Patients with limbic encephalitis present with symptoms attributed to dysfunction of mesial temporal lobe regions of the brain such as the hippocampus. Prominent symptoms include short-term memory loss, behavioral disturbances such as agitation and confusion, and psychiatric problems such as depression and psychosis. Recurrent seizures are a salient feature and often progress to status epilepticus. Limbic encephalitis may occur in the absence of malignancy.
Cerebrospinal fluid analysis may be normal or show mild pleocytosis, elevated protein, increased immunoglobulin G synthesis, and oligoclonal banding. In about 60% of patients, MRI shows hyperintense fluid-attenuated inversion recovery (FLAIR) or T2 signal changes in the mesial temporal lobes, reflecting inflammatory changes.
Autoantibodies identified in autoimmune encephalitis fall under two broad categories:
- Those targeting intracellular (nuclear or cytoplasmic) antigens. Autoantibodies directed to intracellular antigens are believed to arise after cytotoxic T lymphocyte mediated cell injury and exposure of antigens. These syndromes are more likely to be paraneoplastic, cause extensive neuron loss and be less responsive to immunotherapy
- Those targeting antigens on the neuronal surface such as membrane receptors and ion channels. They alter the structure and function of membrane receptors or ion channels, causing neurologic dysfunction. These syndromes are less likely to be paraneoplastic and more likely to respond to immunotherapy.
Autoantibodies associated with limbic encephalitis are summarized in the following table.
| Antigen Location | Antibody | Cancer Frequency | Cancer Association | Neurologic Syndrome |
| Intracellular | ANNA1 (anti-Hu) | >75% | Small Cell Lung | Multiple types |
| Anti-CRMP | >75% | Small cell lung & thymoma | Uveitis, optic neuritis, cerebellar | |
| Anti-Ma2 | ~90% | Testicular germ cell | Limbic or brainstem | |
| Anti-GAD65 | <33% | None | Stiff person syndrome | |
| Cell surface | Anti-NMDA receptor | 38% | Ovarian teratoma | limbic to brainstem |
| Anti-LGI1 | 0 | None | limbic with faciobrachial dystonic seizures | |
| Anti-AMPA receptor | 70% | Thymoma & Breast | limbic | |
| Anti-GABA B receptor | 47% | Small cell lung | limbic |
LGI1 autoantibodies are the most common causes of limbic encephalitis followed by autoantibodies against gamma aminobutyric acid (GABA) type B receptor and autoantibodies against alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Limbic encephalitis can also be associated with paraneoplastic syndromes associated with autoantibodies against intracellular antigens Hu, Ma2, and GAD65.
Reference
Jammoul A et al. Cleveland Clinic Journal of Medicine. 2016 January;83(1):43-53.
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