Neuropathologic Impacts of JAK Inhibitor Treatment in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy characterized by upregulation of type I interferon response. It is associated with increased mortality and severe disabilities. Janus Kinase (JAK) inhibitors have shown effectiveness in treatment of AGS through blocking the downstream effects of interferon activation. We illustrate post-mortem histopathologic findings in a patient with AGS who received baricitinib treatment for a duration of over 4 years, initiating at a remarkably young age of 2 months. We observed global cerebral atrophy, markedly diminished white matter, abundant calcifications involving supratentorial white matter, basal ganglia, dentate nuclei, and brainstem. This study showed profound central nervous system (CNS) sequelae despite early initiation of treatment. Our findings highlight the potential necessity for therapeutic options with enhanced CNS bioavailability.

Safety and tolerability of intravenous immunoglobulin infusion in Down syndrome regression disorder.

Three large multi-center studies have identified the clinical utility of intravenous immunoglobulin (IVIg) in the treatment of Down syndrome regression disorder (DSRD). Yet the tolerability of infusions in individuals with DS and the safety of IVIg remains unknown in this population. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD compared to a real-world cohort of individuals with pediatric onset neuroimmunologic disorders. A single-center, retrospective chart review evaluating clinically documented infusion reactions was performed for individuals meeting international consensus criteria for DSRD and having IVIg infusions between 2019 and 2023. Infusion reactions were evaluated for severity and need for alterations in infusion plan. This cohort was compared against an age and sex matched cohort of children with neuroimmunologic conditions who had also received IVIg infusions. In total, 127 individuals with DSRD and 186 individuals with other neuroimmunologic disorders were enrolled. There was no difference in the overall rate of adverse reactions (AEs) between the DSRD and general neuroimmunology cohorts (p = 0.31, 95% CI: 0.80-2.00), but cardiac-related AEs specifically were more common among the DSRD group (p = 0.02, 95% CI: 1.23-17.54). When AEs did occur, there was no difference in frequency of pharmacologic intervention (p = 0.12, 95% CI: 0.34-1.13) or discontinuation of therapy (p = 0.74, 95% CI: 0.06-7.44). There was a higher incidence of lab abnormalities on IVIG among the general neuroimmunology cohort (p = 0.03, 95% CI: 0.24-0.94) compared to the DSRD cohort. Transaminitis was the most common laboratory abnormality in the DSRD group. In a large cohort of individuals with DSRD, there were no significant differences in the safety and tolerability of IVIg compared to a cohort of children and young adults with neuroimmunologic conditions.

Autoimmune Encephalitis.

Autoimmune encephalitis is a common and treatable cause of encephalitis in children and adults. Individuals present with a variety of symptoms, including altered mental status, behavioral changes, irritability, insomnia, developmental regression, seizures, dyskinetic movements, and autonomic instability. Evaluation includes electroencephalography, magnetic resonance imaging, and lumbar puncture. Once infectious and other causes are reasonably ruled out, treatment should be started empirically without waiting for antibody confirmation. Early clinical suspicion is key, as the outcome depends on early initiation of immunotherapy, including corticosteroids, intravenous immunoglobulin, and/or plasmapheresis. Severe or refractory cases require other treatments, such as rituximab, cyclophosphamide, or other immunotherapies using novel monoclonal antibodies. Psychiatry should be involved early for the management of behavioral issues. Additional considerations include management of seizures and dyskinesias. ICU admission may be required for management of hypoventilation necessitating mechanical ventilation (either intrinsic or iatrogenic, eg, from sedatives), refractory seizures, and dysautonomia. Anti-N-methyl-d-aspartate receptor and other forms of autoimmune encephalitis are less often associated with neoplasia (such as ovarian teratoma) in children compared with adults, but screening and removal of tumor if present should be performed.

HHV-6 and seizure: A systematic review and meta-analysis.

