RARE DISEASE
Epilepsy syndrome
Epilepsy syndrome
Epilepsy syndrome
Drug discovery
7
drugs
With orphan designations
Overview
Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures due to abnormal neuronal activity. It affects all ages and has diverse etiologies, including genetic, structural, and unknown causes. While ~70% achieve seizure control with antiseizure medications (ASMs), 30% develop drug-resistant epilepsy, requiring advanced therapies. The condition carries significant mortality risks, including SUDEP (sudden unexpected death in epilepsy) [4][6][16].
Population
Global: Affects ~51.7 million people (24.2 million idiopathic; 27.5 million secondary) [9][19], with age-standardized prevalence of 307.38/100,000 [2].
Demographics: Highest incidence in children (0–14 years: 61/100,000) [2][19]; mortality peaks in adults ≥70 years (5.67/100,000) [2][19].
Disparities: 80% of cases occur in low- and middle-income countries, with treatment gaps exceeding 75% in some regions [16][19].
Burden
Mortality: Age-standardized death rate of 1.74/100,000 globally [2][19]; SUDEP accounts for 1/1,000 annual deaths in epilepsy patients [4][6].
Disability: 177.85 DALYs/100,000 globally, with males disproportionately affected (201.29 vs. 154.25 in females) [2][19].
Comorbidities: 20–30% have depression/anxiety; 27-fold higher sudden death risk vs. general population [6][16].
Therapies
First-line: ASMs (levetiracetam, valproate) control seizures in ~67% of patients [1][8][16].
Advanced options: Surgical resection, neurostimulation (vagus nerve stimulation, responsive neurostimulation), and ketogenic diet for drug-resistant cases [3][8][13].
Emerging therapies: Cenobamate, cannabidiol, and non-invasive neuromodulation (e.g., transcranial magnetic stimulation) [3][13][18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
3,271 drug discovery papers about Epilepsy syndrome, with 2 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,271 drug discovery papers about Epilepsy syndrome, with 2 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-11 | Severe Epilepsy Syndromes in Childhood: A Comprehensive Review of Clinical Features, Etiologies, and Advancing Therapeutic Landscapes
Severe childhood epilepsy syndromes, encompassing the developmental and epileptic encephalopathies together with related drug-resistant electroclinical constellations, remain among the most challenging conditions in paediatric neurology. They combine frequent, treatment-resistant seizures with developmental impairment, substantial comorbidity, and elevated premature mortality. The past two decades have transformed the field: a revised syndrome classification, an expanding catalogue of monogenic causes, and a succession of syndrome-specific and mechanism-based therapies have altered both diagnosis and management. This critical narrative review synthesises evidence on the clinical features, aetiologies, and therapeutic options for these syndromes, and evaluates the strength, consistency, and limitations of that evidence rather than cataloguing individual studies. Literature was selected from bibliographic searching, citation chaining, and appraisal of consensus statements and clinical guidelines, with every cited reference and its digital object identifier independently verified. Several themes emerge. Aetiological diagnosis, particularly through broad genetic testing, now carries direct management consequences, yet a diagnostic gap persists and genotype does not map cleanly onto phenotype or treatment response. Syndrome-specific pharmacotherapy is supported by robust randomised evidence for a small number of agents in Dravet syndrome, Lennox-Gastaut syndrome, and CDKL5 deficiency disorder, but head-to-head comparisons, long-term developmental outcomes, and effects on the encephalopathy itself remain poorly characterised. Mechanism-based and disease-modifying strategies, including mammalian target of rapamycin inhibition, pre-emptive treatment, and antisense oligonucleotides, represent a conceptual shift from seizure suppression toward disease modification, though the durability and developmental impact of these approaches are not yet established. Sudden unexpected death in epilepsy and other causes of early mortality remain insufficiently mitigated. The available evidence supports cautious optimism: outcomes are improving, but confidence in many conclusions is constrained by small samples, heterogeneous endpoints, short follow-up, and reliance on seizure count as the dominant outcome. Priorities include earlier aetiological diagnosis, developmentally meaningful outcome measures, and trials designed to test disease modification rather than seizure frequency alone.
2026-08-09 | Total bilirubin-to-albumin ratio and systemic immune inflammation index as prognostic indicators in children with febrile infection-related epilepsy syndrome.
Febrile infection-related epilepsy syndrome (FIRES) is associated with high mortality and poor neurological outcomes, yet reliable prognostic indicators are lacking. This study aimed to evaluate the prognostic value of inflammatory indexes in FIRES and to explore their potential role in guiding clinical management. Children with FIRES hospitalized at the Children's Hospital affiliated to Chongqing Medical University between November 2015 and April 2024 and followed for more than 6 months were retrospectively included. Inflammatory indexes were analyzed at admission and after immunotherapy. Patients were categorized into death, KD, and non-KD survival groups according to clinical course and treatment pathway. Multivariate logistic and sequential logistic regression analyses were performed to identify prognostic factors. Receiver operating characteristic (ROC) curves and Gordon's coefficient were used to determine cut-off values. Sankey diagrams and nomograms were applied to validate prognostic stratification. Thirty-six children with FIRES were included (22 males; mean age 6.67 ± 3 years). Nine patients died, none of whom received KD. The KD group had significantly higher 6-month Glasgow Outcome Scale (GOS) scores than the non-KD survival and death groups (4 ± 1 vs. 3 ± 1 vs. 1 ± 0, p < 0.001). Multivariate analyses showed that total bilirubin-to-albumin ratio (TAR) at admission (18.48, 95% CI 6.86∼30.09, p = 0.002) and systemic immune inflammation index (SII) after immunotherapy (-0.001, 95% CI -0.001-0, p = 0.003) were independently associated with prognosis. Cut-off values of 0.145 and 0.195 for TAR and 1292 and 1892 for SII stratified patients into distinct severity groups. Higher TAR values and lower SII values were associated with milder disease and better outcomes. Sankey diagrams and nomograms further illustrated the prognostic stratification based on TAR and SII. TAR at admission and SII after immunotherapy are practical inflammatory indexes associated with disease severity and prognosis in FIRES. These findings support further investigation of early KD initiation, particularly in patients with low TAR at admission or persistently elevated SII after immunotherapy.
2026-07-29 | Therapeutic Use of Medical Cannabis Beyond Pain Management in Physical Medicine and Rehabilitation.
Medical cannabis has emerged as a rapidly evolving therapeutic modality with expanding clinical interest beyond its traditional role in pain management. Particularly relevant to Physical Medicine and Rehabilitation (PM&R), where the focus extends beyond symptom control to functional restoration and optimal quality of life, key non-pain indications described in the literature include management of spasticity, neurologic and seizure disorders, sleep disturbances, and chemotherapy-induced nausea and vomiting (CINV). This PM&R-centered narrative review synthesizes current evidence on the efficacy, mechanisms, and clinical implications of cannabis use for non-pain conditions, with emphasis on its interaction with the endocannabinoid system, including CB1- and CB2-receptor-mediated pathways influencing neuromodulation, inflammation, and homeostasis. Across multiple conditions, cannabinoids demonstrate modest benefits in symptom reduction, including improvements in patient-reported spasticity in multiple sclerosis, significant seizure reduction in treatment-resistant pediatric epileptic syndromes, antiemetic effects in refractory CINV, and appetite stimulation in cachectic states. Additionally, subjective improvements in sleep quality have been observed, though objective changes in sleep architecture remain inconsistent. However, there remains limited evidence supporting meaningful improvements in functional outcomes and quality of life. Cannabis use may negatively impact rehabilitation through dose-dependent cognitive impairment, sedation, impaired motor learning, and increased fall risk. Significant challenges persist, including lack of standardized dosing, variability in formulations and THC:CBD ratios, inconsistent product labeling, and limited high-quality randomized controlled trials assessing long-term functional outcomes. Regulatory barriers, including discrepancies between federal and state laws, further complicate clinical implementation and research. This review highlights the gap between symptomatic relief and functional recovery, emphasizing the need for PM&R-specific research focused on rehabilitation-relevant outcomes that objectively measure functional independence and quality of life. Bridging this gap will be critical to defining a role for medical cannabis within rehabilitation medicine and optimizing patient-centered care that maximizes function.
2026-07-17 | The role of Vagus nerve stimulation in epilepsy with eyelid myoclonia - A case series.
To study the effectiveness of vagus nerve stimulation (VNS) in patients with epilepsy with eyelid myoclonia (EEM, previously known as Jeavons Syndrome). EEM is an epilepsy syndrome characterized by eyelid myoclonia, eyelid closure-induced generalized EEG paroxysms or seizures, and photosensitivity. Many patients have drug-resistant epilepsy; however, the effectiveness of VNS in this epilepsy syndrome has not been well studied. This is a single institution retrospective observational study of patients with EEM. Among a database of 134 patients with EEM, we identified those treated with VNS. Epilepsy history, VNS parameters, and response to VNS were abstracted. We identified 12 patients who were treated with VNS (50% female). The median age of epilepsy onset was 5 (range 4-14) years; age of VNS implantation was 16 (range 6-33) years, and median duration of VNS treatment was 13.5 (range 0-24) years. Four patients (33.3%) were responders reporting greater than 50% improvement in seizure frequency. All four patients (33.3%) showed response with generalized tonic-clonic seizures, myoclonic seizures, and three patients (25%) reported response with eyelid myoclonia and absence seizures. One patient had the VNS explanted due to lack of efficacy and one had it turned off for enrollment in a clinical trial. The median maximum tolerated output current settings for our cohort were 1.75 mA (IQR 1.38-1.94; range 0.75-2.25) with an OFF time of 1.8 min (IQR 1.1-3, range 0.2-3) and median duty cycle of 24% (IQR 16-29; range 12-58). From this small case series of patients with EEM, four (33.3%) were responders to VNS, with improvement noted in multiple seizure types. This indicates the potential role of VNS for patients with EEM.
