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LIMBIC ENCEPHALITIS IS INCREASINGLY NOT PARANEOPLASTIC

Susman, Ed

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SAN FRANCISCO — Neurologists should consider that patients who exhibit memory loss or dementia may be suffering from autoimmune-caused limbic encephalitis – even in subjects in whom no malignancy is found – researchers suggested here at the Annual Meeting of the American Neurological Association in October.

Limbic encephalitis has been described with cancers and is considered to be some sort of immune response to the cancer, said Angela Vincent, MBBS, MSc, Professor of Neuroimmunology at the University of Oxford in England, who presented data at the meeting. (The disorder gets its name because the disease appears to affect the so-called limbic cortex.)

But, she said, “we believe that this disease is relatively common, potentially treatable, and can be non-paraneoplastic.”

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CASES WITHOUT CANCER

Dr. Vincent described 11 cases of voltage-gated potassium channel antibody-associated limbic encephalitis seen during an 18-month period. Nine of the patients were women; the patients' records were drawn from four hospitals.

The patients had memory loss from one week to one year. In addition, they experienced confusion, seizures, and agitation; they had undergone central nervous system (CNS) virology studies, MRI, and paraneoplastic screens.

Dr. Vincent said three patients had evidence of voltage-gated potassium channel antibodies; but only one of the three had cancer.

This discovery prompted her colleagues to explore the possibility that other patients with symptoms – personality changes, irritability, depression, seizures, memory loss, and sometimes dementia – might also have potassium channel antibodies.

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IMMUNOLOGICAL TREATMENTS

“We looked for these antibodies in patients with unexplained limbic symptoms, and treated positive cases with immunological therapies such as plasma exchange, intravenous immunoglobulin, and steroids,” said Dr. Vincent. “Remarkably, the majority of the patients improved considerably following immunological treatments.” Dr. Vincent said steroids were the most effective treatment for these patients.

Dr. Vincent explained that the antibodies mistakenly attack potassium channels necessary for proper functioning in the brain. Steroids appear to turn off the antibodies, even markedly reducing their levels in the patients. Once the antibody level is decreased the patients can recover, some to pre-illness status.

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INFECTION AS THE CAUSE?

Why the antibodies start to increase in the body and attack the potassium channels remains a mystery. However, Dr. Vincent thinks an infection may lead to the autoimmune attacks.

“In the nonparaneoplastic cases, we suspect that the antibody overexpression may be a part of a reaction against an infectious event,” Dr. Vincent said, perhaps the same type of mechanism seen in Guillain-Barré syndrome, in which some unknown organism or molecule triggers an antibody response.

She noted that the disease erupts following a presumed viral infection consistent with a postinfectious autoimmune etiology.

“It is well accepted that autoantibodies directed against neuronal proteins, such as acetylcholine receptors and voltage-gated calcium channels, can cause peripheral neurological diseases,” Dr. Vincent explained.

“There is also growing evidence that antibodies can cause CNS disorders,” she said, based on the fact that patients treated with plasma exchange, which removes antibodies, get better.

Dr. Vincent thinks the nonparaneoplastic form of limbic encephalitis is strongly associated with antibodies to the Kv1.2 subtype of voltage gated potassium channels that is expressed in the molecular layer of the dentate gyrus. This is based on experiments with animal models and other in vitro testing.

“Although we do not know how and where the antibodies gain access to the CNS, nor how they affect CNS functions, we hypothesize that the hippocampus, which strongly expresses the Kv1.2 subtype of voltage-gated potassium channel, is a major target of the antibodies,” she reported.

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COMMENTARY

Steven Vernino, MD, PhD, was not involved in this study, but commented on it from his own experience treating limbic encephalitis. Dr. Vernino, Assistant Professor of Neurology at the Mayo Clinic College of Medicine, has also treated patients with the disorder who do not have cancer.

“Whenever a neuron gets excited, potassium is exchanged,” he explained. The voltage-gated potassium channel antibodies interfere with the potassium exchange, causing a series of symptoms that can be diagnosed as dementia.

“I concur with Dr. Vincent that these disorders are not rare,” he said. “We have treated seven patients with limbic encephalitis that was not caused by cancers.”

All the patients underwent a cancer screen, MRI, and EEG, he said. Six of his patients with limbic encephalitis got better when given high dose steroids, and three of the patients improved dramatically.

“Many of the recoveries were dramatic in a functional way,” he said. “Patients stopped having seizures and their memory improved, so they could return to work or resume driving. Most patients still had short-term memory impairment when they were carefully tested.

“The course of the disease seems to be variable,” he said, “but most of the patients appear to get better within five days after treatment is initiated. I give high dose steroids for four to five days.” He also administers intravenous solumedrol (Serevent) at a dose of about one gram a day.

How many limbic encephalitis cases appear? Dr. Vernino said it is difficult to quantify, but he pointed out that there is a lot of unexplained encephalopathy. “I see about one case of definite limbic encephalitis each month,” he said.

He said that because doctors believe that the condition is due to immune system dysfunction, steroids, which help the overactive immune system calm down, are used in the disorder, and they appear to work.

Dr. Vincent said in vitro and in vivo studies are underway to test theories of how the disease invades the brain as well as triggers of the disease.

©2003 American Academy of Neurology

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