Paraneoplastic limbic encephalitis

Francesc Graus MD PhD (Dr. Graus of the University of Barcelona has no relevant financial relationships to disclose.)
Rimas V Lukas MD, editor. (Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from AstraZeneca as an advisory board member and AbbVie as a guest speaker and advisory board member.)
Originally released May 17, 1994; last updated August 1, 2018; expires August 1, 2021

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 autoimmune encephalitides characterized by the predominant involvement of the limbic system. Patients present with subacute onset of confusion, behavior changes, short-term memory loss, and seizures. Brain MRI shows hyperintense lesions in T2-weighted and FLAIR images involving the medial aspects of temporal lobes. Small cell lung carcinoma is the most common associated neoplasm followed by testicular germ cell tumors, thymomas, and Hodgkin disease. The presence of antineuronal antibodies in patients with limbic encephalitis supports an autoimmune pathogenesis and can guide the search for an underlying tumor. Since the initial description of antibodies that recognized antigens present in the nucleus or cytoplasm of tumor cells and neurons (onconeural antibodies), there has been an ever-growing number of circulating antineuronal antibodies associated with paraneoplastic and nonparaneoplastic limbic encephalitis, and other autoimmune encephalitis that targets neuronal surface antigens. Unlike onconeural antibodies, antibodies against surface antigens do not always indicate that the limbic encephalitis is paraneoplastic, but patients harboring these antibodies usually improve with immunotherapy and they have a more favorable outcome.

Key points

 

• 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.

 

• The diagnosis of paraneoplastic limbic encephalitis requires the presence of a clinical syndrome that fulfills established criteria of limbic encephalitis and the diagnosis of a tumor within the 5 years of diagnosis of the limbic encephalitis.

 

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

 

• The presence of antineuronal (“onconeural”) antibodies or specific antibodies against neuronal surface antigens in a patient with limbic encephalitis raises suspicion for an underlying tumor and can guide the search for the tumor.

 

• A varying proportion of patients with paraneoplastic limbic encephalitis show neurologic improvement with successful tumor treatment or immunosuppressive therapy.

 

• Early diagnosis, the association with antibodies against surface antigens, and prompt treatment increase the likelihood of success.

Historical note and terminology

Paraneoplastic limbic encephalitis as a clinicopathologic entity was first described by Corsellis and colleagues in 1968 (Corsellis et al 1968). Although previous reports had identified the syndrome (Brierley et al 1960), the paper by Corsellis was the first to indicate a potential association of the neurologic symptoms with the underlying cancer. 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 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 (Dalmau and Graus 2018), 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 Hodgkin disease; (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. Analogous to Lambert-Eaton myasthenic syndrome, limbic encephalitis may be idiopathic or have a paraneoplastic etiology. Presently, the nonparaneoplastic form of limbic encephalitis associated with LGI1 antibodies (Irani et al 2010; Lai et al 2010; Vincent et al 2011) is much more frequent than the paraneoplastic limbic encephalitis associated with different types of antibodies.

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 5 years of onset of the neurologic syndrome. The presence of onconeural antibodies (HU, CRMP5, Ma2) or some types of antibodies against neuronal surface receptors, mainly GABAbR or AMPAR antibodies in a patient with limbic encephalitis increases suspicion for an underlying neoplasm, but some patients with paraneoplastic limbic encephalitis do not have demonstrable autoantibodies (Graus et al 2018).

It must be emphasized that not all paraneoplastic encephalitis can be defined as limbic encephalitis. For example, the most common autoimmune encephalitis is that associated with NMDAR antibodies and up to 58% of women between 18 and 35 years with this encephalitis harbor an underlying ovarian teratoma. These women have a paraneoplastic encephalitis but the clinical and radiological profile is very different from that of limbic encephalitis (Dalmau et al 2008; Dalmau et al 2011; Titulaer et al 2013). In a study a panel of neurologists proposed the following clinical criteria to make the diagnosis of limbic encephalitis before the results of the determination of antineuronal antibodies or finding a tumor: (1) subacute onset (rapid progression < 3 months) of working memory deficit (“short-term memory loss”), seizures, or psychiatric symptoms suggesting involvement of the limbic system; (2) bilateral MRI FLAIR/ T2 abnormalities highly restricted to medial temporal lobes; (3) CSF pleocytosis (WBC > 5/mm3) or EEG with epileptic or slow activity involving the temporal lobes; and (4) reasonable exclusion of alternative causes (Graus et al 2016). These criteria should raise the diagnostic confidence and support the onset of immunotherapy as soon as possible.

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