Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3–12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80–1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.
Dario J. Englot, Edward F. Chang and Kurtis I. Auguste
Dario J. Englot, Seunggu J. Han, Michael T. Lawton and Edward F. Chang
Seizures are the most common presenting symptom of supratentorial cerebral cavernous malformations (CCMs) and progress to medically refractory epilepsy in 40% of patients. Predictors of seizure freedom in the resection of CCMs are incompletely understood.
The authors systematically reviewed the published literature on seizure freedom following the resection of supratentorial CCMs in patients presenting with seizures. Seizure outcomes were stratified across 12 potential prognostic variables. A total of 1226 patients with supratentorial CCMs causing seizures were identified across 31 predominantly retrospective studies; 361 patients had medically refractory epilepsy.
Seventy-five percent of the patients were seizure free after microsurgical lesion removal, whereas 25% continued to have seizures. All patients had had preoperative seizures and > 6 months of postoperative follow-up. Modifiable predictors of postoperative seizure freedom included gross-total resection (OR 36.6, 95% CI 8.5–157.5) and surgery within 1 year of symptom onset (OR 1.83, 95% CI 1.30–2.58). Additional prognostic indicators of a favorable outcome were a CCM size < 1.5 cm (OR 15.4, 95% CI 5.2–45.4), the absence of multiple CCMs (OR 2.02, 95% CI 1.13–3.60), medically controlled seizures (OR 2.38, 95% CI 1.29–4.39), and the lack of secondarily generalized seizures (OR 3.33, 95% CI 2.09–5.30). Other factors, including extended resection of the hemosiderin ring, were not significantly predictive.
In the surgical treatment of supratentorial CCMs, gross-total resection and early operative intervention may improve seizure outcome. While surgery should not be considered the first-line treatment for CCM-related epilepsy, it is important to understand the variables associated with seizure freedom in CCM resection given the considerable morbidity and diminished quality of life associated with epilepsy.
Dario J. Englot, Mitchel S. Berger, Nicholas M. Barbaro and Edward F. Chang
Seizures are the most frequent presenting symptom in patients with low-grade gliomas (LGGs), and significantly influence quality of life if they are uncontrolled. Achieving freedom from seizures is of utmost importance in surgical planning, but the factors associated with seizure control remain incompletely understood.
The authors performed a systematic literature review of seizure outcomes after resection of LGGs causing seizures, examining 773 patients across 20 published series. Rates of seizure freedom were stratified across 7 variables: patient age, tumor location, preoperative seizure control with medication, seizure semiology, epilepsy duration, extent of resection, and the use of intraoperative electrocorticography (ECoG).
Gross-total resection was most predictive of complete seizure freedom, when compared with subtotal resection (OR 3.41, 95% CI 2.36–4.93). Other predictors of seizure freedom included preoperative seizure control on antiepileptic medication (OR 2.12, 95% CI 1.33–3.38) and duration of seizures of ≤ 1 year (OR 1.85, 95% CI 1.22–2.79). Patients with simple partial seizure semiology achieved seizure freedom less often than those with complex partial, generalized, or mixed seizure types (OR 0.46, 95% CI 0.26–0.80). No significant differences in seizure outcome were observed between adults versus children, patients with temporal lobe versus extratemporal tumors, or with the use of intraoperative ECoG.
Seizure control is one of the most important considerations in planning surgery for low-grade brain tumors. Gross-total resection is a critical factor in achieving seizure freedom.
Dario J. Englot, Jonathan D. Breshears, Peter P. Sun, Edward F. Chang and Kurtis I. Auguste
While temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults, seizures in children are more often extratemporal in origin. Extra–temporal lobe epilepsy (ETLE) in pediatric patients is often medically refractory, leading to significantly diminished quality of life. Seizure outcomes after resective surgery for pediatric ETLE vary tremendously in the literature, given diverse patient and epilepsy characteristics and small sample sizes. The authors performed a systematic review and meta-analysis of studies including 10 or more pediatric patients (age ≤ 19 years) published over the last 20 years examining seizure outcomes after resective surgery for ETLE, excluding hemispherectomy. Thirty-six studies were examined. These 36 studies included 1259 pediatric patients who underwent resective surgery for ETLE. Seizure freedom (Engel Class I outcome) was achieved in 704 (56%) of these 1259 patients postoperatively, and 555 patients (44%) continued to have seizures (Engel Class II–IV outcome). Shorter epilepsy duration (≤ 7 years, the median value in this study) was more predictive of seizure freedom than longer (> 7 years) seizure history (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.07–2.14), suggesting that earlier intervention may be beneficial. Also, lesional epilepsy was associated with better seizure outcomes than nonlesional epilepsy (OR 1.34, 95% CI 1.19–1.49). Other predictors of seizure freedom included an absence of generalized seizures (OR 1.61, 95% CI 1.18–2.35) and localizing ictal electroencephalographic findings (OR 1.55, 95% CI 1.24–1.93). In conclusion, seizure outcomes after resective surgery for pediatric ETLE are less favorable than those associated with temporal lobectomy, but seizure freedom may be more common with earlier intervention and lesional epilepsy etiology. Children with continued debilitating seizures despite failure of multiple medication trials should be referred to a comprehensive pediatric epilepsy center for further medical and surgical evaluation.
