Application of a computational model of vagus nerve stimulation.

OBJECTIVES: The most widely used and studied neurostimulation procedure for medically refractory epilepsy is vagus nerve stimulation (VNS) Therapy. The goal of this study was to develop a computational model for improved understanding of the anatomy and neurophysiology of the vagus nerve as it pertains to the principles of electrical stimulation, aiming to provide clinicians with a systematic and rational understanding of VNS Therapy. MATERIALS AND METHODS: Computational modeling allows the study of electrical stimulation of peripheral nerves. We used finite element electric field models of the vagus nerve with VNS Therapy electrodes to calculate the voltage field for several output currents and studied the effects of two programmable parameters (output current and pulse width) on optimal fiber activation. RESULTS: The mathematical models correlated well with strength-duration curves constructed from actual patient data. In addition, digital constructs of chronic versus acute implant models demonstrated that at a given pulse width and current combination, presence of a 110-µm fibrotic tissue can decrease fiber activation by 50%. Based on our findings, a range of output current settings between 0.75 and 1.75 mA with pulse width settings of 250 or 500 µs may result in optimal stimulation. CONCLUSIONS: The modeling illustrates how to achieve full or nearly full activation of the myelinated fibers of the vagus nerve through output current and pulse width settings. This knowledge will enable clinicians to apply these principles for optimal vagus nerve activation and proceed to adjust duty cycle and frequency to achieve effectiveness.

Generic antiepileptic drugs and associated medical resource utilization in the United States.

OBJECTIVE: To evaluate whether generic substitution was associated with any difference in medical resource utilization for 5 widely used antiepileptic drugs (AEDs) in the United States. METHODS: Health insurance claims from PharMetrics Database, representing over 90 health plans between January 2000 and October 2007, were analyzed. Adult patients with epilepsy, continuously treated with carbamazepine, gabapentin, phenytoin, primidone, or zonisamide, were selected. An open-cohort design was used to classify patients into mutually exclusive periods of brand vs generic use of AEDs. Pharmacy and medical utilization were compared between the 2 periods with multivariate regression analyses. Results were stratified into epilepsy-related medical services, and stable (< or = 2 outpatient visits per year and no emergency room visit) vs unstable epilepsy. Time-to-event analyses were also performed for all services and epilepsy-related endpoints. RESULTS: A total of 18,125 patients were observed in the stable group and 15,500 patients in the unstable group. After adjustment of covariates, periods of generic AED treatment were associated with increased use of all prescription drugs (incidence rate ratio [IRR] [95% confidence interval (CI)] = 1.13 [1.13-1.14]) and higher epilepsy-related medical utilization rates (hospitalizations: IRR [95% CI] = 1.24 [1.19-1.30]; outpatient visits: IRR [95% CI] = 1.14 [1.13-1.16]; lengths of hospital stays: IRR [95% CI] = 1.29 [1.27-1.32]). Generic-use periods were associated with increased utilization rates in stable and unstable patients and with 20% increased risk of injury, compared to periods with brand use of AEDs. CONCLUSIONS: Generic antiepileptic drug use was associated with significantly greater medical utilization and risk of epilepsy-related medical events, compared to brand use. This relationship was observed even in patients characterized as stable. AED = antiepileptic drug; CI = confidence interval; ER = emergency room; HR = hazard ratio; ICD = International Classification of Diseases; IRR = incidence rate ratio.

The impact of pregnancy and childbirth on the metabolism of lamotrigine.

This study was performed to clarify alterations in lamotrigine (LTG) clearance during pregnancy and childbirth. Fourteen women on LTG monotherapy had LTG concentration samples obtained before conception and monthly. LTG apparent clearance, weight-adjusted relative clearance, and percentages of baseline clearance significantly differed between preconception baseline and each trimester and between trimesters. LTG clearance progressively increased until 32 weeks' gestational age, reaching a peak of >330% of baseline, and then began to decline.

