Sudha Kilaru Kessler

Differences in the experience of active and sham transcranial direct current stimulation

BACKGROUND A limited number of studies have shown that modulation of cortical excitability using transcranial direct current stimulation (tDCS) is safe and tolerable. Few have directly evaluated whether sham and active stimulation are indistinguishable. OBJECTIVE We aimed to demonstrate tDCS safety and tolerability in a large cohort, and to compare the occurrence and severity of side effects between sham and active stimulation sessions. METHODS One hundred thirty-one healthy subjects undergoing 277 tDCS sessions rated on a 1 to 5 scale the perception of side effects during and after stimulation. Proportions of active and sham sessions associated with side effects were compared using Fisher exact test, and distributions of severity ratings were compared using the Kruskal-Wallis test. RESULTS No serious adverse effects occurred. Side effects most commonly reported were tingling (76%), itching (68%), burning (54%), and pain (25%). Side effect severity was mild, with fewer than 2% of responses indicating a severity > 3 on all questions except tingling (15%), itching (20%), burning (7%), pain (5%), and fatigue (3%) during stimulation. Rates of sensory side effects were statistically significantly higher in active stimulation sessions compared with sham sessions. No other stimulation parameters had a statistically significant impact on side effect occurrence. CONCLUSIONS TDCS is a safe well-tolerated technique with no evidence of risk for serious adverse effects. Sensory side effects are common, but the severity is typically low. Because sensory side effects are more frequent and more severe in active compared with sham tDCS, the current method of sham stimulation may not be an adequate control condition for some studies.

Dosage Considerations for Transcranial Direct Current Stimulation in Children: A Computational Modeling Study

Transcranial direct current stimulation (tDCS) is being widely investigated in adults as a therapeutic modality for brain disorders involving abnormal cortical excitability or disordered network activity. Interest is also growing in studying tDCS in children. Limited empirical studies in children suggest that tDCS is well tolerated and may have a similar safety profile as in adults. However, in electrotherapy as in pharmacotherapy, dose selection in children requires special attention, and simple extrapolation from adult studies may be inadequate. Critical aspects of dose adjustment include 1) differences in neurophysiology and disease, and 2) variation in brain electric fields for a specified dose due to gross anatomical differences between children and adults. In this study, we used high-resolution MRI derived finite element modeling simulations of two healthy children, ages 8 years and 12 years, and three healthy adults with varying head size to compare differences in electric field intensity and distribution. Multiple conventional and high-definition tDCS montages were tested. Our results suggest that on average, children will be exposed to higher peak electrical fields for a given applied current intensity than adults, but there is likely to be overlap between adults with smaller head size and children. In addition, exposure is montage specific. Variations in peak electrical fields were seen between the two pediatric models, despite comparable head size, suggesting that the relationship between neuroanatomic factors and bioavailable current dose is not trivial. In conclusion, caution is advised in using higher tDCS doses in children until 1) further modeling studies in a larger group shed light on the range of exposure possible by applied dose and age and 2) further studies correlate bioavailable dose estimates from modeling studies with empirically tested physiologic effects, such as modulation of motor evoked potentials after stimulation.

Transcranial direct current stimulation in pediatric brain: A computational modeling study

Transcranial direct current stimulation (tDCS) is a method of non-invasive brain stimulation which uses weak electric currents applied on the scalp to modulate activity of underlying brain tissue. In addition to being used as a tool for cognitive neuroscience investigations, tDCS has generated considerable interest for use as a therapeutic modality for neurologic disorders. Though the safety and tolerability of tDCS in adults is well-established, there is little information on the safety of tDCS in children. Because there are differences between children and adults in several key parameters (such as skull thickness and cerebrospinal fluid volume) which affect current flow through the brain, special consideration should be given to the stimulation parameters which are used in a pediatric study population. In this study we present cortical electrical field maps at different stimulation intensities and electrode configurations using a high-resolution-MRI derived finite element model of a typically developing, anatomically normal 12 year old child. The peak electrical fields for a given stimulus intensity in the adolescent brain were twice as high as in the adult brain for conventional tDCS and nearly four times as high for a 4×1 High-Definition tDCS electrode configuration. These data suggest that acceptable tDCS stimulation parameters may be different in children compared to adults, and that further modeling studies are needed to help guide decisions about applied current intensity.

