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.

The association of multiple personality and temporolimbic epilepsy. Intracarotid amobarbital test observations.

OBJECTIVE: What is the relationship of "multiple personality disorder" in patients with temporolimbic epilepsy to certain types of hemispheric interaction? DESIGN: Case series. SETTING: Tertiary care referral center. PATIENTS: Two patients with temporolimbic epilepsy considered to be surgical candidates referred for the intracarotid amobarbital sodium procedure (IAP). Each individual had presented with different "personalities" in a characteristic temporal relationship to their seizures. INTERVENTIONS: Intracarotid amobarbital sodium procedure, Wada test, and electroencephalogram. MAIN OUTCOME MEASURES: Behavioral observations made during the performance of the IAP. RESULTS: During the IAP, each patient's peri-ictal "personality" changes were precisely replicated. No seizure activity was noted during the IAPs. CONCLUSIONS: These observations suggest that the association of multiple personality and temporolimbic epilepsy is not dependent on seizure discharges per se, but rather may be related to certain types of hemispheric interaction.

Status epilepticus due to human parvovirus B19 encephalitis in an immunocompetent adult.

Human parvovirus (HPV) B19 is a rare cause of encephalitis in children and immunocompromised adults. The authors describe a case of an otherwise healthy woman who developed encephalitis complicated by prolonged status epilepticus. Human parvovirus B19 infection was suggested by a prodromal, malar rash and established by the presence of specific IgM and IgG antibodies in the patient's serum. This is the first reported case of HPV B19 encephalitis in an immunocompetent adult.

Management issues for women with epilepsy: a review of the literature.

OBJECTIVE: A review of literature referable to management issues for women with epilepsy (WWE) was undertaken for the development of a practice parameter. BACKGROUND: Epilepsy is a common neurologic condition with gender-related management implications. Although reviews of this topic often focus on pregnancy-related issues for WWE, specific health concerns for WWE are present throughout all phases of reproductive life. METHODS: An OVID MEDLINE literature search was conducted for 1965 to 1997 using the following key words/phrases and cross referencing: epilepsy/ seizures and pregnancy, anticonvulsants, antiepileptic drugs (AEDs), teratogenesis, oral contraceptives, birth defects, folate/folic acid, vitamin K, metabolic bone disease, and breast-feeding. RESULTS: Pregnancy outcome literature for WWE spans several decades. Methodology varies and interpretation is complicated by modern management strategies. Contributions of socioeconomic factors, AEDs, maternal epilepsy, and seizures during pregnancy to adverse pregnancy outcomes have not been clearly delineated. There is a biologic basis for recommendations concerning contraception, folate supplementation, vitamin K use in pregnancy, breast-feeding, metabolic bone disease, catamenial epilepsy, and reproductive endocrine disorders, but no outcome studies afford a strong evidence base for practice recommendation. CONCLUSIONS: WWE face health issues for which there is no available outcome literature to guide decision making. The urgent need for studies in many of these areas is highlighted by expanded treatment options with new AEDs and epilepsy surgery.

Fear recognition deficits after focal brain damage: a cautionary note.

OBJECTIVE: To test the hypothesis that fear recognition deficits in neurologic patients reflect damage to an emotion-specific neural network. BACKGROUND: Previous studies have suggested that the perception of fear in facial expressions is mediated by a specialized neural system that includes the amygdala and certain posterior right-hemisphere cortical regions. However, the neuropsychological findings in patients with amygdala damage are inconclusive, and the contribution of distinct cortical regions to fear perception has only been examined in one study. METHODS: We studied the recognition of six basic facial expressions by asking subjects to match these emotions with the appropriate verbal labels. RESULTS: Both normal control subjects (n = 80) and patients with focal brain damage (n = 63) performed significantly worse in recognizing fear than in recognizing any other facial emotion, with errors consisting primarily of mistaking fear for surprise. Although patients were impaired relative to control subjects in recognizing fear, we could not obtain convincing evidence that left, right, or bilateral lesions were associated with disproportionate impairments of fear perception once we adjusted for differences in overall recognition performance for the other five facial emotion categories. The proposed special role of the amygdala and posterior right-hemisphere cortical regions in fear perception was also not supported. CONCLUSIONS: Fear recognition deficits in neurologic patients may be attributable to task difficulty factors rather than damage to putative neural systems dedicated to fear perception.

Vagus nerve stimulation therapy for epilepsy in older adults.

The authors assessed the efficacy, safety, and tolerability of vagus nerve stimulation (VNS) for refractory epilepsy in 45 adults 50 years of age and older. They determined seizure frequency, adverse effects, and quality of life. At 3 months, 12 patients had a >50% decrease in seizure frequency; at 1 year, 21 of 31 studied individuals had a >50% seizure decrease. Side effects were mild and transient. Quality of life scores improved significantly with time.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Differential expression of immediate early genes in the hippocampus in the kindling model of epilepsy.