2026-07-05 | Cenobamate use in super-refractory status epilepticus: A report of three cases.
Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.
proteins
2026-06-29 | Anakinra for tocilizumab-refractory febrile infection-related epilepsy syndrome with normal IL-1β levels: a case report.
Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with limited treatment options. Neuroinflammation, particularly involving IL-1β and IL-6, is a key driver. Evidence on sequential use of IL-6 receptor blockade (tocilizumab) followed by IL-1 receptor blockade (anakinra) is scarce, especially when IL-1β levels are normal. A previously healthy 6-year-old boy developed super-refractory status epilepticus six days after influenza A infection. He failed multiple antiseizure medications, anesthetics, corticosteroids, intravenous immunoglobulin, ketogenic diet, and mild therapeutic hypothermia. Cerebrospinal fluid (CSF) and serum cytokine testing showed elevated IL-6 but normal IL-1β. After initial improvement with tocilizumab, seizures relapsed. Tocilizumab retreatment and plasma exchange were ineffective. Switching to daily subcutaneous anakinra led to rapid seizure control within five days. He was weaned off anesthetics, extubated, and eventually discharged with mild cognitive dysfunction (PCPC score 2). At one-month follow-up, he had rare brief seizures and attended school. This case demonstrates that anakinra can be effective in tocilizumab-refractory FIRES even when CSF and serum IL-1β levels are normal. Anakinra should be considered as a second-line option in selected patients, regardless of IL-1β biomarker status.
2026-06-12 | Table 1_Anakinra for tocilizumab-refractory febrile infection-related epilepsy syndrome with normal IL-1β levels: a case report.docx
Background Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with limited treatment options. Neuroinflammation, particularly involving IL-1β and IL-6, is a key driver. Evidence on sequential use of IL-6 receptor blockade (tocilizumab) followed by IL-1 receptor blockade (anakinra) is scarce, especially when IL-1β levels are normal. Case presentation A previously healthy 6-year-old boy developed super-refractory status epilepticus six days after influenza A infection. He failed multiple antiseizure medications, anesthetics, corticosteroids, intravenous immunoglobulin, ketogenic diet, and mild therapeutic hypothermia. Cerebrospinal fluid (CSF) and serum cytokine testing showed elevated IL-6 but normal IL-1β. After initial improvement with tocilizumab, seizures relapsed. Tocilizumab retreatment and plasma exchange were ineffective. Switching to daily subcutaneous anakinra led to rapid seizure control within five days. He was weaned off anesthetics, extubated, and eventually discharged with mild cognitive dysfunction (PCPC score 2). At one-month follow-up, he had rare brief seizures and attended school. Conclusion This case demonstrates that anakinra can be effective in tocilizumab-refractory FIRES even when CSF and serum IL-1β levels are normal. Anakinra should be considered as a second-line option in selected patients, regardless of IL-1β biomarker status.
2025-11-26 | Case Report: Successful multimodal management of FIRES in a pediatric patient using anakinra, ketogenic diet, and induced hypothermia.
Febrile infection-related epilepsy syndrome is a devastating, refractory epileptic encephalopathy that typically occurs in school-aged, otherwise healthy, children after a brief, non-specific, febrile illness. In this study, we discuss a case of a previously healthy 10-year-old girl with FIRES in whom high dosages of conventional and non-conventional antiepileptic drugs were ineffective in treating refractory status epilepticus, after which a treatment involving intravenous corticosteroids, immunoglobulins, a ketogenic diet, and induced hypothermia was adopted. We conducted a diagnostic workup that included lumbar puncture, blood tests, continuous electroencephalogram monitoring, brain MRI, and autoimmunity and infectious disease panels to shed light on the etiology of the condition. Our patient responded to immunosuppressive therapy and the ketogenic diet, and her condition gradually improved to full recovery with only mild neurocognitive sequelae. Although patients with FIRES have been described in the literature, optimal management has not yet seen the light of day, and therefore, prospective cohort studies are needed. This case highlights the potential benefit of a timely, multimodal therapeutic approach combining immunomodulation, metabolic support, and neuroprotection. Early administration of anakinra and initiation of a ketogenic diet may help control seizures and reduce the duration of ICU stay. Prompt diagnosis and interdisciplinary care are essential to improve outcomes in patients with this life-threatening pediatric condition.
2025-07-28 | Immune dysregulation in new-onset refractory status epilepticus (NORSE): current insights and therapeutic perspectives.
Emerging evidence suggests that cryptogenic new-onset refractory status epilepticus (c-NORSE) arises from innate immunity dysfunction leading to exacerbated inflammation. While immunotherapies have been administered, their efficacy remains variable and unpredictable. We conducted a comprehensive literature review of studies reporting inflammation biomarkers in patients with NORSE or evaluating targeted immunotherapies. Additionally, we discussed future research directions and therapeutic perspectives. A total of 29 studies reporting inflammation biomarkers in at least five patients were analyzed. Most focused on c-NORSE, frequently describing cerebrospinal fluid pleocytosis, often lymphocytic and usually mild, upon admission. Elevated levels of innate immunity-related pro-inflammatory cytokines were consistently reported in c-NORSE. A large international study further demonstrated significantly higher cytokine levels in c-NORSE compared to other refractory status epilepticus patients, suggesting the importance of innate immunity in c-NORSE pathophysiology. One recent study identified subgroups with distinct inflammatory profiles among c-NORSE, suggesting different treatment approaches. More than 30 case series or reports have documented the use of targeted immunotherapies in NORSE. The most commonly used are anakinra (IL1 antagonist) and tocilizumab (IL6 antagonist), both showing seemingly comparable efficacy in seizure control. Recently, intrathecal dexamethasone has gained interest, particularly in pediatric cases, showing promising efficacy with no reported side effects. Other emerging approaches include canakinumab (anti-IL1 antibody), Janus kinase (JAK) inhibitors, and tumor necrosis factor alpha (TNFα) inhibitors. Recent studies have advanced our understanding of innate immunity disturbances in c-NORSE onset and progression. Moreover, they highlight patient heterogeneity, emphasizing the need for personalized strategies targeting specific inflammatory pathways.
2025-07-05 | Retrospective multicenter study on cryptogenic NORSE/FIRES patients treated with anakinra.
Refractory status epilepticus (RSE) is a neurological emergency characterized by persistent seizures despite two appropriate antiseizure medications. It is defined as new-onset RSE (NORSE) when occurring in previously healthy people. NORSE is defined as cryptogenic (cNORSE) when no cause is found. Febrile-infection related epilepsy syndrome (FIRES) is now defined as the cNORSE variant preceded by fever. In 2016 anakinra was reported effective in an anecdotal case. After this experience, second-line immunotherapy has been increasingly used, being incorporated in cNORSE recommendations in 2022. We conducted a retrospective study in an Italian case series of 14 patients with cNORSE (including FIRES cases) treated with anakinra in Italy before implementation of the international recommendations, that could serve as historical reference for futures studies based on the shared recommendations. In our population higher duration of intensive care stay period was associated with later time of anakinra use, although no evidence of efficacy on the long-term neurological outcome was demonstrated. There is an urgent need for well-designed head-to-head multicenter prospective clinical trials to clarify the benefits of available treatments and the role of biomarkers to guide choices.
antibodies
2026-06-19 | Case Report: Tocilizumab in pediatric febrile infection-related epilepsy syndrome.
We describe the clinical characteristics and the therapeutic effect of tocilizumab with Febrile Infection-Related Epilepsy Syndrome (FIRES). FIRES is characterized by super refractory status epilepticus (SRSE) in previously healthy children, following a febrile illness that manifests between 2 weeks and 24 hours prior to the onset of seizure. We collected and summarized the clinical data of two pediatric patients with FIRES and compare with those described previously in the literature. Elevated levels of IL-6 were observed in the two patient's blood samples. Patient 1 consented to receive tocilizumab on the 58th day of the disease progression, resulting in transient relief of seizures. Throughout the follow-up period, the patient remained unconscious and consistently experienced intermittent seizures. Patient 2 was administered tocilizumab on the 7th day of the disease course. During the six-month follow-up, no seizures were observed and no significant cognitive decline. Up to date, 7 patients of pediatric FIRES treated with tocilizumab have been reported. The clinical symptoms of the patients were relatively consistent, characterized by focal seizures and status epilepticus as the primary manifestations. Serum IL-6 may exhibit elevated or normal, whereas cerebrospinal fluid IL-6 demonstrated a significant elevation, indicating a lack of concordance. Now little has been known about the administration of tocilizumab in pediatric FIRES. We posit that early administration of tocilizumab (within 3 weeks from disease onset) positively impacts the treatment of FIRES.
