Rasmussen's Encephalitis Research Articles

Rasmussen encephalitis treated with natalizumab

Rasmussen encephalitis (RE) is characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable seizures. Inflammatory lesions consist of oligoclonally expanded cytotoxic CD8+ T cells attacking neurons and astrocytes.1 Immunotherapies may slow down tissue and function loss, whereas convincing effects on seizure activity have rarely been reported.2 Functional hemispherectomy (HE) is highly effective for elimination of seizures but can only be offered if no indispensable function resides in the affected hemisphere.1 We present a patient with such an HE contraindication who was treated with natalizumab, a blocker of T-cell entry into the CNS. Acknowledgment: The authors thank O. Grauer and C. Gross for supervision of the flow cytometric experiments.

Disease-specific molecular events in cortical multiple sclerosis lesions

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis.

Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response

BackgroundRasmussen encephalitis (RE) is a rare complex inflammatory disease, primarily seen in young children, that is characterized by severe partial seizures and brain atrophy. Surgery is currently the only effective treatment option. To identify genes specifically associated with the immunopathology in RE, RNA transcripts of genes involved in inflammation and autoimmunity were measured in brain tissue from RE surgeries and compared with those in surgical specimens of cortical dysplasia (CD), a major cause of intractable pediatric epilepsy.MethodsQuantitative polymerase chain reactions measured the relative expression of 84 genes related to inflammation and autoimmunity in 12 RE specimens and in the reference group of 12 CD surgical specimens. Data were analyzed by consensus clustering using the entire dataset, and by pairwise comparison of gene expression levels between the RE and CD cohorts using the Harrell-Davis distribution-free quantile estimator method.ResultsConsensus clustering identified six RE cases that were clearly distinguished from the CD cases and from other RE cases. Pairwise comparison showed that seven mRNAs encoding interferon-γ, CCL5, CCL22, CCL23, CXCL9, CXCL10, and Fas ligand were higher in the RE specimens compared with the CD specimens, whereas the mRNA encoding hypoxanthine-guanine phosphoribosyltransferase was reduced. Interferon-γ, CXCL5, CXCL9 and CXCL10 mRNA levels negatively correlated with time from seizure onset to surgery (P <0.05), whereas CCL23 and Fas ligand transcript levels positively correlated with the degree of tissue destruction and inflammation, respectively (P <0.05), as determined from magnetic resonance imaging (MRI) T2 and FLAIR images. Accumulation of CD4+ lymphocytes in leptomeninges and perivascular spaces was a prominent feature in RE specimens resected within a year of seizure onset.ConclusionsActive disease is characterized by a Th1 immune response that appears to involve both CD8+ and CD4+ T cells. Our findings suggest therapeutic intervention targeting specific chemokine/chemokine receptors may be useful in early stage RE.

Rasmussen's encephalitis: a clinicopathologic study

Objective To discuss the clinicopathologic characteristics of surgically-removed tissues in patients with Rasmussen' s encephalitis.Methods The clinicopathologic features and immunohistochemical profiles of 6 patients with Rasmussen encephalitis (age range,3.5-11years at surgery) were retrospectively reviewed.Results All patients had medically intractable seizures (1 to 4 years duration) ; all developed unilateral hemiparesis.Histologically,all cases were characterized by diffuse proliferation of microglial cells,and focal microglial nodule formations.All cases showed intraparenchymal lymphocytic infiltrate.5 cases showed perivascular cuffing by lymphocytes.3 cases showed lymphocytic meningitis.All the lymphocytes consist of primarily of T cell immunophenotype (CD3 +,CD5 +,CD7 +).A predominance of CD8 + lymphoid cells was observed.All cases had rare B lymphocytes (CD79a-,CD20-).Viral inclusions were not noted.Conclusions Most lymphoid cells in Rasmussen's encephalitis have a T--cytotoxic immunophenotype.Hemispherectomy is the only effective therapy. Key words: Rasmussen's encephalitis; Epilepsy; Hemispherectomy; Chronic encephalitis

Rituximab and Cyclophosphamide as an alternative in immunomodulatory therapy in Rasmussen encephalitis

Rituximab and Cyclophosphamide as an alternative in immunomodulatory therapy in Rasmussen encephalitis

Clinico‐pathological investigations of Rasmussen encephalitis suggest multifocal disease progression and associated focal cortical dysplasia