Human herpesvirus-6 (HHV-6) is a common infection in childhood. This systematic review aims to assess the relationship between HHV-6 infection and seizure disorders based on available literature. MEDLINE database was searched using a search strategy. We included studies that were published after 1993 in English, and described patients with HHV-6 infection and accompanying seizure or status epilepticus. We identified 503 articles, and included 147 studies. Meta-analysis results showed a 0.21 detection rate of HHV-6 in febrile seizure patients. In the febrile seizure group (110 cases), 76 patients had simple and 34 had complex febrile seizures. Patients with "HHV-6 infection and status epilepticus" had a mean age of 16.24 months. In children with febrile illnesses, a higher index of clinical suspicion for HHV-6 infection may be required. Further studies including CSF and brain tissue may be needed to validate relationships between HHV6 infection and epilepsy. J. Med. Virol. 89:161-169, 2017. © 2016 Wiley Periodicals, Inc.

Effect of vigabatrin on seizure control and safety profile in different subgroups of children with epilepsy.

OBJECTIVE: To evaluate the efficacy and safety of vigabatrin in pediatric epilepsy. METHODS: We retrospectively reviewed patients with epilepsy treated with vigabatrin over a 2-year period at a pediatric tertiary center. We assessed the relationship between seizure frequency, etiology, vigabatrin dose, adverse events, medication discontinuation reasons, and electroencephalography (EEG) characteristics. RESULTS: One hundred three patients followed at Boston Children's Hospital were treated with vigabatrin and had complete medical records. Within the follow-up interval, 69 (67%) of 103 patients had discontinued vigabatrin therapy. Two patients (1.9%) died during therapy for unknown reasons. Median age at vigabatrin initiation was 8 months (interquartile range [IQR] 5-15). Median starting dose was 48.1 mg/kg per day (IQR 29.8-52.3) with a median target of 100 mg/kg (IQR 81.9-107.9). Median treatment duration was 12.1 months (n = 89, IQR 5.0-22.9) overall, and 13.3 months (IQR 5.2-23.2) for patients who discontinued vigabatrin. The most common reasons for discontinuation were controlled seizures in 31 (43.7%) of 71 and unsatisfactory therapeutic effect in 23 (32.4%) of 71. Median percent seizure reduction from baseline to first follow-up was 83.3% (IQR 27.4-99.8) and 96.7% (IQR 43.3-100) to last follow-up. Twenty-four (38.7%) of 62 patients with a follow-up posttreatment remained seizure-free. Four patients who had initially achieved seizure freedom relapsed. Patients with structural/metabolic etiology had greater median percent seizure reduction at first follow-up than patients with genetic etiology (98.7% vs. 61.4%, respectively, p = 0.001). Hypsarrhythmia resolved after therapy in 18 of 20 (90%, 95% confidence interval [CI] 70-97) patients with pretreatment hypsarrhythmia, and 2 patients presented with hypsarrhythmia posttreatment. Risk of having hypsarrhythmia was reduced by 32% (95% CI 14.9-49.1) posttreatment. SIGNIFICANCE: Vigabatrin is efficacious in all seizure types and resolved hypsarrhythmia in most patients. In this series with a median treatment duration of 12.1 months, vigabatrin had a good safety profile with a low rate of discontinuation due to nonophthalmologic and ophthalmologic adverse effects.

Effectiveness of once-daily high-dose ACTH for infantile spasms.

