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BACKGROUND: Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population. METHODS: A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel. RESULTS: The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%). CONCLUSION: Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.
Subject(s)
Cannabidiol , Drug Resistant Epilepsy , Lennox Gastaut Syndrome , Child , Young Adult , Humans , Female , Male , Cannabidiol/adverse effects , Drug Resistant Epilepsy/drug therapy , Drug Resistant Epilepsy/diagnosis , Anticonvulsants/therapeutic use , Retrospective Studies , Quality of Life , Seizures/drug therapy , Lennox Gastaut Syndrome/drug therapyABSTRACT
Tuberous sclerosis complex (TSC) is a rare genetic disease with neurocutaneous manifestations, often presenting initially to the dermatology clinic. We report a cohort of neonates who presented with a novel finding of white epidermal nevus and were eventually diagnosed with TSC. White epidermal nevus may be yet another dermatological finding that may aid in the early diagnosis of TSC.
Subject(s)
Nevus , Tuberous Sclerosis , Infant, Newborn , Humans , Tuberous Sclerosis/complications , Tuberous Sclerosis/diagnosis , Nevus/diagnosis , ResearchABSTRACT
Introduction: Concerns regarding felbamate adverse effects restrict its widespread use in children with drug-resistant epilepsy. We aimed to examine the efficacy and safety of felbamate in those children and identify the ones who may benefit most from its use. Methods: We retrospectively reviewed the medical files of all patients who were treated with felbamate in a tertiary pediatric epilepsy clinic between 2009-2021. Drug efficacy was determined at the first 3 months of treatment and thereafter. Therapeutic response and adverse reactions were monitored throughout the course of treatment. Results: Our study included 75 children (age 8.9 ± 3.7 years), of whom 53 were treated with felbamate for seizures, 16 for electrical status epilepticus during sleep and 6 for both. The median follow-up time was 16 months (range 1-129 months). The most common cause for epilepsy was genetic (29%). The median number of previous anti-seizure medications was six [4-8]. A therapeutic response ≥50% was documented in 37 (51%) patients, and a complete response in 9 (12%). Nineteen patients (25%) sustained adverse reactions, including three cases of elevated liver enzymes and one case of neutropenia with normal bone marrow aspiration. In all cases, treatment could be continued. All children with intractable epilepsy following herpes encephalitis showed a response to felbamate. Conclusion: Felbamate is an efficacious and safe anti-seizure medication in the pediatric population.
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BACKGROUND: Several retrospective studies on pediatric epilepsy reported positive effects of cannabidiol-enriched artisanal cannabis oil and pure cannabidiol oil on seizure reduction. METHODS: This is a retrospective study of children and adolescents with refractory epilepsy caused by various etiologies who were treated with artisanal cannabis oil during January 2014 to June 2019, with at least one year follow-up. RESULTS: Of 114 patients, 84 (73.3%) reported some improvement in seizure frequency at some point during treatment. Fifty-one (59%) of the 86 patients who continued treatment for at least one year showed >50% improvement in seizure frequency. Seizure etiology, seizure type, and patients' age and sex were not found to be associated with the response to cannabidiol-enriched cannabis oil. Side effects were minor, and positive effects beyond seizure reduction were noted. CONCLUSIONS: Artisanal cannabidiol-enriched cannabis may be an effective and safe long-term treatment for refractory epilepsy.
