BACKGROUND: To describe educational and social outcomes in optic nerve hypoplasia/septo-optic-pituitary dysplasia (ONH/SOD) in Manitoba, Canada. METHODS: A population-based case-control study used administrative health,...BACKGROUND: To describe educational and social outcomes in optic nerve hypoplasia/septo-optic-pituitary dysplasia (ONH/SOD) in Manitoba, Canada. METHODS: A population-based case-control study used administrative health, education, and social data from the Manitoba Population Research Data Repository. A total of 124 ONH/SOD patients diagnosed during 1990-2019 were matched to 620 unrelated population-based controls on area of residence, birth year, and sex. Multivariable logistic regression tested for differences between cases and controls on selected educational and social outcomes. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. RESULTS: Cases had higher odds than controls for requiring specialized educational funding (OR: 13.12, 95% CI: 7.06-24.40). Vulnerability in any five domains of Early Development Instrument, a measure of school readiness, showed higher odds in cases (OR: 2.58, 95% CI: 1.09-6.10). In addition, cases had higher odds of contact with Child and Family Services (OR: 1.81, 95% CI: 1.22-2.69), and being taken into care at any time after birth (OR: 2.10, 95% CI: 1.32-3.35). CONCLUSIONS: Cases with ONH/SOD had a need for greater resources and more adverse educational and social outcomes. It is recommended for social and educational service providers to work together with health care providers to ensure appropriate supports are in place for cases with ONH/SOD.
BACKGROUND: The study aimed to identify the manifestation of isolated Prolyl endopeptidase-like (PREPL) deficiency in children to aid in diagnosis and early intervention. METHODS: We performed a retrospective cohort stud...BACKGROUND: The study aimed to identify the manifestation of isolated Prolyl endopeptidase-like (PREPL) deficiency in children to aid in diagnosis and early intervention. METHODS: We performed a retrospective cohort study, including five children genetically confirmed with PREPL gene mutations. Clinical features, genotypes, and treatment responses were analyzed. RESULTS: The study involved four girls and one boy. The major neuromuscular features were hypotonia and feeding difficulties in the neonatal period. They all had global muscle weakness. Different from typical symptoms of CMS, only one patient had transient unilateral mild ptosis with no obvious fluctuating nature. Minor facial dysmorphism, growth retardation (especially underweight), and significantly delayed motor development were frequently observed. One patient also showed language and cognitive development delay. In addition, two cases had a predominant decrease in insulin-like growth factor 1 at 2.3 and 1.6 years, respectively. The median age at diagnosis was 5 (1-12) months. Eight previously nondescribed mutations were detected among the five patients, in four children with compound heterozygous mutations and one child with homozygous mutations (maternal uniparental disomy). The frameshift mutation site (p. F428fs∗18) was found in two unrelated patients. All patients have received pyridostigmine treatment at median age of 6 (3-14) months. Four cases exhibited significant improvements in motor development. CONCLUSIONS: Isolated PREPL deficiency is a multisystem disease more than just myasthenia. Early referral to diagnosis is crucial to enable timely initiation of treatment. Pyridostigmine is an effective treatment to improve motor development in most children. Monitoring hormone levels, including insulin-like growth factor 1, can assist in early intervention.
Guberman G, Scala M, Striano P
… +5 more, Zara F, Severino M, Argilli E, Sherr EH, Myers KA
Pediatr Neurol
· 2026 Mar · PMID 41539009
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COL18A1 encodes the α1 chain of collagen type XVIII, a nonfibrillar collagen expressed in vascular and epithelial basement membranes. Biallelic pathogenic variants in COL18A1 have been associated with Knobloch syndrome,...COL18A1 encodes the α1 chain of collagen type XVIII, a nonfibrillar collagen expressed in vascular and epithelial basement membranes. Biallelic pathogenic variants in COL18A1 have been associated with Knobloch syndrome, a condition defined by ophthalmologic abnormalities, though patients often have some or all of brain malformations, epilepsy, and intellectual disability. We reviewed our research and clinical databases for patients with seizures and biallelic COL18A1 variants suspected to be pathogenic. Three patients were identified, all of whom had epilepsy and global development impairment, with two having had developmental regression and drug-resistant seizures. None of the patients had severe ophthalmologic disease. All three patients had one heterozygous likely pathogenic frameshift COL18A1 variant on one allele, with the other allele carrying a rare heterozygous missense COL18A1 variant of less certain pathogenicity. These data raise the possibility that COL18A1 disruption could produce phenotypes without severe eye abnormalities but significant neurologic dysfunction.