2026-06-17 | [How I treat pediatric febrile infection-related epilepsy syndrome].
Febrile infection-related epilepsy syndrome (FIRES) mainly affects previously healthy children and adolescents, often leading to severe neurological impairment and long-term sequelae such as drug-resistant epilepsy and cognitive dysfunction. Based on two pediatric FIRES cases, combined with international and domestic guidelines as well as clinical experience, this paper highlights therapeutic strategies and escalation pathways tailored to different inflammatory phases in the acute and chronic stages. Incorporating continuous electroencephalogram monitoring and cerebrospinal fluid inflammatory cytokine profile changes, a phase-specific treatment approach is systematically described, centered on the rapid termination of status epilepticus, targeted cytokine immunotherapy, and multidisciplinary collaborative support, and the active use of tocilizumab, anakinra, and the ketogenic diet is emphasized, to provide practical guidance for clinicians in managing FIRES.
2026-06-05 | The electroencephalographic patterns in the acute phase of febrile infection related epilepsy syndrome in children.
Febrile Infection Related Epilepsy Syndrome is a rare and refractory severe syndrome characterized by status epilepticus and encephalopathy. Early administration of immunotherapy agents has been shown to significantly improve outcomes. This study aims to analyze and summarize the characteristic electroencephalographic features during the acute phase of cryptogenic FIRES in children, in order to facilitate early diagnosis. A retrospective collection of patients diagnosed with cryptogenic FIRES was conducted. The EEG characteristics during the acute phase of these patients were summarized. A total of 31 pediatric patients with FIRES were included (23 males, 8 females), with an age of onset ranging from 2 years old to 13 years and 8 months. All 31 cases exhibited background slowing. Multifocal epileptiform discharges were observed in 30 cases. Extreme δ brushes were noted in 23 cases. Frequent clinical seizures and/or EEG ictal events were recorded in all cases. Ictal EEG exhibited Zig-Zag sharp or spike waves in the θ-β frequency range, with or without the onset of low-amplitude focal fast activity. The ictal discharges exhibited focal, multifocal, and migratory characteristics in an alternating, overlapping, or independent pattern, with relatively localized spread and rarely generalized spread to all leads. "Migratory Zig-Zag Pattern", the relatively characteristic acute-phase ictal EEG finding may serve as an specific electrophysiological feature suggestive of FIRES in children. When combined with other ancillary examinations, they may assist in the early clinical diagnosis of FIRES and guide early immunomodulatory interventions to improve clinical outcome.
2026-06-02 | Systematic Reviews and Meta-Analyses of the Use of Tocilizumab in Treating Central Nervous Diseases.
To perform systematic reviews and meta-analyses on the use of the tocilizumab in the central nervous system (CNS) diseases. A systematic search was carried out in the PubMed, Embase and Cochrane databases for all years until August 2025. The review revealed 618 CNS diseases patients treated with tocilizumab. The proportion of neuromyelitis optica spectrum disorder (NMOSD) relapse-free patients after tocilizumab was 79.00% (95% confidence interval (CI): 0.67, 0.89). There was a significant correlation between remission and positive anti-AQP4 antibody status (p = 0.001). Tocilizumab significantly reduced the standardized mean Annualized Relapse Ratio (-1.3 (95% CI: -1.94, -0.66; p = 0.00191), Extended Disability Status Scale score (-0.48; 95% CI: -0.92, -0.04; p = 0.0329), and fatigue score (-1.08; 95% CI: -1.53, -0.63; p < 0.0001). The proportion of new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and refractory status epilepticus patients who improved after tocilizumab was 95.00% (95% CI: 0.78, 1.00). The proportion of the anti-NMDAR encephalitis patients with a favorable outcome after tocilizumab was 73.00% (95% CI: 0.64, 0.81). Although other CNS diseases showed improvement following tocilizumab, they did not meet the criteria for meta-analyses. Tocilizumab altered several pro- and anti-inflammatory markers in humans, animals, and cell models. The pooled proportion of tocilizumab adverse effects was 45.00% (95% CI: 0.26, 0.65). This study may guide clinicians in managing patients with CNS diseases and in conducting prospective studies and clinical trials. Some of the CNS diseases may be treated with tocilizumab.
2026-05-07 | The Clinical Outcomes of Tocilizumab Usage in Cryptogenic Febrile Infection-Related Epilepsy Syndrome at Both Acute and Chronic Phase: A Retrospective Study.
To provide more observational evidence for potential efficacy of tocilizumab (TCZ) in children with cryptogenic febrile infection-related epilepsy syndrome (FIRES) administered during acute and chronic phase. Data of 22 children with FIRES who received TCZ were collected retrospectively. Patients were categorized into two groups: acute group (TCZ used within 4 weeks post-onset; n = 12) and chronic group (TCZ used beyond 4 weeks post-onset; n = 10). In both groups, patients experienced >50% reduction in seizure frequency, electroencephalogram (EEG) improvements, alleviation on cranial magnetic resonance imaging (MRI), and significantly decreased mRS scores (P < 0.05). In acute group, 6 patients became seizure-free by the last follow-up, and 7 patients reduced their number of antiseizure medications (ASMs). TCZ administration in acute phase shortened status epilepticus (SE) duration. At last follow-up, the acute group exhibited higher rates of seizure freedom and >50% seizure reduction (P < 0.05), lower incidences of motor and speech deficits (P < 0.05), and a greater likelihood of returning to school (P < 0.05). TCZ treatment was associated with reduced seizure frequency, improved EEG and MRI findings, decreased reliance on antiseizure medications, and functional improvement as measured by mRS. Initiation of treatment during the acute phase may be associated with a shortened duration of status epilepticus and, compared to chronic-phase intervention, appears to correlate with more favorable long-term outcomes.
gene therapies
2026-02-02 | Base editing rescues seizures and sudden death in a SCN8A mutation-associated developmental epileptic encephalopathy model.
SCN8A encodes the voltage-gated sodium channel Nav1.6, which plays a key role in facilitating neuronal excitability. Mutations in SCN8A, particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, movement disorders, and sudden unexpected death in epilepsy (SUDEP). The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments, including antiseizure medications, are often ineffective for patients with SCN8A DEE, highlighting the need for targeted therapies. We employed base editing to correct the R1872W SCN8A variant. An adenine base editor and guide RNA (SCN8A-ABE) were packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A-ABE significantly increased survival of mice expressing R1872W and either reduced seizure incidence and severity or eliminated seizure occurrence. Electrophysiological recordings revealed a rescue of seizure-associated neuronal hyperexcitability and suppression of the pathogenic persistent sodium current (INaP) in treated mice. Comorbidities, including diminished mobility and anxiety-like behaviors, were improved by SCN8A-ABE. These effects were achieved by a 32% absolute reduction in mutant transcripts, accompanied by conversion to SCN8A WT transcripts. Our findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEEs by addressing the underlying genetic cause.
2025-06-12 | PQBP1-dependent alternative RNA splicing underlies high calorie diet-induced cognitive impairment.
High calorie-high fat diet (HFD) has been implicated as a pathological modifier of brain diseases including neurodegenerative dementias, but the detailed molecular mechanisms remain largely unknown. Here we report that HFD suppresses PPARγ-mediated transcriptional expression of PQBP1 , a RNA splicing factor implicated in human intellectual disability and Alzheimer's disease. RNAseq-based comprehensive analyses of alternative RNA splicing (AS) in HFD-fed mice for 1 or 6 weeks and in PQBP1-cKO mice reveal their common changes, which weigh on synapse-related genes. Betweenness-based extraction of core molecules from the common changes reveals CASK, Cacnb1 and Cyfip2 as key molecules of the network. Both CASK and Cacnb1 regulate STXBP1, a causative gene for infantile epilepsy syndrome and an essential factor for synapse vesicle release, via their direct interaction. In addition, our analysis suggests that Syt1 plays a role specifically in HFD for 1 week. HFD-induced AS isoforms of CASK, Cacnb1, Cyfip2 and Syt1 impair pre-synapse vesicle release in primary neurons. AAV-PQBP1, AAV-CASK, AAV-Cacnb1, AAV-Cyfip2 or AAV-Syt1 rescues synapse and/or cognitive dysfunctions in HFD mice, genetically supporting the pathological PQBP1-presynase axis in HFD. Moreover, immunohistochemistry experiments suggest that the pathological axis plays roles not only in excitatory neurons, but also in inhibitory neurons of the brain. Collectively, our results unravel a novel molecular mechanism for brain dysfunction when mice are exposed to a HFD.
2025-04-09 | Base Editing Rescue of Seizures and SUDEP in SCN8A Developmental Epileptic Encephalopathy
Abstract SCN8A encodes the sodium channel Na v 1.6; mutations in SCN8A , particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, and seizure-induced death. The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments for SCN8A DEE are often ineffective, highlighting the need for targeted therapies. Here we employed base editing to correct the R1872W SCN8A variant. A modified adenine base editor ( SCN8A -ABE) was packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A -ABE significantly increased survival and reduced or eliminated seizures. Neuronal hyperexcitability and heightened sodium currents were attenuated with SCN8A -ABE treatment, and behavioral comorbidities were improved. These effects were achieved by approximately 30% conversion of mutant to wildtype SCN8A transcripts. These findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEE by addressing the underlying genetic cause.