Subject(s)
Cannabidiol , Cannabis , Drug Resistant Epilepsy , Epilepsy , Adolescent , Anticonvulsants/adverse effects , Cannabidiol/adverse effects , Child , Drug Resistant Epilepsy/drug therapy , Epilepsy/drug therapy , Humans , Retrospective Studies , Seizures/drug therapyABSTRACT
BACKGROUND: Common titration strategies for vagus nerve stimulation (VNS) prioritize monitoring of tolerability during small increases in stimulation intensity over several months. Prioritization of tolerability is partially based on how quickly side effects can be perceived and reported by patients, and the delayed onset of clinical benefits from VNS. However, many practices assess the clinical benefit of VNS at one year after implantation, and excessive caution during the titration phase can significantly delay target dosing or prevent a patient from reaching a therapeutic dose entirely. OBJECTIVE: This study aimed to characterize the relationship between titration speed and the onset of clinical response to VNS. METHODS: To assess differences between more aggressive titration strategies and more conservative ones, we analyzed the relationship between time-to-dose and time-to-response using a weighted Cox regression. The target dose was empirically defined as 1.625 mA output current delivered at 250 microsecond pulse widths at 20 Hz. Patient-level outcomes and dosing data were segregated into fast (<3 months), medium (3-6 months), and slow (>6 months) cohorts based on their titration speed. RESULTS: The statistical model revealed a significant relationship between titration speed and onset of clinical response, defined as a 50% reduction from baseline in seizure frequency. Frequency of adverse events reported between each cohort trended toward higher rates of adverse events in adults who were titrated quickly; however, the pediatric population appeared to be more tolerant of titration at any speed. CONCLUSIONS: This analysis indicates that faster titration yields faster onset of clinical benefit and is especially practical in the pediatric population, though attempts to accelerate adult titration may still be warranted.
Subject(s)
Epilepsy , Vagus Nerve Stimulation , Adult , Child , Heart Rate , Humans , Seizures , Treatment OutcomeABSTRACT
OBJECTIVE: To assess whether white matter (WM) diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) derived measures correlate with tuberous sclerosis complex (TSC) disease severity. COHORT AND METHODS: A multi-shell diffusion protocol was added to the clinical MRI brain scans of thirteen patients including 6 males and 7 females with a mean ± std age of 17.2 ± 5.8 years. Fractional anisotropy (FA) and mean diffusivity (MD) were generated from DTI and neurite density index (NDI), orientation dispersion index (ODI) and free water index (fiso) were generated from NODDI. A clinical score was determined for each patient according to the existence of epilepsy, developmental delay, autism or psychiatric disorders. Whole-brain segmented WM was averaged for each parametric map and 3 group k-means clustering was performed on the NDI and FA maps. MRI quantitative parameters were correlated with the clinical scores. RESULTS: Segmented whole brain WM averages of MD and NDI values showed significant negative (p = 0.0058) and positive (p = 0.0092) correlations with the clinical scores, respectively. Additionally, the contribution of the low and high NDI-based clusters to the whole brain WM significantly correlated with the clinical scores (p = 0.03 and p = 0.00047, respectively). No correlation was found when the clusters were based on the FA maps. CONCLUSION: Advanced diffusion MRI of TSC patients revealed widespread WM alterations. Neurite density showed significant correlations with disease severity and is therefore suggested to reflect an underlying biological process in TSC WM. The quantification of WM alterations by advanced diffusion MRI may be an additional biomarker for TSC and may be advantageous as a complementary MR protocol for the evaluation of TSC patients.
Subject(s)
Leukoaraiosis , Tuberous Sclerosis , White Matter , Adolescent , Adult , Brain/diagnostic imaging , Child , Diffusion Tensor Imaging/methods , Female , Humans , Male , Neurites , Severity of Illness Index , Tuberous Sclerosis/diagnostic imaging , White Matter/diagnostic imaging , Young AdultABSTRACT
Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.
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BACKGROUND: While vagus nerve stimulation (VNS) has been in use for over two decades, little professional guidance exists to describe dosing and titration of therapy which is the consequence of a limited amount of evidence developed during the pre-market phase of therapy development. Post-market surveillance of dosing practice has revealed significant deviations from dosing and titration guidance offered by professional societies as well as the manufacturer. OBJECTIVE: This analysis aims to identify a target dose for VNS Therapy in Epilepsy. METHODS: Herein, VNS clinical outcomes are linked to the patient-specific dosing parameters for each study visit (n = 1178 patients). A generalized linear mixed model was built to ascertain the relationship between key stimulation parameters (i.e., Output Current, Pulse Width, Signal Frequency, and Duty Cycle) and clinical response, defined as a 50% or greater reduction in seizure frequency from baseline. Other demographic parameters of interest, such as duration of epilepsy and age at implant, were also explored. RESULTS: A population level target output current and duty cycle for VNS therapy for epilepsy was identified as 1.61 mA and 17.1% duty cycle. Patients with shorter duration of epilepsy were identified to have a higher likelihood to respond to VNS therapy (p < 0.001). While patients who were on the therapy longer were more likely to respond to the therapy, the effect did not interact with the dosing settings - suggesting that patients who have been chronically underdosed may still benefit from achieving the target dose. CONCLUSION: An opportunity exists to improve upon VNS outcomes by aligning clinical practice around this evidence-based target dose.