Kindling is a phenomenon in which brief afterdischarges (ADs) evoked by periodic electrical stimulation of the brain eventually result in generalized clonic motor seizures. Once present, the enhanced sensitivity to electrical stimulation is lifelong. The mechanism by which brief ADs produce this long-lasting effect may involve a change in gene expression. To begin to investigate changes in gene expression that occur during kindling, we used in situ hybridization histochemistry to examine the time course of expression of mRNAs of the immediate early genes (IEGs) c-fos, c-jun, NGFI-A, and c-myc within the dorsal hippocampus of rats following a kindling AD. Three principal findings resulted from this study. First, the expression of all mRNAs except c-myc was significantly increased (P less than 0.05) within discrete neuronal populations. Second, the time course of expression of the IEGs differed markedly within the same neuronal population. Third, for a given IEG, the time course and anatomic pattern of expression were strikingly different among different neuronal populations of the hippocampus. The prolonged and distinctly different patterns of IEG expression suggest that target genes are differentially regulated in these neuronal populations for prolonged periods following a kindling AD.

Long-term surface cortical cerebral blood flow monitoring in temporal lobe epilepsy.

Long-term subdural surface cortical cerebral blood flow (CBF) and electrocorticographic monitoring was performed in 12 patients with complex partial seizures. A total of 40 seizures were analyzed. Baseline CBF values from nonepileptic and epileptic temporal lobe (mean +/- standard error) were 60.0 +/- 1.0 and 50.2 +/- 1.8 ml/100 g per minute, respectively (P < 0.05). In general, clinical seizure onset was preceded by a 20-minute preictal CBF increase from baseline in the epileptic temporal lobe. Peak early postictal CBF values of nonepileptic and epileptic temporal lobes were 57.7 +/- 13.3 and 89.0 +/- 21.7 ml/100 g per minute (P > 0.05) at 5.2 +/- 2.2 and 2.4 +/- 1.0 minutes (P > 0.05) after clinical seizure onset, respectively. Statistically significant differences between nonepileptic and epileptic temporal lobe CBF were detected at 50 minutes (74.0 +/- 14.2 and 37.5 +/- 9.2 ml/100 g per minute, respectively; P < 0.05) and 60 minutes (75.6 +/- 13.6 and 36.1 +/- 8.5 ml/100 g per minute, respectively; P < 0.05) postictal. The data suggest that the optimal times for CBF analysis to differentiate epileptic from nonepileptic temporal lobe are 1) during the interictal period and 2) late (50 to 60 minutes) postictal. The results of this study should improve the understanding of the dynamic cerebral perfusion patterns in the epileptic human brain.

Temporal lobe seizure interhemispheric propagation time depends on nonepileptic cortical cerebral blood flow.

In some patients with epilepsy, activation of eloquent cortex using various forms of environmental stimulation and mental activity may induce seizures. The increased neuronal activity resulting from cortical stimulation may be associated with increased regional cerebral blood flow. The vascular steal theory of temporal lobe epilepsy suggests that as nonepileptogenic cortical cerebral blood flow (CBFn) increases, temporal lobe epileptogenicity increases as a result, in part, of decreasing interhemispheric propagation time (IHPT). Recently, IHPT has been shown to be a quantitative electrocorticographic measure of temporal lobe epileptogenicity. In the current study, long-term combined subdural-EEG and surface cortical cerebral blood flow (CBF) monitoring was performed to test the hypothesis that IHPT depends upon CBFn. The results show that IHPT is a nonlinear (negative exponential) function of nonepileptic cortical CBF (r=0.507, df=32, t=-2.204, P<0.05). In temporal lobe epilepsy, nonepileptic cortical hypoperfusion may represent a protective mechanism for delaying interhemispheric seizure propagation. The fact that IHPT decreases exponentially with increasing CBFn suggests that small increases in CBFn should substantially decrease IHPT and increase epileptogenicity. This study confirms that inter-hemispheric propagation time depends upon perfusion of nonepileptogenic cortex.

Quantitative analysis of the electroencephalogram in the intracarotid amobarbital procedure: II. Coherence analysis.

Thirty-seven subjects underwent bilateral internal carotid artery injections of amobarbital before surgery for intractable epilepsy. The electroencephalograms (EEG) of these patients were continuously monitored during these 74 procedures and were later subjected to quantitative analysis. Analysis of interhemispheric coherence in the delta, theta, alpha, and beta 1 bands was performed. Prominent changes occurred in interhemispheric coherence, which showed a precipitous drop in the first 2 min after amobarbital injection, followed by a gradual return to near baseline levels. These results suggest that interhemispheric relationships are significantly disrupted by intracarotid amobarbital injection.