2025-03-23 | Epilepsy with myoclonic-atonic seizures: an update on genetic causes, nosological limits, and treatment strategies.
Epilepsy with myoclonic-atonic seizures is a childhood-onset epilepsy syndrome characterised by a range of seizure types, including myoclonic-atonic, atonic, myoclonic, absence, and generalised tonic-clonic seizures. The causes and outcomes of this syndrome are highly variable, with many uncertainties surrounding its classification and prognosis. Traditional antiseizure medications and the ketogenic diet remain the main treatment options. Although two-thirds of children attain remission from seizures without cognitive or behavioural sequelae, some continue to have drug-resistant seizures, intellectual disability, and behavioural problems. The identification of single-gene causes in a substantial subset of patients highlights the importance of genetic testing for development of personalised treatment strategies. However, diagnostic complexities have hindered the development of trials for new therapies. Better recognition of the distinct features of epilepsy with myoclonic-atonic seizures, combined with advances in molecular genetic testing, will pave the way for more focused clinical research and drug development. Future studies should aim to identify genetic causes and tailor treatment options, offering hope for improved long-term outcomes.
2025-02-27 | Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.
Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression. DEEs encompass many epilepsy syndromes, although not all patients with a DEE can be classified into a specific syndrome. Our understanding of the etiologies of DEEs has been revolutionized with next-generation sequencing, with more than 900 genes implicated, in addition to structural causes. It is therefore now possible to consider precision medicine and novel therapeutic approaches for these devastating diseases with trials of repurposed and new drugs, including gene therapies. Trials are being designed to target either DEE diseases more broadly, specific DEE syndromes, or specific genetic DEEs. To serve this purpose, a clear operational definition of DEEs is needed to ensure that appropriate patients are selected for trials with precisely defined, targeted outcome measures. Herein we propose the operational definition of DEEs to set the stage for the development of DEE therapies.
other
2026-03-01 | Uncovering targets and molecular pathways for personalizing treatment in epilepsy.
Despite licensing many new antiseizure drugs over the last few decades, the proportion of pharmacoresistant epileptic seizures has remained largely unchanged at about 30%. However, recent progress in genetics has revealed new and more specific therapeutic targets that can be addressed through improved drug design and advancements in gene therapy, such as improved antisense oligonucleotide chemistry. Furthermore, many of these developing new precision therapies hold the promise of shifting from purely symptomatic toward disease-modifying treatment, particularly in the field of developmental and epileptic encephalopathies. This article focuses on novel potential therapeutic targets, including those encoded by causative genes for epileptic syndromes and those that show promise for favorably impacting common epilepsies or epileptogenesis. The covered areas are organized according to different molecular protein targets. Therapy in the near future will likely be based predominantly on specific small molecules or gene therapies, such as antisense oligonucleotides. Among currently used allele-specific therapeutic designs, only some loss- or gain-of-function pathological variants are expected to profit from them. Allele-specific gene therapy may be a promising treatment for those diseases that would not benefit from currently used allele-nonspecific designs.
2024-12-18 | Circulating miR-134 in mesial temporal lobe epilepsy: implications in hippocampal sclerosis development and drug resistance
Aim miR-134 has been widely reported as upregulated in experimental and human studies of Mesial Temporal Lobe Epilepsy the most common drug-resistant epilepsy (DRE). Studies have shown that the use of antagomirs, anti-miR-134, may be a promising therapeutic approach to these epilepsies. However, data on miR-134 in other epileptic syndromes is scarce. In this study, we aimed to quantify serum levels of miR-134 in a cohort of patients with Mesial Temporal Lobe Epilepsy-Hippocampal Sclerosis (MTLE-HS) and with Genetic Generalized Epilepsies (GGE). Additionally, we explored the correlation between miR-134 serum levels and clinical parameters, such as age at onset or febrile seizures antecedents, to evaluate its potential as a biomarker and therapeutic target in epilepsy. Methods miR-134 levels were evaluated in cell-free serum of 131 patients with epilepsy (75 women, 56 men; age 41.10 ± 13.12 years; 72 with DRE) and 42 healthy individuals (25 women, 17 men; age 42.40 ± 9.80 years). The epilepsy cohort included 77 MTLE-HS patients and 54 GGE patients. Results Patients with elevated miR-134 circulating levels were at higher risk of drug-resistant epilepsy (OR [95% CI] = 2.246 [1.111–4.539], p = 0.021). Other risk factors included an older age (OR [95% CI] = 1.032 [1.004–1.061], p = 0.025), history of febrile seizures (OR [95% CI] = 2.994 [1.385–6.471], p = 0.005) and higher disease duration (OR [95% CI] = 1.038 [1.011–1.066], p = 0.006). The strongest predictor of DRE was hippocampal sclerosis (OR [95% CI] = 10.338 [4.566–23.404], p < 0.001). Circulating miR-134 levels were significantly higher in MTLE-HS patients compared to controls ( p < 0.05) and GGE patients ( p < 0.05). However, the clinical utility of miR-134 in discriminating MTLE-HS patients from controls was only moderated (AUC = 0.651 ± 0.051 95% CI 0.551–0.751, p = 0.007). Conclusion We show that miR-134 circulating levels are associated with DRE, especially in MTLE-HS, a syndrome characterized by severe hippocampal damage, consistent with activity-regulated miR-134 expression. This overexpression likely contributes to disease progression and our results support the potential of targeting miR-134 as a novel therapeutic approach for refractory epilepsy.
2024-11-13 | Pharmacotherapeutic strategies for drug-resistant epilepsy in children.
Drug resistance is defined as the failure of adequate trials of two tolerated and appropriately chosen antiseizure medications to achieve sustained seizure freedom. In case of uncontrolled seizures, pseudo-drug-resistance (poor compliance, a worsening effect of an antiseizure medication, a diagnosis of psychogenic non-epileptic seizure) should be first ruled out in case of pediatric epilepsies. This paper discusses the process of choosing antiseizure medication and the concepts of rationale polytherapy and precision medicine. In drug-resistant epilepsy, when curative surgery is not feasible, the aim of the treatment is focused on the improvement of quality of life rather than on seizure count. In recent years, despite an increase in available antiseizure medications, the incidence of drug-resistant epilepsy has not changed. Precision medicine may offer in rare epilepsies a mechanism-driven treatment, but it is still unclear if this will end up in an improvement of efficacy in drug-resistant epilepsies. Gene therapy with antisense oligonucleotides or Adeno-associated Virus (AAV) is transitioning from the experimental side to the first human trial. It may modify the natural history of selected epileptic syndromes.
2024-11-02 | Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment
The potassium sodium-activated channel subtype T member 1 (KCNT1) gene encodes the Slack channel KNa1.1, which is expressed in neurons throughout the brain. Gain-of-function variants in KCNT1 are associated with a spectrum of epilepsy syndromes, and mice carrying those variants exhibit a robust phenotype similar to that observed in patients. Kcnt1 knockout (KO) mice, however, have a normal lifespan without any epileptic phenotype. To understand the molecular differences between these two models, we conducted a comprehensive proteomic analysis of the cerebral cortices of Kcnt1 KO and Kcnt1R455H/+ mice, an animal model bearing a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. The greatest change observed in Kcnt1 KO mice compared to the wild-type mice was the increased expression of multiple proteins of the inner mitochondrial membrane. Electron microscopy studies of cortical mitochondria from Kcnt1 KO mice further confirmed a significant increase in the density of mitochondrial cristae compared to that in wild-type mice. Kcnt1 reduction by a murine-specific Kcnt1 antisense oligonucleotide (ASO) in Kcnt1R455H/+ mice partially corrected the proteomic dysregulations in the disease model. The results support the hypothesis that ASO-mediated KCNT1 reduction could be therapeutically useful in the treatment of KCNT1 epilepsies.
