Infantile Spasms Research Articles

Purified cannabidiol as add-on therapy in children with treatment-resistant infantile epileptic spasms syndrome

ObjectiveThe aim of this study was to assess efficacy, safety, and tolerability of highly purified cannabidiol oil (CBD) as add-on therapy for the treatment of a series of patients with infantile epileptic spasms syndrome (IESS) who were resistant to antiseizure medications and ketogenic dietary therapy. Material and methodsWe conducted a retrospective analysis of the medical records of 28 infants with treatment-resistant IESS aged 6 to 21 months who received highly purified CBD between July 2021 and June 2023. Data were collected on neurological examinations, EEG, Video-EEG and polygraphic recordings, imaging studies, laboratory testing, and seizure frequency, type, and duration, and adverse effects. As the primary outcome, a reduction of frequency of epileptic spasms (ES) was assessed. ES freedom was considered after a minimal time of 1 month without ES. ResultsSixteen male and 12 female patients, aged 6–21 months, who received CBD for treatment-resistant IESS were included. The etiology was structural in 10, Down syndrome in seven, genetic in nine, and unknown in two. Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2–50).Prior to CBD initiation, patients had a median of 69 ES in clusters per day (range, 41–75) and of 10 focal seizures per week (range, 7–13). After a mean and median follow-up of 15 and 12.5 months (range, 6–26 months), seven patients were ES free and 12 had a >50 % ES reduction. Five of seven patients (71 %) with Down syndrome and 3/5 (60 %) with cerebral palsy responded well. Adverse effects were mild. EEG improvements correlated with ES reductions. ConclusionIn this study evaluating the use of CBD in children with IESS, 19/28 (67.8 %) had a more than 50 % ES reduction with good tolerability.

Initial combination versus early sequential standard therapies for Infantile Epileptic Spasms Syndrome-Feedback from stakeholders.

Initial combination versus early sequential standard therapies for Infantile Epileptic Spasms Syndrome-Feedback from stakeholders.

Synonymous variants in the ATP6AP2 gene may lead to developmental and epileptic encephalopathy.

To the literature, variants in the ATP6AP2 gene may cause abnormal nervous system development and associated neurological symptoms. We report a patient with developmental and epileptic encephalopathy (DEE) carrying an ATP6AP2 c.858G > A (p.Ala286=) synonymous variant. In addition, an overview of reported patients with the same variant were collected and summarized to compare our findings. The patient started experiencing tonic seizures at 3.5 months of age, and magnetic resonance imaging (MRI) indicated impaired brain white matter development and reduced left hippocampal volume. Furthermore, electroencephalography showed multifocal interictal epileptiform discharges. Treatment with various anti-seizure medications yielded unsatisfactory results, and the disorder eventually developed into epileptic spasms. An in vitro splicing assay for the ATP6AP2 gene mRNA revealed that the variant caused a deletion in exon 8 and a corresponding protein truncation. A review of previously reported ATP6AP2-related DEE patients found that synonymous variants in the ATP6AP2 gene can cause early DEE onset, progressive changes in early-life MRI, and exon skipping in all ATP6AP2-related DEE patients. We found that synonymous variants in ATP6AP2 may have significant pathogenicity and are highly correlated with DEE. Due to increased isoform production, ATP6AP2 synonymous variants may cause nervous system developmental disorders by competitively reducing the generation of full-length transcripts, resulting in defects in ATP6AP2-related physiological processes.

Treatment Options for Infantile Spasms Syndrome with SCN8A: A Case Report and Literature Review

Abstract“Infantile spasms syndrome (IS),” previously known as “West syndrome (WS),” is characterized by epileptic spasms (ES), abnormal electroencephalography (EEG) patterns such as hypsarrhythmia, and developmental stagnation or regression in infancy. IS has various etiologies, including genetic abnormalities. SCN8A variants are associated with developmental and epileptic encephalopathy, characterized by developmental delay, seizures starting from infancy, and refractory epilepsy with multiple seizure types. However, previous studies have not focused on the treatment of IS caused by SCN8A variants. We report a case of a previously healthy boy who presented ES and developmental regression at 6 months of age. His EEG revealed hypsarrhythmia, leading to the diagnosis of IS. After admission, the patient was treated with hormonal therapy using intravenous methylprednisolone pulse therapy (MPT). ES and hypsarrhythmia on EEG disappeared in the early stages of MPT administration with no observed treatment complications. Furthermore, we observed no recurrence of EEG abnormalities or seizures at 17 months of age. Genetic testing revealed a novel de novo SCN8A variant (NM_001177984.2:c.2882T > G:p. M961R). The literature review confirmed that 13 patients, including our described patient, were reported to have ES owing to missense variants of SCN8A. While the previous articles do not mention intravenous MPT for ES with SCN8A, our case findings suggest that intravenous MPT therapy may be effective for short-term suppression of ES caused by the SCN8A variant in IS.

