Neuroanatomic Markers of Posttraumatic Epilepsy Based on MR Imaging and Machine Learning.

BACKGROUND AND PURPOSE: Although posttraumatic epilepsy is a common complication of traumatic brain injury, the relationship between these conditions is unclear and early posttraumatic epilepsy detection and prevention remain major unmet clinical challenges. This study aimed to identify imaging biomarkers that predict posttraumatic epilepsy among survivors of traumatic brain injury on the basis of an MR imaging data set. MATERIALS AND METHODS: We performed tensor-based morphometry to analyze brain-shape changes associated with traumatic brain injury and to derive imaging features for statistical group comparison. Additionally, machine learning was used to identify structural anomalies associated with brain lesions. Automatically generated brain lesion maps were used to identify brain regions where lesion load may indicate an increased incidence of posttraumatic epilepsy. We used 138 non-posttraumatic epilepsy subjects for training the machine learning method. Validation of lesion delineation was performed on 15 subjects. Group analysis of the relationship between traumatic brain injury and posttraumatic epilepsy was performed on an independent set of 74 subjects (37 subjects with and 37 randomly selected subjects without epilepsy). RESULTS: We observed significant F-statistics related to tensor-based morphometry analysis at voxels close to the pial surface, which may indicate group differences in the locations of edema, hematoma, or hemorrhage. The results of the F-test on lesion data showed significant differences between groups in both the left and right temporal lobes. We also saw significant differences in the right occipital lobe and cerebellum. CONCLUSIONS: Statistical analysis suggests that lesions in the temporal lobes, cerebellum, and the right occipital lobe are associated with an increased posttraumatic epilepsy incidence.

Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial.

OBJECTIVE: To assess progesterone treatment of intractable seizures in women with partial epilepsy. METHODS: This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles. RESULTS: There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3. CONCLUSION: There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.

Vagus nerve stimulation for epilepsy: is output current correlated with acute response?

OBJECTIVES: Vagus nerve stimulation (VNS) is an effective treatment for intractable epilepsy. It is unknown whether acute response is correlated with the amplitude of output current. The purpose of this study was to determine if the output current of VNS is correlated with percent reductions in seizure frequency and response. MATERIALS AND METHODS: Retrospective analysis of a multicenter randomized trial of three unique paradigms of VNS was carried out in patients with intractable partial onset epilepsy. Output current at 1 and 3 months was correlated with percent reduction in seizure frequency and response rates. RESULTS: Sixty-one subjects were enrolled and completed the study. Output current, ranging from 0.25 to 1.5 mA, was not correlated with reductions in seizure frequency, or with > or = 50% reduction in seizures. Six of seven initial non-responders did experience > or = 50% reductions in seizures after current was increased. CONCLUSIONS: The output current is not a major determinant of acute response to VNS for epilepsy. Many patients respond to low current (<1 mA). Some (20%) initial non-responders may respond to an increase in output current.

Experience with vagus nerve stimulation for intractable epilepsy: some questions and answers.

Vagus nerve stimulation (VNS) is gaining increasing popularity and credibility as a treatment option for patients with intractable epilepsy. VNS is a relatively recent innovation, however, and like many other incipient developments, it has engendered a number of unresolved controversies and perplexities. Limitations in our current understanding of how VNS works lie at the crux of these uncertainties. In this article, we present our clinical experience with VNS and review the fundamental issue which remain unsettled, such as the mechanism of VNS action, the factors underlying variability in patient outcome, and the selection of ideal candidates for VNS therapy. Although many enigmas persist, VNS has proven to be a safe, feasible, and potentially effective method of reducing seizures in select patient populations. It offers several advantages over extant treatments and, as a result, holds much promise for future therapy of medically refractory epilepsy.

Serum neuron-specific enolase in the major subtypes of status epilepticus.

OBJECTIVES: To determine the relative magnitudes of neuron-specific enolase (NSE) levels after complex partial status epilepticus (SE), absence SE, generalized convulsive SE, and subclinical generalized convulsive SE (frequently referred to as acute symptomatic myoclonic status epilepticus). BACKGROUND: NSE is a marker of acute brain injury and blood-brain barrier dysfunction, which is elevated in SE. METHODS: Serum NSE levels were drawn in 31 patients 1, 2, 3, and 7 days after SE. Patients were classified as acute symptomatic or remote symptomatic, and the duration and outcome of SE were determined and correlated with the peak NSE level. RESULTS: NSE was elevated significantly in all four subtypes of SE, but NSE levels were highest in complex partial and subclinical SE. The mean peak NSE level for the complex partial SE group was 23.88 ng/mL (n = 12), 21.5 ng/mL for absence SE (n = 1), 14.10 ng/mL for the generalized convulsive SE group (n = 12), and 37.83 ng/mL for the subclinical SE group (n = 6), all of which was significantly higher than normal control subjects (5.02 ng/mL). Outcome was significantly different between the three groups (p = 0.0007), and was significantly worse for subclinical SE (p = 0.0005, subclinical versus generalized convulsive SE). CONCLUSION: Serum NSE levels were highest in complex partial and subclinical generalized convulsive SE. The extremely high levels of NSE in subclinical SE reflect the severity of the acute neurologic insults and poor outcome common to subclinical SE. High NSE levels in complex partial SE reflects the long duration of SE in this subgroup, and potential for brain injury.