There is insufficient evidence to recommend a specific protocol for treatment of infantile spasms (IS) and a lack of standardization among, and even within, institutions. Twice-daily dosing (for the first two weeks) of high-dose natural ACTH for IS is used by many centers and recommended by the National Infantile Spasms Consortium (NISC). Conversely, it is our practice to use once-daily dosing of high-dose natural ACTH for IS. In order to determine the effectiveness of our center's practice, we retrospectively reviewed 57 cases over the past four years at Boston Children's Hospital (BCH). We found that 70% of infants were spasm-free at 14days from ACTH initiation and 54% continued to be spasm-free at 3-month follow-up. Electroencephalogram showed resolution of hypsarrhythmia (when present on the pretreatment EEG) in all responders. Additionally, once-daily dosing of ACTH was well tolerated. We performed a meta-analysis to compare our results against the reports of published literature using twice-daily high-dose ACTH for treatment of IS. The meta-analysis revealed that our results were comparable to previously published outcomes using twice-daily ACTH administration for IS treatment. Our experience shows that once-daily dosing of ACTH is effective for treatment of IS. If larger prospective trials can confirm our findings, it would obviate the need for additional painful injections, simplify the schedule, and support a universal standardized protocol.

Bedside ultrasonography for verification of shoulder reduction: A long way to go.

PURPOSE: Shoulder dislocation is a common joint dislocation managed by the emergency physicians in the emergency departments. Pre- and post-reduction radiographic examinations have long been the standard practice to confirm the presence of dislocation and the successful reduction. However, shoulder ultrasonography has recently been proposed as an alternative to the radiographic examination. This study aimed to assess the accuracy of ultrasonography in evaluating proper reduction of the dislocated joint. METHODS: This was a prospective observational study. All patients with confirmed anterior shoulder dislocation were examined by both ultrasonography and radiography after the attempt for reduction of the dislocated joint. The examiners were blinded to the result of the other imaging modality. Results of the two methods were then compared. RESULTS: Overall, 108 patients with confirmed anterior shoulder dislocation were enrolled in the study. Ninety-one (84.3%) of the patients were males. Mean age of the participants was (30.11 ± 11.41) years. The majority of the patients had a recurrent dislocation. Bedside ultrasonography showed a sensitivity of 53.8% (95% CI: 29.1%-76.8%) and a specificity of 100% (95% CI: 96.1%-100%) in detecting inadequate reductions. The results of ultrasonography had a statistically significant agreement with the results of radiography (Kappa = 0.672, p < 0.001). CONCLUSION: The results suggest that the sensitivity of post-reduction ultrasound is not sufficient for it to serve as a substitute for radiography.

Outcomes in pediatric patients with nonconvulsive status epilepticus.

Recognition of nonconvulsive status epilepticus (NCSE) is gaining increasing attention in the assessment and evaluation of critically ill pediatric patients. The underlying cause of NCSE is often the most important factor in determining outcome. However, there is a growing body of literature suggesting that electrical seizure burden in NCSE also contributes to unfavorable outcomes. Determination of impact of NCSE on outcome based on current evidence involves consideration of heterogeneous study settings, study populations, and process of care and outcome measures. In addition, the lack of data on neurocognitive function prior to episodes of NCSE as well as limited long-term neurocognitive assessment data confines precise conclusions about neurocognitive changes. This article is part of a Special Issue entitled "Status Epilepticus".

Epidemiology and short-term mortality in traumatic patients admitted to Shariati Hospital in Iran between 2012 and 2013.

PURPOSE: Trauma is an inevitable part of the health burden in every country. Both the preventive and rehabilitative aspects of traumatic injuries are expensive. Since most of the injuries happen in low- and middle-income developing countries, a judicious allocation of the limited resources to the most costefficient strategies is necessary. The present study was designed to report the causes of trauma, injured body regions, trauma severity scores and the one year survival rate of a randomly selected sample of trauma patients in a major referral hospital in Tehran, Iran. METHODS: We chose and analyzed a random subgroup of traumatic patients admitted during the oneyear period of May 2012 to May 2013 to Shariati Hospital, a major University Teaching Hospital in Tehran, Iran. Patients who stayed at the hospital for less than 24 h were excluded. In total, 73 traumatic patients were registered. The mean age was (40.19 ± 20.34) years and 67.1% of them were male. RESULTS: In general, the most common cause of injury was falls (47.9%), followed by road traffic crashes (RTCs, 40.8%). Assault and exposure to inanimate mechanical forces each were only associated with 5.6% of all injuries. The only cause of injury in ages of more than 65 years was fall. The most common cause of injury in ages between 15 and 45 years was RTCs. During the study, two deaths occurred: one was at ICU and the other was at home. The most commonly injured body region was the head (23.8%), followed by the elbow and forearm (19%), hip and thigh (15.9%), and multiple body regions (14.3%). The mean abbreviated injury score was 2.23 ± 1.02; injury severity index was 7.26 ± 7.06; and revised trauma score was 7.84, calculated for 38 patients. CONCLUSION: Prevention strategy of traumatic injury should focus on falls and RTCs, which are respectively the most common cause of trauma in older aged people and young males.