2024-05-10 | Thrombosis With Thrombocytopenia and Post-COVID-Vaccination Syndrome With Anti-G-Protein-Coupled Receptor (GPCR) Antibodies Treated With Therapeutic Plasma Exchange
We present the case of a female who developed cerebral venous thrombosis with thrombocytopenia after inoculation with the anti-coronavirus disease 2019 (COVID-19) Vaxzevria vaccine, followed by splanchnic thrombosis and diffuse hemorrhages. Despite receiving treatment, the complications increased, and hence therapeutic plasma exchange (TPE) was attempted, leading to laboratory and clinical improvements and discharge after a period of intensive care. Almost two years after the first episode, in the interim of which the patient complained of only minor symptoms such as asthenia and difficulty concentrating, she developed an epileptic syndrome that required neurological treatment. In addition, her fatigue and difficulty concentrating worsened and other serious symptoms of dysautonomia appeared, such as trembling of her right arm, loss of stability, and postural orthostatic tachycardia. As serum analysis revealed a significant number of alterations in autoantibodies against various G-protein-coupled receptors (GPCRs) and RAS-related proteins, two further TPEs were performed, resulting in rapid and sustained clinical improvement. This report highlights the role of the different types of autoantibodies produced in response to anti-COVID-19 vaccination, which can have functional, regulatory, and possibly pathogenic effects on the vascular and nervous systems.
small molecules
2026-08-11 | Severe Epilepsy Syndromes in Childhood: A Comprehensive Review of Clinical Features, Etiologies, and Advancing Therapeutic Landscapes
Severe childhood epilepsy syndromes, encompassing the developmental and epileptic encephalopathies together with related drug-resistant electroclinical constellations, remain among the most challenging conditions in paediatric neurology. They combine frequent, treatment-resistant seizures with developmental impairment, substantial comorbidity, and elevated premature mortality. The past two decades have transformed the field: a revised syndrome classification, an expanding catalogue of monogenic causes, and a succession of syndrome-specific and mechanism-based therapies have altered both diagnosis and management. This critical narrative review synthesises evidence on the clinical features, aetiologies, and therapeutic options for these syndromes, and evaluates the strength, consistency, and limitations of that evidence rather than cataloguing individual studies. Literature was selected from bibliographic searching, citation chaining, and appraisal of consensus statements and clinical guidelines, with every cited reference and its digital object identifier independently verified. Several themes emerge. Aetiological diagnosis, particularly through broad genetic testing, now carries direct management consequences, yet a diagnostic gap persists and genotype does not map cleanly onto phenotype or treatment response. Syndrome-specific pharmacotherapy is supported by robust randomised evidence for a small number of agents in Dravet syndrome, Lennox-Gastaut syndrome, and CDKL5 deficiency disorder, but head-to-head comparisons, long-term developmental outcomes, and effects on the encephalopathy itself remain poorly characterised. Mechanism-based and disease-modifying strategies, including mammalian target of rapamycin inhibition, pre-emptive treatment, and antisense oligonucleotides, represent a conceptual shift from seizure suppression toward disease modification, though the durability and developmental impact of these approaches are not yet established. Sudden unexpected death in epilepsy and other causes of early mortality remain insufficiently mitigated. The available evidence supports cautious optimism: outcomes are improving, but confidence in many conclusions is constrained by small samples, heterogeneous endpoints, short follow-up, and reliance on seizure count as the dominant outcome. Priorities include earlier aetiological diagnosis, developmentally meaningful outcome measures, and trials designed to test disease modification rather than seizure frequency alone.
2026-08-09 | Total bilirubin-to-albumin ratio and systemic immune inflammation index as prognostic indicators in children with febrile infection-related epilepsy syndrome.
Febrile infection-related epilepsy syndrome (FIRES) is associated with high mortality and poor neurological outcomes, yet reliable prognostic indicators are lacking. This study aimed to evaluate the prognostic value of inflammatory indexes in FIRES and to explore their potential role in guiding clinical management. Children with FIRES hospitalized at the Children's Hospital affiliated to Chongqing Medical University between November 2015 and April 2024 and followed for more than 6 months were retrospectively included. Inflammatory indexes were analyzed at admission and after immunotherapy. Patients were categorized into death, KD, and non-KD survival groups according to clinical course and treatment pathway. Multivariate logistic and sequential logistic regression analyses were performed to identify prognostic factors. Receiver operating characteristic (ROC) curves and Gordon's coefficient were used to determine cut-off values. Sankey diagrams and nomograms were applied to validate prognostic stratification. Thirty-six children with FIRES were included (22 males; mean age 6.67 ± 3 years). Nine patients died, none of whom received KD. The KD group had significantly higher 6-month Glasgow Outcome Scale (GOS) scores than the non-KD survival and death groups (4 ± 1 vs. 3 ± 1 vs. 1 ± 0, p < 0.001). Multivariate analyses showed that total bilirubin-to-albumin ratio (TAR) at admission (18.48, 95% CI 6.86∼30.09, p = 0.002) and systemic immune inflammation index (SII) after immunotherapy (-0.001, 95% CI -0.001-0, p = 0.003) were independently associated with prognosis. Cut-off values of 0.145 and 0.195 for TAR and 1292 and 1892 for SII stratified patients into distinct severity groups. Higher TAR values and lower SII values were associated with milder disease and better outcomes. Sankey diagrams and nomograms further illustrated the prognostic stratification based on TAR and SII. TAR at admission and SII after immunotherapy are practical inflammatory indexes associated with disease severity and prognosis in FIRES. These findings support further investigation of early KD initiation, particularly in patients with low TAR at admission or persistently elevated SII after immunotherapy.
2026-07-29 | Therapeutic Use of Medical Cannabis Beyond Pain Management in Physical Medicine and Rehabilitation.
Medical cannabis has emerged as a rapidly evolving therapeutic modality with expanding clinical interest beyond its traditional role in pain management. Particularly relevant to Physical Medicine and Rehabilitation (PM&R), where the focus extends beyond symptom control to functional restoration and optimal quality of life, key non-pain indications described in the literature include management of spasticity, neurologic and seizure disorders, sleep disturbances, and chemotherapy-induced nausea and vomiting (CINV). This PM&R-centered narrative review synthesizes current evidence on the efficacy, mechanisms, and clinical implications of cannabis use for non-pain conditions, with emphasis on its interaction with the endocannabinoid system, including CB1- and CB2-receptor-mediated pathways influencing neuromodulation, inflammation, and homeostasis. Across multiple conditions, cannabinoids demonstrate modest benefits in symptom reduction, including improvements in patient-reported spasticity in multiple sclerosis, significant seizure reduction in treatment-resistant pediatric epileptic syndromes, antiemetic effects in refractory CINV, and appetite stimulation in cachectic states. Additionally, subjective improvements in sleep quality have been observed, though objective changes in sleep architecture remain inconsistent. However, there remains limited evidence supporting meaningful improvements in functional outcomes and quality of life. Cannabis use may negatively impact rehabilitation through dose-dependent cognitive impairment, sedation, impaired motor learning, and increased fall risk. Significant challenges persist, including lack of standardized dosing, variability in formulations and THC:CBD ratios, inconsistent product labeling, and limited high-quality randomized controlled trials assessing long-term functional outcomes. Regulatory barriers, including discrepancies between federal and state laws, further complicate clinical implementation and research. This review highlights the gap between symptomatic relief and functional recovery, emphasizing the need for PM&R-specific research focused on rehabilitation-relevant outcomes that objectively measure functional independence and quality of life. Bridging this gap will be critical to defining a role for medical cannabis within rehabilitation medicine and optimizing patient-centered care that maximizes function.
2026-07-17 | The role of Vagus nerve stimulation in epilepsy with eyelid myoclonia - A case series.
To study the effectiveness of vagus nerve stimulation (VNS) in patients with epilepsy with eyelid myoclonia (EEM, previously known as Jeavons Syndrome). EEM is an epilepsy syndrome characterized by eyelid myoclonia, eyelid closure-induced generalized EEG paroxysms or seizures, and photosensitivity. Many patients have drug-resistant epilepsy; however, the effectiveness of VNS in this epilepsy syndrome has not been well studied. This is a single institution retrospective observational study of patients with EEM. Among a database of 134 patients with EEM, we identified those treated with VNS. Epilepsy history, VNS parameters, and response to VNS were abstracted. We identified 12 patients who were treated with VNS (50% female). The median age of epilepsy onset was 5 (range 4-14) years; age of VNS implantation was 16 (range 6-33) years, and median duration of VNS treatment was 13.5 (range 0-24) years. Four patients (33.3%) were responders reporting greater than 50% improvement in seizure frequency. All four patients (33.3%) showed response with generalized tonic-clonic seizures, myoclonic seizures, and three patients (25%) reported response with eyelid myoclonia and absence seizures. One patient had the VNS explanted due to lack of efficacy and one had it turned off for enrollment in a clinical trial. The median maximum tolerated output current settings for our cohort were 1.75 mA (IQR 1.38-1.94; range 0.75-2.25) with an OFF time of 1.8 min (IQR 1.1-3, range 0.2-3) and median duty cycle of 24% (IQR 16-29; range 12-58). From this small case series of patients with EEM, four (33.3%) were responders to VNS, with improvement noted in multiple seizure types. This indicates the potential role of VNS for patients with EEM.
2026-07-05 | Cenobamate use in super-refractory status epilepticus: A report of three cases.
Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.
proteins
2026-06-29 | Anakinra for tocilizumab-refractory febrile infection-related epilepsy syndrome with normal IL-1β levels: a case report.
Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with limited treatment options. Neuroinflammation, particularly involving IL-1β and IL-6, is a key driver. Evidence on sequential use of IL-6 receptor blockade (tocilizumab) followed by IL-1 receptor blockade (anakinra) is scarce, especially when IL-1β levels are normal. A previously healthy 6-year-old boy developed super-refractory status epilepticus six days after influenza A infection. He failed multiple antiseizure medications, anesthetics, corticosteroids, intravenous immunoglobulin, ketogenic diet, and mild therapeutic hypothermia. Cerebrospinal fluid (CSF) and serum cytokine testing showed elevated IL-6 but normal IL-1β. After initial improvement with tocilizumab, seizures relapsed. Tocilizumab retreatment and plasma exchange were ineffective. Switching to daily subcutaneous anakinra led to rapid seizure control within five days. He was weaned off anesthetics, extubated, and eventually discharged with mild cognitive dysfunction (PCPC score 2). At one-month follow-up, he had rare brief seizures and attended school. This case demonstrates that anakinra can be effective in tocilizumab-refractory FIRES even when CSF and serum IL-1β levels are normal. Anakinra should be considered as a second-line option in selected patients, regardless of IL-1β biomarker status.
