Colin B. Josephson

Systematic review and meta-analysis of standard vs selective temporal lobe epilepsy surgery

Objective: To compare standard anterior temporal lobectomy (ATL) with selective amygdalohippocampectomy (SAH) for postoperative seizure control in temporal lobe epilepsy (TLE). Methods: We searched MEDLINE and Embase using Medical Subject Headings and keywords related to ATL and SAH. We included original research that directly compared seizure outcomes in patients undergoing SAH or ATL for TLE. A fixed-effect model was used to derive a pooled risk ratio (RR) for either an Engel Class I (free of disabling seizures) or a composite of an Engel Class I and II (rare disabling seizures) outcome. Results: Of 4,675 abstracts initially identified by the search, 65 were reviewed as full text. Thirteen studies containing data from 8 countries (5 continents) met our inclusion criteria. Eleven studies comprising 1,203 patients demonstrated that participants were statistically more likely to achieve an Engel Class I outcome after ATL compared with SAH (risk ratio 1.32, 95% confidence interval [CI] 1.12–1.57; p < 0.01). The summary risk difference of 8% (95% CI 3%–14%) translates to a number needed to treat of 13 (95% CI 7–33) for 1 additional patient to achieve an Engel Class I outcome after ATL. The result remained significant when 2 studies that contained fewer than 15 participants in at least 1 arm were excluded and in analyses restricted to hippocampal sclerosis. Conclusions: Standard ATL confers an improved chance of achieving freedom from disabling seizures in patients with TLE. Improved seizure freedom must be balanced against the neuropsychological impact of each procedure. A randomized controlled trial is justified.

Outcome After Conservative Management or Intervention for Unruptured Brain Arteriovenous Malformations

IMPORTANCE Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data. OBJECTIVE To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM. DESIGN, SETTING, AND POPULATION Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years. EXPOSURES Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination). MAIN OUTCOMES AND MEASURES Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score ≥2 for ≥2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention). RESULTS Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events; 9.5 vs 9.8 per 100 person-years; adjusted hazard ratio, 0.59; 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events; 1.6 vs 3.3 per 100 person-years; adjusted hazard ratio, 0.37; 95% CI, 0.19-0.72). CONCLUSIONS AND RELEVANCE Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists.

Seizure risk from cavernous or arteriovenous malformations: Prospective population-based study

Objectives: To determine the risk of epileptic seizures due to a brain arteriovenous malformation (AVM) or cavernous malformation (CM). Methods: In a prospective population-based study of new diagnoses of AVMs (n = 229) or CMs (n = 139) in adults in Scotland in 1999–2003, we used annual medical records surveillance, general practitioner follow-up, and patient questionnaires to quantify the risk of seizures between clinical presentation and AVM/CM treatment, last follow-up, or death. Results: The 5-year risk of first-ever seizure after presentation was higher for AVMs presenting with intracranial hemorrhage or focal neurologic deficit (ICH/FND: n = 119; 23%, 95% confidence interval [CI] 9%–37%) than for incidental AVMs (n = 40; 8%, 95% CI 0%–20%), CMs presenting with ICH/FND (n = 38; 6%, 95% CI 0%–14%), or incidental CMs (n = 57; 4%, 95% CI 0%–10%). For adults who had never experienced ICH/FND, the 5-year risk of epilepsy after first-ever seizure was higher for CMs (n = 23; 94%, 95% CI 84%–100%) than AVMs (n = 37; 58%, 95% CI 40%–76%; p = 0.02). Among adults who never experienced ICH/FND and presented with or developed epilepsy, there was no difference in the proportions achieving 2-year seizure freedom over 5 years between AVMs (n = 43; 45%, 95% CI 20%–70%) and CMs (n = 35; 47%, 95% CI 27%–67%). Conclusions: AVM-related ICH confers a significantly higher risk of a first-ever seizure compared to CMs or incidental AVMs. Adults with a CM have a high risk of epilepsy after a first-ever seizure but achieve seizure freedom as frequently as those with epilepsy due to an AVM.

A case series of systemic right ventricular dysfunction post atrial switch for simple D-transposition of the great arteries: the impact of beta-blockade.

BACKGROUND Patients with atrial switch (Mustard or Senning) repair of D-transposition of the great arteries (D-TGA) are at increased risk for atrial arrhythmias, systemic right ventricular (RV) dysfunction and late mortality. OBJECTIVES To evaluate case series from a single-centre experience with beta-blocker use in adult, post atrial switch, simple D-TGA patients. METHODS The Adult Congenital Heart Disease Clinic (Halifax, Nova Scotia) database was used to identify patients with post atrial switch, simple D-TGA. Treatment effect of beta-blockade was evaluated. RESULTS Eight patients were treated with beta-blockers for systemic RV dysfunction (n=2), arrhythmia (n=2) or both (n=4). Median follow-up was three years, at which time seven of eight patients were still on beta-blockade. Of those patients with complete data, two of five had improved systemic ventricular dysfunction, two of four had improved tricuspid regurgitation and four of six had improved functional capacity, as determined by history or exercise testing. Beta-blockade was well tolerated in seven of eight patients without any significant clinical deterioration. CONCLUSIONS Beta-blockade was used infrequently in patients with a prior Mustard procedure. When beta-blockade was prescribed to patients with a prior atrial switch procedure, the drugs were well tolerated and were associated with trends toward improved symptoms, less tricuspid regurgitation and improved functional status in patients with reduced systemic RV function. These data support the need for a randomized trial of beta-blockade in patients with a previous Mustard or Senning operation and RV dysfunction.

