George L. Morris

Functional magnetic resonance imaging of complex human movements

Functional magnetic resonance imaging (FMRI) is a new, noninvasive imaging tool thought to measure changes related to regional cerebral blood flow (rCBF). Previous FMRI studies have demonstrated functional changes within the primary cerebral cortex in response to simple activation tasks, but it is unknown whether FMRI can also detect changes within the nonprimary cortex in response to complex mental activities. We therefore scanned six right-handed healthy subjects while they performed self-paced simple and complex finger movements with the right and left hands. Some subjects also performed the tasks at a fixed rate (2 Hz) or imagined performing the complex task. Functional changes occurred (1) in the contralateral primary motor cortex during simple, self-paced movements; (2) in the contralateral (and occasionally ipsilateral) primary motor cortex, the supplementary motor area (SMA), the premotor cortex of both hemispheres, and the contralateral somatosensory cortex during complex, self-paced movements; (3) with less intensity during paced movements, presumably due to the slower movement rates associated with the paced (relative to self-paced) condition; and (4) in the SMA and, to a lesser degree, the premotor cortex during imagined complex movements. These preliminary results are consistent with hierarchical models of voluntary motor control.

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.

Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy

Objective: To perform an open-label, long-term efficacy and safety/tolerability study of vagus nerve stimulation (VNS) of 454 patients with refractory epilepsy. Methods: Subjects were enrolled from five clinical trials of VNS between 1988 and 1995 after undergoing an implantation of a pulse generator in the chest and a left cervical vagus nerve-stimulating lead coil. Patients were assessed at 6-month intervals until device approval. Seizure frequencies, medication treatment, and adverse events (AEs) were recorded and entered into a database. Results: A total of 454 patients were implanted, and 440 patients yielded assessable data. A ≥50% seizure reduction postimplantation occurred in 36.8% of patients at 1 year, in 43.2% at 2 years, and in 42.7% at 3 years. Median seizure reductions compared with baseline were 35% at 1 year, 44.3% at 2 years, and 44.1% at 3 years. Most common AEs postimplantation at 1 year were hoarseness (28%) and paraesthesias (12%), at 2 years were hoarseness (19.8%) and headache (4.5%), and at 3 years was shortness of breath (3.2%). Continuation rates were 96.7% at 1 year, 84.7% at 2 years, and 72.1% at 3 years. Conclusion: Long-term, open-label vagus nerve stimulation (VNS) provided seizure reduction similar to or greater than acute studies, for median reductions and for those reaching a ≥50% seizure reduction. VNS remained safe and well tolerated, with nearly three-quarters of the patients choosing to continue therapy.

Prospective Long-Term Study of Vagus Nerve Stimulation for the Treatment of Refractory Seizures

Summary: Purpose: To determine the long‐term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short‐term double‐blind trials have demonstrated its safety and efficacy, and one long‐term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long‐term study of VNS to date.

Functional Magnetic Resonance Imaging Mapping of the Motor Cortex in Patients with Cerebral Tumors

OBJECTIVE The purpose of this study was to determine the usefulness of functional magnetic resonance imaging (FMRI) to map cerebral functions in patients with frontal or parietal tumors. METHODS Charts and images of patients with cerebral tumors or vascular malformations who underwent FMRI with an echoplanar technique were reviewed. The FMRI maps of motor (11 patients), tactile sensory (12 patients), and language tasks (4 patients) were obtained. The location of the FMRI activation and the positive responses to intraoperative cortical stimulation were compared. The reliability of the paradigms for mapping the rolandic cortex was evaluated. RESULTS Rolandic cortex was activated by tactile tasks in all 12 patients and by motor tasks in 10 of 11 patients. Language tasks elicited activation in each of the four patients. Activation was obtained within edematous brain and adjacent to tumors. FMRI in three cases with intraoperative electrocortical mapping results showed activation for a language, tactile, or motor task within the same gyrus in which stimulation elicited a related motor, sensory, or language function. In patients with > 2 cm between the margin of the tumor, as revealed by magnetic resonance imaging, and the activation, no decline in motor function occurred from surgical resection. CONCLUSIONS FMRI of tactile, motor, and language tasks is feasible in patients with cerebral tumors. FMRI shows promise as a means of determining the risk of a postoperative motor deficit from surgical resection of frontal or parietal tumors.

