Brain blood-flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: II. prolonged effects at high and low levels of stimulation.

PURPOSE: To measure vagus nerve stimulation (VNS)-induced cerebral blood flow (CBF) effects after prolonged VNS and to compare these effects with immediate VNS effects on CBF. METHODS: Ten consenting partial epilepsy patients had positron emission tomography (PET) with intravenous [15O]H2O. Each had three control scans without VNS and three scans during 30 s of VNS, within 20 h after VNS began (immediate-effect study), and repeated after 3 months of VNS (prolonged study). After intrasubject subtraction of control from stimulation scans, images were anatomically transformed for intersubject averaging and superimposed on magnetic resonance imaging (MRI) for anatomic localization. Changes on t-statistical maps were considered significant at p < 0.05 (corrected for multiple comparisons). RESULTS: During prolonged studies, CBF changes were not observed in any regions that did not have CBF changes during immediate-effect studies. During both types of studies, VNS-induced CBF increases were similarly located in the bilateral thalami, hypothalami, inferior cerebellar hemispheres, and right postcentral gyrus. During immediate-effect studies, VNS decreased bilateral hippocampal, amygdalar, and cingulate CBF and increased bilateral insular CBF; no significant CBF changes were observed in these regions during prolonged studies. Mean seizure frequency decreased by 25% over a 3-month period between immediate and prolonged PET studies, compared with 3 months before VNS began. CONCLUSIONS: Seizure control improved during a period over which some immediate VNS-induced CBF changes declined (mainly over cortical regions), whereas other VNS-induced CBF changes persisted (mainly over subcortical regions). Altered synaptic activities at sites of persisting VNS-induced CBF changes may reflect antiseizure actions.

Perfusion SPECT changes after acute and chronic vagus nerve stimulation in relation to prestimulus condition and long-term clinical efficacy.

UNLABELLED: Left-sided vagus nerve stimulation (VNS) is an efficacious treatment for patients with refractory epilepsy. Previous studies have implicated thalamic and mesial temporal involvement in acute stimulation. In this study, acute and chronic effects of VNS in patients with refractory complex partial seizures with or without secondary generalization (CPS +/- SG) were evaluated with respect to the prestimulus condition and long-term follow-up. METHODS: Twenty-three patients (12 females, 11 males; mean age, 32.4 +/- 10.6 y; mean CPS +/- SG duration, 21.0 +/- 11.7 y) were prospectively included. All patients were considered unsuitable candidates for resective surgery because of nonlocalizing findings in the presurgical evaluation. All underwent a split-dose (99m)Tc-ethyl cysteinate dimer activation study before and immediately after their initial stimulation (0.25 or 0.5 mA, 30 Hz) on a high-resolution triple-head gamma camera. Ten patients also underwent a SPECT activation study 5.7 +/- 1.6 mo after implantation with an additional 0.25-mA stimulus superposed on a therapeutic intensity of 1.5 +/- 0.3 mA. Data were analyzed by an automated semiquantitative volume-of-interest analysis after stereotactic anatomic standardization. RESULTS: In the acute, initial setting, the left thalamus, right parahippocampal gyrus, and right hippocampus were deactivated by VNS (P < 0.011). Acute stimulation in the chronic state resulted in a significant left thalamic activation (P < 0.001). When chronic perfusion was compared with the initial pre-VNS baseline, perfusion decreases were found in both thalami (-5.3% on the left and -3.4% on the right, P < or = 0.04). Perfusion changes in chronic VNS correlated negatively with the prestimulus perfusion pattern, indicating the tendency toward decreased brain activity on VNS. Initial stimulation changes in the right amygdala in the group of 10 patients with chronic assessment were predictive of therapeutic response (P = 0.018); in addition, right chronic hippocampal perfusion changes correlated strongly with the long-term clinical efficacy of VNS (P = 0.004). CONCLUSION: Under initial and chronic conditions, acute VNS stimulation produces different perfusion changes that are related to the interictal perfusion pattern before stimulation. The long-term mechanism of clinically effective VNS may rely on mainly hippocampal/amygdala and thalamic inhibition. Acute amygdala and chronic hippocampal perfusion changes are predictive of long-term therapeutic response in specific patient subgroups.

Vagus nerve stimulation in refractory epilepsy: SPECT activation study.