Subject(s)
Drug Resistant Epilepsy , Epilepsy , Vagus Nerve Stimulation , Drug Resistant Epilepsy/therapy , Epilepsy/therapy , Heart Rate , Humans , Seizures/therapy , Time Factors , Treatment OutcomeABSTRACT
Mobilized peripheral blood cells (MPBCs) graft and peripheral blood cells apheresis are used for bone marrow transplantation and for treatment of graft versus host disease (GvHD). We demonstrate that a short treatment of MPBCs with Fas ligand (FasL, CD95L) for 2 h using a closed automated cell processing system selectively induces apoptosis of specific donor T cells, B cells and antigen presenting cells, but, critically, not CD34+ hematopoietic stem cells and progenitors, all of which may contribute to an increased likelihood of graft survival and functionality and reduced GvHD. Treated cells secreted lower levels of interferon-gamma as compared with control, untreated, cells. Moreover, FasL treatment of immune cells increased signals, which led to their phagocytosis by activated macrophages. FasL treated immune cells also reduced the ability of activated macrophages to secrete pro-inflammatory cytokines. Most importantly, FasL ex vivo treated MPBCs prior to transplantation in NOD-SCID NSG mice prevented GvHD and improved stem cell transplantation in vivo. In conclusion, MPBCs, as well as other blood cell products, treated with FasL by automated manufacturing (AM), may be used as potential treatments for conditions where the immune system is over-responding to both self and non-self-antigens.
Subject(s)
Graft vs Host Disease , Animals , Blood Cells , Fas Ligand Protein , Graft vs Host Disease/prevention & control , Mice , Mice, Inbred NOD , Mice, SCIDABSTRACT
OBJECTIVE: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS). METHODS: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52. RESULTS: The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus. SIGNIFICANCE: Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.
Subject(s)
Drug Resistant Epilepsy , Epilepsy, Absence , Triglycerides , Adolescent , Adult , Anticonvulsants/therapeutic use , Carbohydrate Metabolism, Inborn Errors , Child , Double-Blind Method , Drug Resistant Epilepsy/drug therapy , Drug Therapy, Combination , Epilepsy, Absence/drug therapy , Glucose Transporter Type 1/genetics , Humans , Monosaccharide Transport Proteins/deficiency , Seizures/drug therapy , Treatment Outcome , Triglycerides/therapeutic useABSTRACT
PURPOSE: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Fifty percent of patients with TSC will develop retinal astrocytic hamartoma (RAH). The mammalian target of rapamycin (mTOR) inhibitors interferes with the pathological mechanisms of TSC. Treatment of RAH with mTOR inhibitors has been described in only a few isolated case reports. The purpose of this study was to assess the effect of mTOR inhibitors on RAH in a small cohort of patients. METHODS: The medical records of all consecutive patients with ocular manifestations of TSC that were treated with mTOR inhibitors at the Sheba Medical Center from January 2014 to December 2018 were retrospectively reviewed. Data collection included demographics, medical history, ocular presentation, ocular treatment, and treatment outcome. Tumor size was assessed by a masked observer, before and after treatment. Lesion measurements were made with Heidelberg SD-OCT (HRA + OCT SPECTRALIS), and fundus photos were taken with RetCam3® (Natus, USA) and analyzed by "ImageJ" software. RESULTS: Eleven patients with tuberous sclerosis and astrocytic hamartoma were treated with mTOR inhibitors in the study period. Of them, 6 children (11 eyes, 20 tumors) had proper imaging of tumor size before and after treatment. The analysis included these 11 eyes. All six patients had non-ocular manifestations of TSC, including dermatologic (n = 5), neurologic (n = 5), and renal (n = 3) involvement. Ocular involvement included in five eyes (45%) tumors near the optic disc and in four eyes (37%) foveal tumors. The mean follow-up duration was 2.15 ± 1.4 years (range 10 months to 4.5 years). The average tumor base reduction in the treated group was 17.8% ± 15.9. The average maximal thickness at baseline was 414 ± 174 µm (range 152-686 µm). There was a 14% ± 7.1 reduction after treatment. None of the tumors showed evidence of growth at the final follow-up. CONCLUSION: The findings of this study suggest that mTOR inhibitors can reduce tumor size and that they can be considered as an optional treatment in certain conditions. This preliminary report is the first to quantitatively assess pre- and posttreatment tumor size, in young patients.