Dario J. Englot, Stephen T. Magill, Seunggu J. Han, Edward F. Chang, Mitchel S. Berger and Michael W. McDermott
Meningioma is the most common benign intracranial tumor, and patients with supratentorial meningioma frequently suffer from seizures. The rates and predictors of seizures in patients with meningioma have been significantly under-studied, even in comparison with other brain tumor types. Improved strategies for the prediction, treatment, and prevention of seizures in patients with meningioma is an important goal, because tumor-related epilepsy significantly impacts patient quality of life.
The authors performed a systematic review of PubMed for manuscripts published between January 1980 and September 2014, examining rates of pre- and postoperative seizures in supratentorial meningioma, and evaluating potential predictors of seizures with separate meta-analyses.
The authors identified 39 observational case series for inclusion in the study, but no controlled trials. Preoperative seizures were observed in 29.2% of 4709 patients with supratentorial meningioma, and were significantly predicted by male sex (OR 1.74, 95% CI 1.30–2.34); an absence of headache (OR 1.77, 95% CI 1.04–3.25); peritumoral edema (OR 7.48, 95% CI 6.13–9.47); and non–skull base location (OR 1.77, 95% CI 1.04–3.25). After surgery, seizure freedom was achieved in 69.3% of 703 patients with preoperative epilepsy, and was more than twice as likely in those without peritumoral edema, although an insufficient number of studies were available for formal meta-analysis of this association. Of 1085 individuals without preoperative epilepsy who underwent resection, new postoperative seizures were seen in 12.3% of patients. No difference in the rate of new postoperative seizures was observed with or without perioperative prophylactic anticonvulsants.
Seizures are common in supratentorial meningioma, particularly in tumors associated with brain edema, and seizure freedom is a critical treatment goal. Favorable seizure control can be achieved with resection, but evidence does not support routine use of prophylactic anticonvulsants in patients without seizures. Limitations associated with systematic review and meta-analysis should be considered when interpreting these results.
Dario J. Englot, Doris D. Wang, John D. Rolston, Tina T. Shih and Edward F. Chang
Frontal lobe epilepsy (FLE) is the second-most common focal epilepsy syndrome, and seizures are medically refractory in many patients. Although various studies have examined rates and predictors of seizure freedom after resection for FLE, there is significant variability in their results due to patient diversity, and inadequate follow-up may lead to an overestimation of long-term seizure freedom.
In this paper the authors report a systematic review and meta-analysis of long-term seizure outcomes and predictors of response after resection for intractable FLE. Only studies of at least 10 patients examining seizure freedom after FLE surgery with postoperative follow-up duration of at least 48 months were included.
Across 1199 patients in 21 studies, the overall rate of postoperative seizure freedom (Engel Class I outcome) was 45.1%. No trend in seizure outcomes across all studies was observed over time. Significant predictors of long-term seizure freedom included lesional epilepsy origin (relative risk [RR] 1.67, 95% CI 1.36–28.6), abnormal preoperative MRI (RR 1.64, 95% CI 1.32–2.08), and localized frontal resection versus more extensive lobectomy with or without an extrafrontal component (RR 1.71, 95% CI 1.26–2.43). Within lesional FLE cases, gross-total resection led to significantly improved outcome versus subtotal lesionectomy (RR 1.99, 95% CI 1.47–2.84).
These findings suggest that FLE patients with a focal and identifiable lesion are more likely to achieve seizure freedom than those with a more poorly defined epileptic focus. While seizure freedom can be achieved in the surgical treatment of medically refractory FLE, these findings illustrate the compelling need for improved noninvasive and invasive localization techniques in FLE.
John D. Rolston, Dario J. Englot, Doris D. Wang, Tina Shih and Edward F. Chang
Epilepsy is a devastating disease, often refractory to medication and not amenable to resective surgery. For patients whose seizures continue despite the best medical and surgical therapy, 3 stimulation-based therapies have demonstrated positive results in prospective randomized trials: vagus nerve stimulation, deep brain stimulation of the thalamic anterior nucleus, and responsive neurostimulation. All 3 neuromodulatory therapies offer significant reductions in seizure frequency for patients with partial epilepsy. A direct comparison of trial results, however, reveals important differences among outcomes and surgical risk between devices. The authors review published results from these pivotal trials and highlight important differences between the trials and devices and their application in clinical use.
