RARE DISEASE
Rasmussen subacute encephalitis
Rasmussen subacute encephalitis
Rasmussen subacute encephalitis
Synonyms: Rasmussen syndrome
Synonyms: Rasmussen syndrome
Synonyms: Rasmussen syndrome
Drug discovery
1
drug
With orphan designation
Overview
A rare, immune-mediated chronic encephalitis characterized by progressive unihemispheric inflammation, drug-resistant focal epilepsy (often epilepsia partialis continua), hemiparesis, and cognitive decline. Pathophysiology involves T-cell-driven neuronal damage and microglial activation, leading to cortical atrophy. Diagnosis relies on clinical triad, MRI showing unilateral atrophy, and EEG demonstrating focal epileptiform activity [1][2][4][16].
Burden
Functional: 80–90% develop permanent hemiparesis, cognitive deficits, and refractory epilepsy [1][5][20].
Socioeconomic: High care needs due to progressive disability; surgery costs and rehabilitation burdens [13][20].
Mortality: Low direct mortality but profound morbidity; 50% require lifelong assistance [1][4][8].
Therapies
Immunomodulation: Early steroids, IVIG, or tacrolimus may slow progression; rituximab/natalizumab under investigation [4][6][8].
Surgery: Hemispherectomy/hemispherotomy remains definitive treatment for seizure control but causes permanent deficits (hemiplegia, aphasia) [8][13][19].
Symptomatic care: AEDs for non-EPC seizures; botulinum toxin for focal motor symptoms [2][4][7].
Categories: rare neurological diseases
Research Papers
76 drug discovery papers about Rasmussen subacute encephalitis, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
76 drug discovery papers about Rasmussen subacute encephalitis, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-24 | International consensus recommendations for the diagnosis and treatment of Rasmussen syndrome: A modified Delphi procedure
Rasmussen syndrome (RS) includes a well-described constellation of refractory focal seizures, often including epilepsia partialis continua, hemiplegia with progressive unilateral cortical atrophy, and cognitive/language decline. However, the precise early pathogenesis and reliable biomarkers remain elusive. In addition, we lack operational management guidelines, including diagnostic evaluation, disease-monitoring assessments, and medical and surgical treatment approaches. We aimed to create an expert consensus statement to guide and standardize the treatment of RS, with the goal of providing recommendations applicable to a global population. An expert panel was convened to complete three rounds of a modified Delphi procedure given the lack of high-level evidence, with a focus on workup to exclude mimicking diagnoses, disease-activity metrics, and treatment. Consensus was defined as ≥75% of responses being agree/strongly agree in either two subsequent rounds or in the third and final round. A total of 122 of 143 statements met consensus. Proposed diagnostic evaluation in patients with possible RS is outlined, including physical examination, blood/cerebrospinal fluid analyses, neuroimaging, electroencephalography (EEG), and biopsy. Suggested disease-monitoring assessments include neuropsychological testing and serial magnetic resonance imaging (MRI). Intravenous corticosteroids are recommended as first-line, acute immunotherapy for seizure exacerbations and status epilepticus, with or without the addition of intravenous immunoglobulin. Options for maintenance immunotherapy are outlined, with lack of evidence noted for comparing efficacy of these treatments. Hemispheric disconnection remains the most effective seizure treatment, with parameters including age, function, seizure burden, and patient values influencing candidacy for surgery. This consensus statement offers a guideline to standardize management, as well as suggests future directions to further elucidate underlying pathophysiology and target more-effective, better-tolerated treatments.
2025-08-31 | Immune-mediated inflammatory conditions in epilepsy: role of autoimmunity.
Several studies have demonstrated the relationship between epilepsy and neuroinflammation; syndromes such as Rasmussen syndrome and paraneoplastic limbic encephalitis associated with epilepsy and some cases with refractory status epilepticus are prominent examples of this relationship. However, seizures are one of the symptoms that patients with autoimmune encephalitis frequently present with or are at increased risk for epilepsy, hence the confusion with associated autoimmune epilepsy. Moreover, the etiology of one-third of all epilepsies remains unknown, and it is estimated that approximately 5% of focal epilepsies of unknown cause without clinical suspicion of encephalopathy may be immune-mediated. Autoimmune pathophysiologic mechanisms have been included as one of the etiologies of seizures in the most recent classification by the International League Against Epilepsy. The antigens most associated with epilepsy of autoimmune origin are mainly intracellular antigens such as glutamic acid decarboxylase 65 (GAD65) and neuronal surface antigens such as inactivated glioma leucine-rich protein-1 (LGI1), GABAb receptor, and it has recently been shown that more than one autoantibody can be present in patients with drug-resistant epilepsy. This could cause an overlap of clinical features, thus complicating clinical symptoms and treatment; therefore, early identification of more than one autoantibody, in addition to rigorous clinical diagnosis, imaging studies, and assessment of the response to immunotherapy, is of utmost importance. Thus, new immunomodulatory therapies are emerging that show promising effects, as anticonvulsants (ASM) usually do not stop immune-mediated seizures and are often used for symptomatic control. This manuscript will review the most recent advances in inflammation in developing autoimmune-associated epilepsy, its pathophysiology, diagnosis, and recent treatments.
2025-06-24 | Contribution of activated complements and CD59 to the pathophysiology of Rasmussen syndrome.
