Kanwaljit Singh

Sulforaphane treatment of autism spectrum disorder (ASD)

Significance Autism spectrum disorder (ASD), encompassing impaired communication and social interaction, and repetitive stereotypic behavior and language, affects 1–2% of predominantly male individuals and is an enormous medical and economic problem for which there is no documented, mechanism-based treatment. In a placebo-controlled, randomized, double-blind clinical trial, daily oral administration for 18 wk of the phytochemical sulforaphane (derived from broccoli sprouts) to 29 young men with ASD substantially (and reversibly) improved behavior compared with 15 placebo recipients. Behavior was quantified by both parents/caregivers and physicians by three widely accepted measures. Sulforaphane, which showed negligible toxicity, was selected because it upregulates genes that protect aerobic cells against oxidative stress, inflammation, and DNA-damage, all of which are prominent and possibly mechanistic characteristics of ASD. Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13–27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)—derived from broccoli sprout extracts—or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50–150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015–0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

Severity of manifestations in tuberous sclerosis complex in relation to genotype

Patients with tuberous sclerosis complex (TSC) commonly present with significant neurologic deficits, including seizures, autism, and intellectual disability. Previous evidence suggests that the TSC2 mutation genotype may be associated with a more severe disease phenotype. This study evaluates the association of the TSC1 and TSC2 genotype with patient and disease characteristics in a retrospective review of a large TSC Natural History Database consisting of 919 patients with TSC.

Cardiopulmonary complications during pediatric seizures: A prelude to understanding SUDEP

Sudden unexpected death in epilepsy (SUDEP) is an important, unexplained cause of death in epilepsy. Role of cardiopulmonary abnormalities in the pathophysiology of SUDEP is unclear in the pediatric population. Our objective was to assess cardiopulmonary abnormalities during epileptic seizures in children, with the long‐term goal of identifying potential mechanisms of SUDEP.

Comparison of cardiorespiratory and EEG abnormalities with seizures in adults and children.

Cardiopulmonary dysfunction and postictal generalized EEG suppression (PGES) are proposed as possible risk factors for the occurrence of SUDEP. The evolution of cardiorespiratory abnormalities with seizures has not been systematically studied for any age-related findings. Additionally, not many studies have looked into the possible effect of age-related brain maturation on PGES. The purpose of this study was to compare these SUDEP risk factors in adults versus children. We prospectively recorded cardiopulmonary abnormalities during seizures using pulse oximetry, EKG, and respiratory inductance plethysmography. Linear and logistic regression models adjusting for multiple seizures in a single patient were used to compare the cardiorespiratory and EEG findings between adults and children. We recorded 101 seizures in 26 children and 55 seizures in 22 adults. Ictal central apnea and bradycardia occurred more often in children than in adults (p=0.02 and p=0.008, respectively), while ictal tachycardia occurred more often in adults (p=0.001) than in children. Postictal generalized EEG suppression of longer duration occurred more often in adults (p=0.003) than in children. Minimum O2 saturation and seizure duration/generalization/lateralization did not significantly differ between adults and children (p>0.1). Children had more frontal lobe seizures, and adults had more temporal lobe seizures recorded (p=0.01). There may be an age-related effect on cardiorespiratory and EEG abnormalities associated with seizures, with higher rates of apnea and bradycardia in children and a much higher prevalence of PGES of longer duration in adults. This may indicate why, despite lower rates of cardiopulmonary dysfunction, adults die more frequently from SUDEP than children.

Sleep in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder

Sleep problems are common in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Sleep problems in these disorders may not only worsen daytime behaviors and core symptoms of ASD and ADHD but also contribute to parental stress levels. Therefore, the presence of sleep problems in ASD and ADHD requires prompt attention and management. This article is presented in 2 sections, one each for ASD and ADHD. First, a detailed literature review about the burden and prevalence of different types of sleep disorders is presented, followed by the pathophysiology and etiology of the sleep problems and evaluation and management of sleep disorders in ASD and ADHD.