Subject(s)
Hamartoma , Tuberous Sclerosis , Child , Humans , Retrospective Studies , Sirolimus , TOR Serine-Threonine KinasesABSTRACT
Background: Genetic conditions contribute a significant portion of disease etiologies in children admitted to general pediatric wards worldwide. While exome sequencing (ES) has improved clinical diagnosis and management over a variety of pediatric subspecialties, it is not yet routinely used by general pediatric hospitalists. We aim to investigate the impact of exome sequencing in sequencing-naive children suspected of having monogenic disorders while receiving inpatient care. Methods: We prospectively employed exome sequencing in children admitted to the general pediatric inpatient service at a large tertiary medical center in Israel. Genetic analysis was triggered by general and/or subspecialist pediatricians who were part of the primary inpatient team. We determined the diagnostic yield among children who were referred for exome sequencing and observed the effects of genetic diagnosis on medical care. Results: A total of fifty probands were evaluated and exome sequenced during the study period. The most common phenotypes included were neurodevelopmental (56%), gastrointestinal (34%), and congenital cardiac anomalies (24%). A molecular diagnosis was reached in 38% of patients. Among seven patients (37%), the molecular genetic diagnosis influenced subsequent clinical management already during admission or shortly following discharge. Conclusion: We identified a significant fraction of genetic etiologies among undiagnosed children admitted to the general pediatric ward. Our results support that early application of exome sequencing may be maximized by pediatric hospitalists' high index of suspicion for an underlying genetic etiology, prompting an in-house genetic evaluation. This framework should include a multidisciplinary co-management approach of the primary care team working alongside with subspecialties, geneticists and bioinformaticians.
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PURPOSE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by multiorgan hamartomas, including cerebral lesions, with seizures as a common presentation. Most TSC patients will also experience neurocognitive comorbidities. Our objective was to use machine learning techniques incorporating clinical and imaging data to predict the occurrence of major neurocognitive disorders and seizures in TSC patients. METHODS: A cohort of TSC patients were enrolled in this retrospective study. Clinical data included genetic, demographic, and seizure characteristics. Imaging parameters included the number, characteristics, and location of cortical tubers and the presence of subependymal nodules, SEGAs, and cerebellar tubers. A random forest machine learning scheme was used to predict seizures and neurodevelopmental delay or intellectual developmental disability. Prediction ability was assessed by the area-under-the-curve of receiver-operating-characteristics (AUC-ROC) of ten-fold cross-validation training set and an independent validation set. RESULTS: The study population included 77 patients, 55% male (17.1 ± 11.7 years old). The model achieved AUC-ROC of 0.72 ± 0.1 and 0.68 in the training and internal validation datasets, respectively, for predicting neurocognitive comorbidity. Performance was limited in predicting seizures (AUC-ROC of 0.54 ± 0.19 and 0.71 in the training and internal validation datasets, respectively). The integration of seizure characteristics into the model improved the prediction of neurocognitive comorbidity with AUC-ROC of 0.84 ± 0.07 and 0.75 in the training and internal validation datasets, respectively. CONCLUSIONS: This proof of concept study shows that it is possible to achieve a reasonable prediction of major neurocognitive morbidity in TSC patients using structural brain imaging and machine learning techniques. These tools can help clinicians identify subgroups of TSC patients with an increased risk of developing neurocognitive comorbidities.