Seizure risk with AVM treatment or conservative management Prospective, population-based study

Objectives: To compare the risk of epileptic seizures in adults during conservative management or following invasive treatment for a brain arteriovenous malformation (AVM). Methods: We used annual general practitioner follow-up, patient questionnaires, and medical records surveillance to quantify the 5-year risk of seizures and the chances of achieving 2-year seizure freedom for adults undergoing AVM treatment compared to adults managed conservatively in a prospective, population-based observational study of adults in Scotland, newly diagnosed with an AVM in 1999–2003. Results: We identified 229 adults with a new diagnosis of an AVM, of whom two-thirds received AVM treatment (154/229; 67%) during 1,862 person-years of follow-up (median completeness of follow-up 97%). There was no significant difference in the proportions with a first or recurrent seizure over 5 years following AVM treatment, compared to the first 5 years following clinical presentation in conservatively managed adults, in analyses stratified by mode of presentation (intracerebral hemorrhage, 35% vs 26%, p = 0.5; seizure, 67% vs 72%, p = 0.6; incidental, 21% vs 10%, p = 0.4). For patients with epilepsy, the chances of achieving 2-year seizure freedom during 5-year follow-up were similar following AVM treatment (n = 39; 52%, 95% confidence interval [CI] 36% to 68%) or conservative management (n = 21; 57%, 95% CI 35% to 79%; p = 0.7). Conclusions: In this observational study, there was no difference in the 5-year risk of seizures with AVM treatment or conservative management, irrespective of whether the AVM had presented with hemorrhage or epileptic seizures.

Association of Depression and Treated Depression With Epilepsy and Seizure Outcomes: A Multicohort Analysis

Importance A bidirectional relationship exists between epilepsy and depression. However, any putative biological gradient between depression severity and the risk of epilepsy, and the degree to which depression mediates the influence of independent risk factors for epilepsy, has yet to be examined. Objective To determine the effect of depression on the risk of epilepsy and seizure outcomes. Design, Setting, and Participants An observational study of a population-based primary care cohort (all patients free of prevalent depression and epilepsy at 18-90 years of age who were active after the Acceptable Mortality Reporting date in The Health Improvement Network database) and a prospectively collected tertiary care cohort (all patients whose data were prospectively collected from the Calgary Comprehensive Epilepsy Programme). The analyses were performed on March 16, 2016. Main Outcome and Measures The hazard of developing epilepsy after incident depression and vice versa was calculated. In addition, a mediation analysis of the effect of depression on risk factors for epilepsy and the odds of seizure freedom stratified by the presence of depression were performed. Results We identified 10 595 709 patients in The Health Improvement Network of whom 229 164 (2.2%) developed depression and 97 177 (0.9%) developed epilepsy. The median age was 44 years (interquartile range, 32-58 years) for those with depression and 56 years (interquartile range, 43-71 years) for those with epilepsy. Significantly more patients with depression (144 373 [63%] were women, and 84 791 [37%] were men; P < .001) or epilepsy (54 419 [56%] were women, and 42 758 [44%] were men; P < .001) were female. Incident epilepsy was associated with an increased hazard of developing depression (hazard ratio [HR], 2.04 [95% CI, 1.97-2.09]; P < .001), and incident depression was associated with an increased hazard of developing epilepsy (HR, 2.55 [95% CI, 2.49-2.60]; P < .001) There was an incremental hazard according to depression treatment type with lowest risk for those receiving counselling alone (HR, 1.84 [95% CI, 1.30-2.59]; P < .001), an intermediate risk for those receiving antidepressants alone (HR, 3.43 [95% CI, 3.37-3.47]; P < .001), and the highest risk for those receiving both (HR, 9.85 [95% CI, 5.74-16.90]; P < .001). Furthermore, depression mediated the relationship between sex, social deprivation, and Charlson Comorbidity Index with incident epilepsy, accounting for 4.6%, 7.1%, and 20.6% of the total effects of these explanatory variables, respectively. In the Comprehensive Epilepsy Programme, the odds of failing to achieve 1-year seizure freedom were significantly higher for those with depression or treated depression. Conclusions and Relevance Common underlying pathophysiological mechanisms may explain the risk of developing epilepsy following incident depression. Treated depression is associated with worse epilepsy outcomes, suggesting that this may be a surrogate for more severe depression and that severity of depression is associated with severity of epilepsy.

