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.

Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis

“…In addition to their helper and cytotoxic functions, these CD4+ T-cells are hypothesized to promote CD8+ T-cell effector processes via secreted cytokines [ 1 ]. Our analysis highlights the heterogeneity of patient immune response to RE and could help explain why immunotherapy has been largely ineffective in controlling RE progression [ 58 ].…”

“…RE remains a disease with poorly understood etiology [ 17 , 58 ]. For a decade, studies have implicated microglia and their interaction with infiltrating T-cells in RE disease progression and neurodegeneration [ 42 , 43 , 62 ].…”

“…Lacking distinct disease biomarkers, diagnosis relies on clinical, morphological and electrophysiological criteria [ 41 ]. Atypical presentation can elude clinical diagnosis and there are no specific EEG abnormalities that can distinguish RE from other focal epilepsy [ 41 , 58 ]. Neuroimaging is used to identify the unilateral inflammation and atrophy that characterizes RE but is often negative in early stages [ 62 ].…”

Progress in pathogenesis and therapy of Rasmussen's encephalitis

“…Imaging features of MRI include cortical atrophy predominantly in the perisylvian distribution and caudate followed by putamen involvement, enlargement of ventricular system, cortical and subcortical hyperintensity on T2, and fluid-attenuated inversion recovery (FLAIR) sequence (Figure 1). 7,8 The hemispheric atrophy is gradual evident as the disease progress. The 18 F-fluorodeoxyglucosepositron emission tomography ( 18 F-FDG-PET), as a functional neuroimaging, showed diffuse cerebral hypometabolism in the affected hemisphere, especially insular lobe.…”

COVID-19-associated severe mono-hemispheric encephalitis in a young infant

“…Another important peculiarity of this case is the exclusive unilateral cerebral involvement that is reported only in rare autoimmune encephalitis such as the Rasmussen syndrome, a rare neurological disease, characterized by progressive atrophy of the unilateral hemisphere and clinically by epilepsia partialis continua, invariably hemiparesis, and cognitive impairment. Interestingly, one of the pathogenic hypotheses to explain the mono-hemispheric involvement in the Rasmussen encephalitis is the slow progression of a viral infection and immunotherapy; in particular, steroids or IVIg is one of the first-line treatments in addition to anti-epileptic drugs [ 5 ].…”