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Biomedical subjects

G L Holmes

Publications and source records attributed to G L Holmes.

At least 55 records · Page 3Linked to original sources
PubMed1999

Midazolam and pentobarbital for refractory status epilepticus.

Status epilepticus, a serious, life-threatening emergency characterized by prolonged seizure activity, occurs most commonly in pediatric patients. Although initial therapies with agents such as diazepam, phenytoin, or phenobarbital generally terminate seizure activity within 30-60 minutes, patients with refractory status epilepticus (RSE) lasting longer require additional intervention. High-dose pentobarbital has been the most commonly prescribed agent for the management of RSE in children; however, midazolam has emerged as a new treatment option. This review compares the use of midazolam with pentobarbital in published reports of pediatric RSE. Both drugs effectively terminated refractory seizure activity, although pentobarbital use was complicated by hypotension, delayed recovery, pneumonia, and other adverse effects. Midazolam use was effective and well tolerated, affirming its value in pediatric RSE management.

Adolescent↗
PubMed1999

EEG and clinical predictors of medically intractable childhood epilepsy.

OBJECTIVES: To identify electroencephalographic and clinical factors associated with both seizure control and medical intractability in children with epilepsy. METHODS: We retrospectively reviewed EEGs and medical records from children with well-controlled epilepsy or medically intractable epilepsy. SUBJECTS: Features of the initial EEG and clinical findings were compared in 39 children with well controlled seizures and 144 with intractable epilepsy using both univariate and multivariate analyses. RESULTS: Strong univariate associates were noted between intractability and several EEG factors: abnormal EEG background including diffuse slowing, asymmetry, abnormal amplitude, a high frequency of spikes or sharp waves, and focal spike and wave activity. With multiple logistic regression, independent predictors of intractability were diffuse slowing and focal spike and wave activity. Strong univariate associates of clinical factors with intractability included: an early age of onset, simple partial, tonic, and myoclonic seizures, a history of status epilepticus, a symptomatic etiology of the seizures, and abnormal magnetic resonance imaging of the head. Multivariate analysis detected 4 independent clinical features associated with intractable epilepsy: symptomatic etiology, tonic seizures, simple partial seizures, and an early age of onset. CONCLUSIONS: There are a number of EEG and clinical features that can be identified early in the course of childhood epilepsy that are predictive of outcome. These findings will need to be verified in a prospective study.

Age of Onset↗
PubMed1999

Consciousness in congenitally decorticate children: developmental vegetative state as self-fulfilling prophecy.

According to traditional neurophysiological theory, consciousness requires neocortical functioning, and children born without cerebral hemispheres necessarily remain indefinitely in a developmental vegetative state. Four children between 5 and 17 years old are reported with congenital brain malformations involving total or near-total absence of cerebral cortex but who, nevertheless, possessed discriminative awareness: for example, distinguishing familiar from unfamiliar people and environments, social interaction, functional vision, orienting, musical preferences, appropriate affective responses, and associative learning. These abilities may reflect 'vertical' plasticity of brainstem and diencephalic structures. The relative rarity of manifest consciousness in congenitally decorticate children could be due largely to an inherent tendency of the label 'developmental vegetative state' to become a self-fulfilling prophecy.

Brain↗
PubMed1999

Safety and tolerability of gabapentin as adjunctive therapy in a large, multicenter study.

PURPOSE: To evaluate the tolerability and safety of gabapentin (GBP) as add-on therapy for seizure control. METHODS: Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages < or = 1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP < or =1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow-up contact. RESULTS: A total of 2,216 patients enrolled in this open-label, 16-week study and were evaluable for safety. Of these, 74.0% completed the 16-week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only < or =1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at < or = 1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients. CONCLUSIONS: Gabapentin doses >1,800 mg/day were as well tolerated as doses < or =1,800 mg/day and were not associated with more adverse events.

Acetates↗
PubMed1999

Lamictal (lamotrigine) monotherapy for typical absence seizures in children.

PURPOSE: To investigate whether lamotrigine (LTG) monotherapy is effective and safe for newly diagnosed typical absence seizures in children and adolescents (aged 3-15 years, n = 45). METHODS: A "responder-enriched" study design was used: open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG. Conventional hyperventilation testing with EEG recording was used to confirm diagnoses and assess treatment success defined as complete freedom from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of effectiveness. Safety was assessed by evaluation of adverse events, vital signs, and physical, neurologic, and laboratory examinations. Plasma samples were taken to evaluate the pharmacokinetics of LTG. RESULTS: During initial open-label dose escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis) became seizure free; individual patients responded at doses ranging from 2 to 15 mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the study, statistically significantly more patients remained seizure free when treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat analysis). Mean plasma concentrations of LTG, were linearly related to dose, although there was substantial interindividual variation. No patients were withdrawn from the study for any safety-related reason. CONCLUSIONS: LTG monotherapy is effective for typical absence seizures in children and is generally well tolerated.