UNLABELLED: Left-sided vagus nerve stimulation (VNS) is an efficacious treatment for patients with refractory epilepsy. The exact mechanism of action remains to be elucidated. This study investigated the acute effects of initial VNS in patients with refractory complex partial epilepsy with or without secondary generalization (complex partial seizures [CPS] +/- SG) by means of a perfusion activation study with SPECT. METHODS: Twelve patients (mean age, 32.2 +/- 10.2 y; age range, 12-47 y) with a mean duration of CPS +/- SG of 19.8 +/- 10.0 y (range, 5-33 y) received VNS. All patients were considered unsuitable candidates for resective surgery because of nonlocalizing findings on presurgical evaluation. VNS efficacy was evaluated for patients with at least 4-mo follow-up. VNS-induced regional cerebral blood flow alterations were studied by a (99m)Tc-ethyl cysteinate dimer activation study with a single-day split-dose protocol before and immediately after an initial stimulation. Images were acquired on a triple-head camera with fanbeam collimators. After coregistration to a standardized template, both a semiquantitative analysis using predefined volumes of interest and a voxel-by-voxel analysis of the intrasubject activation (statistical parametric mapping) were performed. RESULTS: Seizure-frequency changes ranged from 100% decrease to 0% after VNS. The semiquantitative analysis revealed a consistent decrease of activity in the left thalamus (ratio stimulator on/off = 0.94 +/- 0.04; P = 0.005). These results were concordant with the voxel-by-voxel analysis in which a significant deactivation in the left thalamus was found with spread to the ipsilateral hippocampus. There was no statistically significant correlation between initial VNS-induced thalamic hypoperfusion and seizure reduction at maximum follow-up. CONCLUSION: Our findings are consistent with the hypothesis that acute VNS reduces seizure onset or propagation through inhibition of the thalamic relay center. Differences with limited H2(15)O PET data may be associated with temporal effects caused by a stimulation-induced local hemodynamic response and need further investigation. SPECT allows study of cerebral physiopathologic effects of vagus nerve electrostimulation in complex partial epilepsy.

Acute single photon emission computed tomographic study of vagus nerve stimulation in refractory epilepsy.

PURPOSE: Left-sided vagus nerve stimulation (VNS) is an efficacious treatment for patients with refractory epilepsy. The precise mechanism of action remains to be elucidated. Only limited data on VNS-induced changes in regional cerebral blood flow (rCBF) are available. The aim of this study was to investigate rCBF changes during initial VNS with single-photon emission computed tomography (SPECT). METHODS: In 12 patients (8 women, 4 men) with mean age of 32 years and mean duration of epilepsy of 19 years, VNS-induced rCBF changes were studied by means of a 99mTc-ethyl cysteinate dimer activation study with a single-day split-dose protocol before and immediately after initial stimulation. Images were acquired on a triple-head camera with fan-beam collimators and were reconstructed with scatter and attenuation correction. After coregistration to a standardized template, both a semiquantitative analysis using predefined volumes-of-interest (VOIs) as well as voxel-by-voxel analysis of the intrasubject activation were performed. During follow-up, efficacy of VNS in terms of seizure-frequency reduction was studied. RESULTS: The semiquantitative analysis, with reference to the total counts in all VOIs, revealed a significant decrease of activity in the left thalamus immediately after the initial stimulation train. These results agreed with voxel-by-voxel analysis. In our study ipsilateral thalamic hypoperfusion was the most significant finding. Mean frequency of complex partial seizures was reduced from 30 per month before implantation to six per month after implantation. CONCLUSIONS: VNS induces rCBF changes immediately after initial stimulation that can be studied with SPECT. VNS-induced changes in the thalamus may play an important role in suppression of seizures. However, no significant relation between the level of hypoperfusion and subsequent clinical efficacy was found.

High-resolution inter-ictal SPET and phased-array MRI in partial epilepsy: an imaging comparison with video/EEG and outcome correlation.

To assess the clinical utility of high-resolution inter-ictal single photon emission tomography (SPET) of regional cerebral perfusion and high-resolution magnetic resonance imaging (MRI) of the brain with a phased-array temporal lobe coil, 35 patients with presumed partial epilepsy were evaluated prospectively by these techniques in addition to prolonged video/electroencephalographic (EEG) monitoring. Twenty of these patients had surgical treatment of partial epilepsy with outcome determinations spanning from 12 months to 3 years at follow-up. There were four categories of imaging findings as compared to scalp/sphenoidal EEG localization. Category I included 12 patients (34% of total) in whom there was complete imaging and EEG concordance. Category II included 4 patients (11%) in whom MRI and EEG were concordant but SPET was divergent or normal. Category III included 13 patients (37%) in whom SPET and EEG were concordant but MRI was divergent or normal. Category IV included 4 patients (11%) in whom neither SPET nor MRI was concordant with EEG. In this study, the relative sensitivities of SPET and MRI for localization of partial epilepsy based on prolonged scalp/sphenoidal video/EEG recordings were 76% and 49%, respectively. We conclude that these neuroimaging techniques (phased-array MRI and inter-ictal cerebral perfusion SPET) are complementary and useful in the pre-operative evaluation of patients with partial epilepsy.

