimmune molecule, in comparison with 21 controls,among them four non-RE epileptics, five with activecerebral inflammation due to lupus, multiple sclerosis,chicken pox or TB, and four normal healthy controls.Glu Specificity Points To Other Neuro-AntibodiesThree of the four RE patients, including C K, wereimmunoreactive to the GluR3 antigen, which correlatedwith their clinical condition, but not to any of the other Glusubunits. The fourth had undergone surgical cortex removaltwo years earlier, and has since been free of seizures. Noneof the controls showed GluR3 antibodies, confirming itsspecificity for Rasmussen's encephalitis.Rogers is now extending this observation into otherneurological diseases, as well as exploring the region of theprotein that's producing the effect. In other words, he said,"we're attempting to identify the epitopes."One idea he's interested in pursuing "is that antibodies notonly to the Glu receptor but to other neurotransmitters _GABA (gamma-amino-butyric acid) or nicotinicacetylcholine _ could be involved in numerous types ofdiseases, with which, of course, an inflammatory responsewould coincide."This leads Rogers to a chicken-and-egg problem: "Do wehave an antibody response initially, or does that responsefollow, say, another immune assault?" n
-- David N. Leff Science Editor
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