Paraneoplastic limbic encephalitis

Edward J Dropcho MD (Dr. Dropcho of Indiana University Medical Center has no relevant financial relationships to disclose.)
Originally released May 17, 1994; last updated June 23, 2013; expires June 23, 2016

This article includes discussion of paraneoplastic limbic encephalitis and paraneoplastic encephalomyelitis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Paraneoplastic limbic encephalitis is a subset of a larger group of noninfectious encephalitides that predominantly affect the limbic system. Small cell lung carcinoma is the most common associated neoplasm in paraneoplastic limbic encephalitis. Paraneoplastic limbic encephalitis is unusual among paraneoplastic neurologic disorders in its recently recognized association with testicular germ cell tumors in young men and with ovarian teratoma in children and young women. There is an ever-growing number of circulating antineuronal antibodies associated with paraneoplastic and nonparaneoplastic limbic encephalitis, or other manifestations of autoimmune encephalitis. Most recent among these are antibodies against the GABA(B) receptor, metabotropic glutamate receptors, or the DPPX subunit of Kv4.2 potassium channels. The presence of antineuronal antibodies in patients with limbic encephalitis supports an autoimmune pathogenesis and can guide the search for an underlying tumor. For some patients with paraneoplastic or nonparaneoplastic limbic encephalitis, prompt diagnosis and therapy improve the likelihood of a favorable neurologic outcome.

Key points

 

• “Paraneoplastic limbic encephalitis” is not a single entity but, rather, a subset of a group of autoimmune disorders that predominantly affect the limbic system, with or without an associated neoplasm.

 

• Patients with limbic encephalitis present with varied combinations of memory loss, seizures, and psychiatric disturbance. Some patients have additional neurologic signs and symptoms. It is not rare for patients to be initially misdiagnosed.

 

• Small cell lung carcinoma, thymoma, testicular germ cell tumors, and ovarian teratoma are the tumors most often associated with limbic encephalitis.

 

• The presence of antineuronal (“onconeural”) antibodies in a patient with limbic encephalitis raises suspicion for an underlying tumor and can guide the search for the tumor, though some patients with limbic encephalitis have antibodies but no associated tumor.

 

• A varying proportion of patients with paraneoplastic limbic encephalitis show neurologic improvement with successful tumor treatment or immunosuppressive therapy. Early diagnosis and prompt treatment increase the likelihood of success.

Historical note and terminology

Limbic encephalitis as a clinicopathologic entity was first described by Brierley in 1960 (Brierley et al 1960), and its frequent association with neoplasia was documented over the next several years (Henson et al 1965; Corsellis et al 1968). In the 1970s and early 1980s, limbic encephalitis was believed to occur nearly always in association with a neoplasm, usually small cell lung carcinoma or, rarely, other tumors. Starting in the mid-1980s the discovery of anti-Hu antibodies and other antineuronal antibodies in some patients lent support to an autoimmune pathogenesis of paraneoplastic limbic encephalitis. Studies over the past 10 to 15 years have yielded much new information, including: (1) identification of an ever-increasing number of antineuronal antibodies associated with limbic encephalitis; (2) expansion of the list of neoplasms most often associated with limbic encephalitis, particularly thymoma, testicular germ cell tumors, and ovarian teratoma; (3) recognition that paraneoplastic limbic encephalitis can largely be divided into subtypes based on linkages among particular tumors, antineuronal antibodies, clinical features, and response to treatment; and (4) realization that paraneoplastic limbic encephalitis should probably be viewed as a subset of autoimmune limbic encephalitis, whose incidence is greater than previously believed. For at least some forms of limbic encephalitis, a similar if not identical autoimmune etiology applies to paraneoplastic and nonparaneoplastic patients, analogous to Lambert-Eaton myasthenic syndrome.

Diagnostic criteria for paraneoplastic limbic encephalitis as outlined in a review of 50 patients published in 2000 (Gultekin et al 2000) and in a review by a multinational European panel (Graus et al 2004) generally include: (1) subacute onset of memory loss, seizures, and psychiatric symptoms; (2) neuropathologic, neuroimaging, or EEG evidence for involvement of the limbic system; and (3) cancer diagnosis within a few years of onset of the neurologic syndrome. The presence of "well-characterized" antineuronal antibodies in a patient with limbic encephalitis increases suspicion for an underlying neoplasm, but antineuronal antibodies may also be present in patients with nonparaneoplastic limbic encephalitis, and some patients with paraneoplastic limbic encephalitis do not have demonstrable autoantibodies.

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