Limitations to plasticity of language network reorganization in localization related epilepsy.

Neural networks for processing language often are reorganized in patients with epilepsy. However, the extent and location of within and between hemisphere re-organization are not established. We studied 45 patients, all with a left hemisphere seizure focus (mean age 22.8, seizure onset 13.3), and 19 normal controls (mean age 24.8) with an fMRI word definition language paradigm to assess the location of language processing regions. Individual patient SPM maps were compared to the normal group in a voxel-wise comparison; a voxel was considered to be significant if its z-value exceeded mid R:2mid R:. Subsequently, we used principal component analysis with hierarchical clustering of variance patterns from individual difference maps to identify four patient sub-groups. One did not differ from normal controls; one had increased left temporal activation on the margin of regions activated in controls; two others had recruitment in right inferior frontal gyrus, middle frontal gyrus and temporal cortex. Right hemisphere activation in these two groups occurred in homologues of left hemisphere regions that sustained task activation. Our study used novel data driven methods to find evidence for constraints on inter-hemispheric reorganization of language in recruitment of right homologues, and, in a subpopulation of patients, evidence for intra-hemispheric reorganization of language limited to the margins of typical left temporal regional activation. These methods may be applied to investigate both normal and pathological variance in other developmental disorders and cognitive domains.

Kindling with rapidly recurring hippocampal seizures.

Bipolar electrodes, stereotactically implanted in the hippocampus of adult rats, were used to deliver 10 s trains of suprathreshold tetanic electrical stimuli every few minutes. As indices of seizure intensity, durations of the afterdischarges triggered by these stimuli were measured, and the accompanying behaviors were scored on a 5-point scale. After 2-3 h, prolonged afterdischarges appeared in conjunction with severe limbic seizures, separated by periods of approximately 60 min. After 3-9 h, the stimulation was withheld until the following day. Upon reinstitution of the stimuli, intense seizures were seen at the onset, and the cycle time between them was shortened. Enhanced responsiveness to a fixed stimulus persisted for several months, the longest period tested. In addition, the enhanced epileptogenicity showed transference and was not stimulus-specific. These studies, using stimuli with low intertrain frequency and short interstimulus intervals, establish a robust and rapidly-developing model of epileptogenesis in the hippocampus that is comparable to traditional kindling.

Seizure control following tumor surgery for childhood cortical low-grade gliomas.

Detailed preoperative electroencephalographic (EEG) studies are now recommended for children with seizures and cortical tumors to define seizure foci prior to surgery. To develop a historical perspective for better evaluation of results from series reporting tumor removal combined with resection of seizure foci, the authors reviewed seizure outcome in 60 children with seizures and low-grade neoplasms treated consecutively since 1981 by surgical resection without concomitant EEG monitoring or electrocortical mapping. Forty-seven of the 60 tumors were totally or near-totally resected; 45 patients were seizure-free and two were significantly improved 1 year following surgery. Of the 50 children in this series with more than five seizures prior to surgery, 36 were seizure-free, two were significantly improved, and 12 were not improved. Factors associated with poor seizure control included a parietal tumor location, a partial tumor resection, and a history of seizures for more than 1 year prior to surgery. The children at highest risk for poor seizure control at 2 years had experienced seizures for more than 1 year prior to surgery and had undergone partial resection of their parietal low-grade glial tumors or gangliogliomas. In contradistinction, the best seizure control was seen in patients with totally resected low-grade gliomas or gangliogliomas who had experienced seizures for less than 1 year (concordance rates for being seizure-free ranged from 78% to 86%). Long-term seizure control remained excellent. These results suggest that seizure control can be obtained 2 years following tumor surgery in the majority of children with presumed tumors after extensive tumor resection without concomitant EEG monitoring or electrocortical mapping.

Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: retrospective study.

This six-center, retrospective study evaluated the effectiveness, tolerability, and safety of vagus nerve stimulation in children. Data were available for 125 patients at baseline, 95 patients at 3 months, 56 patients at 6 months, and 12 patients at 12 months. The typical patient, aged 12 years, had onset of seizures at age 2 years and had tried nine anticonvulsants before implantation. Collected data included preimplant history, seizures, implant, device settings, quality of life, and adverse events. Average seizure reduction was 36.1% at 3 months and 44.7% at 6 months. Common adverse events included voice alteration and coughing during stimulation. Rare adverse events, unique to this age group, included increased drooling and increased hyperactivity. Quality of life improved in alertness, verbal communication, school performance, clustering of seizures, and postictal periods. We concluded that vagus nerve stimulation is an effective treatment for medically refractory epilepsy in children.