Rasmussen encephalitis is a devastating neurological disorder characterised by seizures, brain inflammation, and progressive hemispheric atrophy. The objective of the current study was to systematically characterise patterns of structural lesions in children with Rasmussen encephalitis, referred for modified anatomical hemispherectomy at the Tsinghua University Epilepsy Center in Beijing. Seven consecutive patients were investigated with a mean age at operation of 4.5 years, who suffered from medically intractable seizures for a mean of 1.6 years. Foci of abnormally increased T2 signal intensity were observed in all patients. With the exception of one child, all patients presented with progressive unilateral cerebral atrophy. FDG-PET imaging revealed extensive regions of hypometabolism within the affected cerebral hemisphere in 3 of 4 patients. Diagnosis of Rasmussen encephalitis was confirmed histologically, demonstrating CD68 positive microglial nodules, as well as CD3 and CD8 positive Tlymphocytes invading the cerebral parenchyma. An intriguing observation was the heterogenous distribution of patterns of lesions throughout the affected hemisphere, suggesting multifocal manifestation and distinct sequences of disease progression, from discrete foci of inflammatory infiltrates (stage 1) to extensive cortical destruction (stage 4). Atypical hippocampal sclerosis (HS), with neuronal cell loss affecting most prominently the CA4 region (HS type 3 or end folium sclerosis), was evident in 5 of 7 cases. Four hippocampi also showed chronic inflammation. In addition, we observed associated focal cortical dysplasia (FCD; ILAE type IIId) in 4 of 7 children, supporting the concept of acquired and postmigratory FCD pathomechanisms. Postsurgical seizure freedom was achieved in all children with a mean follow-up period of 2.7 years and continuous antiepileptic medication.

Immunomodulatory therapy versus surgery for Rasmussen syndrome in early childhood

We examined seizure, cognitive, and motor outcomes in patients with Rasmussen syndrome or Rasmussen encephalitis (RS), after recent initiation of immunomodulatory therapies. Among 53 patients with a diagnosis of RS referred from all over Japan, 49 patients (male 22, female 27) with symptoms and findings characteristic of RS were evaluated. Regular intravenous immunoglobulin (IVIg) therapy was administered at a dose of 100mg/kg/day, etc. Regular steroid pulse therapy was conducted with methylprednisolone at a dose of 30mg/kg/day (children) or 1000mg/day (adults) for 3days. Tacrolimus was given at an initial dose of 0.1mg/kg/day (children). Mean onset age was 8.7±10.5years. Seizure-free rate was 71% after treatment by functional hemispherectomy (FH), and response rate for seizures was 81% by regular steroid pulse therapy, 42% by tacrolimus therapy, and 23% by regular IVIg therapy. Rate of patients with IQ higher than 80 (R80) was 50% by regular steroid pulse therapy, 43% by regular IVIg therapy, 29% by tacrolimus therapy, and 0% by FH. R80 after regular steroid pulse therapy was 100% in patients without MRI lesions, and 37% in those with advanced MRI lesions. Improvement of motor function (paresis) was observed only by immunomodulatory therapy. Motor function was aggravated in 100% of patients treated by FH, 62% by regular IVIg, and 10% by regular steroid pulse therapy. We suggest a new treatment strategy for RS using early immunomodulatory therapy: initiation of regular steroid pulse therapy after early diagnosis indicated by biomarkers, then switching to tacrolimus therapy after several months.

Altered transporter‐mediated neocortical GABA release in Rasmussen encephalitis

To learn whether epileptic seizures in Rasmussen encephalitis (RE) may be promoted by insufficient γ-aminobutyric acid (GABA) release. (3) H-GABA was released from neocortical synaptosomes through transporter reversal following intrasynaptosomal Na(+) accumulation by veratridine that prevents inactivation of Na(+) channels. Tissues of three RE patients were compared with those of nine non-RE. In RE, the release was markedly reduced. In non-RE, the extracellular Ca(2+) concentration ([Ca(2+) ]e ) was inversely related to the amount of release. In RE, the percental decline of additional release upon Cae 2+ withdrawal was linked with the presurgical duration of epilepsy. Permanent opening of Na(+) channels by veratridine resembles maximal frequency of action potentials corresponding to epileptic seizures. These are preceded by a fall in [Ca(2+) ]e . Zero [Ca(2+) ]e increased release through the Na(+) /Ca(2+) exchanger additionally elevating intrasynaptosomal Na(+) . This enhanced GABA release probably reflects an antiseizure mechanism. In RE, the additional release gets lost over epilepsy duration.

Bilateral Rasmussen's encephalitis associated with type II focal cortical dysplasia: Dormant 'second' epileptogenic zone in contralateral disease.

