Cot-side imaging of functional connectivity in the developing brain during sleep using wearable high-density diffuse optical tomography.

Studies of cortical function in newborn infants in clinical settings are extremely challenging to undertake with traditional neuroimaging approaches. Partly in response to this challenge, functional near-infrared spectroscopy (fNIRS) has become an increasingly common clinical research tool but has significant limitations including a low spatial resolution and poor depth specificity. Moreover, the bulky optical fibres required in traditional fNIRS approaches present significant mechanical challenges, particularly for the study of vulnerable newborn infants. A new generation of wearable, modular, high-density diffuse optical tomography (HD-DOT) technologies has recently emerged that overcomes many of the limitations of traditional, fibre-based and low-density fNIRS measurements. Driven by the development of this new technology, we have undertaken the first cot-side study of newborn infants using wearable HD-DOT in a clinical setting. We use this technology to study functional brain connectivity (FC) in newborn infants during sleep and assess the effect of neonatal sleep states, active sleep (AS) and quiet sleep (QS), on resting state FC. Our results demonstrate that it is now possible to obtain high-quality functional images of the neonatal brain in the clinical setting with few constraints. Our results also suggest that sleep states differentially affect FC in the neonatal brain, consistent with prior reports.

Reliability and similarity of resting state functional connectivity networks imaged using wearable, high-density diffuse optical tomography in the home setting.

BACKGROUND: When characterizing the brain's resting state functional connectivity (RSFC) networks, demonstrating networks' similarity across sessions and reliability across different scan durations is essential for validating results and possibly minimizing the scanning time needed to obtain stable measures of RSFC. Recent advances in optical functional neuroimaging technologies have resulted in fully wearable devices that may serve as a complimentary tool to functional magnetic resonance imaging (fMRI) and allow for investigations of RSFC networks repeatedly and easily in non-traditional scanning environments. METHODS: Resting-state cortical hemodynamic activity was repeatedly measured in a single individual in the home environment during COVID-19 lockdown conditions using the first ever application of a 24-module (72 sources, 96 detectors) wearable high-density diffuse optical tomography (HD-DOT) system. Twelve-minute recordings of resting-state data were acquired over the pre-frontal and occipital regions in fourteen experimental sessions over three weeks. As an initial validation of the data, spatial independent component analysis was used to identify RSFC networks. Reliability and similarity scores were computed using metrics adapted from the fMRI literature. RESULTS: We observed RSFC networks over visual regions (visual peripheral, visual central networks) and higher-order association regions (control, salience and default mode network), consistent with previous fMRI literature. High similarity was observed across testing sessions and across chromophores (oxygenated and deoxygenated haemoglobin, HbO and HbR) for all functional networks, and for each network considered separately. Stable reliability values (described here as a <10% change between time windows) were obtained for HbO and HbR with differences in required scanning time observed on a network-by-network basis. DISCUSSION: Using RSFC data from a highly sampled individual, the present work demonstrates that wearable HD-DOT can be used to obtain RSFC measurements with high similarity across imaging sessions and reliability across recording durations in the home environment. Wearable HD-DOT may serve as a complimentary tool to fMRI for studying RSFC networks outside of the traditional scanning environment and in vulnerable populations for whom fMRI is not feasible.

Early development of sleep and brain functional connectivity in term-born and preterm infants.

The proper development of sleep and sleep-wake rhythms during early neonatal life is crucial to lifelong neurological well-being. Recent data suggests that infants who have poor quality sleep demonstrate a risk for impaired neurocognitive outcomes. Sleep ontogenesis is a complex process, whereby alternations between rudimentary brain states-active vs. wake and active sleep vs. quiet sleep-mature during the last trimester of pregnancy. If the infant is born preterm, much of this process occurs in the neonatal intensive care unit, where environmental conditions might interfere with sleep. Functional brain connectivity (FC), which reflects the brain's ability to process and integrate information, may become impaired, with ensuing risks of compromised neurodevelopment. However, the specific mechanisms linking sleep ontogenesis to the emergence of FC are poorly understood and have received little investigation, mainly due to the challenges of studying causal links between developmental phenomena and assessing FC in newborn infants. Recent advancements in infant neuromonitoring and neuroimaging strategies will allow for the design of interventions to improve infant sleep quality and quantity. This review discusses how sleep and FC develop in early life, the dynamic relationship between sleep, preterm birth, and FC, and the challenges associated with understanding these processes. IMPACT: Sleep in early life is essential for proper functional brain development, which is essential for the brain to integrate and process information. This process may be impaired in infants born preterm. The connection between preterm birth, early development of brain functional connectivity, and sleep is poorly understood. This review discusses how sleep and brain functional connectivity develop in early life, how these processes might become impaired, and the challenges associated with understanding these processes. Potential solutions to these challenges are presented to provide direction for future research.