Adolescent↗
PubMed1999

Consequences of cortical dysplasia during development in rats.

PURPOSE: To determine whether focal cortical dysplasia alters excitability in regions distant to the region of the dysplasia. METHODS: We studied the physiological consequences of cortical dysplasia induced by either one or three freeze lesions at birth. Seizure susceptibility was assessed at age 35 days by amygdala kindling. c-fos immunostaining was performed after kainic acid-induced seizures at 10, 20, or 30 days to evaluate the patterns of neuronal activation. RESULTS: Freeze lesions consistently produced uniform regions of dysplasia. No significant differences in seizure susceptibility, as measured by afterdischarge threshold and kindling rate, were seen between controls and rats receiving either one or three freeze lesions. c-fos activation after kainic acid injection was not observed in the region of the dysplasia. However, rats with freeze lesions at age 30 days demonstrated asymmetric c-fos staining with greater staining in CA1 ipsilateral, than contralateral, to the lesion. CONCLUSIONS: Focal cortical dysplasia results in enhancement of c-fos activation in regions outside the borders of the dysplasia. However, as indicated by kindling rate, the functional consequences of these alterations do not appear to be robust.

Amygdala↗
PubMed1998

Synaptic reorganization following kainic acid-induced seizures during development.

Prolonged seizures in the adult brain causes neuronal loss in the hippocampus and aberrant growth (sprouting) of granule cell axons (mossy fibers) in the supragranular zone of the fascia dentata and stratum infrapyramidale of CA3. There is considerable evidence that these changes in neuronal growth following seizures are age related, with younger animals having fewer reactive changes following prolonged seizures than older animals. However, there is little information available regarding the age at which seizures in the developing brain result in alterations in axonal growth and synapse formation. In this study, we evaluated the effects of kainic acid (KA)-induced seizures during development on synaptic reorganization using the expression of growth-associated protein-43 (GAP-43), a marker for synaptogenesis and Timm stain which detects the presence of zinc in granule cell axons. Age specific doses of KA were used to induce seizures of similar intensity at various ages (postnatal days (P) 12, 21, 25, 35, 45, 60) in Sprague-Dawley rats. Up to the age of P25, there were no differences in either Timm or GAP-43 staining between animals with KA seizures and controls. In P25 and older KA-treated rats, Timm staining was found in the supragranular layer of the dentate gyrus. This staining increased with age at the time of KA injection. Seizures in adult (P60), but not younger rats also resulted in increased staining in the suprapyramidal layer of the CA3 subfields. Changes in GAP-43 were delayed compared to the Timm staining with no differences between KA-treated animals and controls until P35 when a band of GAP-43 immunostaining appeared in the supragranular inner molecular layer, progressively increasing in intensity and thickness with time. This study demonstrates that seizure-induced reactive synaptogenesis is age-related. Since both Timm and GAP-43 reflect different aspects of reactive synaptogenesis, used in combination these methods provide useful information about the structural changes following seizures during development.

Aging↗
PubMed1998

Seizures in rats treated with kainic acid induce Fos-like immunoreactivity in locus coeruleus.

Kainic acid-triggered seizures (KATS) induce Fos-like immunoreactivity (FLI) in limbic structures, which send efferents to the locus coeruleus (LC). Following KATS, brain stem sections were stained for Fos immunocytochemistry and double immunostained for Fos and dopamine beta-hydroxylase (DBH). KA-treated animals showed significantly greater numbers of FLI neurons in the LC than control animals (p < 0.05). Co-localization of DBH/Fos was observed in 89.7% of the LC neurons in KA-treated animals and in 1.4% of LC neurons in control animals. Thus, KATS heavily induce Fos in DBH-containing neurons in the LC, which are known to project to the hippocampus. However, the role of activation of the LC noradrenergic neurons during KATS is not well understood at this present time.

Animals↗
PubMed1998

Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Boston Circulatory Arrest Study Group.