Response of human epileptic temporal lobe cortical blood flow to hyperventilation.

Bilateral long-term surface cortical cerebral blood flow (CBF) and electrocorticographic (ECoG) monitoring were performed in eight patients with complex partial seizures. In each patient, the epileptic temporal lobe was localized using ictal ECoG. Mean seizure interval (frequency-1) off anticonvulsant medication, a clinical measure of epileptogenicity, was 1.0 +/- 0.3 h (range: 0.4 to 2.5 h). During 13 interictal hyperventilation periods, 3.6 +/- 0.6 min in duration, the mean decrease in epileptic and nonepileptic temporal cortical CBF was 13.7 +/- 2.3 versus 6.4 +/- 1.9 ml/(100 g min) (t = 2.230, d.f. = 16, P < 0.05), representing 20.9% and 10.8% reduction from baseline CBF during hyperventilation, respectively. Seizure interval decreased (i.e. frequency increased) with increasing magnitude of seizure focus CBF reduction during hyperventilation. Seizure interval was significantly correlated with epileptic temporal lobe CBF decrease during hyperventilation (R = 0.763, d.f. = 5, P < 0.05). The data suggest that, compared to nonepileptic brain, epileptic temporal lobe is particularly prone to hypoperfusion during hyperventilation. Epileptogenicity is a function of this seizure focus susceptibility to ischemia. The finding of abnormal seizure focus autoregulation during hyperventilation has implication for epileptic focus localization with cerebral blood flow analysis.

Cerebral blood flow and temporal lobe epileptogenicity.

Long-term surface cerebral blood flow (CBF) monitoring was performed to test the hypothesis that temporal lobe epileptogenicity is a function of epileptic cortical perfusion. Forty-three bitemporal 2-hour periictal CBF studies were performed in 13 patients. Homotopic regions of temporal cortex maintained interictal epileptic cortical hypoperfusion and nonepileptic normal cortical CBF. At 10 minutes preictus, a statistically significant, sustained increase in CBF was detected on the epileptic temporal lobe. Two minutes preictus, there was approximation of CBF in the epileptic and nonepileptic temporal lobes. Thereafter, electrocorticographic (ECoG) and clinical seizure onset occurred. The linear relationship between CBF in the two hemispheres (epileptic and nonepileptic) was the inverse of normal (y = -0.347x + 62.767, r = 0.470, df = 95, p < 0.05). The data indicated a direct linear correlation between epileptic cortical CBF and seizure interval (frequency-1), a clinical measure of epileptogenicity (r = 0.610, df = 49, p < 0.05). Epileptogenicity was also found to be a logarithmic function of the difference between nonepileptic and epileptic cortical perfusion (r = 0.564, df = 58, t = 5.20, p < 0.05). The results showed that progressive hypoperfusion of the epileptic focus correlated with a decreased seizure interval (increased epileptogenicity). Increased perfusion of the epileptic focus correlated with an increased seizure interval (decreased epileptogenicity). The fact that CBF alterations precede ECoG seizure activity suggests that vasomotor changes may produce electrical and clinical seizure onset.

Time from ictal subdural EEG seizure onset to clinical seizure onset: prognostic value for selecting temporal lobectomy candidates.

Long-term subdural EEG recording was performed to test the hypothesis that the duration from ictal subdural EEG seizure onset (ECOT) is prognostic for seizure-free outcome following temporal lobectomy. In 48 patients with complex partial seizures, temporal lobectomy was based on invasive localization of the ictal seizure focus. Subdural EEG data were analyzed for association with seizure-free outcome (seizure-free: yes or no) at a minimum of one year following temporal lobectomy. As the duration from ictal subdural EEG seizure onset to clinical seizure onset increased, the odds of being seizure-free postoperatively increased. The best fitting statistical model for predicting seizure-free outcome included seizure onset (unilateral vs. bilateral) and duration from ictal subdural EEG seizure onset to clinical seizure onset. While selection of temporal lobectomy candidates has increasingly emphasized noninvasive recording, some scalp-EEG monitored patients cannot be offered surgery for various reasons, one of which may include ictal EEG seizure onset following clinical seizure onset. When subdural EEG monitoring is performed for selection of temporal lobectomy candidates, analysis of the duration from subdural EEG seizure onset to clinical seizure onset should improve the prognostic value of the subdural EEG data for seizure-free outcome following temporal lobectomy.

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.

Peripheral neuromuscular dysfunction and falls in an elderly cohort.