Rasmussen's encephalitis (RE) is an inflammatory, probably autoimmune disorder manifested by refractory seizures and progressive deterioration of one cerebral hemisphere [1].Here, we describe the unfortunate history of a girl with a progressive disorder which, upon clinical, neuroimaging, and histopathological evaluation, proved to be bilateral RE associated with type II focal cortical dysplasia. Whether the second pathology is relevant for the extent of the disease is discussed.We demonstrated histopathological evidence of RE and type II FCD in the left hemisphere, which led to EPC on the right hemibody at presentation. In addition, there was unequivocal progressive cortical and subcortical atrophy of the right hemisphere, which accounted for the EPC on the left hemibody. This is highly compatible with RE (+/− FCD) in the right hemisphere as well. Although the association of FCD and RE – as well as the occasional occurrence of bilateral RE – has already been reported [3–5], this is the first such case in which bilateral RE and FCD co-occur.

Rasmussen′s encephalitis

Rasmussen's encephalitis is an uncommon chronic inflammatory disease disorder of unknown etiology. The aim of this report was to create an awareness of Rasmussen's encephalitis in our clinical practice in Africa. We searched online for literature on Rasmussen's encephalitis with an emphasis on documented cases in Africa and in blacks all over the world. Master F.M., a 14-year-old male, presented with history of recurrent seizures on three occasions. The first was after an upper respiratory tract infection, the second was a post-complicated meningo-encephalitis and the third episode was associated with receptive aphasia, hemiparesis and intellectual impairment. Neuroimaging studies revealed cerebellar atrophy and infarction of territory of the middle cerebral artery. His electroencephalogram showed bi-frontal theta activity left>right and poly spikes left>>right, diagnostic of complex partial seizures. In a period of 12 months, his gait and speech had improved while his intellectual impairment permitted re-admission into a lower academic class. He is presently on phenytion and prednisolone tablets only. Master F.M. had all the clinical features buttressed with neuroimaging results of a clinically probable Rasmussen's encephalitis. However, an advanced neuroimaging study is needed to detect and quantify hemispherical volume loss.

Evolución posquirúrgica en pacientes con encefalitis de Rasmussen operados por hemisferotomía

Rasmussen's encephalitis (RE) is a progressive pathology affecting the brain that causes unilateral hemispheric atrophy, neurological dysfunction and refractory epilepsy. Hemispherotomy is considered the most effective treatment today, but some cases present certain peculiarities that can seriously affect the decision to go ahead with this procedure. To evaluate the post-operative progress made by children with RE who have undergone hemispherotomy surgery, and who, in the pre-operative assessment, presented certain characteristics that complicated the decision to perform surgery. The sample selected for study consisted of the cases of RE attended in the Hospital Sao Paulo between 2003 and 2012 who, in the pre-surgery evaluation, presented clinical, electroencephalographic or neuroimaging evidence of involvement of both brain hemispheres, compromise of the dominant brain hemisphere, absence of severe neurological deficit and absence of criteria for refractory epilepsy and atypical crises. The post-operative assessment of the epileptic seizures was evaluated using the Engel scale; motor function was analysed with the Gross Motor Function Classification System and Manual Ability Classification System scales, and language was evaluated clinically. Six cases were selected (four girls), with a mean age at clinical onset of 3.3 ± 1.2 years (range: 2-7 years) and a mean age at hemispherotomy of 6.7 years (range: 2.3-16.5 years). The mean post-surgery follow-up time was three years (range: 0.5-7.2 years). In the post-surgery evaluation of the epileptic seizures, four cases were classified as Engel class I (66%); there was some improvement in motor functioning in five of them, and language improved in all cases. Hemispherotomy must be considered an efficient option for treatment in children with RE.

The Ultimate Stage of Rasmussen?s Encephalitis

Rasmussen encephalitis (RE) is a rare and progressive disease of childhood. We report the case of 14-year-old girl who presented with recurrent partial and generalized epileptic seizures with mental impairment and progressive left sided hemiplegia. EEG showed slowing of the background activity and paroxysmal discharges of slow waves in the right hemisphere. Serial MRI brain scans revealed an important atrophy of the right hemisphere with dilatation of the ipsilateral lateral ventricle. The residual phase, characterized by decrease in seizure frequency and stabilization in the hemiparesis, constitute the ultimate stage of RE.