Cranial Irradiation Increases Risk of Stroke in Pediatric Brain Tumor Survivors

Background and Purpose— The purposes of this study were to determine the incidence of neurovascular events as late complications in pediatric patients with brain tumor and to evaluate radiation as a risk factor. Methods— Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment January 1, 1993, to December 31, 2002, and at least 2 visits with neuro-oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack. Results— Of 431 subjects, 14 had 19 events of stroke or transient ischemic attack over a median follow-up of 6.3 years. The incidence rate was 548/100 000 person-years. Overall, 61.5% of subjects received radiation, including 13 of 14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/transient ischemic attack hazard ratio for any brain irradiation was 8.0 (95% CI, 1.05–62; P=0.045); for the circle of Willis, radiation was 9.0 (95% CI, 1.2–70; P=0.035); and for focal noncircle of Willis, radiation was 3.4 (95% CI, 0.21–55; P=0.38). Conclusions— The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.

Pediatric ICU EEG monitoring: Current resources and practice in the United States and Canada

Purpose: To describe current continuous EEG monitoring (cEEG) utilization in critically ill children. Methods: An online survey of pediatric neurologists from 50 US and 11 Canadian institutions was conducted in August 2011. Results: Responses were received from 58 of 61 (95%) surveyed institutions. Common cEEG indications are altered mental status after a seizure or status epilepticus (97%), altered mental status of unknown etiology (88%), or altered mental status with an acute primary neurologic condition (88%). The median number of patients undergoing cEEG per month per center increased from August 2010 to August 2011 (6 to 10 per month in the United States; 2 to 3 per month in Canada). Few institutions have clinical pathways addressing cEEG use (31%). Physicians most commonly review cEEG twice per day (37%). There is variability regarding which services can order cEEG, the degree of neurology involvement, technologist availability, and whether technologists perform cEEG screening. Conclusions: Among the surveyed institutions, which included primarily large academic centers, cEEG use in pediatric intensive care units is increasing and is often considered indicated for children with altered mental status at risk for nonconvulsive seizures. However, there remains substantial variability in cEEG access and utilization among institutions.

Seizures as a presenting symptom of acute arterial ischemic stroke in childhood

OBJECTIVES To define the incidence of seizures as a presenting symptom of acute arterial ischemic stroke (AIS) in children and to determine whether younger age, infarct location, or AIS etiology were risk factors for seizure at AIS presentation. STUDY DESIGN Children aged 2 months to 18 years presenting with AIS between January 2005 and December 2008 were identified from a single center prospective pediatric stroke registry. Clinical data were abstracted, and a neuroradiologist reviewed imaging studies. RESULTS Among the 60 children who met our inclusion criteria, 13 experienced seizure at stroke presentation (22%). Median age was significantly younger in children who presented with seizures than in those who did not (1.1 years vs 10 years; P = .0009). Seizures were accompanied by hemiparesis in all patients. Three of 4 children with clinically overt seizures at presentation also had nonconvulsive seizures on continuous electroencephalography monitoring. CONCLUSIONS Twenty-two percent of children with acute AIS present with seizures. Seizures were always accompanied by focal neurologic deficits. Younger age was a risk factor for seizures at presentation. Seizure at presentation was not associated with infarct location or etiology. Nonconvulsive seizures may occur during the acute period.

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. METHODS In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. FINDINGS Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. INTERPRETATION Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. FUNDING GW Pharmaceuticals.

Risk of Later Seizure After Perinatal Arterial Ischemic Stroke: A Prospective Cohort Study

OBJECTIVE: Although acute seizures are common among neonates with arterial ischemic stroke (AIS), the incidence of subsequent seizures is unknown. The goals of this study were to determine the incidence of seizures following hospital discharge after perinatal acute AIS, and to assess lesion characteristics associated with later seizure occurrence. METHODS: Neonates with confirmed acute AIS on MRI were identified through a prospective stroke registry. Clinic visits and telephone follow-up identified occurrence of seizures after hospital discharge. MRI scans were graded for size and characteristics of infarct, and associations with seizures after stroke were analyzed. RESULTS: At a mean (SD) follow-up of 31.3 (16.1) months, 11 of 46 (23.9%) patients with perinatal AIS had at least 1 seizure. Five patients had a single episode of seizure, and 6 developed epilepsy. The Kaplan-Meier probability of remaining seizure-free at 3 years was 73%. Stroke size on MRI was significantly associated with development of later seizures, with an incidence rate of later seizures 6.2 times higher among those with larger stroke size. CONCLUSIONS: Seizures occurred in <25% of patients during initial follow-up after perinatal AIS. Of those with seizures, nearly half had a single episode of seizure and not early epilepsy. Larger stroke size was associated with higher risk of seizure. These data suggest that prolonged treatment with anticonvulsant agents may not be indicated for seizure prophylaxis after perinatal AIS. These findings may help guide clinicians in counseling families and could form the basis for much-needed future research in this area.

