Warren Lo

A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures

BACKGROUND Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. METHODS We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at a dosage varying from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses -- one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. RESULTS Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. CONCLUSIONS Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures.

Adeno-Associated Virus-Mediated Gene Transfer to the Brain: Duration and Modulation of Expression

Adeno-associated virus (AAV) is a promising vector for central nervous system (CNS) gene transfer, but a number of issues must be addressed if AAV is to be used for widespread delivery throughout the CNS. Our aim was to test the effect of dose, route of delivery, and hydroxyurea treatment on brain expression of beta-galactosidase activity after cerebral inoculation with an rAAV-lacZ vector (rAAV-beta-gal). We also wished to test whether an immune response appeared against the vector and the transgene product. We found in BALB/c mice that beta-Gal expression increased during the first 2 months after inoculation, then decreased slightly by 4 months, and continued out to 6, 12, and 15 months in single animals. Cerebral injection produced localized beta-Gal expression that did not diffuse to other regions despite a fivefold increase in injection volume. Intraventricular injection resulted in negligible transduction. Antibodies to AAV capsid protein and beta-Gal appeared at low levels at 2 and 4 months, but correlated poorly with beta-Gal expression and did not prevent readministration of rAAV-beta-gal. Hydroxyurea treatment did not result in increased transduction in vivo. We conclude that our study confirms rAAV vectors as having considerable potential for CNS gene transfer; however, several important problems must be addressed if this vector system is to be used for long-term transduction of the entire brain. Sustained, regulatable expression will be needed if rAAV is to be used in the treatment of chronic CNS disease. The difficulty in delivering AAV to diverse regions of the brain is an important problem that must be overcome if these vectors are to be used for anything beyond localized transduction.

Recombinant Adeno-Associated Virus-Mediated Correction of Lysosomal Storage within the Central Nervous System of the Adult Mucopolysaccharidosis Type VII Mouse

The central nervous system (CNS) is a predominant site of involvement in several lysosomal storage diseases (LSDs); and for many patients, these diseases are diagnosed only after the onset of symptoms related to the progressive accumulation of macromolecules within lysosomes. The mucopolysaccharidosis type VII (MPS VII) mice are deficient for the lysosomal enzyme beta-glucuronidase and, by early adulthood, develop a significant degree of glycosaminoglycan storage within neuronal, glial, and leptomeningeal cells. Using this animal model, we investigated whether gene transfer mediated by a recombinant adeno-associated virus (rAAV) vector is capable of reversing the progression of storage lesions within the CNS. Adult MPS VII mice received intracerebral injections of 4 X 10(7) infectious units of a rAAV vector carrying the murine beta-glucuronidase (gus-s(a)) cDNA under the transcriptional direction of the cytomegalovirus immediate-early promoter and enhancer. By 1 month after vector administration, transgene-derived beta-glucuronidase was present surrounding the injection site. Enzyme levels were between 50 and 240% of that found in wild-type mice. This level of beta-glucuronidase activity was sufficient to reduce the degree of lysosomal storage. Moreover, the reduction in storage was maintained for at least 3 months post-rAAV administration. These data demonstrate that rAAV vectors can transduce the diseased CNS of MPS VII mice and mediate levels of transgene expression necessary for a therapeutic response. Thus, rAAV vectors are potential tools in the treatment of the mucopolysaccharidoses and other lysosomal storage diseases.

Gabapentin associated with aggressive behavior in pediatric patients with seizures

Gabapentin (GBP) is a new antiepileptic drug (AED) approved for adjunctive treatment of complex partial seizures with or without seizures secondarily generalization in adults. We report 2 children who received GBP for intractable seizures and who developed intolerable aggressive behavior requiring dose reduction or drug discontinuation. Behavioral changes should be recognized as a possible side effect of GBP, especially in mentally retarded children.

Towards a Consensus-Based Classification of Childhood Arterial Ischemic Stroke

Background and Purpose— The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. Methods— Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinicians current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted &kgr;-statistic. Results— In Group 1 (with training), IRR was improved using CASCADE criteria (&kgr;=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (&kgr;=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (&kgr;=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (&kgr;=0.23, 95% CI=[0.03, 0.36]). Conclusions— A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