2026-06-12 | Table 1_Anakinra for tocilizumab-refractory febrile infection-related epilepsy syndrome with normal IL-1β levels: a case report.docx
Background Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with limited treatment options. Neuroinflammation, particularly involving IL-1β and IL-6, is a key driver. Evidence on sequential use of IL-6 receptor blockade (tocilizumab) followed by IL-1 receptor blockade (anakinra) is scarce, especially when IL-1β levels are normal. Case presentation A previously healthy 6-year-old boy developed super-refractory status epilepticus six days after influenza A infection. He failed multiple antiseizure medications, anesthetics, corticosteroids, intravenous immunoglobulin, ketogenic diet, and mild therapeutic hypothermia. Cerebrospinal fluid (CSF) and serum cytokine testing showed elevated IL-6 but normal IL-1β. After initial improvement with tocilizumab, seizures relapsed. Tocilizumab retreatment and plasma exchange were ineffective. Switching to daily subcutaneous anakinra led to rapid seizure control within five days. He was weaned off anesthetics, extubated, and eventually discharged with mild cognitive dysfunction (PCPC score 2). At one-month follow-up, he had rare brief seizures and attended school. Conclusion This case demonstrates that anakinra can be effective in tocilizumab-refractory FIRES even when CSF and serum IL-1β levels are normal. Anakinra should be considered as a second-line option in selected patients, regardless of IL-1β biomarker status.
2025-11-26 | Case Report: Successful multimodal management of FIRES in a pediatric patient using anakinra, ketogenic diet, and induced hypothermia.
Febrile infection-related epilepsy syndrome is a devastating, refractory epileptic encephalopathy that typically occurs in school-aged, otherwise healthy, children after a brief, non-specific, febrile illness. In this study, we discuss a case of a previously healthy 10-year-old girl with FIRES in whom high dosages of conventional and non-conventional antiepileptic drugs were ineffective in treating refractory status epilepticus, after which a treatment involving intravenous corticosteroids, immunoglobulins, a ketogenic diet, and induced hypothermia was adopted. We conducted a diagnostic workup that included lumbar puncture, blood tests, continuous electroencephalogram monitoring, brain MRI, and autoimmunity and infectious disease panels to shed light on the etiology of the condition. Our patient responded to immunosuppressive therapy and the ketogenic diet, and her condition gradually improved to full recovery with only mild neurocognitive sequelae. Although patients with FIRES have been described in the literature, optimal management has not yet seen the light of day, and therefore, prospective cohort studies are needed. This case highlights the potential benefit of a timely, multimodal therapeutic approach combining immunomodulation, metabolic support, and neuroprotection. Early administration of anakinra and initiation of a ketogenic diet may help control seizures and reduce the duration of ICU stay. Prompt diagnosis and interdisciplinary care are essential to improve outcomes in patients with this life-threatening pediatric condition.
2025-07-28 | Immune dysregulation in new-onset refractory status epilepticus (NORSE): current insights and therapeutic perspectives.
Emerging evidence suggests that cryptogenic new-onset refractory status epilepticus (c-NORSE) arises from innate immunity dysfunction leading to exacerbated inflammation. While immunotherapies have been administered, their efficacy remains variable and unpredictable. We conducted a comprehensive literature review of studies reporting inflammation biomarkers in patients with NORSE or evaluating targeted immunotherapies. Additionally, we discussed future research directions and therapeutic perspectives. A total of 29 studies reporting inflammation biomarkers in at least five patients were analyzed. Most focused on c-NORSE, frequently describing cerebrospinal fluid pleocytosis, often lymphocytic and usually mild, upon admission. Elevated levels of innate immunity-related pro-inflammatory cytokines were consistently reported in c-NORSE. A large international study further demonstrated significantly higher cytokine levels in c-NORSE compared to other refractory status epilepticus patients, suggesting the importance of innate immunity in c-NORSE pathophysiology. One recent study identified subgroups with distinct inflammatory profiles among c-NORSE, suggesting different treatment approaches. More than 30 case series or reports have documented the use of targeted immunotherapies in NORSE. The most commonly used are anakinra (IL1 antagonist) and tocilizumab (IL6 antagonist), both showing seemingly comparable efficacy in seizure control. Recently, intrathecal dexamethasone has gained interest, particularly in pediatric cases, showing promising efficacy with no reported side effects. Other emerging approaches include canakinumab (anti-IL1 antibody), Janus kinase (JAK) inhibitors, and tumor necrosis factor alpha (TNFα) inhibitors. Recent studies have advanced our understanding of innate immunity disturbances in c-NORSE onset and progression. Moreover, they highlight patient heterogeneity, emphasizing the need for personalized strategies targeting specific inflammatory pathways.
2025-07-05 | Retrospective multicenter study on cryptogenic NORSE/FIRES patients treated with anakinra.
Refractory status epilepticus (RSE) is a neurological emergency characterized by persistent seizures despite two appropriate antiseizure medications. It is defined as new-onset RSE (NORSE) when occurring in previously healthy people. NORSE is defined as cryptogenic (cNORSE) when no cause is found. Febrile-infection related epilepsy syndrome (FIRES) is now defined as the cNORSE variant preceded by fever. In 2016 anakinra was reported effective in an anecdotal case. After this experience, second-line immunotherapy has been increasingly used, being incorporated in cNORSE recommendations in 2022. We conducted a retrospective study in an Italian case series of 14 patients with cNORSE (including FIRES cases) treated with anakinra in Italy before implementation of the international recommendations, that could serve as historical reference for futures studies based on the shared recommendations. In our population higher duration of intensive care stay period was associated with later time of anakinra use, although no evidence of efficacy on the long-term neurological outcome was demonstrated. There is an urgent need for well-designed head-to-head multicenter prospective clinical trials to clarify the benefits of available treatments and the role of biomarkers to guide choices.
antibodies
2026-06-19 | Case Report: Tocilizumab in pediatric febrile infection-related epilepsy syndrome.
We describe the clinical characteristics and the therapeutic effect of tocilizumab with Febrile Infection-Related Epilepsy Syndrome (FIRES). FIRES is characterized by super refractory status epilepticus (SRSE) in previously healthy children, following a febrile illness that manifests between 2 weeks and 24 hours prior to the onset of seizure. We collected and summarized the clinical data of two pediatric patients with FIRES and compare with those described previously in the literature. Elevated levels of IL-6 were observed in the two patient's blood samples. Patient 1 consented to receive tocilizumab on the 58th day of the disease progression, resulting in transient relief of seizures. Throughout the follow-up period, the patient remained unconscious and consistently experienced intermittent seizures. Patient 2 was administered tocilizumab on the 7th day of the disease course. During the six-month follow-up, no seizures were observed and no significant cognitive decline. Up to date, 7 patients of pediatric FIRES treated with tocilizumab have been reported. The clinical symptoms of the patients were relatively consistent, characterized by focal seizures and status epilepticus as the primary manifestations. Serum IL-6 may exhibit elevated or normal, whereas cerebrospinal fluid IL-6 demonstrated a significant elevation, indicating a lack of concordance. Now little has been known about the administration of tocilizumab in pediatric FIRES. We posit that early administration of tocilizumab (within 3 weeks from disease onset) positively impacts the treatment of FIRES.
2026-06-17 | [How I treat pediatric febrile infection-related epilepsy syndrome].
Febrile infection-related epilepsy syndrome (FIRES) mainly affects previously healthy children and adolescents, often leading to severe neurological impairment and long-term sequelae such as drug-resistant epilepsy and cognitive dysfunction. Based on two pediatric FIRES cases, combined with international and domestic guidelines as well as clinical experience, this paper highlights therapeutic strategies and escalation pathways tailored to different inflammatory phases in the acute and chronic stages. Incorporating continuous electroencephalogram monitoring and cerebrospinal fluid inflammatory cytokine profile changes, a phase-specific treatment approach is systematically described, centered on the rapid termination of status epilepticus, targeted cytokine immunotherapy, and multidisciplinary collaborative support, and the active use of tocilizumab, anakinra, and the ketogenic diet is emphasized, to provide practical guidance for clinicians in managing FIRES.
2026-06-05 | The electroencephalographic patterns in the acute phase of febrile infection related epilepsy syndrome in children.