Rasmussen syndrome (RS) is an autoimmune-associated epilepsy with refractory seizures and deteriorating motor and cognitive functions. We expect to unveil complex immunological pathophysiology from the viewpoint of complements to establish newer immunomodulatory treatments. We examined CSF levels of activated complements (iC3b, C5a and soluble membrane attack complex (sMAC)) and CD59 (inhibitor of MAC) using ELISA kits in 36 patients with RS and 44 disease controls (DCs). Disease duration from the onset of RS to CSF examination (mean ± SD) was 80.5 ± 89.7 months (n = 73). Seizure frequency at CSF examination was daily in 56, weekly in four, monthly in six, yearly in four and seizure-free in three CSF samples. The level of iC3b was significantly higher in RS than in DCs, but that of C5a, sMAC or CD59 was not different between RS and DCs. Levels of iC3b increased along with duration of disease. The ratio of patients with the levels of CD59 more than zero increased after the acute stage. Levels of CD59 in patients with daily seizure frequency were significantly lower than those with seizure control. The odds ratio between levels of CD59 and IVIg treatment by multiple linear regression analyses was significantly high. Maximum datum of activated complements or CD59 among the course of each patient was not related with final motor, cognitive and seizure outcomes. Reduction of CD59 may be one of crucial pathologies in the early stage of RS.
2024-10-10 | Efficacy of add‐on Cenobamate treatment in refractory epilepsy due to Rasmussen's encephalitis
Abstract Objective To assess antiseizure effects of cenobamate, a new antiseizure medication with at least two mechanisms of action, in the rare, highly pharmacoresistant and progressive epilepsy syndrome related to Rasmussen's encephalitis. Methods Three patients from the epilepsy centers in Freiburg, Kork, and Valencia are reported with focal epilepsy which had been pharmacoresistant to more than 10 prior treatment regimens. Assessment included at least 1 year of follow‐up after cenobamate introduction and included seizure frequency, seizure severity (in particular status epilepticus) and changes in co‐medication. Results In the three patients, cenobamate add on treatment proved superior to all prior antiseizure and immunomodulatory treatments which had been individually applied. Not only were focal to bilateral tonic–clonic seizure completely controlled, but also focal motor status epilepticus no longer occurred. Co‐medication could be reduced in all patients. Significance This case series in a rare and highly pharmacoresistant epilepsy syndrome suggests high efficacy of cenobamate add‐on treatment for seizure control. This may be a valuable information in epilepsy related to Rasmussen encephalitis and calls for further elucidation of the mechanism involved in superior seizure control also compared to prior treatments including sodium channel blockers and benzodiazepines. Plain Language Summary Rasmussen's encephalitis is a rare type of epilepsy that gets worse over time and doesn't respond well to most seizure medications. We describe three patients who tried many treatments without much success, but when they added cenobamate to their treatment, it worked better than the other medications. This also let them lower the overall amount of medication they were taking.
2023-01-20 | Brain molecular mechanisms in Rasmussen encephalitis.
This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. Frozen brain tissue (ages = 2-19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p < .05) and label-free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA-DRB1, HLA-DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10-6 , z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10-13 , z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10-13 , z = 5.61). Proteomics detected fewer altered targets. In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow-up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.
proteins
2023-07-10 | Role of Early Intravenous Immunoglobulins in Halting Clinical and Radiographic Disease Progression in Rasmussen Encephalitis.
Rasmussen encephalitis (RE) is a rare progressive presumed autoimmune disorder characterized by pharmacoresistant epilepsy and progressive motor and cognitive deterioration. Despite immunomodulation, more than half of the patients with RE ultimately require functional hemispherotomy. In this study, we evaluated the potential beneficial effects of early initiation of immunomodulation in slowing disease progression and preventing the need for surgical interventions. A retrospective chart review over a 10-year period was conducted at the American University of Beirut Medical Center to identify patients with RE. Data were collected on seizure characteristics, neurological deficits, electroencephalography, brain magnetic resonance imaging results (including volumetric analyses for an objective assessment of radiographic progression), and treatment modalities. Seven patients met the inclusion criteria for RE. All patients received intravenous immunoglobulins (IVIGs) as soon as the diagnosis was entertained. Five patients with only monthly to weekly seizures at the time of IVIG initiation had favorable outcomes without resorting to surgery, along with a relative preservation of the gray matter volumes in the affected cerebral hemispheres. Motor strength was preserved in those patients, and three were seizure free at their last follow-up visit. The two patients who required hemispherotomy were already severely hemiparetic and experiencing daily seizures at the time of IVIG initiation. Our data suggest that the early initiation of IVIG as soon as a diagnosis of RE is suspected, and particularly before the appearance of motor deficits and intractable seizures, can maximize the beneficial effects of immunomodulation in terms of controlling seizures and reducing the rate of cerebral atrophy.
2019-02-01 | Rasmussen syndrome: absence seizures may be induced by oxcarbazepine
ABSTRACT A female patient with electroclinical and neuroradiological features compatible with Rasmussen syndrome developed a particular clinical and EEG pattern. As the seizures were refractory to valproate at 750 mg/kg/day, oxcarbazepine (OXC) at 30 mg/kg/day was added. Seizures became more frequent and on neurological examination, no hemiparesis was detected. The interictal EEG showed focal spikes and diffuse paroxysms in the right fronto‐temporal regions. Brain MRI revealed right hemiatrophy, mainly at the Sylvian fissure. After initiating OXC daily, brief absence seizures, lasting less than 20 seconds and associated with bilateral and synchronous 2.5‐3‐Hz spike‐and‐waves compatible with typical absences, were observed. OXC was discontinued and the typical absences disappeared. Treatment with intravenous gammaglobulin was started. At the last control visit, at nine years of age, no absence seizures were observed either by the parents or on the EEG recording. Our patient who met the diagnostic criteria for Rasmussen syndrome presented with absence seizures that may have been induced by OXC. The absence seizures disappeared after OXC was discontinued.