Comparison of health related quality of life between two groups of veteran and non-veteran spinal cord injured patients.

BACKGROUND: Patients with spinal cord injury (SCI) have a lower health related quality of life (HRQOL) compared to both healthy controls and the normal population. The aim of this study was to compare HRQOL between two groups of veteran and non-veteran SCI patients. METHODS: All male paraplegic non-veterans who had sustained complete SCI before 1988 and were residents of Tehran province (Iran), and a similar group of SCI veterans who consecutively participated in a health screening program were enrolled in this study. Patients fewer than 35 and older than 65 years of age were not included in this study. The participants were interviewed based on the Persian version of SF-36 questionnaire by two psychologists. Eight sub-scales and two physical and mental component summaries of the instrument were assessed. We used chi-square, odds ratio, Mann-Whitney U, independent t-test and linear regression for analysis. RESULTS: Overall, 25 veterans and 22 non-veterans were enrolled in the study. The mean age, time since injury and the presence of comorbid illnesses were not significantly different between the two groups (P>0.05). A greater number of veterans were married (p= 0.003) and employed (p= 0.047). On average, veterans had more years of formal education than non-veterans (p= 0.001). The mean (SD) bodily pain sub-scale was 72.73(31.253) for non-veterans and 49.7 (28.287) for veterans (p=0.011). Absence of comorbid illnesses was associated with a better physical component summary (p< 0.001). Employment was associated with a better mental component summary (p= 0.022). CONCLUSION: We did not find any differences in HRQOL between the two groups except for the bodily pain sub-scale. Further studies with larger sample sizes are recommended.

Psychometric properties of KIDSCREEN health-related quality of life questionnaire in Iranian adolescents.

INTRODUCTION: Health-related quality of life (HRQOL), which is receiving increasing attention, is a multidimensional concept that encompasses different areas including the physiological, psychological, social, and spiritual aspects of life. The KIDSCREEN-52 questionnaire is designed to measure the HRQOL of 8-18-year-old children and adolescents. The aim of this study was to develop a Persian version of KIDSCREEN-52 and analyze the validity and reliability of the translated version. METHOD: The KIDSCREEN-52 was translated into Persian in keeping with the international cross-cultural translation guidelines. A cross-sectional study was performed in the city of Tehran during 2012-2013. 328 students ranging in age from 8 to 18 years were enrolled in the study. The reliability for each dimension was estimated using Cronbach's alpha coefficient. To examine the validity of the questionnaire, a confirmatory factor analysis (CFA) was conducted. RESULTS: The Cronbach's alpha coefficient was higher than 0.7 in all ten dimensions except self-perception. Validity of this questionnaire was confirmed by CFA. (Relative chi square (χ (2)/df) = 1.73; root-mean-square error of approximation = 0.047; normed fit index = 0.93; Tucker-Lewis index = 0.97; comparative fit index = 0.97; and relative fit index = 0.92.) CONCLUSION: The Persian version of KIDSCREEN-52 is reliable and valid and can be used as a self-administered instrument for measuring HRQOL in children and adolescents in Iran.

Establishment of a regional multicenter traumatic spine fracture/dislocation registry.