BACKGROUND: Etiology is an important predictor for treatment outcomes of infantile epileptic spasms syndrome (IESS). In Thailand, vigabatrin (VGB) is the first-line treatment for all patients due to the unavailability of...BACKGROUND: Etiology is an important predictor for treatment outcomes of infantile epileptic spasms syndrome (IESS). In Thailand, vigabatrin (VGB) is the first-line treatment for all patients due to the unavailability of adrenocorticotropic hormone. We aimed to determine the etiology of IESS using the 2017 International League Against Epilepsy classification and evaluate the clinical response of VGB as a first-line treatment. METHODS: A retrospective cohort study was conducted on IESS-diagnosed patients between January 2013 and December 2022. Etiology was categorized per the 2017 International League Against Epilepsy classification. Clinical outcomes were assessed at days 14-42 and one year after treatment. RESULTS: We included 191 IESS patients (57.6% males). Etiology was identified in 75.4% (structural 61.2%: 48.1% with nontuberous sclerosis complex [non-TSC] and 13.1% with TSC; genetic, 6.3%; infectious, 6.3%; and metabolic, 1.6%). Among the 163 patients who received VGB as first-line treatment, 50 (30.7%) achieved clinical cessation of epileptic spasms at days 14-42, and 44 patients (27.0%) had sustained freedom of epileptic spasms at one year. Patients with TSC etiology were more likely to achieve cessation of epileptic spasms at day 14-42 after treatment (adjusted OR 3.548, 95% confidence interval 1.193, 10.550, P = 0.023). Definite developmental delay at spasm diagnosis decreased the odds of sustained clinical freedom from epileptic spasms at one year (adjusted OR 0.26, 95% confidence interval 0.09, 0.74, P = 0.012). CONCLUSIONS: The etiology of IESS was identified in 75%. VGB was most effective as first-line, short-term treatment in TSC patients, and one-year treatment in children with normal development at diagnosis of IESS.
BACKGROUND: Few studies have examined the participation of children with Duchenne muscular dystrophy (DMD), and further investigation is needed to understand the factors influencing it. This study aimed to compare the pa...BACKGROUND: Few studies have examined the participation of children with Duchenne muscular dystrophy (DMD), and further investigation is needed to understand the factors influencing it. This study aimed to compare the participation of children with DMD to typically developing (TD) male peers, explore the relationship between participation and environmental factors, and assess the role of the environment in participation levels. METHODS: In this cross-sectional study, 30 children with DMD and 30 TD male children aged 5-13 years were included. Participation levels were measured using the Assessment of Life Habits, and environmental conditions were assessed with the European Child Environment Questionnaire. RESULTS: Children with DMD exhibited significantly lower total participation scores compared to TD children (6.45 ± 1.88 vs. 8.67 ± 1.22; P < 0.001). Significant correlations were found between the total participation level and environmental factors (r = -0.526, P = 0.003). Regression analysis showed that environmental factors explained 34.1% of the variance in participation, with the physical environment identified as the sole significant predictor (beta = -0.517, P = 0.041). CONCLUSIONS: These findings highlight the need for occupational therapists to systematically evaluate participation and environmental factors to plan effective interventions.
BACKGROUND: This study evaluated the efficacy and safety of noninvasive pulsed radiofrequency (NiPRF) therapy for childhood migraine and compared its outcomes with calcium channel blockers (CCBs). METHODS: A randomized c...BACKGROUND: This study evaluated the efficacy and safety of noninvasive pulsed radiofrequency (NiPRF) therapy for childhood migraine and compared its outcomes with calcium channel blockers (CCBs). METHODS: A randomized controlled trial included 60 pediatric migraine patients (7-18 years). Patients were randomized into two groups: the CCB group (n = 30), receiving 5 mg flunarizine daily for 3 months, and the NiPRF group (n = 30), undergoing three weekly sessions of transcutaneous pulsed radiofrequency to the greater occipital nerve. Headache severity and frequency were recorded using a headache diary, and migraine-related disability was assessed with the Pediatric Migraine Disability Assessment score at baseline, one month, and 3 months. Two patients in the CCB group were excluded due to elevated transaminase levels and one in the NiPRF group for incomplete sessions, leaving 57 patients for analysis. RESULTS: Both treatments significantly reduced headache frequency and headache severity from baseline at 1 and 3 months. At one month, there was no significant difference between groups. However, at 3 months, the CCB group showed greater headache frequency reduction. Pediatric Migraine Disability Assessment scores improved in both groups, with a greater reduction in the CCB group at 3 months. Two CCB patients experienced transient liver enzyme elevation, while no significant side effects were observed in the NiPRF group. CONCLUSIONS: NiPRF is a safe and effective treatment for childhood migraine, with comparable short-term efficacy to CCBs. Its noninvasive nature and minimal side effects make it a promising alternative. Further studies should assess long-term efficacy and optimize protocols.
