Faculty Bibliography

Rationale: Resective surgery is an important consideration for patients with treatment resistant epilepsy as it may offer the best chance for seizure freedom. Initial patient counseling and the decision to refer a patient to an epilepsy surgery center is usually based on the history and physical exam, routine electroencephalogram (EEG), and brain MRI. The aim of this review is to summarize the literature and identify factors typically available in the general office setting that are reliable predictors of epilepsy surgery outcome. Methods: A literature search was performed using Pubmed and Embase. Inclusion criteria included: English language, sample size e20 patients, MRI performed on e90% of patients, a median age e16 years, average of e1 year follow-up, and predictive value assessment of clinical factors, routine EEG and/or MRI brain for outcome in epilepsy surgical resections. Articles were independently reviewed by at least 2 authors and data on study design and predictive factors were abstracted. Results: Of the 2,248 articles related to predictors of epilepsy surgical outcome identified, 123 met all inclusion criteria. Only 12 articles had a prospective study design. Study populations varied in size and epilepsy characteristics with the majority focusing on mesial temporal lobe epilepsy or lesional epilepsies. The studies focused almost exclusively on patients that had undergone resection rather than all patients considered for surgery or undergoing invasive procedures (intention-to-treat analysis). Predictive factors were not uniformly assessed in most studies, nor were they uniformly defined across studies. For example, in various studies, unilateral routine EEG epileptiform activity was variably categorized as "only ipsilateral spikes", ">70% ipsilateral", ">80% ipsilateral", or ">90% ipsilateral". Although many studies used the Engel or modified Engel classification systems, many utilized non-standardized outcome determinations (e.g. "good"). Only 6 studies had a masked assessment of seizure outcome following surgery. Conclusions: The heterogeneous patient populations, methodologies and outcome determinations significantly limit the existing literature's ability to predict the likelihood of a patient achieving seizure freedom from resective surgery based upon pre-operative data, especially in patients with extra-temporal non-mesial epilepsy. Prospective multicenter studies based upon intention to treat (i.e. enrolling patients prior to invasive procedures to determine the number of patients that are considered for epilepsy surgery that do not progress to a resective procedure) are necessary to better facilitate and encourage early referral to comprehensive epilepsy centers, counsel patients and families and identify new strategies for improving outcomes. By establishing and utilizing accepted, standardized definitions (e.g. treatment resistant epilepsy), one can improve the generalizability of findings across patients and centers

Rationale: Magnetic resonance imaging has revolutionized the detection of small structural abnormalities in patients with epilepsy. However, many focal abnormalities remain undetected in routine visual inspection. Here we used morphometric MRI to quantify imaging features related to epileptogenic cortical malformations to detect abnormal cortical thickness and blurred gray-white matter boundaries that went undetected by routine clinical visual inspection. Methods: Using MRI morphometry at 3T with surface-based spherical averaging techniques that precisely align anatomical structures between individual brains, we compared single patients with known lesions to a large normal control group to detect clusters of abnormal cortical thickness and gray-white matter contrast (GWC). To assess the effects of threshold and smoothing on detection sensitivity and specificity, we systematically varied these parameters with different thresholds and smoothing levels. To establish the effectiveness of the technique, we compared the detected structural abnormalities to resection margins, seizure onset zones based on intracranial EEG and pathological features using post-resection histology. Results: We report optimal parameters by which cortical thickness and GWC features detected previously occult lesions. We present sensitivity and specificity measures for each threshold and smoothing level to allow for selection of parameters based on clinical need. Conclusions: This automated approach may be a valuable additional clinical tool to improve the detection of subtle or previously occult malformations and therefore may improve identification of patients with intractable focal epilepsy who may benefit from surgery