Febrile Infection Related Epilepsy Syndrome is a rare and refractory severe syndrome characterized by status epilepticus and encephalopathy. Early administration of immunotherapy agents has been shown to significantly improve outcomes. This study aims to analyze and summarize the characteristic electroencephalographic features during the acute phase of cryptogenic FIRES in children, in order to facilitate early diagnosis. A retrospective collection of patients diagnosed with cryptogenic FIRES was conducted. The EEG characteristics during the acute phase of these patients were summarized. A total of 31 pediatric patients with FIRES were included (23 males, 8 females), with an age of onset ranging from 2 years old to 13 years and 8 months. All 31 cases exhibited background slowing. Multifocal epileptiform discharges were observed in 30 cases. Extreme δ brushes were noted in 23 cases. Frequent clinical seizures and/or EEG ictal events were recorded in all cases. Ictal EEG exhibited Zig-Zag sharp or spike waves in the θ-β frequency range, with or without the onset of low-amplitude focal fast activity. The ictal discharges exhibited focal, multifocal, and migratory characteristics in an alternating, overlapping, or independent pattern, with relatively localized spread and rarely generalized spread to all leads. "Migratory Zig-Zag Pattern", the relatively characteristic acute-phase ictal EEG finding may serve as an specific electrophysiological feature suggestive of FIRES in children. When combined with other ancillary examinations, they may assist in the early clinical diagnosis of FIRES and guide early immunomodulatory interventions to improve clinical outcome.
2026-06-02 | Systematic Reviews and Meta-Analyses of the Use of Tocilizumab in Treating Central Nervous Diseases.
To perform systematic reviews and meta-analyses on the use of the tocilizumab in the central nervous system (CNS) diseases. A systematic search was carried out in the PubMed, Embase and Cochrane databases for all years until August 2025. The review revealed 618 CNS diseases patients treated with tocilizumab. The proportion of neuromyelitis optica spectrum disorder (NMOSD) relapse-free patients after tocilizumab was 79.00% (95% confidence interval (CI): 0.67, 0.89). There was a significant correlation between remission and positive anti-AQP4 antibody status (p = 0.001). Tocilizumab significantly reduced the standardized mean Annualized Relapse Ratio (-1.3 (95% CI: -1.94, -0.66; p = 0.00191), Extended Disability Status Scale score (-0.48; 95% CI: -0.92, -0.04; p = 0.0329), and fatigue score (-1.08; 95% CI: -1.53, -0.63; p < 0.0001). The proportion of new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and refractory status epilepticus patients who improved after tocilizumab was 95.00% (95% CI: 0.78, 1.00). The proportion of the anti-NMDAR encephalitis patients with a favorable outcome after tocilizumab was 73.00% (95% CI: 0.64, 0.81). Although other CNS diseases showed improvement following tocilizumab, they did not meet the criteria for meta-analyses. Tocilizumab altered several pro- and anti-inflammatory markers in humans, animals, and cell models. The pooled proportion of tocilizumab adverse effects was 45.00% (95% CI: 0.26, 0.65). This study may guide clinicians in managing patients with CNS diseases and in conducting prospective studies and clinical trials. Some of the CNS diseases may be treated with tocilizumab.
2026-05-07 | The Clinical Outcomes of Tocilizumab Usage in Cryptogenic Febrile Infection-Related Epilepsy Syndrome at Both Acute and Chronic Phase: A Retrospective Study.
To provide more observational evidence for potential efficacy of tocilizumab (TCZ) in children with cryptogenic febrile infection-related epilepsy syndrome (FIRES) administered during acute and chronic phase. Data of 22 children with FIRES who received TCZ were collected retrospectively. Patients were categorized into two groups: acute group (TCZ used within 4 weeks post-onset; n = 12) and chronic group (TCZ used beyond 4 weeks post-onset; n = 10). In both groups, patients experienced >50% reduction in seizure frequency, electroencephalogram (EEG) improvements, alleviation on cranial magnetic resonance imaging (MRI), and significantly decreased mRS scores (P < 0.05). In acute group, 6 patients became seizure-free by the last follow-up, and 7 patients reduced their number of antiseizure medications (ASMs). TCZ administration in acute phase shortened status epilepticus (SE) duration. At last follow-up, the acute group exhibited higher rates of seizure freedom and >50% seizure reduction (P < 0.05), lower incidences of motor and speech deficits (P < 0.05), and a greater likelihood of returning to school (P < 0.05). TCZ treatment was associated with reduced seizure frequency, improved EEG and MRI findings, decreased reliance on antiseizure medications, and functional improvement as measured by mRS. Initiation of treatment during the acute phase may be associated with a shortened duration of status epilepticus and, compared to chronic-phase intervention, appears to correlate with more favorable long-term outcomes.
gene therapies
2026-02-02 | Base editing rescues seizures and sudden death in a SCN8A mutation-associated developmental epileptic encephalopathy model.
SCN8A encodes the voltage-gated sodium channel Nav1.6, which plays a key role in facilitating neuronal excitability. Mutations in SCN8A, particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, movement disorders, and sudden unexpected death in epilepsy (SUDEP). The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments, including antiseizure medications, are often ineffective for patients with SCN8A DEE, highlighting the need for targeted therapies. We employed base editing to correct the R1872W SCN8A variant. An adenine base editor and guide RNA (SCN8A-ABE) were packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A-ABE significantly increased survival of mice expressing R1872W and either reduced seizure incidence and severity or eliminated seizure occurrence. Electrophysiological recordings revealed a rescue of seizure-associated neuronal hyperexcitability and suppression of the pathogenic persistent sodium current (INaP) in treated mice. Comorbidities, including diminished mobility and anxiety-like behaviors, were improved by SCN8A-ABE. These effects were achieved by a 32% absolute reduction in mutant transcripts, accompanied by conversion to SCN8A WT transcripts. Our findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEEs by addressing the underlying genetic cause.
2025-06-12 | PQBP1-dependent alternative RNA splicing underlies high calorie diet-induced cognitive impairment.
High calorie-high fat diet (HFD) has been implicated as a pathological modifier of brain diseases including neurodegenerative dementias, but the detailed molecular mechanisms remain largely unknown. Here we report that HFD suppresses PPARγ-mediated transcriptional expression of PQBP1 , a RNA splicing factor implicated in human intellectual disability and Alzheimer's disease. RNAseq-based comprehensive analyses of alternative RNA splicing (AS) in HFD-fed mice for 1 or 6 weeks and in PQBP1-cKO mice reveal their common changes, which weigh on synapse-related genes. Betweenness-based extraction of core molecules from the common changes reveals CASK, Cacnb1 and Cyfip2 as key molecules of the network. Both CASK and Cacnb1 regulate STXBP1, a causative gene for infantile epilepsy syndrome and an essential factor for synapse vesicle release, via their direct interaction. In addition, our analysis suggests that Syt1 plays a role specifically in HFD for 1 week. HFD-induced AS isoforms of CASK, Cacnb1, Cyfip2 and Syt1 impair pre-synapse vesicle release in primary neurons. AAV-PQBP1, AAV-CASK, AAV-Cacnb1, AAV-Cyfip2 or AAV-Syt1 rescues synapse and/or cognitive dysfunctions in HFD mice, genetically supporting the pathological PQBP1-presynase axis in HFD. Moreover, immunohistochemistry experiments suggest that the pathological axis plays roles not only in excitatory neurons, but also in inhibitory neurons of the brain. Collectively, our results unravel a novel molecular mechanism for brain dysfunction when mice are exposed to a HFD.
2025-04-09 | Base Editing Rescue of Seizures and SUDEP in SCN8A Developmental Epileptic Encephalopathy
Abstract SCN8A encodes the sodium channel Na v 1.6; mutations in SCN8A , particularly gain-of-function variants, cause SCN8A developmental and epileptic encephalopathy (DEE), a severe epilepsy syndrome characterized by seizures, cognitive dysfunction, and seizure-induced death. The recurrent SCN8A variant R1872W impairs channel inactivation, causing neuronal hyperexcitability and seizures. Current treatments for SCN8A DEE are often ineffective, highlighting the need for targeted therapies. Here we employed base editing to correct the R1872W SCN8A variant. A modified adenine base editor ( SCN8A -ABE) was packaged within dual PhP.eB-adeno-associated viruses (AAVs) and administered to R1872W mice at P2. SCN8A -ABE significantly increased survival and reduced or eliminated seizures. Neuronal hyperexcitability and heightened sodium currents were attenuated with SCN8A -ABE treatment, and behavioral comorbidities were improved. These effects were achieved by approximately 30% conversion of mutant to wildtype SCN8A transcripts. These findings demonstrate base editing as an effective targeted therapeutic approach for SCN8A DEE by addressing the underlying genetic cause.
2025-03-23 | Epilepsy with myoclonic-atonic seizures: an update on genetic causes, nosological limits, and treatment strategies.
Epilepsy with myoclonic-atonic seizures is a childhood-onset epilepsy syndrome characterised by a range of seizure types, including myoclonic-atonic, atonic, myoclonic, absence, and generalised tonic-clonic seizures. The causes and outcomes of this syndrome are highly variable, with many uncertainties surrounding its classification and prognosis. Traditional antiseizure medications and the ketogenic diet remain the main treatment options. Although two-thirds of children attain remission from seizures without cognitive or behavioural sequelae, some continue to have drug-resistant seizures, intellectual disability, and behavioural problems. The identification of single-gene causes in a substantial subset of patients highlights the importance of genetic testing for development of personalised treatment strategies. However, diagnostic complexities have hindered the development of trials for new therapies. Better recognition of the distinct features of epilepsy with myoclonic-atonic seizures, combined with advances in molecular genetic testing, will pave the way for more focused clinical research and drug development. Future studies should aim to identify genetic causes and tailor treatment options, offering hope for improved long-term outcomes.