The Cost of Pediatric Stroke Care and Rehabilitation

Background and Purpose— There is little data regarding the cost of pediatric stroke care or the elements that contribute to these costs. We examined costs for poststroke care during the first year after diagnosis and compared these costs with the volume of the cerebral infarct and the level of neurological and functional outcome. Methods— We identified 39 children who sustained nontraumatic ischemic or hemorrhagic strokes and confirmed the diagnoses by review of medical and radiology records. Medical costs were tabulated for the year after the diagnosis of stroke. Cerebral infarct volumes were measured from MRI or CT scans. Neurological outcome was assessed by telephone with a modification of the Pediatric Stroke Outcome Measure (PSOM), and functional outcomes were assessed with a standardized quality-of-life measure. Results— The median cost for poststroke care during the year after diagnosis was

Suppression of experimental autoimmune encephalomyelitis by restraint stress: Sex differences

42 338 for the entire group. The cost for stroke care was higher for hemorrhagic stroke than for ischemic stroke. Cost had a significant positive correlation with neurological impairment. The modified PSOM score positively correlated with impairments of physical, emotional, social, and school function. Conclusions— The cost of stroke care may be one measure of stroke severity, with more extensive strokes resulting in greater medical costs. In addition, stroke appears to impair childrens social ability along with their neurological function.

Arteriopathy Diagnosis in Childhood Arterial Ischemic Stroke Results of the Vascular Effects of Infection in Pediatric Stroke Study

We have recently reported that female Lewis rats exhibit significantly higher basal circadian levels of corticosterone (Cort) than male Lewis rats. The studies reported here were designed to explore whether male and female Lewis rats demonstrate a differential suppression of experimental autoimmune encephalomyelitis (EAE) following exposure to an identical regimen of repetitive restraint stress. Rats were restrained for 1 or 9 h/day beginning 5 days before myelin basic protein (MBP) challenge and extending through the recovery period (18 days post challenge). Both clinical signs and histopathological changes of EAE were more significantly suppressed in 9-h-stressed females relative to male Lewis rats. Investigation of the mechanism underlying the stress-induced suppression of EAE revealed that restraint stress did not alter the clinical course of EAE in rats challenged with MBP 68-88 encephalitogenic peptide, suggesting that restraint stress may affect processing and/or presentation of the MBP molecule. Stressed rats exhibited decreased interleukin-2 and interferon gamma production, and the frequency of MBP-reactive lymphocytes was reduced in comparison to non-stressed rats. Finally, repetitive restraint stress had no effect on blood-spinal cord permeability during EAE. The results presented here underscore the importance of such experimental variables as sex, strain, time of day, and the kinetics of immune response development.

Intracranial Hemorrhage in Children: An Evolving Spectrum

Background and Purpose Although arteriopathies are the most common cause of childhood arterial ischemic stroke (AIS), and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with AIS.Background and Purpose— Although arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke. Methods— Vascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step. Results— Cases were aged median 7.6 years (interquartile range, 2.8–14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (&kgr;=0.77, 0.81, and 0.78). Conclusions— Clinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.

Cognitive Outcomes Following Arterial Ischemic Stroke in Infants and Children

BACKGROUND Nontraumatic intracranial hemorrhages (ICHs) are uncommon in children, but are important causes of death and injury. OBJECTIVES To determine whether the risk factors for ICH have changed compared with those in earlier published series and to estimate the residual deficits in the survivors. DESIGN, SETTING, AND PATIENTS We performed a retrospective review of patients admitted to a single tertiary care, academic pediatric hospital from January 1, 2000, through May 31, 2007. Records were retrieved if the diagnostic codes from the International Classification of Diseases, Ninth Revision, were pertinent to ICHs. We searched reports from computed tomograms and magnetic resonance images of the brain for terms pertaining to ICH. MAIN OUTCOME MEASURES Risk factors and functional outcome. Secondary measures were hemorrhage type and clinical presentation. RESULTS We identified 85 children who had nontraumatic ICH. There were 10 subarachnoid, 61 intracerebral, and 14 subdural hemorrhages. Intracranial vascular anomalies were the most frequent risk factor, followed by congenital heart disease and brain tumors. Arteriovenous malformations did not account for as large a percentage as in previous studies. Twenty-nine children died. Of the 48 survivors for whom follow-up information was available, 26 had no reported deficits and 22 had deficits ranging from mild to severe. CONCLUSIONS In this series, brain tumors and congenital heart disease accounted for a greater proportion of ICHs than in previous studies. The mortality due to ICH remains high but may be related as much to the severity of the underlying illnesses as to the hemorrhage itself. We found significant long-term morbidity, but more than half of the survivors for whom follow-up data were available had no detectable deficits. A long-term outcome study of pediatric ICH is needed.