Late infantile epileptic encephalopathy: A distinct developmental and epileptic encephalopathy syndrome.

Within the spectrum of developmental and epileptic encephalopathy (DEE), there are a group of infants with features that are distinct from the well-recognized syndromes of early infantile developmental and epileptic encephalopathy (EIDEE), infantile epileptic spasm syndrome (IESS), and Lennox-Gastaut syndrome (LGS). We refer to this condition as late infantile epileptic encephalopathy (LIEE). Our objective was to highlight the characteristics of this group by analyzing patients who exhibit prototypical features. From July 2022 to May 2023, we searched for LIEE features in pediatric patients who underwent epilepsy follow-up at the University of Chicago Comer Children's Hospital. Out of 850 patients evaluated, thirty patients (3.5%) were identified with LIEE based on electroclinical characteristics. These patients had an average onset of epilepsy at 6.8 months and an average onset of LIEE features at 18.1 months. The epilepsy etiology was most commonly genetic and metabolic (50%), followed by congenital cortical malformations (23%), acquired structural abnormalities (20%), and unknown (7%). The predominant seizure types were myoclonic-tonic (70%), spasm-tonic (50%), epileptic spasms (47%), tonic (43%), and myoclonic (43%) seizures. All patients reported a history of either spasm-tonic or myoclonic-tonic seizures in addition to other types. All patients had EEGs showing discontinuity, electrodecrements, or both along with diffuse slowing, background voltages between 100 and 300 μV, and superimposed multifocal, diffuse epileptiform discharges. Every patient, except one, fulfilled the definition of drug-resistant epilepsy, and all reported either moderate-to-severe or severe developmental delay. Late infantile epileptic encephalopathy (LIEE) is characterized by several unique clinical and electrographic features. Typically, LIEE manifests in patients during the second year of life and occurs before two years of age, hence late infantile onset. The condition is commonly observed in infants with symptomatic epilepsy. Myoclonic-tonic and spasm-tonic seizures are the quintessential seizure types. The inter-ictal EEG exhibits more organization and lower voltages than seen with hypsarrhythmia and lacks the defining EEG characteristics of EIDEE, IESS, or LGS. We propose that LIEE is a distinct electroclinical syndrome within the spectrum of developmental and epileptic encephalopathies.

Metabolic causes of pediatric developmental & epileptic encephalopathies (DEE)- genetic variant analysis in a south Indian cohort

PurposeDrug-resistant epilepsy is seen in patients with inborn errors of metabolism and metabolic dysfunction in neurons is crucial to brain disorders associated with psychomotor impairment. Diagnostic rates of metabolic causes of developmental and epileptic encephalopathy (DEE) using next generation sequencing have been rarely studied in literature. MethodsA prospective hospital study was carried out in 384 children with DEE, who underwent genetic testing. Metabolic disorders were evaluated with biochemical blood/urine assays and when required CSF estimations performed. ResultsA total of 154 pathogenic/likely pathogenic variants in 384 children were identified. Out of 384 children, 89 were clinically suspected to have probable or possible metabolic disorders. Pathogenic/likely pathogenic variants in metabolic genes were identified in 39 out of 89 (43.8 %) and promising VUS in 28 (31.4 %). These included variants for progressive myoclonus epilepsies (21; 53.8 %), DEE with focal/multifocal seizures (8; 20.5 %), generalized epilepsy (5;12.8 %), early myoclonic encephalopathy (2; 5.1 %), LGS (1; 2.6 %) and West syndrome (2; 5.1 %). ConclusionOur cohort demonstrates for the first time from the Indian subcontinent that identification of metabolic variants can guide investigations and has therapeutic implications in patients with variable DEE phenotypes. A high utility is noted with regard to diagnosis and prognostication, given the low yield of available biochemical tests, indicating cost-effectiveness of this approach.