Safety and efficacy of perampanel in children and adults with various epilepsy syndromes: A single-center postmarketing study

INTRODUCTION Perampanel is an AMPA receptor antagonist recently approved for the treatment of partial and generalized epilepsies with tonic-clonic seizures as an add-on therapy. METHODS This single-center postmarketing study retrospectively evaluated the efficacy of perampanel in patients with partial onset and other seizure types, with a special emphasis on its efficacy, safety, and tolerability. RESULTS Review of medical records revealed that adequate data were available on 101 patients taking perampanel. Fifty-seven patients were female. Sixteen patients were of pediatric age range. The average dose of perampanel was 6.5mg, and average treatment duration was 8.2months. After treatment, median seizure frequency reduction was 50% overall, 50% in children, and 33% in adults; 44% in primary generalized, 38% in secondarily generalized, and 33% in partial seizures. Responder rate (50% seizure frequency reduction) was 51% overall, 63% in children, and 49% in adults; 60% in partial seizures, 43% in secondarily generalized tonic-clonic seizures, 53% in primary generalized tonic-clonic seizures, and 56% in other seizure types. Seizure freedom was attained in 6% of cases. Most common adverse events were sleepiness/fatigue (35%), behavioral problems (30%), and dizziness (22%). Adverse events were correlated with dosage. Average dose was 7.3mg in patients with adverse events vs. 5.5mg in those without adverse events. Patients who developed fatigue, cognitive decline, headaches, and weight gain were more likely to discontinue perampanel than those patients who experienced coordination issues and behavioral problems. CONCLUSIONS These findings suggest that perampanel is safe, well-tolerated, and effective in treatment of various types of adult and pediatric epilepsy syndromes. Fatigue, cognitive decline, headache and weight gain were the main causes of perampanel discontinuation.

Obstructive sleep apnea in infancy: A 7-year experience at a pediatric sleep center

To investigate the common indications for polysomnogram (PSG) associated co‐morbid conditions, evaluation strategies, treatment options, and outcomes in a series of infants diagnosed with obstructive sleep apnea (OSA) by a PSG.

Risk factors for recurrence and prognosis of low-grade endometrial adenocarcinoma; Vaginal versus other sites

Endometrial adenocarcinoma is the most common gynecologic cancer in the United States. The prognosis is generally favorable, however, a significant number of patients do develop local or distant recurrence. The most common site of recurrence is vaginal. Our aim was to better characterize patients with vaginal recurrence of low-grade endometrioid adenocarcinoma with respect to associated tumor parameters and clinical outcome. We compiled 255 cases of low-grade (FIGO Grade I or II) endometrioid adenocarcinoma on hysterectomy specimens with lymph node dissection. A total of 113 cases with positive lymph nodes or recurrent disease were included in our study group. Seventy-three cases (13 Grade 1, 60 Grade 2) developed extravaginal recurrence and 40 cases (7 Grade 1, 33 Grade 2) developed vaginal recurrence. We evaluated numerous tumor parameters including: percentage myoinvasion, presence of microcystic, elongated, and fragmented pattern of myoinvasion, lymphovascular space invasion, and cervical involvement. Clinical follow-up showed that 30% (34/113) of all patients with recurrent disease died as a result of their disease during our follow-up period, including 31 (42.5%) with extravaginal recurrence and 3 (7.5%) with primary vaginal recurrence (P=0.001). The 3 patients with vaginal recurrence developed subsequent extravaginal recurrence before death. Vaginal recurrence patients show increased cervical involvement by tumor, but lack other risk factors associated with recurrent disease at other sites. There were no deaths among patients with isolated vaginal recurrence, suggesting that vaginal recurrence is not a marker of aggressive tumor biology.

Sleep Disorders Associated With Traumatic Brain Injury—A Review

BACKGROUND Sleep disorders are common are common following traumatic brain injury. METHODS In this article we review the spectrum and proposed mechanisms of traumatic brain injury associated sleep disorders and discuss the clinical approach to diagnosis and management of these disorders. RESULT Disordered sleep and wakefulness after traumatic brain injury is common. Sleep disruption contributes to morbidity, such as the development of neurocognitive and neurobehavioral deficits, and prolongs the recovery phase after injury. Early recognition and correction of these problems may limit the secondary effects of traumatic brain injury and improve patient outcomes. CONCLUSION Evaluating sleep disorders in traumatic brain injury should be an important component of post-traumatic brain injury assessment and management.

Prevalence of pediatric periodic leg movements of sleep after initiation of PAP therapy

Positive‐airway‐pressure (PAP) is a treatment for obstructive‐sleep‐apnea (OSA). In adults, initiation of PAP‐therapy may unmask periodic‐limb movements‐of‐sleep (PLMS). We present a series of children in whom PLMS was aggravated or induced following initiation of PAP therapy.