Le A, Thibault KA, Yazdani PA
… +15 more, Chapleau A, van Voorst RJ, Bertini E, Nicita F, Pohl D, Venkateswaran S, Keller S, Renaud D, Gonzalez Moron D, Kauffman M, De Assis Pereira D, Vanderver A, van der Knaap MS, Morsa M, Bernard G
BACKGROUND: RNA polymerase III-related hypomyelinating leukodystrophy (POLR3-HLD) is a rare, neurodegenerative, brain white matter disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism....BACKGROUND: RNA polymerase III-related hypomyelinating leukodystrophy (POLR3-HLD) is a rare, neurodegenerative, brain white matter disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Due to the complex and progressive nature of this disorder, parents and siblings of patients face many potential challenges and stressors. We, therefore, sought to explore parents' and siblings' experiences to understand their specific needs and identify modifiable factors to limit familial burden and improve their quality of life. METHODS: We conducted semistructured interviews with parents and siblings of patients with POLR3-HLD. Interview questions focused on the financial, emotional, and psychosocial impacts on parents, as well as siblings' relationship with their affected sibling and the psychosocial impacts they may have experienced. All interviews were recorded, transcribed, and analyzed using reflexive thematic analysis. Through the coding process, themes surrounding the impact on and experiences of parents and siblings were developed. RESULTS: Nineteen semistructured interviews with 24 parents and nine interviews with 9 siblings were completed between March and October 2023 and February and May 2024, respectively. Four themes from parent interviews included extensive caregiver burden, emotional and psychosocial challenges, the importance of parental self-health, and comfort in the leukodystrophy community. Three themes from sibling interviews included the spectrum of emotional impacts, limited knowledge about POLR3-HLD, and adapting to their sibling's needs. CONCLUSIONS: This study provides a comprehensive understanding of the family experience, identifying the common challenges and specific needs of parents and siblings, highlighting areas of improvement in the global care offered to this vulnerable patient population.
BACKGROUND: The study tests a conceptual model in which daily activities and mobility serve as mediators or intervening variables in the association between pain intensity and psychosocial health in young people with spi...BACKGROUND: The study tests a conceptual model in which daily activities and mobility serve as mediators or intervening variables in the association between pain intensity and psychosocial health in young people with spinal cord injury (SCI). A moderated mediation conceptual model is also tested with biological sex as the moderator variable. METHODS: The Pain Intensity Item, Daily Activities Scale and Mobility Scale from the Pediatric Quality of Life Inventory SCI Module and the Pediatric Quality of Life Inventory Generic Core Scales Psychosocial Health Summary Score were completed by 125 young people with SCI ages 8-24 years with an average age of 17.84 years. RESULTS: The findings demonstrate that daily activities and mobility mediate the predictive effects of pain intensity on psychosocial health in young people with SCI. For the full mediator models consisting of age, sex, race/ethnicity demographic covariates, and pain intensity, the daily activities and mobility mediation models separately accounted for 39 percent and 28 percent, respectively, of the variance in psychosocial health, representing large effect sizes. Biological sex was not found to be a significant moderator of the mediation effects, and hence the mediator effects were not conditional on biological sex. CONCLUSIONS: Daily activities and mobility explain in part the mechanism of pain predictive effects on psychosocial health in young people with SCI. Targeting mediators of pain intensity on psychosocial health from the perspective of children, adolescents, and young adults with SCI may inform clinical interventions and future clinical research to improve daily functioning and psychosocial health for these young people.