OBJECTIVE: Trauma is one of the leading causes of mortality and morbidity in adults and a major contributor to health care expenditures. Although spine-related injuries constitute a small proportion of trauma cases, they need special consideration due to poor functional outcomes and substantial burden. Despite relatively extensive previous studies on traumatic spinal injuries, there is still obscurity in some aspects of the issue. The purpose of this study is to establish a regional multicenter traumatic spine fracture/dislocation registry. METHODS: This is a prospective case series study, including all patients with acute traumatic spine lesions admitted to a regional multicenter since 2014. Data is extracted based upon a form developed by Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran. Novel electronic data entry software is initiated and data will be entered to the software. Information remains confidential and security considerations will be taken based on standards of data entry systems. RESULTS: The results of this study will include age and gender distribution of the patients, causes of injury, location of pain and neurological deficit, the American Spinal Injury Association score and Frankel grade on admission, at discharge, after 6 and 12 months and at the latest annual follow-up, radiologic findings, details of operative procedures and methods of external fixation. CONCLUSION: This study will identify prognostic factors that influence the ultimate fate of spine fracture patients and determine short and long-term outcome of different treatment methods. It can lead to a considerable improvement in patient care and will have a great national and transnational impact.

Determinants of risky driving behavior: a narrative review.

Road traffic crashes (RTCs) account for great mortality and morbidity rates worldwide, resulting in substantial global burden. Factors contributing to RTC generally fall into three categories: environmental, vehicle, and human, with the human factor being by far the leading determinant. Obtaining an in-depth exploration of driving behavior and factors underpinning risky driving could be of particular importance to facilitate the establishment of effective policies. The present article provides insight to different aspects of risky driving behavior, at micro and macro levels, from individual attitudes, and psychological factors like personality, temperament, mood and emotions, to socioeconomic context, social norms, cultural backgrounds, level of law enforcement, and internalization of legality in the society. Risky driving behavior is a multidimensional issue and any effort to design and establish modification policies should be based on a comprehensive understanding of its determinants in different aspects.

Sexual Health Education and Quality of Counseling in Pediatric-Onset Multiple Sclerosis.

BACKGROUND: Disease-modifying therapies (DMTs) have revolutionized the management of multiple sclerosis (MS). Many DMTs have a risk of teratogenic outcomes, which is notable as MS disproportionally affects women of reproductive age and the rates of unplanned pregnancies among persons with MS (PwMS) are as high as 34%. Prior research suggests that patients' culture may influence their perspectives surrounding family planning. Given our institution's patient population, we compared the spectrum of knowledge in Hispanic and non-Hispanic patients with pediatric-onset MS (POMS) regarding DMTs and their associated risks during pregnancy and possible disparities in their treatment and counseling. METHODS: A small cohort of patients with POMS (n = 22) were surveyed on their knowledge and beliefs surrounding family planning and sexual health counseling. Odds ratios and 95% confidence intervals were used to evaluate the association between survey question responses and ethnicity. RESULTS: No significant differences in beliefs or knowledge regarding sexual health between Hispanic and non-Hispanic participants were identified, but many valuable themes emerged. Internet access and social relationships heavily influence participants' knowledge surrounding birth control and sexual health. Patients also desired continuous engagement in sexual health counseling. CONCLUSIONS: In this small pilot cohort, cultural views did not significantly influence whether adolescent and young adult patients with POMS seek sexual health resources. Future studies should aim to identify effective interventions for providers to educate PwMS about sexual health and family planning to address the elevated unplanned pregnancy rate in this population and provide the education these patients have vocalized a desire to receive.

Anti-CD20 Therapy in Children With Severe Epstein-Barr Virus-Associated Meningoencephalitis.

