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Rasmussen's encephalitis (RE) is a rare condition of unknown etiology that causes a severe chronically neurological disorder with mostly affecting children. The main clinical feature of RE includes frequent seizures with drug-resistant, unilateral hemispheric atrophy, and progressive neurological deficits. In this review, we summarized five pathogenesis on the basis of the current research including virus infection, antibody-mediated degeneration, cell-mediated immunity, microglia-induced degeneration, and genetic mutations. So far, no exact virus in RE brain tissue or definite antigen in humoral immune system was confirmed as the determined etiology. The importance of cytotoxic CD8 + T lymphocytes and activated microglial and the role of their immune mechanism in RE development are gradually emerging with the deep study. Genetic researches support the notion that the pathogenesis of RE is probably associated with single nucleotide polymorphisms on immune-related genes, which is driven by affecting inherent antiretroviral innate immunity. Recent advances in treatment suggest immunotherapy could partially slows down the progression of RE according to the histopathology and clinical presentation, which aimed at the initial damage to the brain by T cells and microglia in the early stage. However, the cerebral hemispherectomy is an effective means to controlling the intractable seizure, which is accompanied by neurological complications inevitably. So, the optimal timing for surgical intervention is still a challenge for RE patient. On the contrary, exploration on other aspects of pathogenesis such as dysfunction of adenosine system may offer a new therapeutic option for the treatment of RE in future., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To evaluate the influencing factors and cognitive functional changes in Rasmussen encephalitis (RE) patients who received a hemispherectomy., Methods: Forty RE patients underwent a hemispherectomy with at least a 2 years follow- up were included in this study . Postoperative seizure outcomes were evaluated according to the Engle classification scale. Univariate analysis and a multivariate logistic regression model in a backward fashion were used to identify the potential predictors of cognitive function., Results: All 40 patients had an Engle classification outcome at a 2 years follow-up. Univariate and multivariate analyses revealed that seizure duration (OR 10.06, 95% CI 1.54-3.85, p = 0.038), age at surgery (OR 3.06, 95% CI 1.21-3.56, p = 0.043), and MRI score (OR 0.09, 95% CI 0.01-0.67 p = 0.024) are associated with postoperative cognitive outcomes respectively. Moreover,  VIQ and PIQ were negatively correlated linearly with duration of seizures and MRI score. Patients with a good VIQ and PIQ before the operation were more likely to have a better VIQ and PIQ postoperatively (p < 0.001 and p < 0.001, respectively). And, operation side is an important factor affecting cognitive function; therefore, a left hemispherectomy has a greater impact on the patient's IQ and language., Conclusions: RE patients' cognitive dysfunctions are improved after a hemispherectomy. Right-side operation can achieve better postoperative cognitive outcomes especially in VIQ and language. A shorter duration of seizures, early age at surgery, and less severe brain atrophy suggest better cognitive outcomes after a hemispherectomy.

Volumetric magnetic resonance imaging (MRI) atrophy is a hallmark of Rasmussen's encephalitis (RE). Here, we aim to investigate voxel-wise gray matter (GM) atrophy in RE, and its associations with glucose hypometabolism and neurotransmitter distribution utilizing MRI and PET data. In this study, fifteen RE patients and fourteen MRI normal subjects were included in this study. Voxel-wise GM volume and glucose metabolic uptake were evaluated using structural MRI and FDG-PET images, respectively. Spatial Spearman's correlation was performed between GM atrophy of RE with FDG uptake alterations, and neurotransmitter distributions provided in the JuSpace toolbox. Compared with the control group, RE patients displayed extensive GM volume loss not only in the ipsilateral hemisphere, but also in the frontal lobe, basal ganglia, and cerebellum in the contralateral hemisphere. Within the RE group, the insular and temporal cortices exhibited significantly more GM atrophy on the ipsilesional than the contralesional side. FDG-PET data revealed significant hypometabolism in areas surrounding the insular cortices in the ipsilesional hemisphere. RE-related GM volumetric atrophy was spatially correlated with hypomebolism in FDG uptake, and with spatial distribution of the dopaminergic and serotonergic neurotransmitter systems. The spatial concordance of morphological changes with metabolic abnormalities suggest FDG-PET offers potential value for RE diagnosis. The GM alterations associated with neurotransmitter distribution map could provide novel insight in understanding the neuropathological mechanisms and clinical feature of RE., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rasmussen encephalitis (RE) is a severe pediatric inflammatory brain disease characterized by unilateral inflammation and atrophy of the cerebral cortex, drug-resistant focal epilepsy and progressive neurological and cognitive deterioration. The etiology and pathogenesis of RE remain unclear. Our previous results demonstrated that the adenosine A1 receptor (A1R) and the major adenosine-removing enzyme adenosine kinase play an important role in the etiology of RE. Because the downstream pathways of inhibitory A1R signaling are modulated by stimulatory A2AR signaling, which by itself controls neuro-inflammation, glial activation and glial glutamate homeostasis through interaction with glutamate transporter GLT-1, we hypothesized that maladaptive changes in adenosine A2A receptor (A2AR) expression are associated with RE. We used immunohistochemistry and Western blot analysis to examine the expression of A2ARs, glutamate transporter-I (GLT-1) and the apoptotic marker Bcl-2 in surgically resected cortical specimens from RE patients (n = 18) in comparison with control cortical tissue. In lesions of the RE specimen we found upregulation of A2ARs, downregulation of GLT-1 and increased apoptosis of both neurons and astroglia. Double staining revealed colocalization of A2ARs and Bcl-2 in RE lesions. These results suggest that maladaptive changes in A2AR expression are associated with a decrease in GLT-I expression as a possible precipitator for apoptotic cell loss in RE. Because A2AR antagonists are already under clinical evaluation for Parkinson's disease, the A2AR might likewise be a tractable target for the treatment of RE., (© 2019 International Society of Neuropathology.)