2018-10-26 | Rasmussen's Encephalitis. A Case Report
Rasmussen's encephalitis (RE) is a rare but severe immune-mediated brain disorder leading to unilateral hemispheric atrophy, associated progressive neurological dysfunction with intellectual decline, and intractable seizures. It is a well-established cause of pharmacologically intractable epilepsy. The report is on a 17-month-old infant, treated at the Mario Catarino Rivas Hospital Honduras. Family history: grandfather epileptic secondary trauma from 20 years. Personal history: two previous emergency visits (at 16 months and 16 months 8 days) for convulsions for which she was admitted three days and was treated with valproic acid 30 mg/kg per day. The infant is admitted in the emergency, with a history of about three hours after onset of tonic convulsions, focused on left-side with drooling, oculogiros and relaxation of sphincters and fever of 38.5 ° C. Entered as convulsive syndrome in the study, however, as the days passed the number of seizures increased to 60 per day and was gradually presenting alterations in neurodevelopment. MRI reported leukoencephalopathy of undetermined origin and biopsy reported findings consistent with Rasmussen's syndrome. She was treated with immunoglobulin every two weeks for six doses after two months of hospitalization with achieved improvement. Currently, episodes of seizures have decreased significantly and almost not convulsing, she presented alterations in neurodevelopment.
2018-04-25 | Clinical Applications of Intravenous Immunoglobulins in Child Neurology.
While there are guidelines for the use of intravenous immunoglobulins in children with Guillain-Barre syndrome and myasthenia gravis based on high-level evidence studies, data are scarce for the majority of neurologic disorders in this age group. Neuronal antibodies are detected in children with seizures of autoimmune etiology. Intravenous immunoglobulins with their broad immunomodulatory mechanism of action could be ideally effective in different forms of immunedysregulated intractable epilepsies such as autoimmune epilepsy and autoimmune Rasmussen encephalitis. We conducted a systematic review of the literature for evidence of the use of intravenous immunoglobulins in a variety of neurologic diseases in childhood. A comprehensive literature search was conducted using Pubmed as the medical database source without date range. Prospective studies in pediatric groups including objective measures of clinical outcomes were systematically selected. A total of 11 prospective studies were identified in the literature demonstrating a favorable effect of this therapeutic option in children with drug-resistant epilepsy and in cases of encephalitis. No serious adverse effects were reported. No prospective studies about the use of intravenous immunoglobulins in children with demyelinating disorders or neurologic paraneoplasmatic syndromes were found. In this review, we summarize the recent advances in the field of intravenous immunoglobulins used in pediatric neurological diseases. Literature data supports a beneficial effect in this age group. Whilst awaiting the results of large scale studies, administration of intravenous immunoglobulins could be justified in refractory child epilepsy. Otherwise, its use should be guided by the individual needs of each child, depending on the underlying neurological disease.
2016-11-30 | Systematic review of immunoglobulin use in paediatric neurological and neurodevelopmental disorders
A systematic literature review of intravenous immunoglobulin (IVIG) treatment of paediatric neurological conditions was performed to summarize the evidence, provide recommendations, and suggest future research.A MEDLINE search for articles reporting on IVIG treatment of paediatric neuroinflammatory, neurodevelopmental, and neurodegenerative conditions published before September 2015, excluding single case reports and those not in English. Owing to heterogeneous outcome measures, meta-analysis was not possible. Findings were combined and evidence graded.Sixty-five studies were analysed. IVIG reduces recovery time in Guillain-Barré syndrome (grade B). IVIG is as effective as corticosteroids in chronic inflammatory demyelinating polyradiculoneuropathy (grade C), and as effective as tacrolimus in Rasmussen syndrome (grade C). IVIG improves recovery in acute disseminated encephalomyelitis (grade C), reduces mortality in acute encephalitis syndrome with myocarditis (grade C), and improves function and stabilizes disease in myasthenia gravis (grade C). IVIG improves outcome in N-methyl-d-aspartate receptor encephalitis (grade C) and opsoclonus-myoclonus syndrome (grade C), reduces cataplexy symptoms in narcolepsy (grade C), speeds recovery in Sydenham chorea (grade C), reduces tics in selected cases of Tourette syndrome (grade D), and improves symptoms in paediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (grade B).IVIG is a useful therapy in selected neurological conditions. Well-designed, prospective, multi-centre studies with standardized outcome measures are required to compare treatments.
antibodies
2026-06-15 | NEUROIMAGING SPECTRUM OF CEREBRAL HEMIATROPHY ON MRI: A CLINICORADIOLOGICAL STUDY
Background Cerebral hemiatrophy is an uncommon clinicoradiological entity characterized by unilateral cerebral volume loss resulting from diverse congenital and acquired etiologies.Patients commonly present with seizures, hemiparesis, developmental delay, and cognitive impairment.Magnetic resonance imaging (MRI) plays a pivotal role in identifying the underlying etiology and associated structural abnormalities.This Materials and Methods retrospective clinicoradiological study included ten patients with cerebral hemiatrophy who underwent MRI evaluation at a tertiary care centre.Clinical presentation and neuroimaging findings were analyzed to determine the underlying etiology and imaging spectrum.MRI was performed using a 1.5-T scanner and included T1-weighted, T2-weighted, FLAIR, DWI/ADC, and SWI sequences.Post-contrast imaging was performed when clinically indicated.A total of Results ten patients with cerebral hemiatrophy were included in the study.The age of patients ranged from 4 to 36 years.Seizures were the most common presenting symptom and were observed in all patients.Hemiparesis and developmental delay were also frequent clinical manifestations.The etiological distribution included Rasmussen encephalitis (n = 4), Sturge-Weber syndrome (n = 3), and Dyke-Davidoff-Masson syndrome (n = 3).MRI demonstrated unilateral cerebral volume loss in all patients, with associated ex-vacuo ventricular dilatation being the most consistent imaging finding.Additional findings included cerebral peduncular atrophy, calvarial thickening, hyperpneumatization of paranasal sinuses, leptomeningeal vascular malformations, and cortical calcifications depending on the underlying etiology.Conclusion MRI is indispensable in the evaluation of cerebral hemiatrophy, enabling differentiation among various etiologies based on characteristic imaging patterns and facilitating appropriate clinical management.Table 1: Etiological distribution of cerebral Table 2: Major MRI findings hemiatrophy
2026-06-03 | Centroparietal periodic sharp-wave discharges and biphasic complexes: Novel EEG biomarkers for early diagnosis of Rasmussen encephalitis.