Quantification of Hypsarrhythmia in Infantile Spasmatic EEG: A Large Cohort Study.

Infantile spasms (IS) is a neurological disorder causing mental and/or developmental retardation in many infants. Hypsarrhythmia is a typical symptom in the electroencephalography (EEG) signals with IS. Long-term EEG/video monitoring is most frequently employed in clinical practice for IS diagnosis, from which manual screening of hypsarrhythmia is time consuming and lack of sufficient reliability. This study aims to identify potential biomarkers for automatic IS diagnosis by quantitative analysis of the EEG signals. A large cohort of 101 IS patients and 155 healthy controls (HC) were involved. Typical hypsarrhythmia and non-hypsarrhythmia EEG signals were annotated, and normal EEG were randomly picked from the HC. Root mean square (RMS), teager energy (TE), mean frequency, sample entropy (SamEn), multi-channel SamEn, multi-scale SamEn, and nonlinear correlation coefficient were computed in each sub-band of the three EEG signals, and then compared using either a one-way ANOVA or a Kruskal-Wallis test (based on their distribution) and the receiver operating characteristic (ROC) curves. The effects of infant age on these features were also investigated. For most of the employed features, significant ( ) differences were observed between hypsarrhythmia EEG and non-hypsarrhythmia EEG or HC, which seem to increase with increased infant age. RMS and TE produce the best classification in the delta and theta bands, while entropy features yields the best performance in the gamma band. Our study suggests RMS and TE (delta and theta bands) and entropy features (gamma band) to be promising biomarkers for automatic detection of hypsarrhythmia in long-term EEG monitoring. The findings of our study indicate the feasibility of automated IS diagnosis using artificial intelligence.

Study on the gut microbiota, HPA, and cytokine levels in infantile spasms.

The mechanisms driving the progression of infantile spasms are not well understood. We aimed to investigate the changes and correlations of the gut microbiota, the hypothalamus-pituitary-adrenal (HPA) axis hormones, and the inflammatory cytokines in children with infantile spasms before and after treatment in order to provide a reference for future pathogenesis research. Children with infantile spasms who were admitted to our hospital were recruited into the case group. The case group was divided into the pre-treatment group (group A, n = 14), the 2 weeks after treatment group (group B), and the 1 month after treatment group (group C). On the other hand, healthy children with the same sex ratio as the case group were recruited into the control group (group D, n = 14). Three stool and blood samples were collected before treatment, 2 weeks after treatment, and 1 month after treatment. The serum samples were analyzed using cytometric bead array (CBA), enzyme-linked immunosorbent assay (ELISA), and chemiluminescent immunoassay (CLIA) to measure the levels of HPA axis hormones and inflammatory cytokines. The collected stool samples were sequenced using 16S rDNA. The pre-treatment group demonstrated elevated levels of corticotropin-releasing hormone (CRH), interleukin 2 (IL-2), IL-4, IL-6, and IL-17α, which decreased with treatment. The level of CRH was lower in the effective group than that in the ineffective group. Sutterellaceae was lower in the pre-treatment group than that in the control group. Lachnospiracea_incertae_sedis was positively associated with CRH concentration (p < 0.05). After treatment, Sutterellaceae was negatively associated with IL-2 and TNF-α (p < 0.05). This study found that imbalance of the gut microbiota may be involved in the pathogenesis of infantile spasms and is related to the response to adrenocorticotropic hormone (ACTH). Lachnospiraceae and Lachnospiracea_incertae_sedis might be involved in the disease onset. Sutterellaceae might have a link to children's improved health.

Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective.

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype-phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.

The Association Between Serum Levels of Glial Biomarkers, Clinical Severity and Electro-encephalography Features in Idiopathic West and Lennox-Gastaut Syndromes.

