Rasmussen's encephalitis: mechanisms update and potential therapy target

Abstract

Rasmussen's encephalitis (RE) is rare neurological diseases characterized as epilepsia partialis continua, invariably hemiparesis, and cognitive impairment. This disease is encountered frequently in childhood and presents with progressive atrophy of the unilateral hemisphere, and there are also sustained neurological complications. Owing to uncertain pathogenesis, the most effective way to limit the influence of seizures currently is cerebral hemispherectomy. In this review, we focus on four main lines of pathogenesis: virus infection, antibody-mediated, cell-mediated immunity, and microglia activation. Although one or more antigenic epitopes may give rise to infiltrating T cell responses in RE brain tissue, no exact antigen was confirmed as the definite cause of the disease. On the other hand, the appearance of antibodies related with RE seem to be a secondary pathological process. Synthetic studies have suggested an adaptive immune mechanism mediated by CD8⁺ T cells and an innate immune mechanism mediated by activated microglia and neuroglia. Accordingly, opinions have been raised that immunomodulatory treatments aimed at initial damage to the brain that are induced by cytotoxic CD8⁺ T cell lymphocytes and microglia in the early stage of RE slow down disease progression. However, systematic exploration of the theory behind these therapeutic effects based on multicenter and large sample studies are needed. In addition, dysfunction of the adenosine system, including the main adenosine removing enzyme adenosine kinase and adenosine receptors, has been demonstrated in RE, which might provide a novel therapeutic target for treatment of RE in future.

Keywords: Rasmussen’s encephalitis; adenosine; cytotoxic T cells; microglia activation; pathogenesis; therapeutic directions.

Figure 1.

MRI imaging features of RE. This is a 5-year-old patient; image acquisition was at 17 months after seizure onset. (A–F) Left hemisphere atrophy in T1, T2, and T2 FLAIR image from axial and coronal scan. (G–H) PET showed left hemisphere hypometabolism. (I–J) T2 FLAIR image after surgical treatment of anatomic hemispherectomy. (K) EEG showing focal slow wave activity in the left hemisphere, which increased during the interictal period. (L) EEG showing EPC at right lower limbs in the ictal period. EEG, electroencephalography; EPC, epilepsia partialis continua; MRI, magnetic resonance imaging; PET, positron emission tomography; RE, Rasmussen encephalitis.

Figure 2.

Characteristic neuropathological changes of RE. (A) Perivascular lymphocytic cuffing (arrow, H&E staining). (B) Microglial nodule formation (arrow, H&E staining). (C) Neuron undergoing neuronophagia (H&E stain). (D) Neuronal degeneration in the cerebral cortex (H&E stain). (E) Parenchymal lymphocytic in the cerebral cortex (arrows, CD8 immunostaining). (F) Perivascular lymphocytic cuffing in the cerebral cortex (CD8 immunostaining). H&E, hematoxylin and eosin; RE, Rasmussen encephalitis.