BACKGROUND: The outcome of infants who have transient seizures after open heart surgery has not been studied. Using the database of the Boston Circulatory Arrest Study involving 171 children with D-transposition of the great arteries, we explored the relationship between early postoperative clinical and EEG seizures and neurodevelopmental outcomes at ages 1 and 2 1/2 years. METHODS AND RESULTS: At 1 year, children returned for developmental and neurological evaluations and MRI. Parent-completed developmental questionnaires were collected at 2 1/2 years of age. At 1 year, children with early postoperative seizures had lower Psychomotor Development Index (motor function) scores (clinical seizures: 12.9 mean difference [MD]; 95% confidence interval [CI], 2.2 to 23.6; P=.02; EEG seizures: 13.3 MD; 95% CI, 6.8 to 19.7; P<.001). Mental Developmental Index scores of children with clinical or EEG seizures were also lower, but the differences were not statistically significant. Infants with seizures were more likely to have an abnormal neurological examination (clinical seizures: 78% versus 31%; P=.008; EEG seizures: 58% versus 34%; P=.04). Children with EEG seizures were more likely to have MRI abnormalities (43% versus 13%, P=.002). At age 2 1/2, children with EEG seizures had lower scores in several areas of function. CONCLUSIONS: In infants undergoing the arterial switch operation for correction of D-transposition of the great arteries, transient postoperative clinical and EEG seizures were associated with worse neurodevelopmental outcomes at ages 1 and 2 1/2 years as well as neurological and MRI abnormalities at 1 year of age. The occurrence of such seizures may provide an early sign of brain injury with neurological and developmental sequelae.

Age Factors↗
PubMed1998

A multicenter study of the efficacy of the ketogenic diet.

OBJECTIVE: To determine the efficacy of the ketogenic diet in multiple centers. DESIGN: A prospective study of the change in frequency of seizures in 51 children with intractable seizures who were treated with the ketogenic diet. SETTING: Patients were enrolled from the clinical practices of 7 sites. The diet was initiated in-hospital and the patients were followed up for at least 6 months. PATIENTS: Fifty-one children, aged 1 to 8 years, with more than 10 seizures per week, whose electroencephalogram showed generalized epileptiform abnormalities or multifocal spikes, and who had failed results when taking at least 2 appropriate anti-epileptic drugs. INTERVENTION: The children were hospitalized, fasted, and a 4:1 ketogenic diet was initiated and maintained. MAIN OUTCOME MEASURES: Frequency of seizures was documented from parental calendars and efficacy was compared with prediet baseline after 3, 6, and 12 months. The children were categorized as free of seizures, greater than 90% reduction, 50% to 90% reduction, or lower than 50% reduction in frequency of seizures. RESULTS: Eighty-eight percent of all children initiating the diet remained on it at 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, frequency of seizures was decreased to greater than 50% in 54%. At 6 months, 28 (55%) of the 51 initiating the diet had at least a 50% decrease from baseline, and at 1 year, 40% of those starting the diet had a greater than 50% decrease in seizures. Five patients (10%) were free of seizures at 1 year. Age, sex, principal seizure type, and electroencephalogram were not statistically related to outcome. CONCLUSION: The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.

Child↗
PubMed1998

Consequences of neonatal seizures in the rat: morphological and behavioral effects.

Whereas neonatal seizures are a predictor of adverse neurological outcome, there is controversy regarding whether seizures simply reflect an underlying brain injury or can cause damage. We subjected neonatal rats to a series of 25 brief flurothyl-induced seizures. Once mature the rats were compared with control littermates for spatial learning and activity level. Short-term effects of recurrent seizures on hippocampal excitation were assessed by using the intact hippocampus formation preparation and long-term effects by assessing seizure threshold. Brains were analyzed for neuronal loss, sprouting of granule cell axons (mossy fibers), and neurogenesis. Compared with controls, rats subjected to neonatal seizures had impaired learning and decreased activity levels. There were no differences in paired-pulse excitation or inhibition or duration of afterdischarges in the intact hippocampal preparation. However, when studied as adults, rats with recurrent flurothyl seizures had a significantly lower seizure threshold to pentylenetetrazol than controls. Rats with recurrent seizures had greater numbers of dentate granule cells and more newly formed granule cells than the controls. Rats with recurrent seizures also had sprouting of mossy fibers in CA3 and the supragranular region. Recurrent brief seizures during the neonatal period have long-term detrimental effects on behavior, seizure susceptibility, and brain development.

Animals↗
PubMed1998

Activation of the locus coeruleus after amygdaloid kindling.

PURPOSE: Substantia nigra (SN) and locus coeruleus (LC) neurons are implicated in the propagation and suppression of amygdaloid seizures. Both structures are activated concomitant with amygdaloid seizure discharges. Their mechanisms of activation, however, remain to be elucidated. SN firing is not associated with the induction of Fos immunoreactivity (ir), a marker of excitatory neuronal activation. LC has not been studied. The purpose of this investigation was to determine if amygdala-kindled generalized seizures could induce Fos-ir in the LC. METHODS: Female Sprague-Dawley rats were killed after generalized seizures induced by amygdala electrical stimulation and stained by using Fos immunocytochemistry. The number of Fos-ir neurons was compared between 15 animals with generalized seizures and four implanted, unstimulated controls. RESULTS: LC-ir neurons were significantly (p < 0.05) more prevalent after seizures than in control animals. Their numbers correlated very highly with Fos-ir in the central nucleus of the amygdala (p < 0.0001). No Fos induction was observed in LC in controls or in the SN in either group. CONCLUSIONS: Amygdala-induced generalized seizures result in Fos-ir in the LC but not in the SN. This is consistent with different mechanisms of activation possibly involving disinhibition in the SN and direct excitation in the LC.

