Clinical and Immunological Diversity of Limbic Encephalitis: A Model for Paraneoplastic Neurologic Disorders

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Historical Remarks

Limbic encephalitis causes impressive deficits that are characteristically dominated by rapid and severe loss of short-term memory, but recognition of this syndrome did not occur until the 1960s, when most other PNDs were already known. It was Brierley and colleagues [8] who initially reported three patients who had “subacute encephalitis of later adult life, mainly affecting the limbic areas”; two of the patients had evidence of cancer (one confirmed at autopsy), but the investigators

Recognizing the Syndrome

Paraneoplastic limbic encephalitis usually presents with irritability, depression, insomnia or hypersomnia, seizures, hallucinations, and short-term memory loss that may progress to frank dementia [14]. Psychomotor or temporal lobe seizures predominate over generalized seizures [15]. Most patients have EEG abnormalities that may include foci of epileptic activity in one or both temporal lobes or focal or generalized slow activity [16]. In patients who have seizures, the memory deficits can be

Recognizing the Paraneoplastic Etiology

There are several disorders unrelated to cancer that may cause limbic dysfunction (Table 2). A paraneoplastic etiology can only be established with the demonstration of paraneoplastic antibodies in serum or CSF or with the demonstration of a tumor [4]. Neuropathologic studies do not establish a paraneoplastic etiology, because similar inflammatory infiltrates, neuronal loss, microglial activation, and gliosis can be observed in non-paraneoplastic disorders.

The antibodies that are reliable

Diagnostic Dilemmas

In 40% to 50% of patients who have a clinical syndrome compatible with limbic encephalitis, no paraneoplastic antibodies are identified [14], [20]. Additionally there are other patients whose symptoms of limbic dysfunction are atypical or develop in association with clinical and neuroimaging findings, suggesting involvement outside the limbic system [21]. Because the CSF of these patients often demonstrates pleocytosis and intrathecal IgG synthesis, and because symptoms may respond to

Encephalitis Associated with Antibodies Against the Neuropil and Dendrites of Hippocampus

Using modified immunohistochemical techniques, Ances and colleagues [6] found that patients who had encephalitis predominantly involving the temporal lobes harbored serum or CSF antibodies to antigens expressed in the cell membrane of neurons and dendritic processes of the neuropil of the hippocampus. These antibodies are detected using paraformaldehyde fixed tissue from nonperfused animals and are missed by immunoblot, immunoprecipitation with dendrotoxin (used to detect VGKC antibodies), and

Clinical-Immunologic Phenotypes of Paraneoplastic Limbic Encephalitis

Based on these studies the authors propose three groups of immune-mediated limbic encephalitis, each likely including several sub-phenotypes as outlined here and in Table 3.

Summary

The authors recently proposed a logical approach to the management of limbic encephalitis and postulated that many patients who do not have well-characterized antineuronal antibodies harbor novel immune responses. This approach takes into consideration the type of syndrome, the neuroimaging and CSF findings, and whether the autoantigens are intracellular or located in the cell membrane. Disorders related with the first class of autoantigens usually associate with antibodies and cytotoxic T-cell

Acknowledgment

This work has been supported in part by RO1CA89054 and RO1CA107192 (JD). We thank Dr. Myrna R. Rosenfeld for critical review of the manuscript.

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