PURPOSE: Monotherapy approvals have been difficult to obtain from the U.S. Food and Drug Administration (FDA), and have almost all been achieved using a trial design entitled 'withdrawal to monotherapy' in treatment-resistant patients, which employs a so-called 'pseudo-placebo' as a comparator arm. The authors submitted a white paper to the FDA advocating use of a virtual placebo historical control as an alternative to pseudo-placebo. Such an approach reduces patient risk that would result from exposure to pseudo-placebo. In this article, we present the data submitted to the FDA to justify a historical control. METHODS: We analyzed individual patient data from eight previously completed withdrawal to monotherapy studies, which we determined had similar design. All studies employed percent meeting predetermined exit criteria (denoting worsening of seizure control) as the outcome measure. Kaplan-Meier estimates of the percent exiting were calculated at 112 days. RESULTS: The percent meeting exit criteria were uniformly high, ranging from 74.9-95.9%. The eight studies appear to meet the criteria set forth for use of historical control. The estimate of the combined percent exit based on the noniterative mixed-effects model is 85.1%, with a lower bound of the 95% prediction interval of 65.3%, and 72.2% for an 80% prediction interval. CONCLUSION: There is justification for proposing that these data can serve as a historical control for future monotherapy studies, obviating the need for a placebo/pseudo-placebo arm in trials intended to demonstrate the efficacy of approved drugs as monotherapy in treatment-resistant patients

OBJECTIVE: To explore efficacy and safety/tolerability of adjunctive brivaracetam (BRV), a novel, high-affinity synaptic vesicle protein 2A ligand, which also inhibits neuronal voltage-dependent sodium channels, in patients with refractory partial-onset seizures (POS). METHODS: This was an exploratory, phase IIb, double-blind, randomized, parallel-group, placebo-controlled, dose-ranging study in patients 16-65 years with epilepsy experiencing > or =4 POS during 4-week baseline despite 1-2 concomitant antiepileptic drugs. Patients were randomized (1:1:1:1) to placebo, BRV 5 mg/day (BRV5), BRV 20 mg/day (BRV20), or BRV 50 mg/day (BRV50), administered BID without uptitration during a 7-week treatment period. Primary efficacy endpoint was POS frequency/week during the treatment period relative to placebo. RESULTS: A total of 208 patients constituted the intention-to-treat population; 197 completed the study. Estimated percentage reductions over placebo in POS frequency/week were 9.8% (BRV5; p = 0.240), 14.9% (BRV20; p = 0.062), and 22.1% (BRV50; p = 0.004). Median percent reductions from baseline in POS frequency/week were 21.7% (placebo), 29.9% (BRV5; p = 0.086), 42.6% (BRV20; p = 0.014), and 53.1% (BRV50; p < 0.001); > or =50% responder rates were 16.7% (placebo), 32.0% (BRV5; p = 0.047), 44.2% (BRV20; p = 0.002), and 55.8% (BRV50; p < 0.001); seizure freedom rates (POS) during the 7-week treatment period were 1.9% (placebo), 8.0% (BRV5; p = 0.193), 7.7% (BRV20; p = 0.193), and 7.7% (BRV50; p = 0.201). BRV was well-tolerated. Most adverse events were mild to moderate and occurred with similar incidence in placebo and BRV groups, and discontinuations due to treatment-emergent adverse events were infrequent (placebo 3.7%; BRV 2.6%). CONCLUSIONS: This interventional study provides preliminary Class I evidence that adjunctive BRV was efficacious and well-tolerated in patients aged 16-65 years with POS

Comparative effectiveness research (CER) is the study of the relative effects of treatments to determine which will be most likely to improve overall health for a specific condition. This area has received a great deal of political focus, and substantial funding for CER is included in the American Reinvestment and Recovery Act of 2009. The results of CER are intended to inform evidence-based guidelines and to improve the quality and effectiveness of medical care. In the absence of such research, guidelines often depend on consensus to rank available therapies. We believe that an increase in CER would clearly enhance evidence-based guidelines. However, the research must be performed and analyzed with great care to avoid reaching unhelpful, or even harmful, conclusions. Specifically, individual patient characteristics must be taken into account, study endpoints must approximate the most important patient outcomes, therapies must be used optimally within the studies, and the most relevant therapies for a given indication must be included for comparison. CER that is not performed or interpreted correctly could have the potential to affect negatively our choices of therapies. The neurology community must help inform the process of CER to ensure the highest-quality research, which in turn will result in the most valid outcomes