Clinical spectrum of secondary parkinsonism in childhood: a reversible disorder.

Parkinsonism is an uncommon movement disorder in childhood. Six unusual cases of acquired parkinsonism in hospitalized children are described. Clinical manifestations included an akinetic-rigid syndrome with and without tremor, the combination of parkinsonism and dystonia, and a parkinsonism-plus syndrome. Altered mental status, mutism, dysphagia, and sialorrhea were frequent associations. Etiologies included hypoxic-ischemic encephalopathy; haloperidol treatment with and without neuroleptic malignant syndrome; toxicity of cytosine arabinoside, cyclophosphamide, amphotericin B, and methotrexate; St. Louis encephalitis and other encephalitides; and a pineal tumor with hydrocephalus. Cranial magnetic resonance imaging results ranged from normal to profound cerebral and cerebellar atrophy with chemotherapeutic toxicity. The illnesses usually were severe enough to require pharmacotherapy. Incorrect diagnoses of depression or catatonia delayed treatment or aggravated the problem. Acute treatment included amantadine, levodopa/carbidopa with or without selegiline, diphenhydramine, or benztropine. The concentration of CSF homovanillic acid was normal in a neuroleptic-associated patient, but the level was low in an encephalitic patient. All patients demonstrated dramatic improvement, including two who were not treated; some had complete resolution of symptoms and none required continued antiparkinsonian drugs despite poor scores on the Unified Parkinson's Disease Rating Scale and the Modified Hoehn and Yahr Rating Scales. The causes of parkinsonism described are more common in a general pediatric hospital than the parkinsonism associated with the popularized Segawa syndrome.

Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome.

OBJECTIVE: To evaluate efficacy and safety of clobazam, a 1,5-benzodiazepine, as adjunctive therapy for Lennox-Gastaut syndrome (LGS). METHODS: Patients aged 2-60 years were randomized to placebo or clobazam 0.25, 0.5, or 1.0 mg/kg/day. Study consisted of 4-week baseline, 3-week titration, and 12-week maintenance phases, followed by a 2- or 3-week taper or continuation in an open-label extension. Primary endpoint was percentage decrease in mean weekly drop seizure rates during maintenance vs baseline phases for modified intention-to-treat (mITT) population. Secondary outcomes included other seizure types, responder rates, and physicians' and caregivers' global assessments. RESULTS: A total of 305 patients were screened, 238 were randomized, and 217 composed the mITT population. Of patients enrolled after a protocol amendment, 125/157 (79.6%) completed. Average weekly drop seizure rates decreased 12.1% for placebo vs 41.2% (p = 0.0120), 49.4% (p = 0.0015), and 68.3% (p < 0.0001) for the clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Responder rates (≥50%) were 31.6% (placebo) vs 43.4% (p = 0.3383), 58.6% (p = 0.0159), and 77.6% (p < 0.0001) for clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Physicians' and caregivers' assessments indicated clobazam significantly improved symptoms. Somnolence, pyrexia, upper respiratory infections, and lethargy were the most frequent adverse events reported for clobazam. CONCLUSIONS: Clobazam significantly decreased weekly drop seizure rates in LGS. No new safety signals were identified. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that clobazam as adjunctive therapy is efficacious, in a dosage-dependent manner, in reducing mean weekly drop seizure rates of patients with LGS over 12 weeks.

Interhemispheric and intrahemispheric language reorganization in complex partial epilepsy.

OBJECTIVE: To investigate interhemispheric and intrahemispheric reorganization in patients with localization-related epilepsy. METHOD: We studied 50 patients with a left hemispheric focus and 20 normal right-handed controls with a 3T echoplanar imaging blood oxygen level dependent functional MRI auditory-based word definition decision task. Data were analyzed using SPM 2. Using region of interest for Broca and Wernicke areas and an asymmetry index (AI), patients were categorized as left language (LL; AI > or = 0.20) or atypical language (AL; AI <0.20) for region. The point maxima activation for normal controls (p <0.05 corrected FDR) was identified in Broca and midtemporal regions and then used as a point of reference for individual point maxima identified at p < 0.001, uncorrected. RESULTS: Patient groups showed increased frequency of having activation in right homologues. Activation in AL groups occurred in homologous right regions; distances for point maxima activation in homologous regions were the same as point maxima distances in normal control activation in left regions. Distances for LL patient in left regions showed a trend for differences for midtemporal gyrus (6 mm posterior, 3 mm superior) but variability around mean difference distance was significant. There was no effect of age at epilepsy onset, duration, or pathology on activation maxima. CONCLUSIONS: Right hemisphere language regions in patients with left hemispheric focus are homologues of left hemisphere Broca and broadly defined Wernicke areas. We found little evidence for intrahemispheric reorganization in patients with left hemisphere epilepsy who remain left language dominant by these methods.