Child Neurology: Hemiconvulsion-hemiplegia-epilepsy syndrome

I read with interest the clinical case of a 21-month-old boy with hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome reported by Drs. Tenney and Schapiro.1 The authors do not mention Rasmussen encephalitis (RE) – also known as chronic focal encephalitis. In the acute stage, RE may have a presentation identical to the authors' case with frequent and often intractable seizures, regression of motor skills and speech, hemiparesis, and cognitive decline. The disorder is classically characterized by inflammation of one hemisphere and in the acute phase patients may present with focal onset seizures and almost no hemiparesis. Progression of the disease course is accompanied by increased frequency of focal motor seizures and development of hemiparesis and cerebral hemiatrophy. Steroids and IV immunoglobulin are beneficial both in the acute stage as short-term high dose therapies as well as in lower doses for long-term treatment. Seizures are generally refractory to standard anti-epileptic drugs and hemispherectomy may be palliative.

Pearls &amp; Oy-Sters: Ocular ischemic syndrome

In reference to “Pearls & Oy-sters: Ocular ischemic syndrome,” Dr. Venketasubramanian questions the use of the Valsalva maneuver over breath-holding to assess cerebrovascular reserve and points out a possible error in the text of the article. The authors explain their methodology and agree with his correction. Dr. Sethi and authors Tenney and Schapiro discuss Rasmussen's encephalitis as another differential diagnosis in the case of a 21-month old boy with Hemiconvulsion-hemiplegia-epilepsy.

Rasmussen encephalitis: Incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins

Rasmussen encephalitis (RE) leads to progressive tissue and function loss of one brain hemisphere and often intractable epilepsy. This is the first randomized prospective treatment trial in RE. Germany-wide, patients with suspected recent-onset RE were recruited and if eligible randomized to tacrolimus or intravenous immunoglobulins (IVIGs). A loss of motor function or hemispheric volume by ≥ 15% (in patients >12 years at disease onset: ≥ 8%) led to study exit. Untreated patients served as a historical control group. Over 6.3 years, 21 patients with recent-onset RE were identified. Sixteen were randomized to tacrolimus (n = 9) or IVIG (n = 7). Immunotreated patients had a longer "survival" than the historical controls. Neither treatment was more efficacious than the other. Two tacrolimus patients experienced serious adverse events. No immunotreated but several untreated patients developed intractable epilepsy. No patient with refractory epilepsy became treatment-responsive under immunotherapy. The countrywide incidence rate of diagnosed RE is estimated as 2.4 cases/10⁷ people ≤ age 18/year. Treatment with tacrolimus or IVIG may slow down tissue and function loss and prevent development of intractable epilepsy. However, immunotherapy may "arrest" patients in a dilemma state of pharmacoresistant epilepsy but too good function to be offered functional hemispherectomy. These compounds may therefore contribute to the therapeutic armamentarium for RE patients without difficult-to-treat epilepsies.

Big epilepsy surgery for little people

Hemispherectomy is the most dramatic type of brain resection performed for epilepsy. Introduced by McKenzie in 1938,(1) it is indicated for intractable seizures that predominantly first occur in infancy and early childhood, arise diffusely from one hemisphere, and are associated with unihemispheric insults. These include hemimegalencephaly, other multilobar cortical dysplasias, perinatal strokes, Sturge-Weber syndrome, and Rasmussen encephalitis. Improvements in surgical techniques and patient selection criteria have resulted in lower complication rates, including lower mortality. Because hemispherectomy is often performed in children who already have moderate to severe hemiplegia, the added motor deficits from the surgery are generally low. Furthermore, given the plasticity in the developing brain, surgery when done early may allow reorganization and preservation of both motor and cognitive function.

Seizure and developmental outcomes after hemispherectomy in children and adolescents with intractable epilepsy

The aim of this study is to describe a series of pediatric hemispherectomies, reviewing pathologic substrate, epilepsy characteristics and seizure outcome as well as developmental profiles, before and after surgery, in different domains. Seventeen patients with full pre-surgical work-up, minimum follow-up of 12months, and at least one post-surgical neuropsychological evaluation were selected. Three had Rasmussen encephalitis (RE), five hemispheric malformations of cortical development (MCD), and nine hemispheric vascular lesions. At latest follow-up, all patients with RE and 66.7% of those with vascular lesions are in Engel's class I; in the latter group, pre-surgical independent contralateral EEG discharges statistically correlated with a worse seizure outcome. Patients with MCD showed the worst seizure outcome. Pre-surgical language transfer to the right hemisphere was confirmed in a boy with left RE, operated on at 6years of age. Patients with MCD and vascular lesions already showed severe global developmental delay before surgery, which persists afterwards. A linear correlation was found between earlier age at surgery and better outcome in personal-social, gross motor, and adaptive domains, in the vascular lesions group. The case with highest cognitive improvement had continuous spike and wave during sleep on pre-surgical EEG. Pathologic substrate was the main factor related with seizure outcome. In children with MCD and vascular lesions, although developmental progression is apparent, significant post-surgical improvements are restricted by the severity of pre-surgical neuropsychological disturbances and a slow maturation. Early surgery assessment is recommended to enhance the possibilities for a better quality of life in terms of seizure control, as well as better autonomy and socialization.

