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  • Updated 06.01.2021
  • Released 05.17.1994
  • Expires For CME 06.01.2024

Paraneoplastic limbic encephalitis

Introduction

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 neuronal 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 intracellular antigens present in tumor cells and neurons (onconeural antibodies), there has been an ever-growing number of circulating neuronal 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 short-term memory loss, seizures, and psychiatric disturbance.

• The definite diagnosis of paraneoplastic limbic encephalitis requires: (1) the presence of a clinical syndrome that fulfills established criteria of limbic encephalitis, (2) a positive neuronal antibody associated with paraneoplastic neurologic syndromes, and (3) the diagnosis of a tumor within 5 years of limbic encephalitis diagnosis.

• 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 onconeural antibodies or particular 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.

• Early diagnosis, the association with antibodies against surface antigens, and prompt treatment increase the likelihood of response to tumor treatment and immunotherapy.

Historical note and terminology

Paraneoplastic limbic encephalitis as a clinicopathologic entity was first described in 1968 (18). Although previous reports had identified the syndrome (15), the paper by Corsellis was the first to indicate a potential association of the neurologic symptoms with the underlying cancer. Starting in the mid-1980s, the discovery of anti-Hu (ANNA1) antibodies in some patients lent support to an autoimmune pathogenesis of paraneoplastic limbic encephalitis. Until year 2000, limbic encephalitis was believed to occur nearly always in association with a neoplasm, usually small cell lung carcinoma or, rarely, other tumors (41). However, studies over the past 10 to 15 years have yielded much new information (21), 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, neuronal 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 (51; 57; 97) is much more frequent than the paraneoplastic limbic encephalitis associated with several types of antibodies.

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 (23; 89). 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 (39). These criteria should raise the diagnostic confidence and support the onset of immunotherapy as soon as possible.

Abnormalities in temporal lobes indicative of limbic encephalitis

Axial FLAIR MRI showing increased signal abnormalities in the medial aspect of temporal lobes (arrows). (Contributed by Dr. Francesc Graus.)

Table 1. Diagnostic Criteria of Limbic Encephalitis

All 4 of the following requirements:*

(1) Subacute onset (rapid progression < 3 months) of working (“short-term memory loss”) and episodic memory deficit, seizures, or psychiatric symptoms suggesting involvement of the limbic system.

(2) Bilateral MRI FLAIR/T2 abnormalities highly restricted to amygdala and medial temporal lobes.**

(3) At least 1 of the following:

(a) CSF pleocytosis (WBC > 5/mm3)

(b) EEG with epileptic or slow activity involving the temporal lobes

(4) Reasonable exclusion of alternative causes.

* If 1 of the first 3 requirements is missing the level of “definite” and can only be reached by the detection of antibodies against cell surface, synaptic, or onconeural proteins.
** [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) can be used to fulfil this requirement.


(39)

The definite diagnosis of paraneoplastic limbic encephalitis requires, in addition to the criteria summarized in Table 1, the presence of a neuronal antibody and the histological confirmation of a tumor concordant with the antibody detected (for example anti-Hu and small cell lung cancer). If the tumor found is not expected, the expression by the tumor cells of the antigen recognized by the associated neuronal antibody is required for a definite diagnosis of paraneoplastic limbic encephalitis (40). Although the presence of a neuronal antibody is required for a definite diagnosis, it is important to remember that approximately 10% of patients with paraneoplastic limbic encephalitis do not have demonstrable neuronal antibodies (35).

Expression of Hu antigen in a patient with sensory neuronopathy, Hu antibodies, and breast cancer

Photomicrograph of tumor immunostained with biotinylated anti-Hu IgG showing staining of some nuclei of tumor cells (dark blue color). Counterstaining with hematoxylin produces the light blue color of the negative cell nuclei. ...

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