2025-02-27 | Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.
Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression. DEEs encompass many epilepsy syndromes, although not all patients with a DEE can be classified into a specific syndrome. Our understanding of the etiologies of DEEs has been revolutionized with next-generation sequencing, with more than 900 genes implicated, in addition to structural causes. It is therefore now possible to consider precision medicine and novel therapeutic approaches for these devastating diseases with trials of repurposed and new drugs, including gene therapies. Trials are being designed to target either DEE diseases more broadly, specific DEE syndromes, or specific genetic DEEs. To serve this purpose, a clear operational definition of DEEs is needed to ensure that appropriate patients are selected for trials with precisely defined, targeted outcome measures. Herein we propose the operational definition of DEEs to set the stage for the development of DEE therapies.
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2026-03-01 | Uncovering targets and molecular pathways for personalizing treatment in epilepsy.
Despite licensing many new antiseizure drugs over the last few decades, the proportion of pharmacoresistant epileptic seizures has remained largely unchanged at about 30%. However, recent progress in genetics has revealed new and more specific therapeutic targets that can be addressed through improved drug design and advancements in gene therapy, such as improved antisense oligonucleotide chemistry. Furthermore, many of these developing new precision therapies hold the promise of shifting from purely symptomatic toward disease-modifying treatment, particularly in the field of developmental and epileptic encephalopathies. This article focuses on novel potential therapeutic targets, including those encoded by causative genes for epileptic syndromes and those that show promise for favorably impacting common epilepsies or epileptogenesis. The covered areas are organized according to different molecular protein targets. Therapy in the near future will likely be based predominantly on specific small molecules or gene therapies, such as antisense oligonucleotides. Among currently used allele-specific therapeutic designs, only some loss- or gain-of-function pathological variants are expected to profit from them. Allele-specific gene therapy may be a promising treatment for those diseases that would not benefit from currently used allele-nonspecific designs.
2024-12-18 | Circulating miR-134 in mesial temporal lobe epilepsy: implications in hippocampal sclerosis development and drug resistance
Aim miR-134 has been widely reported as upregulated in experimental and human studies of Mesial Temporal Lobe Epilepsy the most common drug-resistant epilepsy (DRE). Studies have shown that the use of antagomirs, anti-miR-134, may be a promising therapeutic approach to these epilepsies. However, data on miR-134 in other epileptic syndromes is scarce. In this study, we aimed to quantify serum levels of miR-134 in a cohort of patients with Mesial Temporal Lobe Epilepsy-Hippocampal Sclerosis (MTLE-HS) and with Genetic Generalized Epilepsies (GGE). Additionally, we explored the correlation between miR-134 serum levels and clinical parameters, such as age at onset or febrile seizures antecedents, to evaluate its potential as a biomarker and therapeutic target in epilepsy. Methods miR-134 levels were evaluated in cell-free serum of 131 patients with epilepsy (75 women, 56 men; age 41.10 ± 13.12 years; 72 with DRE) and 42 healthy individuals (25 women, 17 men; age 42.40 ± 9.80 years). The epilepsy cohort included 77 MTLE-HS patients and 54 GGE patients. Results Patients with elevated miR-134 circulating levels were at higher risk of drug-resistant epilepsy (OR [95% CI] = 2.246 [1.111–4.539], p = 0.021). Other risk factors included an older age (OR [95% CI] = 1.032 [1.004–1.061], p = 0.025), history of febrile seizures (OR [95% CI] = 2.994 [1.385–6.471], p = 0.005) and higher disease duration (OR [95% CI] = 1.038 [1.011–1.066], p = 0.006). The strongest predictor of DRE was hippocampal sclerosis (OR [95% CI] = 10.338 [4.566–23.404], p < 0.001). Circulating miR-134 levels were significantly higher in MTLE-HS patients compared to controls ( p < 0.05) and GGE patients ( p < 0.05). However, the clinical utility of miR-134 in discriminating MTLE-HS patients from controls was only moderated (AUC = 0.651 ± 0.051 95% CI 0.551–0.751, p = 0.007). Conclusion We show that miR-134 circulating levels are associated with DRE, especially in MTLE-HS, a syndrome characterized by severe hippocampal damage, consistent with activity-regulated miR-134 expression. This overexpression likely contributes to disease progression and our results support the potential of targeting miR-134 as a novel therapeutic approach for refractory epilepsy.
2024-11-13 | Pharmacotherapeutic strategies for drug-resistant epilepsy in children.
Drug resistance is defined as the failure of adequate trials of two tolerated and appropriately chosen antiseizure medications to achieve sustained seizure freedom. In case of uncontrolled seizures, pseudo-drug-resistance (poor compliance, a worsening effect of an antiseizure medication, a diagnosis of psychogenic non-epileptic seizure) should be first ruled out in case of pediatric epilepsies. This paper discusses the process of choosing antiseizure medication and the concepts of rationale polytherapy and precision medicine. In drug-resistant epilepsy, when curative surgery is not feasible, the aim of the treatment is focused on the improvement of quality of life rather than on seizure count. In recent years, despite an increase in available antiseizure medications, the incidence of drug-resistant epilepsy has not changed. Precision medicine may offer in rare epilepsies a mechanism-driven treatment, but it is still unclear if this will end up in an improvement of efficacy in drug-resistant epilepsies. Gene therapy with antisense oligonucleotides or Adeno-associated Virus (AAV) is transitioning from the experimental side to the first human trial. It may modify the natural history of selected epileptic syndromes.
2024-11-02 | Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment
The potassium sodium-activated channel subtype T member 1 (KCNT1) gene encodes the Slack channel KNa1.1, which is expressed in neurons throughout the brain. Gain-of-function variants in KCNT1 are associated with a spectrum of epilepsy syndromes, and mice carrying those variants exhibit a robust phenotype similar to that observed in patients. Kcnt1 knockout (KO) mice, however, have a normal lifespan without any epileptic phenotype. To understand the molecular differences between these two models, we conducted a comprehensive proteomic analysis of the cerebral cortices of Kcnt1 KO and Kcnt1R455H/+ mice, an animal model bearing a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. The greatest change observed in Kcnt1 KO mice compared to the wild-type mice was the increased expression of multiple proteins of the inner mitochondrial membrane. Electron microscopy studies of cortical mitochondria from Kcnt1 KO mice further confirmed a significant increase in the density of mitochondrial cristae compared to that in wild-type mice. Kcnt1 reduction by a murine-specific Kcnt1 antisense oligonucleotide (ASO) in Kcnt1R455H/+ mice partially corrected the proteomic dysregulations in the disease model. The results support the hypothesis that ASO-mediated KCNT1 reduction could be therapeutically useful in the treatment of KCNT1 epilepsies.
2024-05-10 | Thrombosis With Thrombocytopenia and Post-COVID-Vaccination Syndrome With Anti-G-Protein-Coupled Receptor (GPCR) Antibodies Treated With Therapeutic Plasma Exchange
We present the case of a female who developed cerebral venous thrombosis with thrombocytopenia after inoculation with the anti-coronavirus disease 2019 (COVID-19) Vaxzevria vaccine, followed by splanchnic thrombosis and diffuse hemorrhages. Despite receiving treatment, the complications increased, and hence therapeutic plasma exchange (TPE) was attempted, leading to laboratory and clinical improvements and discharge after a period of intensive care. Almost two years after the first episode, in the interim of which the patient complained of only minor symptoms such as asthenia and difficulty concentrating, she developed an epileptic syndrome that required neurological treatment. In addition, her fatigue and difficulty concentrating worsened and other serious symptoms of dysautonomia appeared, such as trembling of her right arm, loss of stability, and postural orthostatic tachycardia. As serum analysis revealed a significant number of alterations in autoantibodies against various G-protein-coupled receptors (GPCRs) and RAS-related proteins, two further TPEs were performed, resulting in rapid and sustained clinical improvement. This report highlights the role of the different types of autoantibodies produced in response to anti-COVID-19 vaccination, which can have functional, regulatory, and possibly pathogenic effects on the vascular and nervous systems.
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Drug Discovery Landscape
7 orphan drug designations for Epilepsy syndrome, including 2 approved therapies.
7 orphan drug designations for Epilepsy syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
diazepam | small molecules | FDA | 2016-11-10 | — | Aquestive Therapeutics |
topiramate injection | small molecules | FDA | 2013-07-24 | — | CURx Pharmaceuticals, Inc. |
intravenous carbamazepine [CARNEXIV] | small molecules | FDA | 2013-06-27 | 2016-10-07 | Lundbeck LLC |
diazepam auto-injector | small molecules | FDA | 2013-05-30 | — | Meridian Medical Technologies, Inc. |
midazolam | small molecules | FDA | 2006-05-08 | — | UCB, Inc |
Stiripentol [Diacomit] | small molecules | EMA | 2001-12-05 | — | Biocodex |
Diazepam viscous solution for rectal administration [Diastat] | small molecules | FDA | 1992-02-25 | 1997-07-29 | Valeant Pharmaceuticals |
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