An immunotherapy effect analysis in Rasmussen encephalitis

Abstract

Background Immune-mediated mechanisms substantially contribute to the Rasmussen encephalitis (RE) pathology, but for unknown reasons, immunotherapy is generally ineffective in patients who have already developed intractable epilepsy; overall laboratory data regarding the effect of immunotherapy on patients with RE are limited. We analyzed multiple samples from seven differently treated children with RE and evaluated the effects of immunotherapies on neuroinflammation. Immunotherapy was introduced to all patients at the time of intractable epilepsy and they all had to undergo hemispherothomy. Methods Immunohistochemistry, flow cytometry, Luminex multiplex bead and enzyme-linked immunosorbent assay techniques were combined to determine: 1) inflammatory changes and lymphocyte subpopulations in 45 brain tissues; 2) lymphocyte subpopulations and the levels of 12 chemokines/cytokines in 24 cerebrospinal fluid (CSF) samples and 30 blood samples; and 3) the dynamics of these parameters in four RE patients from whom multiple samples were collected. Results Sustained T cell-targeted therapy with cyclophosphamide, natalizumab, alemtuzumab, and intrathecal methotrexate (ITMTX), but not with azathioprine, substantially reduced inflammation in brain tissues. Despite the therapy, the distributions of CD8+ T cells and the levels of C-X-C motif ligand (CXCL) 10, CXCL13, and B cell activating factor (BAFF) in patients’ CSF remained increased compared to controls. A therapeutic approach combining alemtuzumab and ITMTX was the most effective in producing simultaneous reductions in histopathological inflammatory findings and in the numbers of activated CD8+ T cells in the brain tissue, as well as in the overall CD8+ T cell population and chemokine/cytokine production in the CSF. Conclusions We provide evidence that various T cell-targeted immunotherapies reduced inflammation in the brains of RE patients. The observation that intractable epilepsy persisted in all of the patients suggests a relative independence of seizure activity on the presence of T cells in the brain later in the disease course. Thus, new therapeutic targets must be identified. CXCL10, CXCL13 and BAFF levels were substantially increased in CSF from all patients and their significance in RE pathology remains to be addressed.

Seizure control after late introduction of anakinra in a patient with adult onset Rasmussen’s encephalitis

“…This is interesting because neuropathological and immunological studies support the theory that RE is probably driven by a response to one or more antigenic epitopes, with potential additional contribution by autoantibodies [4] . The mode of action of anakinra differs from those of the substances used in the study by Liba et al [6] . IL-1Ra has been used in the treatment of FIRES.…”

“…Rasmussen’s encephalitis (RE) is a slowly progressive disease characterized by drug-resistant focal epilepsy often in the form of Epilepsia Partialis Continua, hemiparesis and progressive cognitive decline with cerebral hemiatrophy [3] , [4] , [5] . Neuropathological and immunological studies support the notion that RE is an immune-mediated disease associated with both adaptative immune reactions, with T-lymphocyte responses, and microglia-induced degeneration [4] , [6] .…”

“…A recent publication from Liba et al, reported on seven patients with RE who were treated with different immunosuppressive agents [6] , but none of medications was targeting IL-1R. Although T cell-targeted therapy substantially reduced inflammation in brain tissues, intractable epilepsy persisted clinically in these patients.…”

Medical treatment of Rasmussen's Encephalitis: A systematic review

“…Another case report did not find efficacy of natalizumab [59]. Liba et al also reported that in a patient without clinical efficacy of natalizumab and who underwent hemispherotomy, the inflammatory load and T-cell infiltration in the brain tissue was lower than with other immunotherapy (cyclophosphamide) [81] (Table 7). In view of the experimental data in mice (efficacy if used early, ineffectiveness once the acute phase has passed) [27], it would seem useful to study its efficacy in the very early phase of the disease.…”

Rasmussen’s encephalitis: mechanisms update and potential therapy target

“… 89 Another recent research study into the effectiveness of different immunotherapies reported that drugs targeting T-cells, such as cyclophosphamide, natalizumab and alemtuzumab, but not azathioprine, could reduce the inflammatory reaction of RE patients. 90 At present, there is more and more research into RE immunotherapy, with most studies focusing on the positive effectiveness of treatments, causing failed attempts to be neglected. Despite research into various immunotherapeutic strategies, therapeutic effects required to be verified through multicenter and large sample studies.…”