Vagus nerve stimulation in pediatric epilepsy: a review.

Therapeutic options for intractable epilepsy include new and investigational antiepileptic drugs, ketogenic diet, epilepsy surgery, and, now, vagus nerve stimulation, which is approved by the U.S. Food and Drug Administration for the treatment of refractory partial seizures in adolescents and adults. The exact mechanisms of action are unknown. Although the use of vagus nerve stimulation in children has increased, including those younger than 12 years of age or those with generalized epilepsy, there has been no large controlled pediatric study to date. The identification of favorable prognostic indicators, especially in children, would be useful. Preliminary results suggest that children with Lennox-Gastaut syndrome may have a favorable response, with improvement in both seizure control and global evaluation scores. Improved global evaluation scores have occurred even without an associated improvement in seizure control.

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.

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.

Topiramate and metabolic acidosis in pediatric epilepsy.

PURPOSE: Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3-). METHODS: Clinical data from 30 children who received TPM as adjunctive therapy for medically refractory epilepsy were reviewed at Children's Hospital, Boston. Serum HCO3- levels were assessed before, during, and after discontinuing TPM (n = 9). When multiple data were available, mean values were used for analysis. RESULTS: Of the 30 patients, 21 had a >10% decrease in HCO3- levels. The mean decrease in HCO3- among the 21 patients was 4.7 mEq/L, and maximum was 10 mEq/L. No clinical symptoms occurred, and HCO3- supplement was not needed, except for one patient who developed tachypnea from worsened acidosis after prolonged status epilepticus during a suspected viral illness. Among the 21 patients, TPM was discontinued in seven children because of a lack of efficacy, and in two because of anorexia. After discontinuing TPM, the serum HCO3- returned to the previous level before starting TPM in all nine. CONCLUSIONS: Decreased HCO3- levels occurred in the majority of patients reviewed, usually only to a small to moderate extent, but by 8 and 10 mEq/L in two cases. In patients at risk for acidosis, the decrease in HCO3- may cause significant consequences, such as severe acidosis or renal calculi. Monitoring HCO3- levels before and during TPM therapy may be indicated, especially with conditions that predispose to acidosis.

MRI signal changes in the white matter after corpus callosotomy.

Magnetic resonance imaging (MRI) changes reported after corpus callosotomy include hyperintensity in the corpus callosum, perifalcine hyperintensity caused by surgical retraction, and acute changes associated with surgical complications. The authors have observed MRI signal changes in the cerebral white matter of corpus callosotomy patients that are separate from the sectioned callosum and not clearly related to surgical manipulation or injury. Brain MRI scans were retrospectively reviewed in 25 of 38 patients who underwent anterior, posterior, or total callosotomy for refractory seizures between 1988 and 1995. Nine patients had signal changes in the cerebral white matter on postoperative MRI. Six of these patients had preoperative MRI studies available for comparison, and none of the white matter signal abnormalities were evident preoperatively. T2 prolongation or hyperintensity on proton-density images was observed in areas including the centrum semiovale, forceps major, and forceps minor. Three patients had signal changes that had distinct borders extending only to the posterior limit of the callosotomy. MRI signal changes in the cerebral white matter after corpus callosotomy have not been previously reported and may represent distant effects of callosal section. Wallerian degeneration occurring in the neuronal processes cut during surgery could account for the signal changes.

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.

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.

Case study: seizure disorder presenting as panic disorder with agoraphobia.

Seizure disorders can produce anxiety that is almost indistinguishable from psychiatric disorders. There are few reports of adolescents with seizure disorders that produce fear. The first case of an adolescent female who presented with panic disorder and agoraphobia which was a consequence of seizure activity is reported. Careful diagnostic evaluation and correlation with video electroencephalography were important in distinguishing seizure activity from panic disorder.

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.

Pharyngeal dysesthesia as an aura in temporal lobe epilepsy.