The world is facing an unprecedented crisis due to the harms associated with climate change. The universal impacts of these changes are creating as yet poorly acknowledged health crises, disproportionately affecting peop...The world is facing an unprecedented crisis due to the harms associated with climate change. The universal impacts of these changes are creating as yet poorly acknowledged health crises, disproportionately affecting people with neurodisabilities. These disruptions are experienced differentially, related to sociodemographic and political factors that offer relative protection for some and ever-increasing vulnerability for others. This essay offers an overview of key contributing factors that are likely to exacerbate this climate crisis for individuals with neurodisabilities and provides recommendations regarding how to recognize and seize opportunities to confront the ever-growing threats of climate change for these people, their families, and communities. These perspectives are grounded in broader critical disability studies, strategies addressing social vulnerability, and environmental justice. Climate adaptation is extremely complex and far broader than disaster risk readiness and response. It would therefore be understandable to feel powerless in the face of human-created climate events that impel the world toward the brink. There are, however, many reasons for hope. This essay argues in favor of working to capture people's lived experiences and resourcefulness. We must recognize the creative and improvised strategies they are able to devise, and describe and promote the ensuing actions that we can take for the wellbeing of the people we service. In our professional roles in research and in direct health, social and educational services, and working in collaboration with families of individuals with neurodisabilities, we have the power to act and advocate. This is a time, as never before, for thoughtful and concerted action.
BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations occurring sporadically, or secondary to a familial cavernoma syndrome. While focal seizures are commonly associated with CCMs, epileptic spas...BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations occurring sporadically, or secondary to a familial cavernoma syndrome. While focal seizures are commonly associated with CCMs, epileptic spasms are rare. METHODS: We report four patients with epileptic spasms associated with CCM. All four patients were female and developed epileptic spasms aged 5 months, 17 months, 9 years, and 10 years. RESULTS: The 17-month-old presented with raised intracranial pressure aged 4 months, with a magnetic resonance imaging demonstrating a giant left hemisphere CCM in the context of a familial cavernoma syndrome. She developed epileptic spasms aged 17 months with developmental regression and hypsarrhythmia on electroencephalogram. The 10-year-old presented with epileptic spasms following several years of focal seizures associated with a solitary CCM in the left precuneus. The five-month-old presented with infantile epileptic spasms syndrome with a modified hypsarrhythmia and a CCM in the left temporal lobe in the context of a familial cavernoma syndrome. The nine-year-old presented with focal seizures followed by a period of altered awareness associated with periodic complexes on electroencephalogram associated with a CCM in the right precuneus. All patients underwent epilepsy surgery to remove their CCM and surrounding hemosiderin-stained cortex. Epileptic spasms resolved following resective surgery in all, although one child continued to have focal seizures. CONCLUSION: These cases demonstrate that CCM may rarely present with epileptic spasms. Factors potentially predisposing to the development of epileptic spasms, rather than focal epilepsies include large lesion volume, lesion location within the precuneus, and the presence of a familial cavernoma syndrome.
The field of leukodystrophies (LDs) has undergone a paradigm shift in recent decades. Several factors underlie this change: newborn screening, advanced genetic and metabolic testing, improved understanding and medical ma...The field of leukodystrophies (LDs) has undergone a paradigm shift in recent decades. Several factors underlie this change: newborn screening, advanced genetic and metabolic testing, improved understanding and medical management of disease, and targeted therapies addressing underlying molecular etiologies. Recent trials as well as regulatory approvals are testimony to the transformative effects of gene therapy. However, the risks of these treatments remain incompletely understood and include malignancies/premalignancies, immune-mediated hepatic injury, and thrombotic microangiopathy, among others. The implementation of newborn screening for individual LDs allows for improved monitoring and earlier treatment but also extends the measured lifespan following diagnosis, skewing survival data compared to historical data based on symptomatic diagnosis. Lastly, population screening leads to identification of genetic variants with milder or uncertain pathogenicity. In this article, we review the shifting framework impacting life expectancy and decision-making in the LDs along with the risks and uncertainties that have arisen in the setting of recent advancements.
Biallelic pathogenic variants in the WW domain-containing oxidoreductase (WWOX) gene have been identified as causes of WWOX-related epileptic encephalopathy. We report vigabatrin-associated brain abnormalities on magneti...Biallelic pathogenic variants in the WW domain-containing oxidoreductase (WWOX) gene have been identified as causes of WWOX-related epileptic encephalopathy. We report vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM) in two children affected by WWOX-related epileptic encephalopathy. The clinical presentation included microcephaly, hypertonia, dysphagia, profound global developmental delay, and early infantile onset drug-resistant epilepsy. Initial neuroimaging was characterized by periventricular white matter volume loss and atrophy of the corpus callosum. Brain magnetic resonance imaging during vigabatrin treatment revealed new symmetrical signal changes in the globus pallidi and thalami consistent with VABAM. Further research is warranted to investigate whether children with genetic epilepsy related to the GABAergic pathway or delayed myelination are more susceptible to VABAM.