Subject(s)
Tuberous Sclerosis , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Machine Learning , Magnetic Resonance Imaging , Male , Neurocognitive Disorders/complications , Retrospective Studies , Seizures/diagnostic imaging , Seizures/etiology , Tuberous Sclerosis/complications , Tuberous Sclerosis/diagnostic imaging , Young AdultABSTRACT
Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.
Subject(s)
Abnormalities, Multiple/diagnosis , Exome Sequencing/economics , Financing, Government , Genetic Testing/economics , Neurodevelopmental Disorders/diagnosis , Abnormalities, Multiple/economics , Abnormalities, Multiple/genetics , Adolescent , Adult , Child , Child, Preschool , Cost-Benefit Analysis , Feasibility Studies , Female , Genetic Counseling/economics , Genetic Counseling/methods , Genetic Counseling/statistics & numerical data , Genetic Testing/methods , Genetic Testing/statistics & numerical data , Humans , Infant , Infant, Newborn , Israel , Male , Maternal Age , Neurodevelopmental Disorders/economics , Neurodevelopmental Disorders/genetics , Paternal Age , Pregnancy , Prenatal Diagnosis/economics , Prenatal Diagnosis/methods , Program Evaluation , Retrospective Studies , Tertiary Care Centers/economics , Tertiary Care Centers/statistics & numerical data , Exome Sequencing/statistics & numerical data , Young AdultABSTRACT
There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. METHODS: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009-2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (ß-hydroxybutyrate) were measured in blood and/or urine. RESULTS: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. CONCLUSIONS: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.
Subject(s)
Age Factors , Diet, Ketogenic , Ketones/blood , Adolescent , Aged , Brain Neoplasms/diet therapy , Child , Child, Preschool , Diet, Carbohydrate-Restricted , Diet, High-Fat , Epilepsy/diet therapy , Female , Glioma/diet therapy , Humans , Infant , Ketones/urine , Ketosis/blood , Ketosis/etiology , Male , Metabolic Diseases/diet therapy , Middle Aged , Prospective Studies , Retrospective StudiesABSTRACT
Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.
Subject(s)
Brain Diseases , Epilepsy , 4-Aminopyridine/therapeutic use , Gain of Function Mutation , Humans , Kv1.2 Potassium Channel/genetics , MutationABSTRACT
AIM: We aimed to describe the experience of a large single-center cohort for the clinical, radiological, and genetic characteristics, as well as to determine the efficacy of different anti-epileptic strategies in children and adults with tuberous sclerosis complex (TSC). METHODS: We carried out a historical cohort study on 91 TSC patients treated in a single center between 2008 and 2018. RESULTS: Our cohort comprised 46 males and 45 females, with a median age of 15.6 years at the last follow-up. Mean follow-up time was 2.5 ± 0.75-5.5 years (range 0-9.5 years). Of those tested, a disease-causing mutation was identified in 90% of patients, 53% in TSC2, and 37% in TSC1. Epilepsy prevalence was similar among TSC1 and TSC2 mutated patients. The most common radiological finding were cortical tubers in 95% of patients, while subependymal giant cell astrocytoma (SEGA) were detected in 36% of patients. Notably, infantile spasms (IS) were diagnosed in 29%, with SEGA representing the only finding significantly different in prevalence between those with and without IS (62% vs. 28%, respectively, p = 0.009). Lastly, we did not find any difference in efficacy between three anti-epileptic treatments: Vagus nerve stimulation (VNS), CBD-based products, and the ketogenic diet, all showing approximately 30%-40% response rates. SIGNIFICANCE: Altogether, we provide a comprehensive description of our experience in treating TSC, which could serve to expand current knowledge of the disease and its treatments.
Subject(s)
Astrocytoma , Epilepsy , Tuberous Sclerosis , Adolescent , Anticonvulsants/therapeutic use , Cohort Studies , Epilepsy/epidemiology , Epilepsy/etiology , Epilepsy/therapy , Female , Humans , Male , Tuberous Sclerosis/diagnostic imaging , Tuberous Sclerosis/epidemiology , Tuberous Sclerosis/therapyABSTRACT
Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.