PURPOSE: Because oral, buccal, and sometimes oral-pharyngeal manifestations in epilepsy are linked to the central-temporal region, we studied 3 patients with childhood-onset partial seizures that consistently began with pharyngeal dysesthesias, described as either throat tingling or burning, to localize seizure onset. METHODS: Because of an intractable clinical course, each patient underwent invasive video-EEG monitoring, which localized the epileptogenic zone to the mesial temporal lobe. The 3 patients underwent temporal lobe resections. RESULTS: All 3 patients achieved remission of the pharyngeal auras and a 90-100% reduction in the frequency of their seizures. CONCLUSIONS: Pharyngeal dysesthesias can be the initial manifestation of complex partial seizures (CPS) of temporal lobe origin.

Differential diagnosis of staring spells in children: a video-EEG study.

Staring is frequently a nonepileptic manifestation in children. To differentiate epileptic versus nonepileptic staring, we reviewed clinical and video-EEG findings in 143 patients, aged 5 months to 43 years, monitored for staring episodes. In 79 patients staring was of epileptic origin; 46 had partial seizures and 33 atypical absence. Thirty-five had behavioral staring, 8 psychogenic seizures, 1 a migraine equivalent, and in 20 no staring spells were recorded. In all patients with epileptic staring, epilepsy was suspected clinically. Only 22 of the admissions for behavioral staring and 3 for pseudoseizures were to exclude a possible nonepileptic phenomenon. Review of their clinical histories revealed that certain findings strongly support a nonepileptic origin. In conclusion, a careful clinical history will differentiate between epileptic and nonepileptic staring episodes in most patients. Video-monitoring is helpful to adjust treatment or to exclude nonepileptic events in patients with refractory staring spells.

Behavioral side effects of gabapentin in children.

We report 7 children who received gabapentin (GBP) as adjunctive medic ation and subsequently developed behavioral side effects. These behavioral changes consisted of intensification of baseline behaviors as well as new behavioral problems. Behaviors that parents considered most troublesome were tantrums, aggression directed toward others, hyperactivity, and defiance. All behavioral changes were reversible and were managed by dose reduction or discontinuation of GBP. All children had baseline attention deficit hyperactivity disorder and developmental delays.

The preoperative evaluation of the child with epilepsy.

This article reviews the preoperative evaluation of the child with intractable epilepsy. The importance of the history and the clinical manifestations of the seizures, and the results of electrophysiology, neurophysiology, and neuroimaging studies are discussed.

Pseudoseizure manifestations in two preschool age children.

We report two patients with epilepsy with pseudoseizures at age 6 years. Both presented with intractable staring spells. Pseudoseizures were provoked and aborted by suggestion, leading to the diagnosis. In both patients, evidence of a neuropsychological disturbance was later found and psychotherapy started. Monitoring of intractable staring episodes is recommended prior to escalating antiepileptic drug levels or resorting to polytherapy. In addition, differentiation from other non-epileptic phenomena is necessary to initiate proper therapy.

EEG prior to hemispherectomy: correlation with outcome and pathology.

Hemispherectomy, for the treatment of seizures, is highly successful but has a significant morbidity rate. The procedure is usually restricted to patients with an intractable seizure disorder and hemiparesis. Because of the inherent risk of surgery, patient selection is a critical issue. This report describes the evaluation of background activity and ictal patterns on surface and invasive EEG in 12 children who underwent both anatomical (7) and functional (5) hemispherectomy in order to determine the role of electroencephalography in the selection of patients for hemispherectomy, and to correlate EEG findings with underlying pathology and outcome. A favorable outcome was predicted by an interictal EEG with two or more of the following: suppression over the abnormal hemisphere, absence of contralateral slowing, absence of generalized discharges and absence of bilateral independent spiking; or by unilateral onset of ictal discharges on invasive intracerebral EEG recording. Outcome did not correlate with the underlying pathology. Hemispherectomy can be successful in patients with a variety of predominantly unilateral pathologic entities.