In a prospective study of 169 tenants of senior citizen housing in New Jersey in 1986-1987, the relations between tests of peripheral sensory and motor functions in the lower extremities and the rate of first falls were evaluated. The mean age of the cohort was 79.8 years. Fifty-seven persons fell at least once during the follow-up period (mean, 5.6 months). After adjustment for history of stroke, heart failure, emphysema, and use of a walker or cane, rate ratios for first falls were elevated in subjects with reduced toe joint position sense (rate ratio (RR) = 2.2) and sharp-dull discrimination (RR = 2.0), but to a lesser extent for reduced ankle strength (RR = 1.5). Presence of one or more of these three deficits was defined as a peripheral neuromuscular dysfunction and was associated with first falls after adjustment for multiple covariates (RR = 2.4, 95% confidence interval 1.3-4.5). Having two or all three sensory or motor deficits increased the rate of falling 3.9 times (95% confidence interval 2.1-7.0) compared with persons without these deficits. These data suggest that impaired sensory and motor function of the lower extremities plays an important role in falls in the elderly.

Disturbances of amino acids from temporal lobe synaptosomes in human complex partial epilepsy.

We have studied the levels of neuroactive amino acids in synaptosomes (P2 fraction) isolated from brain tissue of ten patients with medically intractable epilepsy who were undergoing temporal lobectomy. First, lateral temporal tissue (nonfocal) was removed followed by medial temporal tissue (focal). A synaptosomal fraction (P2) was immediately prepared from each tissue and analyzed for free amino acid concentrations. Statistically significant reductions were seen in glutamine and GABA concentrations in focal tissue compared to nonfocal tissue. The ratio of excitatory amino acids (aspartate and glutamate) to inhibitory amino acids (taurine and GABA) was significantly higher in focal tissue compared to nonfocal. The glutamine/glutamate ratio was significantly reduced. These data support the hypothesis that alterations in the balance between excitatory and inhibitory amino acids may be involved in the expression of epilepsy.

Quantitative analysis of hemispatial neglect in the intracarotid sodium amobarbital (ISA) test.

There are dramatic changes in the electroencephalogram of the inactivated hemisphere in the intracarotid sodium amobarbital test. One of the more profound behavioral changes during this procedure is left hemispatial neglect accompanying right hemisphere inactivation. The present study was designed to ascertain whether there was a clear relationship between the degree of hemispheric inactivation (as measured by the electroencephalogram) and the degree of left hemispatial neglect during this procedure. Sixty-nine participants undergoing right hemisphere intracarotid sodium amobarbital testing were presented with a random letter cancellation test at various points during the procedure. Neglect was quantified as significant, moderate, minimal, or none, based on how many target letters the patients missed. The simultaneous electroencephalogram from each of these testing points was spectrally analyzed and topographic maps were generated. The degree of neglect was then compared with the comparable topographic map. It was found that as the amobarbital-induced right hemispheric dysfunction regressed, the degree of neglect lessened in a systematic fashion, as did the profound electroencephalographic changes induced by the drug. Thus, there is a clear relation between the degree of hemispheric inactivation induced by the amobarbital and the degree of left hemispatial neglect. This relationship held regardless of side of hemispheric language dominance or epileptic focus. These results replicate previous findings that right hemisphere inactivation during the intracarotid sodium amobarbital test results in left hemispatial neglect. They extend these findings by clearly showing that neglect changes in a quantitative fashion (rather than being an all-or-none phenomenon) and further, show that there is a clear relationship between the severity of neglect and the degree of hemispheric dysfunction.

Affective self-report during the intracarotid sodium amobarbital test: group differences.

Emotional reactions are sometimes observed during the intracarotid sodium amobarbital test. For instance, euphoric/indifference reactions can be seen during right hemisphere inactivation and catastrophic reactions may accompany left hemisphere inactivation. Less dramatic changes can also be detected in affective self-report during left and right hemisphere amobarbital tests, with more negative affect reported during left hemisphere inactivation and either neutral or mildly positive affective states reported during right hemisphere inactivation. The current study not only replicated this effect, but in addition, found significant group differences. The first group (right way) showed a pattern of affective self-report during left and right amobarbital tests entirely consistent with prior findings, while a second group (wrong way) showed results that behaved in a diametrically opposite fashion. A third group (no change) showed little, if any, difference in affective self-report during left and right amobarbital tests. The major factor distinguishing the wrong way group from the other two appeared to be an asymmetrical distribution of left and right temporal lobe lesions in the former group. In contrast, the factor differentiating the right way group from the no change group appeared to be the relative degree of left hemisphere inactivation during the left hemisphere amobarbital test. The results are discussed not only in terms of their impact on theories of cerebral lateralization for emotion, but also in terms of methodological issues in this field.