Rasmussen encephalitis (RE) is a rare, chronic inflammatory brain disorder that predominantly affects one hemisphere in children. It is characterized by progressive neurological deterioration and refractory seizures. Early diagnosis remains challenging due to nonspecific initial symptoms and diagnostic features that overlap with other neurological conditions. To identify early and specific EEG patterns that may support timely initiation of immunomodulatory therapies. Continuous long-term video-EEG monitoring was repeatedly conducted in a female patient who experienced her first seizures at age 16, soon after a febrile illness. Identification of two distinctive EEG patterns-focal periodic sharp-wave discharges and biphasic complexes-allowed early diagnosis prior to the onset of severe deficits or epilepsia partialis continua. The biphasic complexes occurred alongside unilateral slow-wave activity, whereas focal periodic sharp-wave discharges were initially observed on an otherwise normal background. The biphasic complexes appear to herald evolution to the acute phase of the disease. Prompt immunomodulatory therapy (intravenous immunoglobulin followed by adalimumab) successfully halted disease progression, nearly normalized EEG background activity, and reduced seizure frequency. This case underscores the prognostic value of recurrent focal periodic sharp-wave discharges and biphasic complexes as prodromal EEG biomarkers for RE, aligning with one prior study linking these biphasic complexes to early-stage disease (Beaumanoir et al., 1997). Early recognition of these patterns is essential. Early initiation of immunotherapy may prevent irreversible neurological damage, highlighting the critical role of recognizing these electrographic patterns for timely diagnosis and intervention.
2025-06-05 | Child Neurology: A Case of Rasmussen Syndrome Without Seizures.
Rasmussen syndrome (RS) is a neuroimmune disease typically characterized by refractory focal epilepsy, epilepsia partialis continua, progressive focal neurologic deficits, and cognitive impairment. Seizures are often a presenting and prominent symptom, but RS may be diagnosed in the absence of seizures when a patient has 2 of the 3 Part B Bien criteria: (1) consistent histopathologic findings, (2) progression in unilateral cortical deficits, or (3) progression in focal cortical atrophy. We describe a patient who presented with hemiparesis and unihemispheric atrophy, meeting Bien criteria through progressive clinical changes and consistent histopathology on a brain biopsy. She did not have progression in focal cortical atrophy on imaging at the time of diagnosis. The patient has not developed seizures in the 4.5 years of monitoring after symptom onset. Our case illustrates that the underlying pathophysiology of RS is an immune-driven, progressive neurodegenerative disorder, which frequently-but not always-causes seizures.
2025-03-28 | Assessing the diagnostic performance of investigations in pediatric myoclonic epilepsies: A retrospective cohort study.
The primary purpose was to assess the diagnostic performance of investigations in children with myoclonic epilepsy. The secondary objectives were to examine the definitive syndromic diagnoses and report the outcomes of pediatric myoclonic epilepsies. We conducted a retrospective monocentric study from a pediatric center for rare epilepsies. We included pediatric patients investigated for myoclonic epilepsy at our center from 2009 to 2022. Data were collected from their medical records. Forty-one children were included; 32 (78%) underwent untargeted etiological investigations, including brain magnetic resonance imaging and diverse laboratory tests to rule out an underlying etiology for progressive myoclonus epilepsy (PME). These investigations led to an etiological diagnosis of epilepsy for two patients, exclusively based on genetic investigations. At the final follow-up, an underlying etiology for epilepsy was established for nine patients (22%). The definitive syndromic diagnoses were diverse, comprising myoclonic epilepsy in infancy, epilepsy with myoclonic absences, Rasmussen syndrome, and PME. Some patients were diagnosed with nonsyndromic developmental and epileptic encephalopathy or unclassified nonsyndromic myoclonic epilepsy. Developmental delay or regression at the initial evaluation was found to be significantly associated with an unfavorable neurological outcome, the total number of antiseizure medications (ASMs) prescribed, and the unlikelihood of achieving ASM freedom. No patients with an abnormal head circumference or born of a consanguineous union were in the favorable neurological outcome group, although this finding did not reach statistical significance. Except for the need to promptly identify diseases for which precision medicine treatments are available, a first-line genetic approach seems reasonable to investigate children diagnosed with epileptic myoclonus.
2022-03-11 | Targeting Inflammatory Mediators in Epilepsy: A Systematic Review of Its Molecular Basis and Clinical Applications
Recent studies prompted the identification of neuroinflammation as a potential target for the treatment of epilepsy, particularly drug-resistant epilepsy, and refractory status epilepticus. This work provides a systematic review of the clinical experience with anti-cytokine agents and agents targeting lymphocytes and aims to evaluate their efficacy and safety for the treatment of refractory epilepsy. Moreover, the review analyzes the main therapeutic perspectives in this field.A systematic review of the literature was conducted on MEDLINE database. Search terminology was constructed using the name of the specific drug (anakinra, canakinumab, tocilizumab, adalimumab, rituximab, and natalizumab) and the terms "status epilepticus," "epilepsy," and "seizure." The review included clinical trials, prospective studies, case series, and reports published in English between January 2016 and August 2021. The number of patients and their age, study design, specific drugs used, dosage, route, and timing of administration, and patients outcomes were extracted. The data were synthesized through quantitative and qualitative analysis.Our search identified 12 articles on anakinra and canakinumab, for a total of 37 patients with epilepsy (86% febrile infection-related epilepsy syndrome), with reduced seizure frequency or seizure arrest in more than 50% of the patients. The search identified nine articles on the use of tocilizumab (16 patients, 75% refractory status epilepticus), with a high response rate. Only one reference on the use of adalimumab in 11 patients with Rasmussen encephalitis showed complete response in 45% of the cases. Eight articles on rituximab employment sowed a reduced seizure burden in 16/26 patients. Finally, one trial concerning natalizumab evidenced a response in 10/32 participants.The experience with anti-cytokine agents and drugs targeting lymphocytes in epilepsy derives mostly from case reports or series. The use of anti-IL-1, anti-IL-6, and anti-CD20 agents in patients with drug-resistant epilepsy and refractory status epilepticus has shown promising results and a good safety profile. The experience with TNF inhibitors is limited to Rasmussen encephalitis. The use of anti-α4-integrin agents did not show significant effects in refractory focal seizures. Concerning research perspectives, there is increasing interest in the potential use of anti-chemokine and anti-HMGB-1 agents.