Atypical language in lesional and nonlesional complex partial epilepsy.

OBJECTIVE: We investigated the relationship between partial epilepsy, MRI findings, and atypical language representation. METHODS: A total of 102 patients (4 to 55 years) with left hemisphere epileptogenic zones were evaluated using three fMRI language tasks obtained at 1.5 or 3T with EPI BOLD techniques: verbal fluency, reading comprehension, and auditory comprehension. fMRI maps were visually interpreted at a standard threshold and rated as left or atypical language. RESULTS: Atypical language dominance occurred in 30 patients (29%) and varied with MRI type (p < 0.01). Atypical language representation occurred in 36% (13/36) with normal MRI, 21% (6/29) with mesial temporal sclerosis, 14% (4/28) with focal cortical lesions (dysplasia, tumor, vascular malformation), and all (6/6) with a history of stroke. Multivariate logistic regression analysis found handedness, seizure onset, and MRI type accounted for much of the variance in language activation patterns (chi(2) = 24.09, p < 0.01). Atypical language was more prevalent in patients with early seizure onset (43.2%, p < 0.05) and atypical handedness (60%, p < 0.01). None of the three clinical factors were correlated with each other (p > 0.40). Patients with atypical language had lower verbal abilities (F = 6.96, p = 0.01) and a trend toward lower nonverbal abilities (F = 3.58, p = 0.06). There were no differences in rates of atypical language across time, age groups, or MRI scanner. CONCLUSION: Early seizure onset and atypical handedness, as well as the location and nature of pathologic substrate, are important factors in language reorganization.

Seizure focus affects regional language networks assessed by fMRI.

OBJECTIVE: To investigate the degree of language dominance in patients with left and right hemisphere seizure foci compared to normal volunteers using a fMRI reading comprehension task. METHODS: Fifty patients with complex partial epilepsy, aged 8 to 56 years and 33 normal volunteers, aged 7 to 34 had fMRI (1.5 T) and neuropsychological testing. Participants silently named an object described by a sentence compared to a visual control. Data were analyzed with region of interest (ROI) analysis based on t maps for inferior frontal gyrus (IFG), midfrontal gyrus (MFG), and Wernicke area (WA). Regional asymmetry indices (AIs) were calculated [(L - R)/(L + R)]; AI > 0.20 was deemed left dominant and AI < 0.20 as atypical language. RESULTS: Left hemisphere focus patients had a higher likelihood of atypical language than right hemisphere focus patients (21% vs 0%, chi2 < 0.002). Left hemisphere focus patients, excluding those with atypical language, had lower regional AI in IFG, MFG, and WA than controls. Right hemisphere focus patients were all left language dominant and had a lower AI than controls in WA and MFG, but not for IFG. AI in MFG and WA were similar between left hemisphere focus/left language patients and right hemisphere focus patients. Patients activated more voxels than healthy volunteers. Lower AIs were attributable to greater activation in right homologous regions. Less activation in the right-side WA correlated with better verbal memory performance in right focus/left hemisphere-dominant patients, whereas less strongly lateralized activation in IFG correlated better with Verbal IQ in left focus/left hemisphere-dominant patients. CONCLUSIONS: Patients had lower asymmetry indices than healthy controls, reflecting increased recruitment of homologous right hemisphere areas for language processing. Greater right hemisphere activation may reflect greater cognitive effort in patient populations, the effect of epilepsy, or its treatment. Regional activation patterns reflect adaptive efforts at recruiting more widespread language processing networks that are differentially affected based on hemisphere of seizure focus.

Pediatric congenital bilateral perisylvian syndrome: clinical and MRI features in 12 patients.