Amygdala↗
PubMed1998

Comparison of valproate and phenobarbital treatment after status epilepticus in rats.

OBJECTIVE: To investigate the long-term effects of two widely used antiepileptic medications, valproate and phenobarbital, on learning and behavior in the kainic acid (KA) model of epilepsy. BACKGROUND: Prior clinical and animal studies have demonstrated that phenobarbital administered during development may result in subsequent cognitive impairment. It is unclear whether these adverse effects of phenobarbital extend to other antiepileptic drugs. METHODS: A convulsant dose of KA was administered to rats on postnatal day (P) 35. From P36-75 rats received daily injections of phenobarbital (PH), valproate (VPA), or saline and spontaneous seizure frequency was monitored with video recordings. After tapering of the drugs, the rats were tested in the water maze (a measure of visuospatial memory) and handling test (a measure of emotionality). Brains were then analyzed for histologic lesions. RESULTS: KA caused status epilepticus in all the rats. In the PH- and saline-treated groups, there was impaired learning in the water maze, increased emotionality, recurrent seizures, and histologic lesions in the hippocampal areas CA3, CA1, and dentate hilus. However, VPA-treated rats had no spontaneous seizures, abnormalities in handling, or deficits in visuospatial learning, and had fewer histologic lesions than animals receiving KA alone. CONCLUSIONS: The long-term consequences of AED treatment during development are related to the drug used. VPA treatment after KA-induced status epilepticus prevents many of the neurologic sequelae typically seen after KA.

Animals↗
PubMed1997

Basic fibroblast growth factor-induced seizures in rats.

The neurotrophic effects of basic fibroblast growth factor on hippocampal neurons have been well documented. However, the acute effects of basic fibroblast growth factor on hippocampal electrical activities in vivo have not yet been studied. To assess the impact of basic fibroblast growth factor on hippocampal electroencephalographic (EEG) activity, two doses of basic fibroblast growth factor were injected into the right ventral hippocampus of freely moving animals. Unilateral injection of 50 ng of basic fibroblast growth factor into the dentate region of the hippocampus resulted in immediate EEG ictal discharges and behavioral seizures in 7/9 rats. These seizures lasted about 2 h following the injection. Injection of 25 ng of basic fibroblast growth factor into the same sites induced ictal discharges of approximately 60 min duration in 3/7 rats. Injection with heat-inactivated basic fibroblast growth factor into the same sites did not cause any EEG or behavioral modifications. These results suggest that in addition to growth-promoting effects, basic fibroblast growth factor is able to acutely alter the electrical activity of hippocampal neurons and cause seizures.

Animals↗
PubMed1997

Seizure-induced glutamate release in mature and immature animals: an in vivo microdialysis study.

A glutamate biosensor was used to measure extracellular glutamate concentrations in the hippocampus of mature and immature animals. Significant elevations of extracellular glutamate were observed following seizures induced by either kainic acid or pilocarpine. The degree of glutamate increase following seizures was similar in both mature and immature animals. These results suggest that excitotoxicity may play a role in seizure-induced brain damage in the adult brain. In the immature brain, however, no brain damage is seen after seizures, suggesting that glutamate release may not cause as significant excitotoxic damage early in development.

Aging↗
PubMed1997

Perioperative electroencephalographic seizures in infants undergoing repair of complex congenital cardiac defects.

Many infants with cardiac anomalies undergo repair early in life. Both commonly used support techniques, deep hypothermic circulatory arrest (DHCA) and low-flow cardiopulmonary bypass (LFB), may be associated with adverse neurological outcomes, including seizures. In a single center study, 171 infants undergoing correction for D-transposition of the great arteries were randomized to one of these support techniques. Incidence and onset times of EEG seizures during continuous EEG-video monitoring in the first 48 h postoperatively and clinical seizures in the first postoperative week were compared. EEG seizures were characterized by time, duration, and localization of onset. Incidence of EEG seizures (20%) was more than 3 times that of clinical seizures (6%). Most infants with EEG seizures had multiple seizures beginning between 13 and 36 h postoperatively. Durations ranged from 6 s to 980 min. Onset of EEG seizures occurred most commonly in frontal and central regions. Factors associated with EEG seizures included randomization to DHCA, longer duration of circulatory arrest, and diagnosis of VSD. In this study EEG seizures were common following this type of cardiac surgery, illustrating the importance of EEG monitoring in detecting seizures. This data adds insight into mechanisms of seizures in infants undergoing cardiac surgery.

Brain↗