small molecules
2026-04-24 | International consensus recommendations for the diagnosis and treatment of Rasmussen syndrome: A modified Delphi procedure
Rasmussen syndrome (RS) includes a well-described constellation of refractory focal seizures, often including epilepsia partialis continua, hemiplegia with progressive unilateral cortical atrophy, and cognitive/language decline. However, the precise early pathogenesis and reliable biomarkers remain elusive. In addition, we lack operational management guidelines, including diagnostic evaluation, disease-monitoring assessments, and medical and surgical treatment approaches. We aimed to create an expert consensus statement to guide and standardize the treatment of RS, with the goal of providing recommendations applicable to a global population. An expert panel was convened to complete three rounds of a modified Delphi procedure given the lack of high-level evidence, with a focus on workup to exclude mimicking diagnoses, disease-activity metrics, and treatment. Consensus was defined as ≥75% of responses being agree/strongly agree in either two subsequent rounds or in the third and final round. A total of 122 of 143 statements met consensus. Proposed diagnostic evaluation in patients with possible RS is outlined, including physical examination, blood/cerebrospinal fluid analyses, neuroimaging, electroencephalography (EEG), and biopsy. Suggested disease-monitoring assessments include neuropsychological testing and serial magnetic resonance imaging (MRI). Intravenous corticosteroids are recommended as first-line, acute immunotherapy for seizure exacerbations and status epilepticus, with or without the addition of intravenous immunoglobulin. Options for maintenance immunotherapy are outlined, with lack of evidence noted for comparing efficacy of these treatments. Hemispheric disconnection remains the most effective seizure treatment, with parameters including age, function, seizure burden, and patient values influencing candidacy for surgery. This consensus statement offers a guideline to standardize management, as well as suggests future directions to further elucidate underlying pathophysiology and target more-effective, better-tolerated treatments.
2025-08-31 | Immune-mediated inflammatory conditions in epilepsy: role of autoimmunity.
Several studies have demonstrated the relationship between epilepsy and neuroinflammation; syndromes such as Rasmussen syndrome and paraneoplastic limbic encephalitis associated with epilepsy and some cases with refractory status epilepticus are prominent examples of this relationship. However, seizures are one of the symptoms that patients with autoimmune encephalitis frequently present with or are at increased risk for epilepsy, hence the confusion with associated autoimmune epilepsy. Moreover, the etiology of one-third of all epilepsies remains unknown, and it is estimated that approximately 5% of focal epilepsies of unknown cause without clinical suspicion of encephalopathy may be immune-mediated. Autoimmune pathophysiologic mechanisms have been included as one of the etiologies of seizures in the most recent classification by the International League Against Epilepsy. The antigens most associated with epilepsy of autoimmune origin are mainly intracellular antigens such as glutamic acid decarboxylase 65 (GAD65) and neuronal surface antigens such as inactivated glioma leucine-rich protein-1 (LGI1), GABAb receptor, and it has recently been shown that more than one autoantibody can be present in patients with drug-resistant epilepsy. This could cause an overlap of clinical features, thus complicating clinical symptoms and treatment; therefore, early identification of more than one autoantibody, in addition to rigorous clinical diagnosis, imaging studies, and assessment of the response to immunotherapy, is of utmost importance. Thus, new immunomodulatory therapies are emerging that show promising effects, as anticonvulsants (ASM) usually do not stop immune-mediated seizures and are often used for symptomatic control. This manuscript will review the most recent advances in inflammation in developing autoimmune-associated epilepsy, its pathophysiology, diagnosis, and recent treatments.
2025-06-24 | Contribution of activated complements and CD59 to the pathophysiology of Rasmussen syndrome.
Rasmussen syndrome (RS) is an autoimmune-associated epilepsy with refractory seizures and deteriorating motor and cognitive functions. We expect to unveil complex immunological pathophysiology from the viewpoint of complements to establish newer immunomodulatory treatments. We examined CSF levels of activated complements (iC3b, C5a and soluble membrane attack complex (sMAC)) and CD59 (inhibitor of MAC) using ELISA kits in 36 patients with RS and 44 disease controls (DCs). Disease duration from the onset of RS to CSF examination (mean ± SD) was 80.5 ± 89.7 months (n = 73). Seizure frequency at CSF examination was daily in 56, weekly in four, monthly in six, yearly in four and seizure-free in three CSF samples. The level of iC3b was significantly higher in RS than in DCs, but that of C5a, sMAC or CD59 was not different between RS and DCs. Levels of iC3b increased along with duration of disease. The ratio of patients with the levels of CD59 more than zero increased after the acute stage. Levels of CD59 in patients with daily seizure frequency were significantly lower than those with seizure control. The odds ratio between levels of CD59 and IVIg treatment by multiple linear regression analyses was significantly high. Maximum datum of activated complements or CD59 among the course of each patient was not related with final motor, cognitive and seizure outcomes. Reduction of CD59 may be one of crucial pathologies in the early stage of RS.