Medical vs invasive therapy in AVM-related epilepsy Systematic review and meta-analysis

Objective: To compare invasive arteriovenous malformation (AVM) therapy to conservative management using only antiepileptic drugs (AEDs) for achieving seizure freedom in patients with AVM-related epilepsy. Methods: We searched Medline, Embase, and Cochrane Central up to June 2015 using epilepsy and AVM Medical Subject Headings and keywords. We included original research involving controlled observational cohort studies or randomized controlled trials (RCTs) comparing seizure outcomes between invasive AVM treatments vs AED management alone, and uncontrolled case series of invasive AVM therapy for seizures that contained ≥20 patients. The estimates of seizure freedom were pooled using meta-analysis for the controlled trials, while the estimates for the case series were evaluated using descriptive statistics. Results: Of 2,166 identified abstracts, 98 were reviewed in full text, of which 31 were included in the final dataset. We identified 2 controlled observational studies (n = 106 patients) and 29 uncontrolled case series. We identified 1 RCT but it did not report seizure outcomes. The pooled risk ratio for seizure freedom in controlled studies (0.99; 95% confidence interval [CI] 0.69, 1.43) did not indicate superiority to either approach. Seizure freedom in case series varied from 19% (95% CI 11, 30%) to 95% (95% CI 76, 99%) at last follow-up. Conclusions: There is insufficient evidence available to determine if invasive AVM management is superior to AED only for controlling seizures. An RCT of interventional vs medical management using standardized epilepsy-specific presurgical protocols is warranted.

Psychiatric comorbidities in epilepsy

Abstract Psychiatric comorbidities, including mood, anxiety, and psychotic disorders, are common in epilepsy, often occurring at rates 2–3-fold or higher than in the general population without epilepsy. This article discusses the epidemiology of psychiatric disorders in epilepsy, hypotheses regarding the pathogenesis of these comorbidities, and treatment implications. More specifically, it addresses: (1) How common are major depressive disorder, anxiety disorders, and psychotic disorders in epilepsy? (2) How does one screen for these psychiatric disorders in persons with epilepsy? (3) Why do psychiatric conditions occur in epilepsy? (4) Is the treatment of psychiatric comorbidity in epilepsy associated with seizures? The important topic of suicide and suicidal ideation in epilepsy, risk factors for their occurrence, and how to screen for these co-existent conditions is also discussed. Finally, gaps in knowledge regarding psychiatric conditions in epilepsy are briefly discussed.

A systematic review of clinical decision rules for epilepsy

Clinical decision rules (CDRs) have been empirically demonstrated to improve patient satisfaction and enhance cost-effective care. The use of CDRs has not yet been robustly explored for epilepsy. We performed a systematic review of MEDLINE (from 1946) and Embase (from 1947) using Medical Subject Headings and keywords related to CDRs and epilepsy. We included original research of any language deriving, validating, or implementing a CDR using standardized definitions. Study quality was determined using a modified version of previously published criteria. A bivariate model was used to meta-analyze studies undergoing sequential derivation and validation studies. Of 2445 unique articles, 5 were determined to be relevant to this review. Three were derivation studies (three diagnostic and one therapeutic), one validation study, and one combined derivation and validation study. No implementation studies were identified. Study quality varied but was primarily of a moderate level. Two CDRs were validated and, thus, able to be meta-analyzed. Although initial measures of accuracy were high (sensitivity ~80% or above), they tended to diminish significantly in the validation studies. The pooled estimates of sensitivity and specificity both exhibited wide 95% confidence and prediction intervals that may limit their utility in routine practice. Despite the advances in therapeutic and diagnostic interventions for epilepsy, few CDRs have been developed to guide their use. Future CDRs should address common clinical scenarios such as efficient use of diagnostic tools and optimal clinical treatment decisions. Given their potential for advancing efficient, evidence-based, patient-centered healthcare, CDR development should be a priority in epilepsy.

Intracranial Vascular Malformations and Epilepsy

Among the spectrum of intracranial vascular malformations (IVMs), arteriovenous malformations (AVMs), and cavernous malformations (CCMs) are of particular importance for epilepsy. Seizures are a common mode of presentation for both conditions. Seizures may occur de novo or secondary to intracerebral hemorrhage. Timely imaging is thus crucial for patients with seizures and AVMs or CCMs. Patients with a first-ever AVM- or CCM-related seizure can now be considered to have epilepsy according to the International League Against Epilepsy criteria. Observational studies and case series suggest that between 45 to 78% of patients with AVM-related epilepsy and 47 to 60% of patients with CCM-related epilepsy may achieve seizure freedom through antiepileptic drugs (AEDs) alone. Invasive procedures are available although current evidence suggests that epilepsy-specific preintervention evaluations are underused. Randomized controlled trials and population-based studies have demonstrated worse short-term functional outcomes after routine intervention on unruptured AVMs or CCMs when compared with conservative management. The role of invasive therapy for IVM-related epilepsy has yielded mixed results. Case series have reported high estimates of seizure freedom although these results have not been replicated in controlled observational studies. Randomized controlled trials of immediate invasive therapy versus conservative management, in addition to usual care with AEDs and of different types of treatment and their timing, are warranted for AVMs and CCM-related epilepsy.