Although the contribution of enhanced glial activity in seizure induction is increasingly recognized, the role of glia-induced neuroinflammation in the physiopathology of epileptic encephalopathy (EE) has been scarcely investigated. To delineate the contribution of glial activity in EE, we measured levels of glia-derived mediators with previously described biomarker value, including glial fibrillary acidic protein (GFAP), high mobility group box 1 (HMGB1), chitinase-3-like protein 1 (CHI3L1), soluble CD163 (sCD163) and triggering receptor expressed on myeloid cells 2 (TREM2) by ELISA in sera of patients with idiopathic West syndrome (WS, n=18), idiopathic Lennox-Gastaut syndrome (LGS, n=13) and healthy controls (n=31). Patients with EE showed significantly higher CHI3L1 levels compared to healthy controls. Levels of HMGB1, CHI3L1, sCD163 and TREM2 were higher in LGS patients than WS patients and/or healthy controls. One or more of the investigated mediators were associated with treatment responsiveness, disease severity and presence of pathological features on electroencephalography (EEG). To our knowledge, our findings provide the initial patient-based evidence that astrocyte- and microglia-mediated neuroinflammation might be involved in the pathogenesis of LGS and WS. Moreover, glial mediators may serve as prognostic biomarkers in patients with idiopathic EE.

Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation.

There are more than 70 million people worldwide living with epilepsy, with most experiencing the onset of epilepsy in childhood. Despite the availability of more than 20 anti-seizure medications, approximately 30% of epilepsy patients continue to experience unsatisfactory treatment outcomes. This situation places a heavy burden on patients' families and society. Childhood epilepsy is a significant chronic neurological disease that is closely related to genetics. Col4a2, the gene encoding the α2 chain of type IV collagen, is known to be associated with multiple diseases due to missense mutations. The Col4a2 variant of collagen type IV is associated with various phenotypes, including prenatal and neonatal intracranial hemorrhage, porencephaly, porencephaly with cataracts, focal cortical dysplasia, schizencephaly, strokes in childhood and adolescence, and sporadic delayed hemorrhagic stroke. Although epilepsy is recognized as a clinical manifestation of porencephaly, the specific mechanism of Col4a2-related epileptic phenotypes remains unclear. A total of 8 patients aged 2 years and 2 months to 18 years who were diagnosed with Col4a2-related infantile epileptic spasm syndrome were analyzed. The seizure onset age ranged from 3 to 10 months. Initial EEG results revealed hypsarrhythmia or multiple and multifocal sharp waves, spike waves, sharp slow waves, or spike slow waves. Elevated levels of the cytokines IL-1β (32.23±12.58 pg/ml) and IL-6 (45.12±16.03 pg/ml) were detected in the cerebrospinal fluid of these patients without any signs of infection. Following antiseizure treatment, decreased IL-1β and IL-6 levels in the cerebrospinal fluid were noted when seizures were under control. Furthermore, we aimed to investigate the role of Col4a2 mutations in the development of epilepsy. Through the use of immunofluorescence assays, ELISA, and Western blotting, we examined astrocyte activity and the expression of inflammatory cytokines such as IL-1β, IL-6, and TNF-α after overexpressing an unreported Col4a2 (c.1838G>T) mutant in CTX-TNA cells and primary astrocytes. We found that the levels of the inflammatory factors IL-1β, IL-6, and TNF-α were increased in both CTX-TNA cells (ELISA: p = 0.0087, p<0.001, p<0.001, respectively) and primary astrocytes (ELISA: p = 0.0275, p<0.001, p<0.001, respectively). Additionally, we conducted a preliminary investigation of the role of the JAK/STAT pathway in Col4a2 mutation-associated epilepsy. Col4a2 mutation stimulated astrocyte activation, increasing iNOS, COX-2, IL-1β, IL-6, and TNF-α levels in both CTX-TNA cells and primary astrocytes. This mutation also activated the JAK/STAT signaling pathway, leading to increased phosphorylation of JAK2 and STAT3. Treatment with the JAK/STAT inhibitor WP1066 effectively counteracted this effect in primary astrocytes and CTX-TNA cells. To date, the genes who mutations are known to cause developmental and epileptic encephalopathies (DEEs) are predominantly grouped into six subtypes according to function. Our study revealed that an unreported mutation site Col4a2Mut (c.1838G>T) of which can cause neuroinflammation, may be a type VII DEE-causing gene.