TWO INTERESTING CASES OF NMDAR ENCEPHALITIS AND A TYPICAL BUT SERONEGATIVE CASE WITH OVARIAN TERATOMA

Autoantibodies against the N-methyl-D-aspartate receptor (NMDAR) have been associated with a complex encephalitis syndrome, which was first described in a case series of 12 young women presenting with a consistent...

Clinical association of intrathecal and mirrored oligoclonal bands in paediatric neurology

Biomarkers such as autoantibodies, neopterin, and oligoclonal bands (OCBs) are increasingly used for the diagnosis of treatable inflammatory central nervous system (CNS) disorders. We investigated the correlation between the results of OCB testing and clinical diagnoses in a large contemporary cohort of children with a broad range of neurological conditions. Cerebrospinal fluid (CSF) and serum from 200 children (94 females, 106 males; age range 2 mo-15 y 10 mo, mean age 6 y 9 mo, SD ±4.9) who underwent CSF investigation for their neurological condition were tested for OCBs using isoelectric focusing. The patients were divided into those with inflammatory (n=58) and non-inflammatory (n=142) CNS disorders. Intrathecal OCBs (OCBs restricted to the CSF) were found in 11 out of 58 (19%) of those with inflammatory CNS disorders compared with none of the 142 patients with non-inflammatory CNS disorders (p<0.001). Diseases associated with intrathecal OCB were multiple sclerosis, Rasmussen encephalitis, N-methyl-d-aspartate receptor (NMDAR) encephalitis, voltage-gated potassium channel (VGKC) encephalopathy, herpes (HSV) encephalitis, 'other' encephalitides, acute cerebellar ataxia, and aseptic meningitis. Mirrored OCBs (identical OCBs in the serum and CSF) were less specific but were still found in 14 out of 58 (24%) children with inflammatory CNS disorders compared with only 6 out of 142 (4%) children with non-inflammatory CNS disorders (p<0.001). Diseases associated with mirrored OCBs included acute disseminated encephalomyelitis (ADEM), VGKC encephalopathy, West syndrome, NMDAR encephalitis, 'other' encephalitides, polio-like illness, Rasmussen encephalitis, cerebral vasculitis, metachromatic leukodystrophy, and bacterial meningitis. Intrathecal OCBs and mirrored OCBs had a positive predictive value for inflammatory CNS disease of 1 (95% confidence interval [CI] 0.68-1) and 0.7 (95% CI 0.46-0.87) respectively. Intrathecal OCBs were restricted to patients with inflammatory CNS disorders. They are a useful, but non-specific, biomarker of CNS inflammation of multiple causes. Mirrored OCBs are less specific, but still support a possible inflammatory CNS disorder. The presence of either intrathecal or mirrored OCBs should raise suspicion of an inflammatory CNS disorder.

Etiology, clinical features and outcome of epilepsia partialis continua in cohort of 51 children

The objective of the study was to evaluate etiology, clinical characteristics and outcome in children with epilepsia partialis continua (EPC). The investigation included 51 children with EPC aged 0.2-18 years treated in the period 1993-2009. The median period from the onset of underlying disorder to EPC was 6 months (0-72 months). EPC was caused by different pathologies: inflammatory and immune-mediated (52%), metabolic (13.7%), structural brain abnormalities (11.8%), cryptogenic (7.8%), vascular (5.9%), dual (5.9%), postoperative (2%). Median duration of EPC was 15 days (1-200 days). EPC involved more frequently the right side of the body comparing to the left one. The outcome was assessed at the end of the follow up period (mean 6.5 years, ranged 0.2-16 years). Unchanged neurological status was observed in 10 (19.6%) children, neurological consequences in 33 (64.7%) children and lethal outcome in 8 (15.7%) children. The most frequent etiology in our cohort was inflammatory and immune-mediated disease of central nerve system including Rasmussen's encephalitis. The duration of EPC was prolonged, most frequently involving the right upper limb. The outcome of EPC in children was unfavorable.