Primary mitochondrial diseases comprise a clinically, genetically, and biochemically heterogenous group of disorders associated with multisystemic involvement and significant morbidity and mortality of various etiologies...Primary mitochondrial diseases comprise a clinically, genetically, and biochemically heterogenous group of disorders associated with multisystemic involvement and significant morbidity and mortality of various etiologies. To date, no disease modifying therapies have been FDA approved, and treatment is largely symptomatic and supportive. Because of the rarity of mitochondrial specialists, most patients with mitochondrial diseases are cared for by clinicians without mitochondrial-specific expertise. Therefore, these clinicians by necessity rely on existing literature or older prognostic approaches which may be discordant with modern clinical practice and evolving therapeutic strategies and outcomes. Furthermore, existing literature may be skewed to the more severe end of the spectrum as publications may disproportionately focus on the most severe or unusual cases. Prognostic, therapeutic, and palliative discussions should ideally take place in a multidisciplinary setting where shared decision making can take place between the patient, family, and clinician team. Prognosis is increasingly shaped by the unprecedented development of various therapeutic modalities and personalized medicine. We aim to highlight the multipronged challenges and considerations faced in counseling patients and caregivers and draw from our own patient cohorts and observations in contemporary mitochondrial medicine to offer additional insights and future considerations for approaching patient counseling and prognostication.
BACKGROUND: Cenobamate is an antiseizure medication (ASM) for the treatment of focal-onset seizures in adults aged 18 years and older-while currently used off-label in children and adolescents, its pediatric potential is...BACKGROUND: Cenobamate is an antiseizure medication (ASM) for the treatment of focal-onset seizures in adults aged 18 years and older-while currently used off-label in children and adolescents, its pediatric potential is significant. Studies demonstrated a promising median seizure reduction of up to 65% in patients with treatment-resistant focal epilepsy. METHODS: This study aimed to investigate the effectiveness and safety of cenobamate as an adjunctive ASM in epilepsy patients under 18 years. The primary objective was to assess the effectiveness of cenobamate by examining seizure reduction. Secondary end points included adverse drug reactions (ADRs) and the median dose. Data were summarized using descriptive statistics, including mean, standard deviation, median, interquartile range, and percentages. RESULTS: Among 31 patients, 52% experienced a 75-100% reduction in seizure frequency, 16% had a 50-75% reduction, 13% had a 25-50% reduction, and 19% had no reduction or an increase in seizure frequency upon initiating cenobamate. These outcomes correspond to a median seizure reduction rate of 80%. The most common ADR was sedation (32.3%), followed by aggression and other mood changes. The median maintenance dose was 150 mg; patients weighing <50 kg received a median dose of 137.5 mg/day (5.2 mg/kg/day). Notably, patients were on a median of five ASMs before starting cenobamate, which decreased to two with cenobamate, suggesting a potential role in simplifying treatment regimens. CONCLUSIONS: Our study showed that initiating cenobamate as adjunctive therapy was effective and safe for pediatric patients with treatment-resistant epilepsy, reducing seizure frequency and establishing improved seizure control.
Duchenne Muscular Dystrophy (DMD) is a progressive and life-limiting neuromuscular disorder with profound implications for affected individuals and their families. Advances in genetic and molecular therapies, including e...Duchenne Muscular Dystrophy (DMD) is a progressive and life-limiting neuromuscular disorder with profound implications for affected individuals and their families. Advances in genetic and molecular therapies, including exon skipping agents, gene therapy, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based approaches have ushered in a new era of disease-modifying treatments. However, these breakthroughs also introduce complex ethical and psychosocial challenges. As we continue to extend life expectancy and improve motor outcomes for individuals with DMD, there is also a need to ensure autonomy-supportive environments, particularly during the transition to adulthood. This review provides a comprehensive exploration of the evolving landscape of DMD management, the long-term and ethical considerations of experimental therapies, and the psychosocial impacts on patients and caregivers. In the context of recent major advancements in medical care, we reflect on the impact of the growing group of DMD "boys" navigating the transition to adulthood. Lastly, this review highlights the critical need for multidisciplinary care models that address not only the biological but also the evolving psychological and social dimensions of the disease. By synthesizing perspectives from treatment innovation and ethical discourse, this article equips readers with a holistic understanding of the transformative potential and challenges associated with DMD therapies. This review aims to support multidisciplinary neuromuscular clinics to more fully meet the needs of an increasingly diverse population of patients with an ever-expanding potential.