Functional analysis of epilepsy-linked pathogenic variants of the Munc18-1 gene in the inhibitory nervous system of Caenorhabditis elegans.

Heterozygous de novo mutations in Munc18-1, which is essential for neurotransmitter release, cause early infantile epileptic encephalopathy. Munc18-1-linked epilepsy is currently an untreatable disorder and its precise disease mechanism remains elusive. Here, we investigated how Munc18-1 pathogenic variants affect inhibitory neurons using Caenorhabditis elegans . Expression analysis revealed that three missense mutant proteins form aggregates in the cell body of gamma-aminobutyric-acid (GABA)-ergic motoneurons, resulting in a strong reduction of their expression in axons. Their defects of axonal expression correlated closely with pentylenetetrazol-induced convulsions, suggesting that the degree of instability of each mutant protein account for the severity of the epileptic phenotypes.

New evidence supports RYR3 as a candidate gene for developmental and epileptic encephalopathy.

The ryanodine receptor 3 (RYR3) is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum and subsequent T-tubule depolarization. It is also expressed in the brain, and variants in the RYR3 gene can lead to congenital myopathy type 20 (MIM: #620310). We retrospectively analyzed the clinical characteristics and prognosis of a case of West syndrome, developmental and epileptic encephalopathy (DEE) caused by a missense variant in the RYR3 gene. We also reviewed and summarized the literature on epilepsy cases caused by RYR3 gene variants. A 10-month-old female child with delayed psychomotor development and recurrent spasm-like seizures was diagnosed with infantile spasm syndrome and DEE. Treatment with various antiepileptic drugs resulted in initial improvement but ultimately failed to control the seizures. Whole-exome sequencing revealed a novel heterozygous variant c.10943C > T/p.T3648M in the RYR3 gene, and genome-wide sequencing ruled out other potentially pathogenic variants. Three previous reports have described RYR3 variants causing DEE, two of which were attributed to de novo heterozygous variants, and one was a compound heterozygote. The present case of DEE caused by a RYR3 heterozygous variant is consistent with previous rare cases of epilepsy caused by RYR3 gene variants in terms of pathogenesis and clinical features, but significantly different from congenital myopathy type 20. Our findings provide important evidence for the diagnosis of RYR3-related DEE, and we hypothesize that RYR3 gain-of-function variants resulting in "leaky" Ca2+ release channels may be a molecular genetic feature leading to DEE rather than myopathy.

Seizure Detection of West Syndrome Based on Hybrid Optimization of Entropies with Multisensor EEG Data

Seizure Detection of West Syndrome Based on Hybrid Optimization of Entropies with Multisensor EEG Data

Retraction Notice - Early Identification of DMD in the Setting of West Syndrome. Child Neurology Open.

[This retracts the article DOI: 10.1177/2329048X211036546.].

Optimization of EEG-EMG Fusion Network for West Syndrome Seizure Detection Based on Enhanced Artificial Rabbit Algorithm

Optimization of EEG-EMG Fusion Network for West Syndrome Seizure Detection Based on Enhanced Artificial Rabbit Algorithm

Dental Considerations and Treatment Approaches in West Syndrome—Infantile Spasms: A Case Report

Dental Considerations and Treatment Approaches in West Syndrome—Infantile Spasms: A Case Report

Do vaccines cause epilepsy? Review of cases in the National Vaccine Injury Compensation Program.

The National Childhood Vaccine Injury Act of 1986 created the National Vaccine Injury Compensation Program (VICP), a no-fault alternative to the traditional tort system. Since 1988, the total compensation paid exceeds $5 billion. Although epilepsy is one of the leading reasons for filing a claim, there has been no review of the process and validity of the legal outcomes given current medical information. The objectives were to review the evolution of the VICP program in regard to vaccine-related epilepsy and assess the rationale behind decisions made by the court. Publicly available cases involving epilepsy claims in the VICP were searched through Westlaw and the US Court of Federal Claims websites. All published reports were reviewed for petitioner's theories supporting vaccine-induced epilepsy, respondent's counterarguments, the final decision regarding compensation, and the rationale underlying these decisions. The primary goal was to determine which factors went into decisions regarding whether vaccines caused epilepsy. Since the first epilepsy case in 1989, there have been many changes in the program, including the removal of residual seizure disorder as a vaccine-related injury, publication of the Althen prongs, release of the acellular form of pertussis, and recognition that in genetic conditions the underlying genetic abnormality rather than the immunization causes epilepsy. We identified 532 unique cases with epilepsy: 105 with infantile spasms and 427 with epilepsy without infantile spasms. The petitioners' experts often espoused outdated, erroneous causation theories that lacked an acceptable medical or scientific foundation and were frequently criticized by the court. Despite the lack of epidemiological or mechanistic evidence indicating that childhood vaccines covered by the VICP result in or aggravate epilepsy, these cases continue to be adjudicated. After 35 years of intense litigation, it is time to reconsider whether epilepsy should continue to be a compensable vaccine-induced injury.