Wearable, Integrated EEG-fNIRS Technologies: A Review.

There has been considerable interest in applying electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) simultaneously for multimodal assessment of brain function. EEG-fNIRS can provide a comprehensive picture of brain electrical and hemodynamic function and has been applied across various fields of brain science. The development of wearable, mechanically and electrically integrated EEG-fNIRS technology is a critical next step in the evolution of this field. A suitable system design could significantly increase the data/image quality, the wearability, patient/subject comfort, and capability for long-term monitoring. Here, we present a concise, yet comprehensive, review of the progress that has been made toward achieving a wearable, integrated EEG-fNIRS system. Significant marks of progress include the development of both discrete component-based and microchip-based EEG-fNIRS technologies; modular systems; miniaturized, lightweight form factors; wireless capabilities; and shared analogue-to-digital converter (ADC) architecture between fNIRS and EEG data acquisitions. In describing the attributes, advantages, and disadvantages of current technologies, this review aims to provide a roadmap toward the next generation of wearable, integrated EEG-fNIRS systems.

Conversational analysis of consciousness during seizures.

OBJECTIVE: The objectives of the study were to 1) investigate how patients with epilepsy describe the subjective, conscious experience of having a seizure and 2) determine whether certain themes and descriptions correspond to specific types of epilepsy. METHODS: We interviewed thirteen patients with electroencephalographically confirmed epilepsy about their subjective experience of having a seizure and used conversational analysis (CA) to analyze the language they used to describe this experience. RESULTS: Seven patients had focal to bilateral tonic-clonic seizures (FBTCS), 7 had focal impaired awareness seizures (FIAS), 1 had focal aware seizures (FAS), and one had generalized onset tonic-clonic (GTC) seizures. Three had multiple types of seizures. Focal seizure origin was frontal in 2 patients, right hemisphere in 1, parieto-occipital in 1, and temporal in 8. Focal to bilateral tonic-clonic and GTC seizures were most frequently associated with descriptions of a total loss of consciousness (n = 8), whereas FIAS were most frequently associated with a perceived loss of consciousness but able to describe some aspects of being unconscious (n = 5). Temporal seizures most frequently accompanied reports of memory loss/impairment (n = 4). Ten patients provided specific descriptions of the transition between the interictal and ictal state or auras. Descriptions consciousness and unconsciousness ranged significantly, resembling a continuum rather than corresponding to distinct levels. CONCLUSION: The subjective experience of consciousness for patients with epilepsy may differ by seizure type and origin. These may reflect different involvement of brain regions involved in producing consciousness and arousal. Conversational analysis and narrative approaches can significantly aid clinicians in the diagnosis and management of epilepsy.

Social impairments in alternating hemiplegia of childhood.

AIM: To evaluate presence and severity of social impairments in alternating hemiplegia of childhood (AHC) and determine factors that are associated with social impairments. METHOD: This was a retrospective analysis of 34 consecutive patients with AHC (19 females, 15 males; mean age: 9y 7mo, SD 8y 2mo, range 2y 7mo-40y), evaluated with the Social Responsiveness Scale, Second Edition (SRS-2). RESULTS: SRS-2 scores, indicating level of social impairment, were higher than population means (75, SD 14 vs 50, SD 10, p<0.001). Of these, 27 out of 34 had high scores: 23 severe (>76), four moderate (66-76). All subscale domains, including social cognition, social communication, social awareness, social motivation, restricted interests, and repetitive behavior, had abnormal scores compared to population means (p<0.001). High SRS-2 scores were associated with the presence of autism spectrum disorder (ASD) and epilepsy (p=0.01, p=0.04), but not with other scales of AHC disease symptomatology. All nine patients who received formal evaluations for ASD, because they had high SRS-2 scores, were diagnosed with ASD. INTERPRETATION: Most patients with AHC have impaired social skills involving multiple domains. ASD is not uncommon. High SRS-2 scores in patients with AHC support referral to ASD evaluation. Our findings are consistent with current understandings of the pathophysiology of AHC and ASD, both thought to involve GABAergic dysfunction. WHAT THIS PAPER ADDS: Most patients with alternating hemiplegia of childhood (AHC) have impaired social skills involving multiple domains. These impairments are significant compared to population means. Most patients with AHC have high Social Responsiveness Scale, Second Edition (SRS-2) scores. Patients with AHC with high SRS-2 scores are likely to have autism spectrum disorder.

Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood.

AIM: To determine the neuropsychological abnormalities that occur in alternating hemiplegia of childhood (AHC) and report on our experience in managing them. METHOD: Patients underwent evaluations according to our standardized AHC pathway. Data were entered into our prospective AHC database and then analyzed. RESULTS: Of the cohort of 25 consecutive patients (ages 15mo-42y), eight had initial chief complaints about cognition, 14 language, five attention, and 11 behavior. As compared to population norms means, neuropsychological and behavioral assessment tools (including Child Behavior Checklist, Vineland Adaptive Behavior Scales, Peabody Picture Vocabulary, and Wechsler Intelligence Quotient tests) showed significant impairments in multiple domains: cognition, expressive and receptive language, executive function/attention, and behavior (p<0.05 in all comparisons). Evaluations generated management recommendations in all patients. Twenty had neuropsychiatric diagnoses: 10 attention-deficit/hyperactivity disorder (ADHD), seven disruptive behavior, and three anxiety disorder. Eight out of nine patients with ADHD who were prescribed medications responded to pharmacotherapy. INTERPRETATION: Patients with AHC have developmental difficulties related to impairments in multiple neuropsychological domains. This supports the hypothesis that the underlying AHC pathophysiology involves diffuse neuronal dysfunction. Testing generated recommendations to help manage these difficulties. Patients with AHC also have a range of neuropsychiatric diagnoses, the most common being ADHD which responds to pharmacotherapy. WHAT THIS PAPER ADDS: Patients with alternating hemiplegia of childhood (AHC) have developmental difficulties with underlying neuropsychological impairments. The findings in this study are consistent with an underlying AHC pathophysiology which involves diffuse neuronal, probably largely GABAergic, dysfunction. Patients with AHC have a range of neuropsychiatric diagnoses, the most common being attention-deficit/hyperactivity disorder.

Motor function domains in alternating hemiplegia of childhood.

AIM: To characterize motor function profiles in alternating hemiplegia of childhood, and to investigate interrelationships between these domains and with age. METHOD: We studied a cohort of 23 patients (9 males, 14 females; mean age 9y 4mo, range 4mo-43y) who underwent standardized tests to assess gross motor, upper extremity motor control, motor speech, and dysphagia functions. RESULTS: Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure-88 (GMFM-88), Manual Ability Classification System (MACS), and Revised Melbourne Assessment (MA2) scales manifested predominantly mild impairments; motor speech, moderate to severe; Modified Dysphagia Outcome and Severity Scale (M-DOSS), mild-to moderate deficits. GMFCS correlated with GMFM-88 scores (Pearson's correlation, p=0.002), MACS (p=0.038), and MA2 fluency (p=0.005) and accuracy (p=0.038) scores. GMFCS did not correlate with motor speech (p=0.399), MA2 dexterity (p=0.247), range of motion (p=0.063), or M-DOSS (p=0.856). Motor speech was more severely impaired than the GMFCS (p<0.013). There was no correlation between any of the assessment tools and age (p=0.210-0.798). INTERPRETATION: Our data establish a detailed profile of motor function in alternating hemiplegia of childhood, argue against the presence of worse motor function in older patients, identify tools helpful in evaluating this population, and identify oropharyngeal function as the more severely affected domain, suggesting that brain areas controlling this function are more affected than others.

Temporal Dynamics and Physical Priori Multimodal Network for Rehabilitation Physical Training Evaluation.