A systematic review
Dario J. Englot, John D. Rolston, Doris D. Wang, Peter P. Sun, Edward F. Chang and Kurtis I. Auguste
Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is responsible for 15%–20% of epilepsy cases in children. Class I evidence strongly supports the use of temporal lobectomy for intractable TLE in adults, but fewer studies have examined seizure outcomes and predictors of seizure freedom after temporal lobectomy in pediatric patients. The authors performed a systematic review and meta-analysis of studies including 10 or more pediatric patients (age ≤ 19 years) published over the last 20 years examining seizure outcomes after temporal lobectomy for TLE. Thirty-six studies met their inclusion criteria. These 36 studies included 1318 pediatric patients with a mean age (± SEM) of 10.7 ± 0.3 years. Overall, seizure freedom (Engel Class I outcome) was achieved in 1002 cases (76%); 316 patients (24%) continued to have seizures (Engel Class II–IV outcome). All patients had at least 1 year of follow-up. Statistically significant predictors of seizure freedom after surgery included lesional epilepsy etiology (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.02–1.15), abnormal findings on preoperative MRI (OR 1.27, 95% CI 1.16–1.40), and lack of generalized seizures (OR 1.36, 95% CI 1.20–1.56). Among lesional epilepsy cases, there was a trend toward better outcome with gross-total lesionectomy than with subtotal resection. Approximately three-fourths of pediatric patients with TLE attain seizure freedom after temporal lobectomy. Favorable outcomes may be predicted by lesional epilepsy etiology, abnormal MRI, and lack of generalized seizures. Pediatric patients with medically refractory TLE should be referred to a comprehensive pediatric epilepsy center for surgical evaluation.
Nathan C. Rowland, Dario J. Englot, Tene A. Cage, Michael E. Sughrue, Nicholas M. Barbaro and Edward F. Chang
Focal cortical dysplasia (FCD) is one of the most common causes of medically refractory epilepsy leading to surgery. However, seizure control outcomes reported in isolated surgical series are highly variable. As a result, it is not clear which variables are most crucial in predicting seizure freedom following surgery for FCD. The authors' aim was to determine the prognostic factors for seizure control in FCD by performing a meta-analysis of the published literature.
A MEDLINE search of the published literature yielded 37 studies that met inclusion and exclusion criteria. Seven potential prognostic variables were determined from these studies and were dichotomized for analysis. For each variable, individual studies were weighted by inverse variance and combined to generate an odds ratio favoring seizure freedom. The methods complied with a standardized meta-analysis reporting protocol.
Two thousand fourteen patients were included in the analysis. The overall rate of seizure freedom (Engel Class I) among patients undergoing surgery for FCD in the cohort of studies was 55.8% ± 16.2%. Partial seizures, a temporal location, detection with MRI, and a Type II Palmini histological classification were associated with higher rates of postoperative seizure control. As a treatment-related factor, complete resection of the anatomical or electrographic abnormality was the most important predictor overall of seizure freedom. Neither age nor electroencephalographic localization of the ictal onset significantly affected seizure freedom after surgery.
Using a large population cohort pooled from the published literature, an analysis identified important factors that are prognostic in patients with epilepsy due to FCD. The most important of these factors—diagnostic imaging and resection—provide modalities through which improvements in the impact of FCD can be effected.
Dario J. Englot, John D. Rolston, Doris D. Wang, Kevin H. Hassnain, Charles M. Gordon and Edward F. Chang
In the US, approximately 500,000 individuals are hospitalized yearly for traumatic brain injury (TBI), and posttraumatic epilepsy (PTE) is a common sequela of TBI. Improved treatment strategies for PTE are critically needed, as patients with the disorder are often resistant to antiepileptic medications and are poor candidates for definitive resection. Vagus nerve stimulation (VNS) is an adjunctive treatment for medically refractory epilepsy that results in a ≥ 50% reduction in seizure frequency in approximately 50% of patients after 1 year of therapy. The role of VNS in PTE has been poorly studied. The aim of this study was to determine whether patients with PTE attain more favorable seizure outcomes than individuals with nontraumatic epilepsy etiologies.
Using a case-control study design, the authors retrospectively compared seizure outcomes after VNS therapy in patients with PTE versus those with nontraumatic epilepsy (non-PTE) who were part of a large prospectively collected patient registry.
After VNS therapy, patients with PTE demonstrated a greater reduction in seizure frequency (50% fewer seizures at the 3-month follow-up; 73% fewer seizures at 24 months) than patients with non-PTE (46% fewer seizures at 3 months; 57% fewer seizures at 24 months). Overall, patients with PTE had a 78% rate of clinical response to VNS therapy at 24 months (that is, ≥ 50% reduction in seizure frequency) as compared with a 61% response rate among patients with non-PTE (OR 1.32, 95% CI 1.07–1.61), leading to improved outcomes according to the Engel classification (p < 0.0001, Cochran-Mantel-Haenszel statistic).
Vagus nerve stimulation should be considered in patients with medically refractory PTE who are not good candidates for resection. A controlled prospective trial is necessary to further examine seizure outcomes as well as neuropsychological outcomes after VNS therapy in patients with intractable PTE.