2024-10-10 | Efficacy of add‐on Cenobamate treatment in refractory epilepsy due to Rasmussen's encephalitis
Abstract Objective To assess antiseizure effects of cenobamate, a new antiseizure medication with at least two mechanisms of action, in the rare, highly pharmacoresistant and progressive epilepsy syndrome related to Rasmussen's encephalitis. Methods Three patients from the epilepsy centers in Freiburg, Kork, and Valencia are reported with focal epilepsy which had been pharmacoresistant to more than 10 prior treatment regimens. Assessment included at least 1 year of follow‐up after cenobamate introduction and included seizure frequency, seizure severity (in particular status epilepticus) and changes in co‐medication. Results In the three patients, cenobamate add on treatment proved superior to all prior antiseizure and immunomodulatory treatments which had been individually applied. Not only were focal to bilateral tonic–clonic seizure completely controlled, but also focal motor status epilepticus no longer occurred. Co‐medication could be reduced in all patients. Significance This case series in a rare and highly pharmacoresistant epilepsy syndrome suggests high efficacy of cenobamate add‐on treatment for seizure control. This may be a valuable information in epilepsy related to Rasmussen encephalitis and calls for further elucidation of the mechanism involved in superior seizure control also compared to prior treatments including sodium channel blockers and benzodiazepines. Plain Language Summary Rasmussen's encephalitis is a rare type of epilepsy that gets worse over time and doesn't respond well to most seizure medications. We describe three patients who tried many treatments without much success, but when they added cenobamate to their treatment, it worked better than the other medications. This also let them lower the overall amount of medication they were taking.
2023-01-20 | Brain molecular mechanisms in Rasmussen encephalitis.
This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. Frozen brain tissue (ages = 2-19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p < .05) and label-free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA-DRB1, HLA-DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10-6 , z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10-13 , z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10-13 , z = 5.61). Proteomics detected fewer altered targets. In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow-up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.
proteins
2023-07-10 | Role of Early Intravenous Immunoglobulins in Halting Clinical and Radiographic Disease Progression in Rasmussen Encephalitis.
Rasmussen encephalitis (RE) is a rare progressive presumed autoimmune disorder characterized by pharmacoresistant epilepsy and progressive motor and cognitive deterioration. Despite immunomodulation, more than half of the patients with RE ultimately require functional hemispherotomy. In this study, we evaluated the potential beneficial effects of early initiation of immunomodulation in slowing disease progression and preventing the need for surgical interventions. A retrospective chart review over a 10-year period was conducted at the American University of Beirut Medical Center to identify patients with RE. Data were collected on seizure characteristics, neurological deficits, electroencephalography, brain magnetic resonance imaging results (including volumetric analyses for an objective assessment of radiographic progression), and treatment modalities. Seven patients met the inclusion criteria for RE. All patients received intravenous immunoglobulins (IVIGs) as soon as the diagnosis was entertained. Five patients with only monthly to weekly seizures at the time of IVIG initiation had favorable outcomes without resorting to surgery, along with a relative preservation of the gray matter volumes in the affected cerebral hemispheres. Motor strength was preserved in those patients, and three were seizure free at their last follow-up visit. The two patients who required hemispherotomy were already severely hemiparetic and experiencing daily seizures at the time of IVIG initiation. Our data suggest that the early initiation of IVIG as soon as a diagnosis of RE is suspected, and particularly before the appearance of motor deficits and intractable seizures, can maximize the beneficial effects of immunomodulation in terms of controlling seizures and reducing the rate of cerebral atrophy.
2019-02-01 | Rasmussen syndrome: absence seizures may be induced by oxcarbazepine
ABSTRACT A female patient with electroclinical and neuroradiological features compatible with Rasmussen syndrome developed a particular clinical and EEG pattern. As the seizures were refractory to valproate at 750 mg/kg/day, oxcarbazepine (OXC) at 30 mg/kg/day was added. Seizures became more frequent and on neurological examination, no hemiparesis was detected. The interictal EEG showed focal spikes and diffuse paroxysms in the right fronto‐temporal regions. Brain MRI revealed right hemiatrophy, mainly at the Sylvian fissure. After initiating OXC daily, brief absence seizures, lasting less than 20 seconds and associated with bilateral and synchronous 2.5‐3‐Hz spike‐and‐waves compatible with typical absences, were observed. OXC was discontinued and the typical absences disappeared. Treatment with intravenous gammaglobulin was started. At the last control visit, at nine years of age, no absence seizures were observed either by the parents or on the EEG recording. Our patient who met the diagnostic criteria for Rasmussen syndrome presented with absence seizures that may have been induced by OXC. The absence seizures disappeared after OXC was discontinued.
2018-10-26 | Rasmussen's Encephalitis. A Case Report
Rasmussen's encephalitis (RE) is a rare but severe immune-mediated brain disorder leading to unilateral hemispheric atrophy, associated progressive neurological dysfunction with intellectual decline, and intractable seizures. It is a well-established cause of pharmacologically intractable epilepsy. The report is on a 17-month-old infant, treated at the Mario Catarino Rivas Hospital Honduras. Family history: grandfather epileptic secondary trauma from 20 years. Personal history: two previous emergency visits (at 16 months and 16 months 8 days) for convulsions for which she was admitted three days and was treated with valproic acid 30 mg/kg per day. The infant is admitted in the emergency, with a history of about three hours after onset of tonic convulsions, focused on left-side with drooling, oculogiros and relaxation of sphincters and fever of 38.5 ° C. Entered as convulsive syndrome in the study, however, as the days passed the number of seizures increased to 60 per day and was gradually presenting alterations in neurodevelopment. MRI reported leukoencephalopathy of undetermined origin and biopsy reported findings consistent with Rasmussen's syndrome. She was treated with immunoglobulin every two weeks for six doses after two months of hospitalization with achieved improvement. Currently, episodes of seizures have decreased significantly and almost not convulsing, she presented alterations in neurodevelopment.
2018-04-25 | Clinical Applications of Intravenous Immunoglobulins in Child Neurology.