Sensor-based rehabilitation physical training assessment methods have attracted significant attention in refined evaluation scenarios. A refined rehabilitation evaluation method combines the expertise of clinicians with advanced sensor-based technology to capture and analyze subtle movement variations often unobserved by traditional subjective methods. Current approaches center on either body postures or muscle strength, which lack more sophisticated analysis features of muscle activation and coordination, thereby hindering analysis efficacy in deep rehabilitation feature exploration. To address this issue, we present a multimodal network algorithm that integrates surface electromyography (sEMG) and stress distribution signals. The algorithm considers the physical knowledge a priori to interpret the current rehabilitation stage and efficiently handles temporal dynamics arising from diverse user profiles in an online setting. Besides, we verified the performance of this model using a learned-nonuse phenomenon assessment task in 24 subjects, achieving an accuracy of 94.7%. Our results surpass those of conventional feature-based, distance-based, and ensemble baseline models, highlighting the advantages of incorporating multimodal information rather than relying solely on unimodal data. Moreover, the proposed model presents a network design solution for rehabilitation physical training that requires deep bioinformatic features and can potentially assist real-time and home-based physical training work.

Characteristics of non-sleep related apneas in children with alternating hemiplegia of childhood.

BACKGROUND: Non-sleep related apnea (NSA) has been observed in alternating hemiplegia of childhood (AHC) but has yet to be characterized. GOALS: Investigate the following hypotheses: 1) AHC patients manifest NSA that is often severe. 2) NSA is usually triggered by precipitating events. 3) NSA is more likely in patients with ATP1A3 mutations. METHODS: Retrospective review of 51 consecutive AHC patients (ages 2-45 years) enrolled in our AHC registry. NSAs were classified as mild (not needing intervention), moderate (needing intervention but not perceived as life threatening), or severe (needing intervention and perceived as life threatening). RESULTS: 19/51 patients (37 %) had 52 NSA events (6 mild, 11 moderate, 35 severe). Mean age of onset of NSA (± Standard Error of the Mean (SEM)): 3.8 ± 1.5 (range 0-24) years, frequency during follow up was higher at younger ages as compared to adulthood (year 1: 2.2/year, adulthood: 0.060/year). NSAs were associated with triggering factors, bradycardia and with younger age (p < 0.008 in all) but not with mutation status (p = 0.360). Triggers, observed in 17 patients, most commonly included epileptic seizures in 9 (47 %), anesthesia, AHC spells and intercurrent, stressful, conditions. Management included use of pulse oximeter at home in nine patients, home oxygen in seven, intubation/ventilatory support in seven, and basic CPR in six. An additional patient required tracheostomy. There were no deaths or permanent sequalae. CONCLUSIONS: AHC patients experience NSAs that are often severe. These events are usually triggered by seizures or other stressful events and can be successfully managed with interventions tailored to the severity of the NSA.

Review of recent advances in frequency-domain near-infrared spectroscopy technologies [Invited].

Over the past several decades, near-infrared spectroscopy (NIRS) has become a popular research and clinical tool for non-invasively measuring the oxygenation of biological tissues, with particular emphasis on applications to the human brain. In most cases, NIRS studies are performed using continuous-wave NIRS (CW-NIRS), which can only provide information on relative changes in chromophore concentrations, such as oxygenated and deoxygenated hemoglobin, as well as estimates of tissue oxygen saturation. Another type of NIRS known as frequency-domain NIRS (FD-NIRS) has significant advantages: it can directly measure optical pathlength and thus quantify the scattering and absorption coefficients of sampled tissues and provide direct measurements of absolute chromophore concentrations. This review describes the current status of FD-NIRS technologies, their performance, their advantages, and their limitations as compared to other NIRS methods. Significant landmarks of technological progress include the development of both benchtop and portable/wearable FD-NIRS technologies, sensitive front-end photonic components, and high-frequency phase measurements. Clinical applications of FD-NIRS technologies are discussed to provide context on current applications and needed areas of improvement. The review concludes by providing a roadmap toward the next generation of fully wearable, low-cost FD-NIRS systems.

Adolescent and Young Adult Perspectives on Quality and Value in Health Care.