Epilepsy and EEG features in Angelman syndrome

Аngelman syndrome (AS) is an orphan disease caused by loss of function of the maternal allele of the UBE3A gene on chromosome 15 (region 15q11.2-q13), characterized by severe mental and speech retardation, movement disorders, unique behavior in the form of frequent laughter, and epileptic seizures with characteristic anomalies in EEG. Epilepsy is often drug-resistant, generalized seizure types dominate, among which myoclonic seizures and atypical absences are the most common. Infantile spasms are rare in AS children, but the EEG pattern, especially in infancy, in the form of diffuse slow-wave activity with multiregional and generalized epileptiform activity, may resemble a hypsarrhythmia pattern. We present own observation of a child in whom the EEG was incorrectly described as a hypsarrhythmia pattern, and hormonal therapy was prescribed with suspicion of epileptic spasms. In this article, we made a brief review of the literature on the treatment of epilepsy in AS patients with a recommended algorithm for choosing an antiepileptic drug (AED). In young children with developmental delay, a routine EEG pattern similar to hypsarrhythmia, but with out of clinical and EEG patterns of spasms, it is necessary to conduct video-EEG monitoring with recording of sleep, to exclude the “pseudo-hypsarrhythmia” pattern, which is especially important when Angelman syndrome is suspected. In the treatment of epilepsy in Angelman syndrome, it is necessary to adhere to the recommended, according to the literature, algorithm for choosing AEDs

Long-term predictors of developmental outcome and disease burden in SCN1A-positive Dravet syndrome.

Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. Prospective data on long-term developmental and clinical outcomes are limited; this study seeks to evaluate the clinical course of Dravet syndrome over a 10-year period and identify predictors of developmental outcome. SCN1A mutation-positive Dravet syndrome patients were prospectively followed up in the UK from 2010 to 2020. Caregivers completed structured questionnaires on clinical features and disease burden; the Epilepsy & Learning Disability Quality of Life Questionnaire, the Adaptive Behavioural Assessment System-3 and the Sleep Disturbance Scale for Children. Sixty-eight of 113 caregivers (60%) returned posted questionnaires. Developmental outcome worsened at follow-up (4.45 [SD 0.65], profound cognitive impairment) compared to baseline (2.9 [SD 1.1], moderate cognitive impairment, P < 0.001), whereas epilepsy severity appeared less severe at 10-year follow-up (P = 0.042). Comorbidities were more apparent at 10-year outcome including an increase in autistic features (77% [48/62] versus 30% [17/57], χ2 = 19.9, P < 0.001), behavioural problems (81% [46/57] versus 38% [23/60], χ2 = 14.1, P < 0.001) and motor/mobility problems (80% [51/64] versus 41% [24/59], χ2 = 16.9, P < 0.001). Subgroup analysis demonstrated a more significant rise in comorbidities in younger compared to older patients. Predictors of worse long-term developmental outcome included poorer baseline language ability (P < 0.001), more severe baseline epilepsy severity (P = 0.003) and a worse SCN1A genetic score (P = 0.027). Sudden unexpected death in epilepsy had not been discussed with a medical professional in 35% (24/68) of participants. Over 90% of caregivers reported a negative impact on their own health and career opportunities. Our study identifies important predictors and potential biomarkers of developmental outcome in Dravet syndrome and emphasizes the significant caregiver burden of illness. The negative impact of epilepsy severity at baseline on long-term developmental outcomes highlights the importance of implementing early and focused therapies whilst the potential impact of newer anti-seizure medications requires further study.