In 1926, Foix, Chavany and Marie described an acquired syndrome of fasciopharyngoglossomasticatory diplegia resulting from bilateral infarction of the anterior operculum. Clinical features consisted of facial diplegia, dysarthria, pseudobulbar palsy, mild to severe mental retardation, and seizures. A developmental form, similar in presentation in adults with MRI findings consisting of bilateral perisylvian cortical malformation consistent with polymicrogyria involving the sylvian fissure and opercular cortex, has been recognized; but few pediatric cases of congenital bilateral perisylvian syndrome (CBPS) have been reported. Over the past four years, we have encountered 12 cases of CBPS presenting in childhood. Age ranges were from 1 week to 11 years with a median of 2.25 years; six were less than two years of age. Seven were male and five female. Ten had bilateral perisylvian polymicrogyria on MRI; two had unilateral perisylvian schizencephaly with contralateral perisylvian polymicrogyria. Clinical manifestations included developmental delay in 7; poor palatal function in 5; hypotonia in 4; arthrogryposis in 4; hemiparesis in 3; apnea in 3; paraparesis in 2; micrognathia in 2; pectus excavatum in 2; quadriparesis in 1; and hearing loss in 1. Seizures occurred in seven (58%) and consisted of infantile spasms (n = 1), generalized tonic-clonic (n = 1), complex partial (n = 2), partial motor (n = 2; 1 with secondary generalization), and febrile convulsions (n = 1). CBPS has different manifestations in the pediatric population than in adults. CBPS is more common than previously thought, is recognizable by MRI and should be suspected clinically in any infant or child presenting with oromotor dysfunction/pseudobulbar signs and developmental delay, especially if there are associated congenital malformations. Epilepsy is not a constant feature in the pediatric presentation and is variable in type and severity.

Rapidly progressive posthemorrhagic hydrocephalus. Treatment with external ventricular drainage.

Nineteen premature infants with progressive posthemorrhagic hydrocephalus with increased intracranial pressure were treated with external ventricular drainage. Progression of hydrocephalus was arrested during the drainage period in each patient. Three of the 19 infants required no further therapy. Sixteen had recurrence of progressive ventricular dilatation, and all but one eventually had placement of a ventriculoperitoneal shunt, although under more favorable medical conditions than existed at the time of institution of external ventricular drainage. Three of the 19 infants died of causes unrelated to the external ventricular drainage. Of the 16 survivors, seven infants had a developmental quotient or formal IQ of over 75. Outcome was poorest for those infants with accompanying intracerebral hemorrhage. We consider ventriculostomy to be an effective temporizing measure in small infants with rapidly progressive posthemorrhagic hydrocephalus with increased intracranial pressure in whom ventricular decompression is necessary and placement of a ventriculoperitoneal shunt is not feasible.

Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome.

PURPOSE: Vagus nerve stimulation (VNS) is approved for use for refractory partial seizures. Nevertheless, information regarding VNS therapy for special populations, including Lennox-Gastaut syndrome (LGS) is limited. We discuss the effectiveness, tolerability, and safety of VNS therapy in patients with LGS. METHODS: A six-center, retrospective study evaluated the effectiveness of VNS therapy in patients with LGS at 3 and 6 months and compared preimplant and postimplant seizure frequency. Adverse effects and quality of life (QOL) were included as secondary measures. RESULTS: Fifty patients, median age 13 years, with medically refractory epilepsy, were implanted. Median age at onset of seizures was 1.4 years, and a median of nine anticonvulsants (AEDs) had been tried before implantation. Data-collection forms were designed for retrospectively gathering data on each patient's preimplant history, seizures, implants, device settings, QOL, and adverse events. Median reductions in total seizures were 42% at 1 month, 58.2% at 3 months, and 57.9% at 6 months. The most common adverse events reported were voice alteration and coughing during stimulation. Other uncommon adverse events included increased drooling and behavioral changes. Investigators noted that QOL had improved for some patients in the study. CONCLUSIONS: VNS is an effective treatment for medically refractory epilepsy in LGS. This treatment is well tolerated, safe, and may improve QOL.

Encephalopathy with parkinsonian features in children following bone marrow transplantations and high-dose amphotericin B.

Encephalopathy, leukoencephalopathy, and secondary parkinsonism occurred in 3 children with refractory leukemia undergoing allogenic bone marrow transplantation (BMT) who were treated with high-dose amphotericin B for pulmonary aspergillosis or sinus aspergillosis that did not involve the nervous system. Treatment included high-dose cytosine arabinoside, cyclophosphamide, and total body irradiation prior to the BMT. The children developed a progressively worsening encephalopathy and parkinsonian features, characterized by resting tremor, cogwheel rigidity, and masklike facies. Neuroimaging studies showed cerebellar, cerebral, and basal ganglia atrophy, as well as frontal and temporal lobe white matter involvement. Two of the 3 patients recovered, although 1 has residual intellectual impairment. The third succumbed to non-central nervous system Epstein-Barr virus-lymphoproliferative disease and had autopsy-confirmed leukoenephalopathy.

Disturbances of brain maturation and neurodevelopment during chronic renal failure in infancy.