Rasmussen's encephalitis (RE) is a rare pediatric neurological disorder, and the exact etiology is not clear. Viral infection may be involved in the pathogenesis of RE, but conflicting results have reported. In this study, we evaluated the expression of both Epstein-Barr virus (EBV) and human herpes virus (HHV) 6 antigens in brain sections from 30 patients with RE and 16 control individuals by immunohistochemistry. In the RE group, EBV and HHV6 antigens were detected in 56.7% (17/30) and 50% (15/30) of individuals, respectively. In contrast, no detectable EBV and HHV6 antigen expression was found in brain tissues of the control group. The co-expression of EBV and HHV6 was detected in 20.0% (6/30) of individuals. In particular, a 4-year-old boy had a typical clinical course, including a medical history of viral encephalitis, intractable epilepsy, and hemispheric atrophy. The co-expression of EBV and HHV6 was detected in neurons and astrocytes in the brain tissue, accompanied by a high frequency of CD8 + T cells. Our results suggest that EBV and HHV6 infection and the activation of CD8 + T cells are involved in the pathogenesis of RE.

Rasmussen's encephalitis (RE) is a rare pediatric neurological disorder, the etiology of which remains unclear. It has been speculated that the immunopathogenesis of RE involves damage to neurons, which eventually leads to the occurrence of RE. Viral infection may be a critical factor in triggering RE immunopathogenesis. In this study, we analyzed the expression of Epstein-Barr virus (EBV) antigens as well as of Toll-like receptor 3 (TLR3), TLR9, and downstream adapter TIRdomain-containing adapter-inducing interferon-β (TRIF) in the brain tissues of 26 patients with RE and 16 control individuals using immunohistochemistry (IHC). In the RE group, EBV antigens were detected in 53% of individuals at various expression levels. In contrast, there was no detectable EBV antigen expression in control brain tissues. Moreover, we found marked increases in the expression of TLR3, TLR9, and TRIF in the brain tissues of RE patients compared with levels in the control group. Furthermore, among RE cases, EBV expression and high TLR3 expression were associated with more severe brain atrophy. Our results suggest that the elevated expression of EBV and TLRs may be involved in RE occurrence through the activation of downstream molecules.

Rasmussen encephalitis (RE) is a rare neurological disorder characterized by unilateral inflammation of cerebral cortex and other structures, most notably the hippocampus, progressive cognitive deterioration, and pharmacoresistant focal epilepsy. The pathogenesis of RE with unilateral cortical atrophy and focal seizures is still enigmatic. Activation of adenosine A1 receptors (A1R) has been proven to prevent the spatial spread of seizures. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in neuronal A1R expression. Immunnohistochemistry was used to examine the expression of A1R and adenosine kinase (ADK) in cortical specimens from RE (n = 12), and compared with control cortical tissue. The quantification of A1R and ADK expression was evaluated by Western blot. A1R was predominantly localized in perinuclear of neurons and not in astrocytes or microglia. Upregulation of neuronal A1R was observed in the lesions of RE. Reactive astrocytes and subpopulation of remaining neurons demonstrated over-expression of the ADK within the lesions of RE. Significant increase of A1R and ADK expression in RE compared with controls was confirmed by Western blot. These results suggest that over-expression of ADK is a common pathologic hallmark of RE, and that upregulation of neuronal A1R in RE is crucial in preventing the spread of seizures., (© 2017 American Association of Neuropathologists, Inc. All rights reserved.)