Epstein-Barr virus meningoencephalitis is a rare central nervous system infection that lacks standardized treatment. Immunocompetent and immunosuppressed individuals with this condition frequently have poor prognostic outcomes, making the need to identify therapeutic interventions high. Here, we report 2 pediatric cases of severe Epstein-Barr virus meningoencephalitis, both unresponsive to immunoglobulin and corticosteroid therapy, who demonstrated rapid clinical recovery following rituximab administration. Prognostic outcomes revealed marked improvements in symptoms, neurologic function, and quality of life. Rituximab may offer therapeutic potential in severe and refractory Epstein-Barr virus meningoencephalitis through the medication's target of Epstein-Barr virus harboring B cells. This report emphasizes the need for timely evaluation and consideration of rituximab therapy in immunocompetent pediatric patients with Epstein-Barr virus meningoencephalitis.

Delayed initiation of disease modifying therapy increases relapse frequency and motor disability in pediatric onset multiple sclerosis.

OBJECTIVE: To evaluate association between time to initiation of disease modifying treatment (DMT) and outcomes in pediatric-onset Multiple Sclerosis (POMS). METHODS: A retrospective analysis of children with POMS from two tertiary referral pediatric Neuroimmunology clinics. Outcome measures comprised annualized relapse rate (ARR), MRI lesion burden (T1, T2-FLAIR, and post-GAD contrast sequences), EDSS, and 25-ft walk duration at the latest follow-up visit. Univariate and multivariate analysis using linear and logistic regression models were used to assess associations between patient characteristics and outcomes. RESULTS: In total, 68 patients were reviewed. More than half of patients were female (62 %) and 32 (47 %) were Hispanic/LatinX. Median age at diagnosis was 14.2 years (IQR: 11.0-16.5), and median duration from diagnosis to the latest follow-up was 2.5 years (IQR: 1.6-4.6). Sensory (29.4 %), brainstem (23.5 %), and pyramidal (19.1 %) symptoms were most common. Interferon beta (32.4 %), dimethyl fumarate (27.9 %) and rituximab (26.5 %) were the most frequently used first-line DMT. Patients had a median ARR of 0.5 (IQR: 0.08-0.84), and EDSS score of 1.0 (IQR: 0.0-2.0) at the most recent follow-up. Delayed DMT initiation correlated with higher ARR (R = 0.38, p = 0.0016) and longer 25-ft walk duration (R = 0.34, p = 0.0077). In multivariate analysis, delayed DMT remained a significant predictor of higher ARR (p = 0.002) and longer 25-ft walk duration (p = 0.047). Delayed DMT initiation and use of low/moderate efficacy DMT predicted GAD enhancing lesions at the latest follow-up (p = 0.004 and 0.019 respectively). CONCLUSION: Delayed DMT initiation in POMS is linked to unfavorable outcomes, including higher ARR and longer 25-ft walk duration.

Down Syndrome and Autoimmune Disease.

Down syndrome is the most common genetic cause of intellectual disability and has previously been associated with a variety of autoimmune disorders affecting multiple organ systems. The high prevalence of autoimmune disease, in conjunction with other inflammatory and infectious diseases, in this population suggests an intrinsic immune dysregulation associated with triplication of chromosome 21. Emerging data on the role of chromosome 21 in interferon activation, cytokine production, and activation of B-cell mediated autoimmunity are emerging hypotheses that may explain the elevated prevalence of autoimmune thyroid disease, celiac disease, type I diabetes, autoimmune skin disease, and a variety of autoimmune neurologic conditions. As the life expectancy for individuals with Down syndrome increases, knowledge of the epidemiology, clinical features, management and underlying causes of these conditions will become increasingly important. Disorders such as Hashimoto's thyroiditis are prevalent in between 13 and 34% of individuals with Down syndrome but only 3% of the neurotypical population, a pattern similarly recognized in individuals with Celiac Disease (5.8% v 0.5-2%), alopecia areata (27.7% v. 2%), and vitiligo (4.4% v. 0.05-1.55%), respectively. Given the chronicity of autoimmune conditions, early identification and management can significantly impact the quality of life of individuals with Down syndrome. This comprehensive review will highlight common clinical autoimmune conditions observed in individuals with Down syndrome and explore our current understanding of the mechanisms of disease in this population.