Fifteen infants with moderate to severe congenital renal disease were prospectively studied by serial renal, neurodevelopmental, neurophysiologic, and anthropometric assessments. The observation period ranged from 3 to 25 months (mean = 10.9). Eight patients maintained a Mental Development Index (MDI) above the 16th percentile (greater than -1 SD) and comprised group 1. Of the remaining seven patients (group 2), three had an MDI less than 16th percentile when first studied and four had serial decreases of the MDI to less than 16th percentile. Although motor development was more delayed in group 2 at study entry, there were no significant changes of motor performance levels for either group during the study period. Group 2 patients had smaller length (p less than 0.05) and head circumference (p less than 0.05) standard deviation scores in comparison with group 1, and they had higher serum creatinine values (mean = 3.8 vs 1.3 mg/dl, respectively; p less than 0.01). By spectral electroencephalography, the expected progressive increase of the frequency of cerebral cortical background activity with age was demonstrated in group 1 but was not seen in group 2 (multivariate analysis of variance p less than 0.03). This increase of faster-frequency activity was primarily manifested in the left cerebral hemisphere of group 1 patients (p less than 0.01), a finding that was also absent in group 2. The frequent occurrence of neurodevelopmental abnormalities in infants with renal failure is possibly a consequence of impaired dominant hemispheric maturation in the first several years of life, which is clinically manifested as deterioration of cognitive function.

Emergency brain computed tomography in children with seizures: who is most likely to benefit?

OBJECTIVE: To determine whether the recently published guidelines on neuroimaging in patients with new-onset seizures are applicable to children. METHODS: We carried out a retrospective analysis of 107 neurologically normal children (excluding children with simple febrile seizures) who had undergone neuroimaging when they presented to the emergency department with a possible "first seizure." RESULTS: Eight of the 107 children had nonepileptic events (gastroesophageal reflux, syncopal event, rigor). Of the remaining 99 children, 49 had provoked seizures (complicated febrile seizure, meningo-encephalitis, toxic or metabolic abnormalities), and 50 had unprovoked seizures. A total of 19 children had brain abnormalities identified on computed tomography (CT) scan; 7 received further investigation or intervention as a result of CT scan findings (2 with tumors, 3 with vascular anomalies, 1 with cysticercosis, and 1 with obstructive hydrocephalus). CT scan abnormalities requiring treatment or monitoring were more frequently seen in children with their first unprovoked seizure (P < .01) and in those children whose seizure onset had been focal or who had focal abnormalities identified on postictal neurologic examination (P < .04). CONCLUSION: In a child, a seizure in the setting of a fever rarely indicates the presence of an unexpected CT scan lesion requiring intervention.

An open-label study of repeated use of diazepam rectal gel (Diastat) for episodes of acute breakthrough seizures and clusters: safety, efficacy, and tolerance. North American Diastat Group.

PURPOSE: To assess safety of diazepam rectal gel (DZPRG) for control of acute seizures in epilepsy patients and to evaluate tolerance with repeated use of DZPRG at intervals of > or =5 days. METHODS: Subjects were persons with epilepsy, age 2 years or older, with seizure clusters or prolonged seizures. Onset of a treatable episode was defined; caregivers were trained to administer DZPRG and to monitor respiration, seizures, and adverse effects (AEs). DZPRG was dispensed in a single-use, prefilled syringe; dosage was determined by age and weight. Maximal use was > or =5-day intervals, < or =5 times/month. After use, caregivers returned data booklets and syringe. Caregivers and physicians completed global ratings yearly. RESULTS: In 149 subjects treated, 77% of 1,578 administrations resulted in seizure freedom for the next 12 h. One hundred twenty-five received two or more treatments (two to 78; median, 8), 0.03-4.3/month (median, 0.4). To evaluate tolerance, subjects with two or more episodes were divided into low (two to seven episodes) and high use (eight to 78 episodes treated). There was no difference in proportion seizure free 12 h after the first administration versus last administration, for either infrequent or frequent administration. Sedation occurred in 17%, attributed to DZPRG in 9%. No respiratory depression was attributable to DZPRG. Three subjects withdrew because of AEs attributable to (agitation) or possibly attributable to DZPRG (chest pain, rash). Five subjects withdrew because of AEs unrelated to DZPRG. Caregiver and physician global ratings were highly positive at both 12 and 24 months. CONCLUSIONS: DZPRG is safe and effective in children and adults with epilepsy with breakthrough seizures. Neither tolerance nor significant medication-related AEs were seen with repeated DZPRG administration at intervals > or =5 days.

Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.

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.