OBJECTIVE: To describe adolescent and young adult (AYA) perspectives on defining quality and value in health care and to gain understanding of their knowledge of value-based payment. METHODS: A text message-based survey was sent to a convenience sample of AYAs aged 14 to 24 in 2019. Participants were asked 4 open-ended questions: 1) how they would define "good health care," 2) what factors to consider in rating doctors, 3) whose opinions should matter most when rating doctors, and 4) the best ways to collect AYA opinions on doctors, and one yes/no question on their awareness of value-based payment. Analyses included descriptive demographic statistics and an inductive thematic approach with multivariable models comparing adolescent (14-18) and young adult (19-24) responses. RESULTS: Response rate was 61.0% (782/1283). Most participants were White (63.3%), female (53.3%), and adolescents (55.6%). Common themes from the first 2 questions included accessibility (specifically affordability), coverage benefits, and care experience (including compassion, respect, and clinical competence). Young adults more commonly mentioned affordability than adolescents (54.4% vs 43.3%, P = .001) and more commonly felt their opinion should matter more than their parents when rating doctors (80.6% vs 62.0%, P < .001). Only 21.0% of AYAs were familiar with the potential value-based link between physician payment and care quality. CONCLUSIONS: When considering quality and value in health care, AYAs expressed their desired agency in rating the quality of their care and clinicians. AYAs' perspectives on health care quality, including the importance of care accessibility and affordability, should be considered when designing youth-centered care delivery and value-based payment models.

Role of Pediatricians, Pediatric Associations, and Academic Departments in Ensuring Optimal Early Childhood Development Globally: Position Paper of the International Pediatric Association.

ABSTRACT: Early childhood (birth-8 years), particularly the first 3 years, is the most critical time in development because of the highly sensitive developing brain. Providing appropriate developmental care (i.e., nurturing care, as defined by the World Health Organization [WHO]) during early childhood is key to ensuring a child's holistic development. Pediatricians are expected to play a critical role in supporting early childhood development (ECD) through providing developmental services such as developmental monitoring, anticipatory guidance, screening, and referral to medical and/or community-based services when delay is identified. Pediatricians are also expected to serve as advocates within their clinics and communities for improved delivery of ECD services, such as advocating for increasing funding for ECD initiatives, increasing insurance coverage of ECD services, and working to increase other pediatricians' awareness of the principles of ECD and how to deliver developmental services. However, this does not always occur. Typically, pediatricians' training and practice emphasizes treating disease rather than enhancing ECD. Pediatricians are further hindered by a lack of uniformity across nations in guidelines for developmental monitoring and screening. In this article, we present the vision of the International Pediatric Association (IPA) of the roles that pediatricians, academic departments, medical training programs, and pediatric associations should fulfill to help support ECD, including raising ECD to higher levels of priority in routine pediatric care. First, we present the challenges that face these goals in supporting ECD. We then propose, with supportive literature, strategies and resources to overcome these challenges in collaboration with local and international stakeholders, including the IPA, the WHO, UNICEF, and the World Bank.

Characterization of sedation and anesthesia complications in patients with alternating hemiplegia of childhood.

BACKGROUND: Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications. GOALS: Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications. METHODS: Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency). STATISTICS: Fisher Exact test, Spearman correlations. RESULTS: These patients underwent 129 procedures (3.79 ± 2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation. CONCLUSIONS: During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures.

Alternating hemiplegia of childhood: evolution over time and mouse model corroboration.

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by ATP1A3 mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort (n = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France (n = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool- mice at prepubescent and adult ages (n = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores: P < 0.0001 for the non-paroxysmal disability index, intellectual disability scale and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score (P = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score (P = 0.035). More patients with EEG background slowing were noted at last follow-up as compared to initial (P = 0.015). Similar worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score (P = 0.001) and first and last non-paroxysmal disability index score scores significantly differed (P = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that ATP1A3 disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of ATP1A3-related neurodegeneration.

Viral-Mediated Gene Replacement Therapy in the Developing Central Nervous System: Current Status and Future Directions.