Subject(s)
Electron Transport Complex I/metabolism , HSP40 Heat-Shock Proteins/genetics , Mutation , Optic Atrophy, Hereditary, Leber/genetics , Optic Atrophy, Hereditary, Leber/metabolism , Adolescent , Adult , Cell Line , Child, Preschool , Electron Transport Complex I/chemistry , Female , Gene Knockout Techniques , Genes, Recessive , HSP40 Heat-Shock Proteins/deficiency , HSP40 Heat-Shock Proteins/metabolism , Homozygote , Humans , Male , Middle Aged , Pedigree , Penetrance , Phenotype , Protein Subunits , Reactive Oxygen Species/metabolism , Young AdultABSTRACT
PURPOSE: Childhood epilepsy is often associated with cognitive impairments and psychosocial problems. However, it is not clear which factors mediate symptom severity and child's resilience. Emotional and behavioral problems have been associated with various home and school environments, suggesting that information collected may vary depending on both context and informant. In this study we examined the mediating effect of child's cognitive functions on the association between child and epilepsy-related factors and psychosocial problems. Additionally, the differences in psychosocial problems reported by various informants (parents, teachers) in different school settings were explored. METHODS: Participants were 155 children with epilepsy (50 % girls), age range 5-18 years who completed a brief neuropsychological battery. Parents completed the Child Behavior Checklist (CBCL) and teachers completed the corresponding Teacher's Rating Form (TRF), to assess a child's emotional and behavior problems. RESULTS: The cognitive profile of the sample was within average to low-average range. Parents and teachers both reported high levels of emotional and behavioral problems, and teachers reported relatively higher levels of symptoms. A mediation effect of cognition on the association between child and epilepsy-related factors (i.e., number of antiseizure medications and illness duration) and child's emotional and behavioral problems was evident only for teachers' reports. CONCLUSIONS: The results emphasize that the complex interactions between epilepsy, cognition and psychosocial outcomes are perceived differently in diverse contexts by different informants. The incongruities in informants' perceptions regarding the role of cognition in child's psychological state should be acknowledged and incorporated when planning effective educational and rehabilitation interventions for children with epilepsy.
Subject(s)
Child Behavior Disorders , Epilepsy , Problem Behavior , Adolescent , Child , Child Behavior Disorders/epidemiology , Child Behavior Disorders/etiology , Child, Preschool , Cognition , Emotions , Epilepsy/complications , Female , Humans , ParentsABSTRACT
INTRODUCTION: The new anticonvulsant brivaracetam is a levetiracetam analog which binds to the synaptic vesicle protein 2A, and inhibits excitatory neurotransmitters' release. Brivaracetam was Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved in 2016 as adjunctive treatment for focal onset seizures in patients over 16â¯years of age, and in 2018 for children over four years of age. Our aim was to describe effectiveness and tolerability in real-life pediatric epilepsy clinic. METHODS: Cross-sectional retrospective chart review of patients under 20â¯years of age, treated with brivaracetam. Positive response to treatment was considered when 50% decrease in seizure frequency was noted. In responders to levetiracetam, positive effect was regarded if switching to brivaracetam maintained at least the same seizure control. RESULTS: Thirty-one patients (67.7% males), aged 13.8⯱â¯4.07 (6.9-20â¯years), were treated with brivaracetam 3.8â¯mg/kg⯱â¯1.8. Age of onset of epilepsy was 5.7⯱â¯3.7â¯years; 20 patients had focal epilepsies; and 11 had epileptic syndromes (5 - Lennox-Gastaut, 3 - myoclonic absence, 3 - myoclonic-atonic). Responder rate was 45.2%, with no statistical difference under and over 16â¯years of age (40% vs. 54.5%, Fisher's exact test). Eight patients had better response to seizures compared to levetiracetam. Gender, duration of epilepsy, and dosage did not affect epilepsy control. Six patients had seizure aggravation. Adverse effects were rare: mild somnolence (6.4%), psychosis (3.2%), and nausea (3.2%). CONCLUSION: Brivaracetam is an effective add-on treatment in focal, as well as generalized seizures in children, with negligible side effects, including children who failed previously on levetiracetam. Seizure exacerbation may occur, but it's reason is unclear.