Providing quality care for people with CDKL5 deficiency disorder: A European expert panel opinion on the patient journey.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy caused by variants in the CDKL5 gene. The disorder is characterized by intractable early-onset seizures, severe neurodevelopmental delay, hypotonia, motor disabilities, cerebral (cortical) visual impairment and microcephaly. With no disease-modifying therapies available for CDD, treatment is symptomatic with an initial focus on seizure control. Another unmet need in the management of people with CDD is the lack of evidence to aid standardized care and guideline development. To address this gap, experts in CDD and representatives from patient advocacy groups from Denmark, Finland, France, Germany, Italy, Poland, Spain, and the United Kingdom convened to form an Expert Working Group. The aim was to provide an expert opinion consensus on how to ensure quality care in routine clinical practice within the European setting, including in settings with limited experience or resources for multidisciplinary care of CDD and other developmental and epileptic encephalopathies. By means of one-to-one interviews around the current treatment landscape in CDD, insights from the Expert Working Group were collated and developed into a Europe-specific patient journey for individuals with CDD, which was later validated by the group. Further discussions followed to gain consensus of opinions on challenges and potential solutions for achieving quality care in this setting. The panel recognized the benefit of early genetic testing, a holistic personalized approach to seizure control (taking into consideration various factors such as concomitant medications and comorbidities), and age- and comorbidity-dependent multidisciplinary care for optimizing patient outcomes and quality of life. However, their insights and experiences also highlighted much disparity in management approaches and resources across different European countries. Development of standardized European recommendations is required to align realistic diagnostic criteria, treatment goals, and management approaches that can be adapted for different settings. PLAIN LANGUAGE SUMMARY: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare condition caused by a genetic mutation with a broad range of symptoms apparent from early childhood, including epileptic seizures that do not respond to medication and severe delays in development. Due to the lack of guidance on managing CDD, international experts and patient advocates discussed best practices in the care of people with CDD in Europe. The panel agreed that early testing, a personalized approach to managing seizures, and access to care from different disciplines are beneficial. Development of guidelines to ensure that care is standardized would also be valuable.

Real-world data on cannabidiol treatment of various epilepsy subtypes: A retrospective, multicenter study.

OBJECTIVE: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes. METHODS: In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. RESULTS: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). SIGNIFICANCE: Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age.

Safety and efficacy of rufinamide in children and adults with Lennox-Gastaut syndrome: A post hoc analysis from Study 022.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged <16 years) and adults (aged ≥16 years). METHODS: Randomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline. RESULTS: Of 138 enrolled patients, 74 received rufinamide (<16 years, n = 49 [66%]) and 64 received placebo (<16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age <16 years (-41% vs. -6%), age ≥16 years (-55% vs. +16%) (p < 0.025; both age groups). In patients aged <16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively. CONCLUSIONS: In this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.

Clinical and Genetic Features in Patients With Reflex Bathing Epilepsy.

OBJECTIVE: To describe the clinical and genetic findings in a cohort of individuals with bathing epilepsy, a rare form of reflex epilepsy. METHODS: We investigated by Sanger and targeted resequencing the SYN1 gene in 12 individuals from 10 different families presenting with seizures triggered primarily by bathing or showering. An additional 12 individuals with hot-water epilepsy were also screened. RESULTS: In all families with bathing epilepsy, we identified 8 distinct pathogenic or likely pathogenic variants and 2 variants of unknown significance in SYN1, 9 of which are novel. Conversely, none of the individuals with hot-water epilepsy displayed SYN1 variants. In mutated individuals, seizures were typically triggered by showering or bathing regardless of the water temperature. Additional triggers included fingernail clipping, haircutting, or watching someone take a shower. Unprovoked seizures and a variable degree of developmental delay were also common. CONCLUSION: Bathing epilepsy is genetically distinct reflex epilepsy caused mainly by SYN1 mutations.

Unresponsive Wakefulness Syndrome in Children after Near-Drowning: Long-Term Outcome and Impact on the Families.

Among 131 children admitted to our institution for early phase rehabilitation after freshwater near-drowning (ND) between the year 1986 and 2000, 87 were in unresponsive wakefulness syndrome (UWS) for at least 4 weeks after the accidents. An anonymous questionnaire was sent to the families after 0.5 to 15.0 years (median: 4.6) and 48 mothers and 51 fathers of 55 of these 87 children were interviewed after 6.6 to 23.8 years (median: 13.8) of ND. At the time of the interviews, 8/55 children were able to perform daily living activities independently, 36/55 children were not able to do so (many of them suffered from chronic medical conditions like spasticity or disorders of swallowing), and 11/55 children had died. Health-related quality of life (HRQoL) was, however, similar to the normal population for mothers, and even higher for fathers. Furthermore, the ND accident had apparently not lead to a higher rate of separations of parents but had increased their likelihood to have further children. Feelings of guilt were highly prevalent (23/47 mothers, 20/47 fathers), and correlated with lower HRQoL of the respective parent. We found correlations between duty of supervision and feelings of guilt and between outcome and HRQoL for only the fathers. In conclusion, we found that after 4 weeks in UWS, the long-term neurological outcome of pediatric ND victims is often but not always poor. Despite often severe disabilities or death of the child during long-term care, parents surprisingly report little impact on their HRQoL, on the stability of their partnership or on their wish to have further children. Our findings may help parents and physicians to choose the best treatment for a child in UWS due to different etiologies striking the balance between rehabilitation and palliative care.

Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease.

OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation. METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge. CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Seizure Freedom in Patients with Dravet Syndrome with Contraceptives: A Case Report with Two Patients.

Dravet syndrome is a rare and malignant epileptic syndrome that is typically resistant to antiepileptic drugs. There is a growing interest in the antiepileptic properties of neurosteroids. Especially progesterone is known to act as an anticonvulsive agent. However, contraceptives that act as orally given neurosteroids often lead to increased seizures in women with epilepsy.We report on two girls with Dravet syndrome, who gained seizure freedom under therapy with contraceptives. The first patient received an oral contraceptive, a combination of an estrogen, and a gestagen, due to hypermenorrhea. The second received a pure gestagen implant for contraception.The antiepileptic effect of progesterone is mainly attributed to its conversion into allopregnanolone and related neurosteroids, which are positive modulators of gamma-aminobutyric acid A receptors. It is unclear whether the observed effect of these contraceptives containing synthetic progesterone derivatives may be specific for the Dravet syndrome, and it is unclear whether and how this observation can be used therapeutically.

Bromide in patients with SCN1A-mutations manifesting as Dravet syndrome.

We report a retrospective analysis of bromide therapy in 32 patients suffering from Dravet syndrome with SCN1A-mutations who received bromide. After 3 months of bromide treatment, 26 patients (81%) showed a relevant improvement with a reduction of seizure frequency by >50% (>75%) in 18 (12) patients (56 and 37%, respectively). After 12 months, we observed a reduction of >50% (>75%) in 15 (9) patients (47 and 28%, respectively). Long-term response was noted in 18 patients (56%). Adverse reactions were mainly mild or moderate leading to treatment termination in 5/32 patients; no aggravation was reported. We conclude that bromide holds promise in patients with SCN1A-mutations suffering from Dravet syndrome.