Objective: To describe the surgery outcomes of RE patients in one centerto identify the indication for surgical treatment that results in the most favorable outcome., Method: Forty-five RE patients from a single center were retrospectively reviewed. Preoperative evaluations included assessments of clinical manifestations, cognitive status, a physical examination, MRI, positron emission tomography (PET), electroencephalography (EEG), and magnetoencephalography (MEG). The surgical outcomes included seizure outcome, neurological function, EEG, a cognitive evaluation, and antiepileptic drug withdrawal., Results: A total of 45 children (29 male) with RE were included in this study. The mean follow-up period from the first operation was 31.7months (range 6-96). The patients who underwent anatomical hemispherectomy or hemisphere disconnection had better seizure outcomes without greater perioperative complications compared with the patients who underwent functional hemispherectomy. Reoperative hemispherectomy was a safe and effective treatment for patients with postoperative epilepsy recurrence. After the last surgery, 34 patients (74.4%) were evaluated as Engel class I. Most of the patients had favorable neurological outcomes. Analysis revealed that the patientswith IQs greater 70 who underwent operations were more likely to suffer from IQ declines but were also more likely to have higher IQs in the future., Significance: Compared with functional hemispherectomy and hemisphere disconnection, anatomical hemispherectomy elicited better seizure outcomes with an acceptable level of complications. Early stage operations might lead to better cognitive status, but they are associated with a high risk of IQ decline., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rasmussen's encephalitis (RE) is a rare and severe progressive epileptic syndrome with unknown etiology. Infection by viruses, including human cytomegalovirus (HCMV), has been speculated to be a potential trigger for RE. However, no viral antigens have been detected in the brains of patients with RE; thus, a possible clinical linkage between viral infections and RE has not been firmly established. In this study, we evaluated the expression of HCMV pp65 antigen in brain sections from 26 patients with RE and 20 non-RE patients by immunohistochemistry and in situ hybridization, and assessed the associations between HCMV infection and clinical parameters. Elevated expression of HCMV pp65 protein and DNA was observed in 88.5% (23/26) and 69.2% (18/26) of RE cases, respectively. In the non-RE group, HCMV pp65 antigen was detected only in two cases (10%), both of which were negative for DNA staining. Additionally, the intensity of HCMV pp65 staining was correlated with a shorter duration of the prodromal stage, younger age of seizure onset, and more severe unilateral cortical atrophy. Elevated expression of HCMV pp65 was observed in RE brain tissue and was correlated with the clinical features of RE disease. In summary, our results suggested that HCMV infection may be involved in the occurrence and progression of RE disease. Thus, further studies are needed to determine whether early treatment with anti-HCMV antibodies could modulate the course of RE.

Objects: To investigate the expression of human papillomavirus (HPV)-specific antigen in the brain tissue of patients with Rasmussen's Encephalitis (RE) and its possible link to the clinical manifestation of RE., Methods: The correlation between RE and HPV antigen expression in brain tissue sections was investigated using immunohistochemical (IHC) staining, pathological examination, MRI and clinical manifestations., Results: HPV antigen expression was elevated in three out of four patients with RE, whereas there were no detectable HPV antigens in six control patients. Significant staining for HPV antigen was located mainly around or in the nucleus and cytoplasm of neurons. Among these RE patients, three with elevated expression of HPV antigens had obvious hemisphere atrophy, whereas the patient with negative staining for HPV antigens had mild atrophy., Conclusions: Elevated expression of HPV antigens was observed in the brain tissue of RE patients, which may correlate with hemisphere atrophy. Thus, our results may suggest that HPV infection or being a carrier of HPV may play a role in the initiation and progression of RE., (Copyright © 2016. Published by Elsevier B.V.)

