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Antibodies and Limbic Encephalitis
Abstract & Commentary
By Joseph E. Safdieh, MD, Assistant Professor of Neurology, Weill Medical College, Cornell University. Dr. Safdieh reports no financial relationships relevant to this field of study.
Synopsis: In addition to previously identified antibodies that cause limbic encephalitis, novel antibodies directed against cell membrane antigens may cause many of the "antibody-negative" cases, and these cases seem to respond favorably to immunosuppressive treatment.
Sources: Bataller L, et al. Autoimmune limbic encephalitis in 39 patients: Immunophenotypes and outcomes. J Neurol Neurosurg Psychiatry. 2007;78:381-385.
Bien CG. Limbic encephalitis: extension of the diagnostic armamentarium. J Neurol Neurosurg Psychiatry. 2007;78:332-333.
Samarasekera SR, et al. Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies. J Neurol Neurosurg Psychiatry. 2007;78:391-394.
Limbic encephalitis is an immune-mediated disorder with an acute or subacute presentation of seizures, short-term memory loss and psychiatric symptoms. The neurological symptoms can be explained by specific damage to the medial temporal lobes and hippocampi. Limbic encephalitis has traditionally been considered one of the major paraneoplastic syndromes. However, case reports and case series in the literature over the past 10-15 years have described a group of patients with a clinical presentation of limbic encephalitis without an occult malignancy or detectable antibodies, and others with antibodies not considered to be of paraneoplastic origin—voltage-gated potassium channel antibodies (VGKC). More recently, a novel set of limbic encephalitis-related antibodies targeting novel cell membrane antigens (nCMAg) have been described.
The paper by Bataller and colleagues is a prospective clinical case study of the immunophenotypes and outcomes of 39 patients with limbic encephalitis identified over a 4-year period. Nineteen of these patients demonstrated the presence of previously characterized antibodies, including anti-Hu, anti Ma2 and anti-VGKC. Seventeen patients demonstrated novel antibodies that were detected only with immunohistochemical methods, all demonstrating intense labeling of nCMAg. These antibodies strongly labeled rat hippocampal cell membranes in live culture. Only 3 patients had no detectable auto-antibodies. In all, 82% of patients demonstrated CNS directed antibodies.
There were some differences among the immunophenotypes in the 39 patients reported. The patients with nCMAg antibodies were less likely to demonstrate the typical MRI changes characteristic of limbic encephalitis. Additionally and interestingly, 76% of patients with nCMAg antibodies had teratomas or thymic tumors. The majority of these teratomas were ovarian. Clinically, patients with nCMAg antibodies had a high frequency of hyperkinetic movements (41%), and depressed level of consciousness with hypoventilation (59%). Of the 39 patients, treatment response and follow-up was available for 35. Treatment of the patients included therapy for the underlying tumor, if one was present, and immunosuppression with corticosteroids and other agents. At median follow-up of 19 months, a significant association with response to treatment was noted in those patients with antibodies to VGKC and nCMAg, compared to those with the more traditional paraneoplastic antibodies, Hu and Ma2.
The paper by Samarasekera and colleagues summarizes the cases of 4 patients with limbic encephalitis, who did not demonstrate the presence of paraneoplastic antibodies or anti-VGKC antibodies. These patients did not demonstrate the presence of an underlying malignancy with a median of 18-months of follow-up. These 4 patients all demonstrated an infective prodrome followed by an acute presentation of limbic encephalitis, all demonstrating the typical MRI changes. CSF analysis in these 4 patients demonstrated minimal or no pleocytosis (range 0-5 WBC), normal to mildly elevated protein and negative oligoclonal banding. All 4 patients demonstrated variable recovery, all with persisting residual cognitive deficits and epilepsy. Of note, these patients were not screened for nCMAg antibodies.
These studies shed new light on the diagnostic approach to limbic encephalitis. It is likely that many previously "antibody negative limbic encephalitis" cases are not antibody negative at all, but instead represented cases caused by antibodies directed against neuronal cell membrane antigens. Testing for the novel antibodies directed against nCMAg is not commercially available. However, given the large number of patients with limbic encephalitis who might have these antibodies, and the fact that these patients tend to improve with treatment, the ability to test for these antibodies would represent a significant benefit to patients.
In light of these findings, what should be the neurologist's approach to a patient who presents with limbic encephalitis? The patient should undergo testing for the commercially available antibodies known to be associated with this condition from the serum and the CSF. An age appropriate malignancy screen should be initiated. If an underlying tumor is found, initial treatment should be directed against the tumor. In all cases, whether or not a tumor or antibodies are detected, a trial of immunotherapy, with corticosteroids, IVIG or plasma exchange, should be considered and initiated. In addition, serum should be stored for future assay of novel antibodies.