While there are guidelines for the use of intravenous immunoglobulins in children with Guillain-Barre syndrome and myasthenia gravis based on high-level evidence studies, data are scarce for the majority of neurologic disorders in this age group. Neuronal antibodies are detected in children with seizures of autoimmune etiology. Intravenous immunoglobulins with their broad immunomodulatory mechanism of action could be ideally effective in different forms of immunedysregulated intractable epilepsies such as autoimmune epilepsy and autoimmune Rasmussen encephalitis. We conducted a systematic review of the literature for evidence of the use of intravenous immunoglobulins in a variety of neurologic diseases in childhood. A comprehensive literature search was conducted using Pubmed as the medical database source without date range. Prospective studies in pediatric groups including objective measures of clinical outcomes were systematically selected. A total of 11 prospective studies were identified in the literature demonstrating a favorable effect of this therapeutic option in children with drug-resistant epilepsy and in cases of encephalitis. No serious adverse effects were reported. No prospective studies about the use of intravenous immunoglobulins in children with demyelinating disorders or neurologic paraneoplasmatic syndromes were found. In this review, we summarize the recent advances in the field of intravenous immunoglobulins used in pediatric neurological diseases. Literature data supports a beneficial effect in this age group. Whilst awaiting the results of large scale studies, administration of intravenous immunoglobulins could be justified in refractory child epilepsy. Otherwise, its use should be guided by the individual needs of each child, depending on the underlying neurological disease.
2016-11-30 | Systematic review of immunoglobulin use in paediatric neurological and neurodevelopmental disorders
A systematic literature review of intravenous immunoglobulin (IVIG) treatment of paediatric neurological conditions was performed to summarize the evidence, provide recommendations, and suggest future research.A MEDLINE search for articles reporting on IVIG treatment of paediatric neuroinflammatory, neurodevelopmental, and neurodegenerative conditions published before September 2015, excluding single case reports and those not in English. Owing to heterogeneous outcome measures, meta-analysis was not possible. Findings were combined and evidence graded.Sixty-five studies were analysed. IVIG reduces recovery time in Guillain-Barré syndrome (grade B). IVIG is as effective as corticosteroids in chronic inflammatory demyelinating polyradiculoneuropathy (grade C), and as effective as tacrolimus in Rasmussen syndrome (grade C). IVIG improves recovery in acute disseminated encephalomyelitis (grade C), reduces mortality in acute encephalitis syndrome with myocarditis (grade C), and improves function and stabilizes disease in myasthenia gravis (grade C). IVIG improves outcome in N-methyl-d-aspartate receptor encephalitis (grade C) and opsoclonus-myoclonus syndrome (grade C), reduces cataplexy symptoms in narcolepsy (grade C), speeds recovery in Sydenham chorea (grade C), reduces tics in selected cases of Tourette syndrome (grade D), and improves symptoms in paediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (grade B).IVIG is a useful therapy in selected neurological conditions. Well-designed, prospective, multi-centre studies with standardized outcome measures are required to compare treatments.
antibodies
2026-06-15 | NEUROIMAGING SPECTRUM OF CEREBRAL HEMIATROPHY ON MRI: A CLINICORADIOLOGICAL STUDY
Background Cerebral hemiatrophy is an uncommon clinicoradiological entity characterized by unilateral cerebral volume loss resulting from diverse congenital and acquired etiologies.Patients commonly present with seizures, hemiparesis, developmental delay, and cognitive impairment.Magnetic resonance imaging (MRI) plays a pivotal role in identifying the underlying etiology and associated structural abnormalities.This Materials and Methods retrospective clinicoradiological study included ten patients with cerebral hemiatrophy who underwent MRI evaluation at a tertiary care centre.Clinical presentation and neuroimaging findings were analyzed to determine the underlying etiology and imaging spectrum.MRI was performed using a 1.5-T scanner and included T1-weighted, T2-weighted, FLAIR, DWI/ADC, and SWI sequences.Post-contrast imaging was performed when clinically indicated.A total of Results ten patients with cerebral hemiatrophy were included in the study.The age of patients ranged from 4 to 36 years.Seizures were the most common presenting symptom and were observed in all patients.Hemiparesis and developmental delay were also frequent clinical manifestations.The etiological distribution included Rasmussen encephalitis (n = 4), Sturge-Weber syndrome (n = 3), and Dyke-Davidoff-Masson syndrome (n = 3).MRI demonstrated unilateral cerebral volume loss in all patients, with associated ex-vacuo ventricular dilatation being the most consistent imaging finding.Additional findings included cerebral peduncular atrophy, calvarial thickening, hyperpneumatization of paranasal sinuses, leptomeningeal vascular malformations, and cortical calcifications depending on the underlying etiology.Conclusion MRI is indispensable in the evaluation of cerebral hemiatrophy, enabling differentiation among various etiologies based on characteristic imaging patterns and facilitating appropriate clinical management.Table 1: Etiological distribution of cerebral Table 2: Major MRI findings hemiatrophy
2026-06-03 | Centroparietal periodic sharp-wave discharges and biphasic complexes: Novel EEG biomarkers for early diagnosis of Rasmussen encephalitis.
Rasmussen encephalitis (RE) is a rare, chronic inflammatory brain disorder that predominantly affects one hemisphere in children. It is characterized by progressive neurological deterioration and refractory seizures. Early diagnosis remains challenging due to nonspecific initial symptoms and diagnostic features that overlap with other neurological conditions. To identify early and specific EEG patterns that may support timely initiation of immunomodulatory therapies. Continuous long-term video-EEG monitoring was repeatedly conducted in a female patient who experienced her first seizures at age 16, soon after a febrile illness. Identification of two distinctive EEG patterns-focal periodic sharp-wave discharges and biphasic complexes-allowed early diagnosis prior to the onset of severe deficits or epilepsia partialis continua. The biphasic complexes occurred alongside unilateral slow-wave activity, whereas focal periodic sharp-wave discharges were initially observed on an otherwise normal background. The biphasic complexes appear to herald evolution to the acute phase of the disease. Prompt immunomodulatory therapy (intravenous immunoglobulin followed by adalimumab) successfully halted disease progression, nearly normalized EEG background activity, and reduced seizure frequency. This case underscores the prognostic value of recurrent focal periodic sharp-wave discharges and biphasic complexes as prodromal EEG biomarkers for RE, aligning with one prior study linking these biphasic complexes to early-stage disease (Beaumanoir et al., 1997). Early recognition of these patterns is essential. Early initiation of immunotherapy may prevent irreversible neurological damage, highlighting the critical role of recognizing these electrographic patterns for timely diagnosis and intervention.