Outcome prediction by motor and pupillary responses in children treated with therapeutic hypothermia after cardiac arrest

Objective: Clinical neurologic signs considered predictive of adverse outcome after pediatric cardiac arrest may have a different prognostic value in the setting of therapeutic hypothermia. We aimed to determine the prognostic value of motor and pupillary responses in children treated with therapeutic hypothermia after cardiac arrest. Design: Prospective cohort study. Setting: Pediatric intensive care unit in tertiary care hospital. Patients: Children treated with therapeutic hypothermia after cardiac arrest. Measurements and Main Results: Thirty-five children treated with therapeutic hypothermia after cardiac arrest were prospectively enrolled. Examinations were performed by emergency medicine physicians and intensive care unit bedside nurses. Examinations were performed after resuscitation, 1 hr after achievement of hypothermia, during the last hour of hypothermia, 1 hr after achievement of normothermia, after 24 hrs of normothermia, and after 72 hrs of normothermia. The primary outcome was unfavorable outcome at intensive care unit discharge, defined as a pediatric cerebral performance category score of 4–6 at hospital discharge. The secondary outcome was death (pediatric cerebral performance category = 6). The associations between exam responses and unfavorable outcomes (as both pediatric cerebral performance category 4, 5, 6 and pediatric cerebral performance category 6) are presented as positive predictive values, for both all subjects and subjects not receiving paralytics. Statistical significance for these comparisons was determined using Fishers exact test. At all examination times and examination categories, positive predictive values were higher for the unfavorable outcome pediatric cerebral performance category 4, 5, 6 than the pediatric cerebral performance category 6. By normothermia hour 24, absent motor and pupil responses were highly predictive of unfavorable outcome (pediatric cerebral performance category 4, 5, 6) (positive predictive value 100% and p < .03 for all categories), while at earlier times the predictive value was lower. Conclusions: Absent motor and pupil responses are more predictive of unfavorable outcome when defined more broadly than when defined as only death. Absent motor and pupil responses during hypothermia and soon after return of spontaneous circulation were not predictive of unfavorable outcome while absent motor and pupil responses once normothermic were predictive of unfavorable short-term outcome. Further study is needed using more robust short-term and long-term outcome measures.

16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort.

Chromosome 16p11.2 deletions and duplications are among the most frequent genetic etiologies of autism spectrum disorder (ASD) and other neurodevelopmental disorders, but detailed descriptions of their neurologic phenotypes have not yet been completed. We utilized standardized examination and history methods to characterize a neurologic phenotype in 136 carriers of 16p11.2 deletion and 110 carriers of 16p11.2 duplication—the largest cohort to date of uniformly and comprehensively characterized individuals with the same 16p copy number variants (CNVs). The 16p11.2 deletion neurologic phenotype is characterized by highly prevalent speech articulation abnormalities, limb and trunk hypotonia with hyporeflexia, abnormalities of agility, sacral dimples, seizures/epilepsy, large head size/macrocephaly, and Chiari I/cerebellar tonsillar ectopia. Speech articulation abnormalities, hypotonia, abnormal agility, sacral dimples, and seizures/epilepsy are also seen in duplication carriers, along with more prominent hyperreflexia; less, though still prevalent, hyporeflexia; highly prevalent action tremor; small head size/microcephaly; and cerebral white matter/corpus callosum abnormalities and ventricular enlargement. The neurologic phenotypes of these reciprocal 16p11.2 CNVs include both shared and distinct features. Reciprocal phenotypic characteristics of predominant hypo‐ versus hyperreflexia and macro‐ versus microcephaly may reflect opposite neurobiological abnormalities with converging effects causing the functional impairments shared between 16p11.2 deletion and duplication carriers (i.e., abnormal motor agility and articulation). While the phenotypes exhibit overlap with other genetically‐caused neurodevelopmental disorders, clinicians should be aware of the more striking features—such as the speech and motor impairments, growth abnormalities, tremor, and sacral dimples—when evaluating individuals with developmental delay, intellectual disability, ASD, and/or language disorders.