An institutional experience with cervical vagus nerve trunk stimulation for medically refractory epilepsy: rationale, technique, and outcome.

OBJECTIVE: Intermittent stimulation of the left cervical vagus nerve trunk is emerging as a novel adjunct in the treatment of medically refractory seizures. We sought to evaluate theoretical and practical issues attendant to this concept. We review the anatomic and physiological background arguing for clinical application of vagus nerve stimulation, discuss salient aspects of patient selection and the nuances of surgical technique, and present our observations of and results from application of the method. METHODS: Each of 18 patients with medically refractory epilepsy and at least six complex partial or secondarily generalized seizures per month underwent placement of a NeuroCybernetic Prosthesis pulse generator (Cyberonics, Webster, TX) in the chest, connected to helical platinum leads applied to the left cervical vagus nerve trunk. The patients were then randomized in a double-blinded fashion to receive either high (presumably therapeutic) or low (presumably less therapeutic) levels of vagus nerve stimulation. Reduction in seizure frequency, global assessments of quality of life, physiological measurements, and adverse events were recorded during a 3-month period. Patients in the low group were then crossed over to high-stimulation paradigms during a 15-month extension trial. RESULTS: All operations were successful, uneventful, and without adverse postoperative sequelae. One patient was excluded from analysis because of inadequate seizure calendars. Of the seven patients initially assigned to high stimulation, the mean reduction in seizure frequency was 71% at 3 months and 81% at 18 months. Five (72%) of these patients had a greater than 75% reduction in seizure frequency, and one (14%) remained seizure-free after more than 1.5 years of follow-up. The mean reduction in seizure frequency among the low-stimulation group was only 6% at 3 months. No serious complications, device failures, or physiological perturbations occurred. CONCLUSION: In our experience, vagus nerve stimulation has proven to be a safe, feasible, and potentially effective method of reducing seizures in select patient populations. However, the elements of strict definition for the application of the method require further study.

Status epilepticus increases CSF levels of neuron-specific enolase and alters the blood-brain barrier.

Neuron-specific enolase (NSE) is a sensitive marker of brain damage in stroke, global ischemia, and coma. Serum NSE is also correlated with the duration and outcome of status epilepticus (SE). CSF-NSE levels have not been previously reported in SE. We report the CSF concentrations of NSE in 11 patients with cryptogenic/remote symptomatic SE. CSF obtained within 24 hours of SE showed increased concentrations of NSE in 9 of 11 patients. The mean CSF-NSE for the group was elevated compared with the levels for normal control subjects (30.8 +/- 18.33 versus 10.76 +/- 3.08 ng/mL; p = 0.002). Further, CSF-NSE levels were elevated compared with simultaneous serum levels in the same group of patients (p = 0.01). In addition, the CSF/serum albumin ratio (QAlb), a measure of the integrity of the blood-brain barrier, was increased in SE patients compared with control individuals (33.4 versus 4.79 x 10(-3); p = 0.0001). An increase of QAlb correlated with CSF-NSE (rs = 0.66, p = 0.04) and serum NSE levels (rs = 0.83, p = 0.004). CSF-NSE is a promising in vivo marker for brain injury after SE.

Neuron-specific enolase, a marker of acute neuronal injury, is increased in complex partial status epilepticus.

PURPOSE: To determine whether complex partial status epilepticus (CPSE) causes brain injury in humans. Serum neuron-specific enolase (s-NSE) is an accepted marker of acute brain injury, and increases in s-NSE have been correlated with the duration and outcome of generalized convulsive status epilepticus. s-NSE levels in CPSE are unknown. Increase in s-NSE in CPSE would provide new information about the degree of brain injury in CPSE and would help confirm that CPSE is a medical emergency. METHODS: This was a pilot prospective study of serial levels of s-NSE and outcome in CPSE. Eight patients with confirmed CPSE and no acute neurologic deficit were identified prospectively. Results were compared with those of normal and epileptic control groups, and outcome was assessed at hospital discharge or at 7 days with the Glasgow Oucome Scale (GOS). RESULTS: The mean peak s-NSE was 21.81 ng/ml, which for the 8 patients with CPSE was four times higher than that of normal controls (mean s-NSE = 5.36 SD = 1.66, p = 0.0003) and epileptic controls (mean s-NSE = 4.61 SD = 1.74, p. = 0.001). CONCLUSION: The increase in s-NSE provides new evidence that CPSE causes brain injury in humans.