2025-06-05 | Child Neurology: A Case of Rasmussen Syndrome Without Seizures.
Rasmussen syndrome (RS) is a neuroimmune disease typically characterized by refractory focal epilepsy, epilepsia partialis continua, progressive focal neurologic deficits, and cognitive impairment. Seizures are often a presenting and prominent symptom, but RS may be diagnosed in the absence of seizures when a patient has 2 of the 3 Part B Bien criteria: (1) consistent histopathologic findings, (2) progression in unilateral cortical deficits, or (3) progression in focal cortical atrophy. We describe a patient who presented with hemiparesis and unihemispheric atrophy, meeting Bien criteria through progressive clinical changes and consistent histopathology on a brain biopsy. She did not have progression in focal cortical atrophy on imaging at the time of diagnosis. The patient has not developed seizures in the 4.5 years of monitoring after symptom onset. Our case illustrates that the underlying pathophysiology of RS is an immune-driven, progressive neurodegenerative disorder, which frequently-but not always-causes seizures.
2025-03-28 | Assessing the diagnostic performance of investigations in pediatric myoclonic epilepsies: A retrospective cohort study.
The primary purpose was to assess the diagnostic performance of investigations in children with myoclonic epilepsy. The secondary objectives were to examine the definitive syndromic diagnoses and report the outcomes of pediatric myoclonic epilepsies. We conducted a retrospective monocentric study from a pediatric center for rare epilepsies. We included pediatric patients investigated for myoclonic epilepsy at our center from 2009 to 2022. Data were collected from their medical records. Forty-one children were included; 32 (78%) underwent untargeted etiological investigations, including brain magnetic resonance imaging and diverse laboratory tests to rule out an underlying etiology for progressive myoclonus epilepsy (PME). These investigations led to an etiological diagnosis of epilepsy for two patients, exclusively based on genetic investigations. At the final follow-up, an underlying etiology for epilepsy was established for nine patients (22%). The definitive syndromic diagnoses were diverse, comprising myoclonic epilepsy in infancy, epilepsy with myoclonic absences, Rasmussen syndrome, and PME. Some patients were diagnosed with nonsyndromic developmental and epileptic encephalopathy or unclassified nonsyndromic myoclonic epilepsy. Developmental delay or regression at the initial evaluation was found to be significantly associated with an unfavorable neurological outcome, the total number of antiseizure medications (ASMs) prescribed, and the unlikelihood of achieving ASM freedom. No patients with an abnormal head circumference or born of a consanguineous union were in the favorable neurological outcome group, although this finding did not reach statistical significance. Except for the need to promptly identify diseases for which precision medicine treatments are available, a first-line genetic approach seems reasonable to investigate children diagnosed with epileptic myoclonus.
2022-03-11 | Targeting Inflammatory Mediators in Epilepsy: A Systematic Review of Its Molecular Basis and Clinical Applications
Recent studies prompted the identification of neuroinflammation as a potential target for the treatment of epilepsy, particularly drug-resistant epilepsy, and refractory status epilepticus. This work provides a systematic review of the clinical experience with anti-cytokine agents and agents targeting lymphocytes and aims to evaluate their efficacy and safety for the treatment of refractory epilepsy. Moreover, the review analyzes the main therapeutic perspectives in this field.A systematic review of the literature was conducted on MEDLINE database. Search terminology was constructed using the name of the specific drug (anakinra, canakinumab, tocilizumab, adalimumab, rituximab, and natalizumab) and the terms "status epilepticus," "epilepsy," and "seizure." The review included clinical trials, prospective studies, case series, and reports published in English between January 2016 and August 2021. The number of patients and their age, study design, specific drugs used, dosage, route, and timing of administration, and patients outcomes were extracted. The data were synthesized through quantitative and qualitative analysis.Our search identified 12 articles on anakinra and canakinumab, for a total of 37 patients with epilepsy (86% febrile infection-related epilepsy syndrome), with reduced seizure frequency or seizure arrest in more than 50% of the patients. The search identified nine articles on the use of tocilizumab (16 patients, 75% refractory status epilepticus), with a high response rate. Only one reference on the use of adalimumab in 11 patients with Rasmussen encephalitis showed complete response in 45% of the cases. Eight articles on rituximab employment sowed a reduced seizure burden in 16/26 patients. Finally, one trial concerning natalizumab evidenced a response in 10/32 participants.The experience with anti-cytokine agents and drugs targeting lymphocytes in epilepsy derives mostly from case reports or series. The use of anti-IL-1, anti-IL-6, and anti-CD20 agents in patients with drug-resistant epilepsy and refractory status epilepticus has shown promising results and a good safety profile. The experience with TNF inhibitors is limited to Rasmussen encephalitis. The use of anti-α4-integrin agents did not show significant effects in refractory focal seizures. Concerning research perspectives, there is increasing interest in the potential use of anti-chemokine and anti-HMGB-1 agents.
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Drug Discovery Landscape
1 orphan drug designation for Rasmussen subacute encephalitis.
1 orphan drug designation for Rasmussen subacute encephalitis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
rituximab | antibodies | FDA | 2016-11-09 | — | Keck Graduate Institute of Applied Life Sciences |
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