Rasmussen encephalitis (RE) is a rare neurological disorder of childhood characterized by uni-hemispheric inflammation, progressive neurological deficits and intractable focal epilepsy. The pathogenesis of RE is still enigmatic. Activation of endogenous high-mobility group box-1 (HMGB1) and Toll-like receptor (TLR) has been proved to be with pro-inflammatory as well as pro-convulsant effects. We hypothesized that the epileptogenic mechanisms underlying RE are related to activation of HMGB1/TLR signaling. Immunnohistochemistry approach was used to examine the expression of HMGB1, TLR2, TLR4, receptor for advanced glycation end products (RAGE) in surgically resected human epileptic cortical specimens from RE (n=12), and compared that with control cortical issue (n=6). HMGB1 was ubiquitously detected in nuclei of astrocytes while its receptors were not detected in control cortex specimens. Marked expression of the receptors were observed in the lesions of RE. In particular, HMGB1 was in stead detected in cytoplasm of reactive astrocytes in RE cortex, predictive its release from glial cells. Significant greater HMGB1 and its receptors expression in RE vs. control was demonstrated by western blot. These results provide the novel evidence of intrinsic activation of these pro-inflammation pathways in RE, which suggest the specific targets in the treatment of epilepsy associated with RE., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Rasmussen encephalitis (RE) is a rare progressive encephalitis that results in intractable seizures, cognitive decline and hemiparesis. Surgery seems to be the only effective way to control seizures in RE patients., Objective: To describe the clinical, electrophysiological, neuroradiological and histological findings of our patients with RE and to evaluate the outcome of their surgical treatment., Methods: A total of 20 patients were identified by the criteria of RE. Surgery was conducted in the left hemisphere in 6 patients and in the right hemisphere in 14. The surgical methods included anatomical hemispherectomy, functional hemispherectomy, hemispherotomy, lesion resection, multilobar resection, selective resection and bipolar electrocoagulation of functional cortexes., Results: The mean follow-up period was 5.45 years (range 3-8). After surgery, 16 patients (80%) were evaluated as being Engel class I. All of the patients had increases in cognitive abilities after surgery except 1 patient with bilateral RE. After surgery, most patients could walk independently, but the fine movement of the hands was lost. Postoperative hydrocephalus was observed in 1 patient after functional hemispherectomy, and there was no death in this series., Conclusion: Hemispherectomy and hemispherotomy were both confirmed as beneficial procedures in controlling seizures and improving quality of the life in RE cases., (© 2014 S. Karger AG, Basel.)

Rasmussen encephalitis (RE) is a rare neurologic disorder of childhood characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable focal epilepsy. The pathogenesis of RE is still enigmatic. Adenosine is a key endogenous signaling molecule with anticonvulsive and anti-inflammatory effects, and our previous work demonstrated that dysfunction of the adenosine kinase (ADK)-adenosine system and astrogliosis are the hallmarks of epilepsy. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in ADK expression and that those changes might be associated with the development of epilepsy in RE patients. Immunohistochemistry was used to examine the expression of ADK and glial fibrillary acidic protein in surgically resected human epileptic cortical specimens from RE patients (n = 12) and compared with control cortical tissues (n = 6). Adenosine kinase expression using Western blot and enzymatic activity for ADK were assessed in RE versus control samples. Focal astrogliosis and marked expression of ADK were observed in the lesions of RE. Significantly greater ADK expression in RE versus controls was demonstrated by Western blot, and greater enzymatic activity for ADK was demonstrated using an enzyme-coupled bioluminescent assay. These results suggest that upregulation of ADK is a common pathologic hallmark of RE and that ADK might be a target in the treatment of epilepsy associated with RE.

Rasmussen encephalitis (RE) is a rare, chronic, inflammatory neurological disorder that usually affects one hemisphere of the brain. RE is characterized by frequent and severe seizures, progressive neurological dysfunction, and unilateral brain atrophy. This article documents a case of RE with bilateral involvement occurring at the age of 2. The patient's seizures consisted of focal motor seizures (epilepsia partialis continua in the fingers on the right hand); tonic convulsions of the right arm and head turning to the right with impairment of consciousness; and secondarily generalized tonic-clonic seizures. Antiepileptic drugs did not effectively control the seizures. The pathology of the left frontoparietal lobe biopsy of the abnormal MRI signal showed typical neuronal loss, abundant lymphocytic infiltration into the perivascular space, and numerous microglial nodules. Bipolar electrocoagulation on functional cortexes, which failed to alter the course of the illness, was followed by high-dose prednisone (about 2 weeks worth), without improvement. Both functional hemispherectomies and anatomical hemispherectomies failed to halt the course of the illness, and contralateral seizures developed and became apparent after the operation, suggesting bilateral RE., (Copyright © 2010 Elsevier Inc. All rights reserved.)