Neuroimaging abnormalities associated with immunotherapy responsiveness in Down syndrome regression disorder.

OBJECTIVE: To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses. METHODS: A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities. RESULTS: In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities. INTERPRETATION: This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy.

De novo variants in immune regulatory genes in Down syndrome regression disorder.

BACKGROUND: Down Syndrome Regression Disorder (DSRD) is a rare and poorly understood disorder of the central nervous system, characterized by acute or subacute neuropsychiatric symptoms in previously healthy individuals with Down syndrome (DS). Many patients exhibit immunotherapy-responsiveness, indicative of immune dysregulation as a potential underlying etiology. While hypotheses are emerging regarding the role of interferon signaling in DSRD and other autoimmune conditions associated with DS, it is unclear why a small subset of individuals with DS develop DSRD. The aim of this study was to investigate genes of immune regulation in persons with DSRD. METHODS: This study included individuals with DSRD aged 10-30 years with trio exome sequencing performed during the diagnostic work up. Descriptive statistics and univariate analysis (Chi-square and Fisher's exact test) were used to describe and compare the characteristics of individuals with and without variants. RESULTS: Forty-one individuals with DSRD had trio exome sequencing results. Eight (20%) had heterozygous de novo variants of immune regulatory genes, with four variants being pathogenic or likely pathogenic (UNC13D, XIAP, RNASEH2A, and DNASE1L3). All genes harboring pathogenic variants were associated with interferon type-1 inflammatory response. Individuals harboring variants were more likely to have a preceding trigger (p = 0.03, 95% CI 1.21-97.06), rapid clinical decline in less than 1 month (p = 0.01, 95% CI 1.67-52.06), and MRI abnormalities (p < 0.001, 95% CI 4.89-527.71). DISCUSSION: A distinct subset of individuals with DSRD exhibited pathogenic variants in immune regulation genes associated with interferon-mediated inflammatory response, coinciding with previously established links between these genes and interferonopathies such as Aicardi-Goutieres syndrome. Our observations suggest that these variants might potentially contribute to the development of DSRD in individuals with DS.

EEG Biomarkers of Repository Corticotropin Injection Treatment.

PURPOSE: Hypsarrhythmia is one of the major diagnostic and treatment response criteria in infantile spasms (IS). The clinical and electrophysiological effect of repository corticotropin injection treatment on IS was evaluated using electrophysiological biomarkers. METHODS: Consecutive infants (<24 months) treated with repository corticotropin injection for IS were included in this retrospective descriptive study. Inclusion criteria were (1) clinical IS diagnosis, (2) repository corticotropin injection treatment, and (3) consecutive EEG recordings before and after repository corticotropin injection treatment. Patients with tuberous sclerosis complex were excluded. Response to treatment was defined as freedom from IS for at least 7 consecutive days during the treatment and resolution of hypsarrhythmia. The authors defined "relapse" as the recurrence of seizures after an initial response. Electrophysiological biomarker assessment included evaluation of semiautomatic spike counting algorithm, delta power, and delta coherence calculation during non-REM sleep EEG. RESULTS: One hundred fifty patients (83 males; 55%; median age of IS onset: 5.9 months) with complete data were included, including 101 responders (67%, 71 with sustained response, and 30 relapses). Fifty patients (33%) with complete EEG data also underwent advanced EEG analysis. Baseline delta coherence was higher in sustained responders than in nonresponders or patients who relapsed. Greater decreases in semiautomatic spike counting algorithm, delta power, and delta coherence were found in sustained responders compared with nonresponders or patients who relapsed. CONCLUSIONS: Repository corticotropin injection treatment was associated with a 67% response rate in patients with IS. Computational biomarkers beyond hypsarrhythmia may provide additional information during IS treatment, such as early determination of treatment response and outcome assessment.