A case of infantile spasms: epileptic apnea as partial seizures at onset.

We report a 2-month-old boy who presented with apneic attacks as a manifestation of epileptic seizures at onset and eventually progressed to infantile spasms. At onset, at 2 months of age, apneic attacks were the sole symptom of epileptic fits. Although these seizures were accompanied by cyanosis, bradycardia was not noted. An ictal electroencephalogram showed focal paroxysmal discharges in the temporal area. Treatment with sodium valproate was not effective to control his seizures. By 6 months of age, he progressed to infantile spasms. Although his seizures could be completely controlled with the use of zonisamide, vitamin B6 or high-dose immunoglobulin, his mental and behavioral development was retarded severely. There have been no previously published cases with infantile spasms that evolved from epileptic apnea as partial seizures.

Brain single-photon emission tomography using technetium-99m bicisate (ECD) in a case of complex partial seizure.

The clinical application of technetium-99m bicisate (ethyl cysteinate dimer, ECD) for ictal and interictal studies of regional cerebral blood flow (rCBF) in a patient suffering from medically intractable simple and complex partial seizures is reported. The interictal study was performed 60 min p.i. and the ictal studies were performed at 60 min p.i. using an annular crystal single photon emission tomography (SPET) system dedicated for high-resolution brain SPET imaging. Visual evaluation of the studies was carried out, as well as semiquantitative measurement of regional tracer uptake. Magnetic resonance imaging (MRI) scans revealed atrophy of almost the complete left frontal lobe and the ventral parts of the left temporal lobe, including in part the temporomesial structures. The left parietal and occipital structures and the right hemisphere were normal. The interictal study showed a large perfusion defect involving the whole left frontal lobe as well as the left temporal lobe with remaining small areas of normal cortical tracer uptake. The ictal studies detected circumscribed hyperperfusion within the left mesial temporal lobe (ventral part of the hippocampus). Additionally an increase in perfusion could be seen within the entire remaining left temporal lobe. Semiquantitative evaluation of tracer uptake comparing both studies detected markedly increased uptake within the focus compared to the remaining left temporal lobe. On this basis the newly available tracer for studies of rCBF, 99mTc-bicisate, seems to be of value for the detection of epileptogenic foci. Additionally, the value of ictal rCBF studies in the presurgical evaluation of those patients presenting severe morphological alterations on MRI is clearly underlined by this case.

The effect of naloxone on cerebral blood flow and glucose metabolism in patients with complex partial seizures.

We used positron emission tomography with [15O]water and [18F]fluoro-2-deoxyglucose (FDG) to study the effect of naloxone on cerebral blood flow (CBF) and glucose metabolism (LCMRglc) in patients with complex partial seizures. There was no effect on glucose metabolism, but blood flow was reduced 7-12% 45-60 min after infusion of 1 mg/kg naloxone, as was the degree of lateral temporal CBF asymmetry in patients with > 10% baseline hypoperfusion. Endogenous opiates are involved in regulation of human CBF, and possibly in hypoperfusion in epileptic foci. Since [18F]FDG PET measures mean LCMRglc over the tracer uptake and scanning periods, it is inferior to [15O]H2O PET for detecting drug effects which may be time dependent.

Lateralization of human focal epilepsy by 31P magnetic resonance spectroscopic imaging.

We attempted to lateralize the epileptogenic focus (seven temporal lobe hippocampal foci, one frontal lobe focus) in medically refractory unilateral complex partial seizures, using noninvasive 31P magnetic resonance spectroscopic imaging (MRSI) blindly and interictally to compare hippocampal or frontal regions. The seizure foci were more alkaline (intracellular pH = 7.17 +/- 0.03) compared with the contralateral region (7.06 +/- 0.02, p < 0.01) in all eight cases; the inorganic phosphate was relatively increased (240 +/- 50% of contralateral, seven of eight cases, p < 0.01); and phosphomonoesters were relatively reduced (68 +/- 9% of contralateral, seven of eight cases, p < 0.01). Other phosphorus metabolites were symmetric (+/- 10%). 31P MRSI correctly lateralized the seizure focus in all eight cases. By comparison, imaging correctly lateralized four cases and SPECT, two cases. In conclusion, 31P MRSI is a useful tool for the noninvasive clinical assessment of focal epilepsy and can accurately lateralize the epileptogenic focus.