The past few years have witnessed rapid developments in viral-mediated gene replacement therapy for pediatric central nervous system neurogenetic disorders. Here, we provide pediatric neurologists with an up-to-date, comprehensive overview of these developments and note emerging trends for future research. This review presents the different types of viral vectors used in viral-mediated gene replacement therapy; the fundamental properties of viral-mediated gene replacement therapy; the challenges associated with the use of this therapy in the central nervous system; the pathway for therapy development, from translational basic science studies to clinical trials; and an overview of the therapies that have reached clinical trials in patients. Current viral platforms under investigation include adenovirus vectors, adeno-associated viral vectors, lentiviral/retroviral vectors, and herpes simplex virus type 1 vectors. This review also presents an in-depth analysis of numerous studies that investigated these viral platforms in cultured cells and in transgenic animal models for pediatric neurogenetic disorders. Viral vectors have been applied to clinical trials for many different pediatric neurogenetic disorders, including Canavan disease, metachromatic leukodystrophy, neuronal ceroid lipofuscinosis, mucopolysaccharidosis III, spinal muscular atrophy, and aromatic l-amino acid decarboxylase deficiency. Of these diseases, only spinal muscular atrophy has a viral-mediated gene replacement therapy approved for marketing. Despite significant progress in therapy development, many challenges remain. Surmounting these challenges is critical to advancing the current status of viral-mediated gene replacement therapy for pediatric central nervous system neurogenetic disorders.

Characterization of Severe and Extreme Behavioral Problems in Patients With Alternating Hemiplegia of Childhood.

BACKGROUND: Alternating hemiplegia of childhood often manifests severe or extreme behavioral problems, the nature of which remains to be fully characterized. METHODS: We analyzed 39 consecutive patients with alternating hemiplegia of childhood for occurrence of behavioral problems and categorized those by severity: mild (not requiring intervention), moderate (requiring intervention but no risk), severe (minor risk to self, others, or both), and extreme (major risk). We then analyzed behavioral manifestations, concurrent morbidity, and medication responses in patients with severe or extreme symptoms. RESULTS: Two patients had mild behavioral problems, five moderate, 10 severe, six extreme, and 16 none. Extreme cases exhibited disruptive behaviors escalating to assaults. Triggers, when present, included peer-provocation, low frustration tolerance, limits set by others, and sleep disruption. Reversible psychotic symptoms occurred in two patients: in one triggered by infection and trihexyphenidyl, and in another triggered by sertraline. Of the 16 patients with severe or extreme symptoms, 13 had concurrent neuropsychiatric diagnoses. Occurrence of severe or extreme symptoms did not correlate with age, puberty, severity of intellectual disability, or mutation status (P > 0.05). A multidisciplinary team including mental health professionals comanaged all patients with severe or extreme symptoms with either behavioral therapy, medications, or both. When considering medications prescribed to more than four patients, medicines that demonstrated efficacy or partial efficacy in more than 50% of patients were alpha-adrenergic agonists and selective-serotonin-reuptake-inhibitors. CONCLUSIONS: Patients with alternating hemiplegia of childhood (41%) often experience severe or extreme behavioral problems and, rarely, medication-triggered psychotic symptoms. These observations are consistent with current understanding of underlying alternating hemiplegia of childhood brain pathophysiology. Increasing awareness of these behavioral problems facilitates alternating hemiplegia of childhood management and anticipatory guidance.

Alternating Hemiplegia of Childhood: gastrointestinal manifestations and correlation with neurological impairments.

BACKGROUND: Alternating Hemiplegia of Childhood (AHC) is caused by mutations of the ATP1A3 gene which is expressed in brain areas that include structures controling autonomic, gastrointestinal, gut motility and GABAergic functions. We aimed to investigate, in a cohort of 44 consecutive AHC patients, two hypotheses: 1) AHC patients frequently manifest gastrointestinal, particularly motility, problems. 2) These problems are often severe and their severity correlates with neurological impairments. RESULTS: 41/44 (93%) exhibited gastrointestinal symptoms requiring medical attention. For these 41 patients, symptoms included constipation (66%), swallowing problems (63%), vomiting (63%), anorexia (46%), diarrhea (44%), nausea (37%), and abdominal pain (22%). Symptoms indicative of dysmotility occurred in 33 (80%). The most common diagnoses were oropharyngeal dysphagia (63%) and gastroesophageal reflux (63%). 16 (39%) required gastrostomy and two fundoplication. Severity of gastrointestinal symptoms correlated with non-paroxysmal neurological disability index, Gross Motor Function Classification System scores, and with the presence/absence of non-gastrointestinal autonomic dysfunction (p = 0.031, 0.043, Spearman correlations and 0.0166 Cramer's V, respectively) but not with the paroxysmal disability index (p = 0.408). CONCLUSIONS: Most AHC patients have gastrointestinal problems. These are usually severe, most commonly are indicative of dysmotility, often require surgical therapies, and their severity correlates with that of non-paroxysmal CNS manifestations. Our findings should help in management-anticipatory guidance of AHC patients. Furthermore, they are consistent with current understandings of the pathophysiology of AHC and of gastrointestinal dysmotility, both of which involve autonomic and GABAergic dysfunction.