Use of preoperative functional neuroimaging to predict language deficits from epilepsy surgery

Background: Left anterior temporal lobectomy (L-ATL) may be complicated by confrontation naming deficits. Objective: To determine whether preoperative fMRI predicts such deficits in patients with epilepsy undergoing L-ATL. Methods: Twenty-four patients with L-ATL underwent preoperative language mapping with fMRI, preoperative intracarotid amobarbital (Wada) testing for language dominance, and pre- and postoperative neuropsychological testing. fMRI laterality indexes (LIs), reflecting the interhemispheric difference between activated volumes in left and right homologous regions of interest, were calculated for each patient. Relationships between the fMRI LI, Wada language dominance, and naming outcome were examined. Results: Both the fMRI LI (p < 0.001) and the Wada test (p < 0.05) were predictive of naming outcome. fMRI showed 100% sensitivity and 73% specificity in predicting significant naming decline. Both fMRI and the Wada test were more predictive than age at seizure onset or preoperative naming performance. Conclusions: Preoperative fMRI predicted naming decline in patients undergoing left anterior temporal lobectomy surgery.

Evidence-based guideline update: Vagus nerve stimulation for the treatment of epilepsy Report of the Guideline Development Subcommittee of the American Academy of Neurology

Objective: To evaluate the evidence since the 1999 assessment regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients >12 years. Methods: We reviewed the literature and identified relevant published studies. We classified these studies according to the American Academy of Neurology evidence-based methodology. Results: VNS is associated with a >50% seizure reduction in 55% (95% confidence interval [CI] 50%–59%) of 470 children with partial or generalized epilepsy (13 Class III studies). VNS is associated with a >50% seizure reduction in 55% (95% CI 46%–64%) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies). VNS is associated with an increase in ≥50% seizure frequency reduction rates of ∼7% from 1 to 5 years postimplantation (2 Class III studies). VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies). Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio 3.4, 95% CI 1.0–11.2). VNS is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy. VNS may have improved efficacy over time. Recommendations: VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after VNS implantation.

Oxcarbazepine Double-blind, randomized, placebo-control, monotherapy trial for partial seizures

Objective: To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. Methods: A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. Results: Analysis of the primary efficacy variable—time to meeting one of the exit criteria—showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables—percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)—were also statistically significant in favor of oxcarbazepine. Conclusion: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.OBJECTIVE To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. METHODS A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. RESULTS Analysis of the primary efficacy variable--time to meeting one of the exit criteria--showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables--percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)--were also statistically significant in favor of oxcarbazepine. CONCLUSION These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.

Effects of Vagal Nerve Stimulation on Cognition and Quality of Life in Epilepsy

To evaluate the cognitive and quality-of-life (QOL) impacts of vagal nerve stimulation (VNS), 160 patients with uncontrolled partial seizures from 20 sites were enrolled in a double-blind study. Patients were randomly assigned to low (minimal) stimulation (n = 82) or high (now clinically used) stimulation (n = 78) conditions and given a group of cognitive and QOL tests before implantation and after 12-16 weeks of VNS treatment. Results showed no clear cognitive changes. However, fewer emotional and physical problems were reported by the High Group than the Low Group at the end of the study. The 32 patients who had at least 50% seizure relief showed slightly more improvement in QOL variables than those patients who did not demonstrate this degree of seizure reduction. Overall, a small number of favorable QOL but no cognitive changes were associated with levels of VNS stimulation that are now typically used clinically.

Functional magnetic resonance imaging of somatosensory stimulation

Functional magnetic resonance imaging (FMRI) has detected changes in regional cerebral blood flow and volume in response to motor movements, visual stimuli, and auditory stimuli in each of their respective primary cortices. This experiment was conducted to determine whether signal changes in the somatosensory cortex secondary to tactile stimulation could be demonstrated. The palm of the right hand was periodically stimulated while the subject was undergoing echo-planar imaging with a 1.5-T magnetic resonance scanner equipped with local gradient and radio frequency coils. Sagittal and coronal images of 10- to 15-mm slice thickness were selected to include the postcentral gyrus and surrounding regions. Temporally correlated signal changes of 1% to 5% occurred in the peri-rolandic region in each of six subjects. The time course of signal changes was comparable to that found in other primary sensory and motor cortices. The results provide preliminary evidence of the sensitivity of FMRI to activation of the somatosensory cortex with tactile stimulation and support FMRI as a promising noninvasive technique for study of the functional organization and integrity of the cerebrum.