Magnetic resonance imaging volumetric analysis in patients with Alternating hemiplegia of childhood: A pilot study.

Quantitative MRI is increasingly being used as a biomarker in neurological disorders. Cerebellar atrophy occurs in some Alternating Hemiplegia of Childhood (AHC) patients. However, it is not known if cerebellar atrophy can be a potential biomarker in AHC or if quantitative MRI is a reliable method to address this question. Here we determine the reproducibility of an MRI-volumetrics method to investigate brain volumes in AHC and apply it to a population of 14 consecutive AHC patients (ages 4-11 years). We studied method reproducibility in the first 11 patients and then performed correlation of cerebellar volumes, relative to published normal population means, with age in all 14. We used FreeSurfer 6.0.0 to automatically segment MRI images, then performed manual resegmentation correction by two different observers. No significant differences were observed in any of ten brain regions between the two reviewers: p > .591 and interclass Correlation Coefficient (ICC) ≥0.975 in all comparisons. Additionally, there were no significant differences between the means of the two reviewers and the automatic segmentation values: p ≥ .106 and ICC ≥0.994 in all comparisons. We found a negative correlation between cerebellar volume and age (R = -0.631, p = .037), even though only one patient showed any cerebellar atrophy upon formal readings of the MRIs by neuroradiology. Sample size did not allow us to rule out potential confounding variables. Thus, findings from this cross-sectional study should be considered as exploratory. Our study supports the prospective investigation of quantitative MRI-volumetrics of the cerebellum as a potential biomarker in AHC.

The epileptology of alternating hemiplegia of childhood.

OBJECTIVE: To report our experience and investigate 5 original hypotheses: (1) multiple types of epileptic seizures occur in alternating hemiplegia of childhood (AHC), and these can be the initial presentation; (2) epileptiform abnormalities often appear well after clinical seizures; (3) nonepileptic reduced awareness spells (RAS) occur frequently; (4) epilepsy is commonly drug resistant but may respond to vagal nerve stimulation (VNS); and (5) status epilepticus (SE) is common and is usually refractory and recurrent. METHODS: We analyzed a cohort of 51 consecutive patients with AHC. RESULTS: Thirty-two of 51 patients had epilepsy: 18 focal seizures, frontal more frequently than temporal, and then posterior. Eleven had primary generalized seizures (tonic-clonic, myoclonic, and/or absence). Epileptic seizures preceded other AHC paroxysmal events in 8 (lag 5.63 ± 6.55 months; p = 0.0365). In 7 of 32, initial EEGs were normal, with the first epileptiform EEG lagging behind by 3.53 ± 4.65 years (p = 0.0484). RAS occurred equally in patients with epilepsy (16 of 32) and patients without epilepsy (10 of 19, p = 1.0). Twenty-eight patients had video-EEG; captured RAS showed no concomitant EEG changes. Nineteen patients (59%) were drug resistant. VNS resulted in >50% reduction in seizures in 5 of 6 (p < 0.04). Twelve patients (38%) had SE (9 of 12 multiple episodes), refractory/superrefractory in all (p < 0.001), and 4 of 12 had regression after SE. CONCLUSIONS: Epilepsy in AHC can be focal or generalized. Epileptic seizures may be the first paroxysmal symptom. EEG may become epileptiform only on follow-up. Epilepsy, although frequently drug resistant, can respond to VNS. RAS are frequent and nonepileptic. SE often recurs and is usually refractory/superrefractory. Our observations are consistent with current data on AHC-ATP1A3 pathophysiology.