Paul A. Nakonezny

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

The Brief Adherence Rating Scale (BARS) validated against electronic monitoring in assessing the antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder

Among outpatients with schizophrenia, antipsychotic non-adherence is common, grossly under-detected by patients and their prescribers, and is associated with poor clinical outcomes. Using electronic monitoring (EM) as the reference standard we evaluated the reliability and validity as well as the sensitivity and specificity of a recently developed, brief, pencil-paper, clinician-administered adherence instrument [the Brief Adherence Rating Scale (BARS)] to assess the oral antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. EM and BARS adherence and symptom severity ratings were gathered at baseline and prospectively at 6 monthly visits in 61 participants (n=35 with schizophrenia; n=26 with schizoaffective disorder). A significant positive relationship was found between mean BARS and EM adherence (beta=0.98; rs=0.59, p<0.0001). Cronbachs coefficient alpha revealed very high internal reliability for the BARS (alpha=0.92). A moderate-to-strong degree of test-retest reliability was also found for the BARS (beta ranged from 0.53 to 0.92 and rs ranged from 0.46 to 0.86). Regarding concurrent validity of the BARS, greater mean BARS adherence was significantly related to lower mean PANSS total scores (beta=-0.40; rs=-0.39, p=0.002) and to lower mean Positive symptom sub-scale scores (beta=-0.08, p=.007; rs=-0.28, p=.02). An initial 3-month monitoring period with the BARS also demonstrated good sensitivity (73%) and specificity (74%) in identifying non-adherent outpatients (defined as <70% mean EM adherence). Relative to EM, the BARS appears to provide valid, reliable, sensitive, and specific estimates of antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. The BARS appears to be a promising candidate as a brief adherence assessment instrument for feasible use in community-based settings.

The Effect of Vitamin B12 Deficiency on Older Veterans and Its Relationship to Health

OBJECTIVE: To examine the effect of vitamin B12 deficiency on older veterans and its relationship to general health and cognitive impairment.

Pro-Inflammatory Cytokines as Predictors of Antidepressant Effects of Exercise in Major Depressive Disorder

Exercise is an efficacious treatment for major depressive disorder (MDD) and has independently been shown to have anti-inflammatory effects in non-depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a selective serotonin reuptake inhibitor were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12-week exercise period (P<0.0001). In addition, a significant positive correlation between change in IL-1β and change in depression symptom scores was observed (P=0.04). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes.

Cognitive-Behavioral Therapy to Prevent Relapse in Pediatric Responders to Pharmacotherapy for Major Depressive Disorder

OBJECTIVE We present results of a feasibility test of a sequential treatment strategy using continuation phase cognitive-behavioral therapy (CBT) to prevent relapse in youths with major depressive disorder (MDD) who have responded to acute phase pharmacotherapy. METHOD Forty-six youths (ages 11-18 years) who had responded to 12 weeks of treatment with fluoxetine were randomized to receive either 6 months of continued antidepressant medication management (MM) or antidepressant MM plus relapse prevention CBT (MM+CBT). Primary outcome was time to relapse, defined as a Childhood Depression Rating Scale-Revised score of 40 or higher and 2 weeks of symptom worsening or clinical deterioration warranting alteration of treatment to prevent full relapse. RESULTS Cox proportional hazards regression, adjusting for depression severity at randomization and for the hazard of relapsing by age across the trial, revealed that participants in the MM treatment group had a significantly greater risk for relapse than those in the MM+CBT treatment group (hazard ratio = 8.80; 95% confidence interval 1.01-76.89; chi = 3.86, p =.049) during 6 months of continuation treatment. In addition, patient satisfaction was significantly higher in the MM+CBT group. No differences were found between the two treatment groups on attrition rate, serious adverse events, and overall global functioning. CONCLUSIONS These preliminary results suggest that continuation phase CBT reduces the risk for relapse by eightfold compared with pharmacotherapy responders who received antidepressant medication alone during the 6-month continuation phase.

Variations of weight loss following gastric bypass and gastric band.

Objective:To compare and describe the weight loss outcomes from gastric bypass and gastric band so as to define the variation of excess weight loss (EWL) among individual patients, the time to onset of effect, and the durability of weight loss in severely obese adults. Summary Background Data:Gastric bypass and gastric band are the most common operations for obesity performed in the United States, but few reports have compared these 2 procedures. Methods:Patients (N = 1733, aged 18–65 years) met National Institutes of Health criteria for obesity surgery and underwent either gastric bypass or gastric band between March 1997 and November 2006. The selection of bypass versus band was based on patient/ surgeon discussion. The evaluable sample consisted of 1518 patients. The percentage of EWL was assessed over 2 years. Successful weight loss was defined a priori as ≥40% EWL in each of four 6-month postoperative measurement periods. The analyses included a mixed model and generalized estimating equation (GEE) model with repeated measures. Odds ratios and descriptive analyses were also provided. Results:Gastric bypass was associated with less individual variation in weight loss than gastric band. Both procedures were associated with a significant EWL benefit (Treatment Group effect P < 0.0001), but they differed in terms of time to effect (Treatment Group × Period interaction effect P < 0.0001). The mean EWL for gastric bypass was greater at each measurement period (6, 12, 18, 24 months) compared with gastric band (P < 0.0001). Furthermore, at each of the postoperative measurement periods within each treatment group (bypass and band), the mean EWL was greater for those who had preoperative body mass index (BMI) ≤50 kg/m2 than for those who had preoperative BMI >50 kg/m2 (P < 0.0001). Gastric bypass was consistently associated with a greater likelihood of at least a 40% EWL in each of the 6-month postoperative measurement periods (GEE, P < 0.0001). The odds ratio estimates at months 6, 12, 18, and 24 were 18.2, 20.6, 15.5, and 9.1, respectively. Despite these clinically meaningful outcome differences, nearly all (≥93%) bypass and band patients who had ≥40% EWL at 6, 12, or 18 months postoperatively maintained at least this level of success at 2 years. Conclusions:Gastric bypass produced more rapid, greater, and more consistent EWL across individuals over a 2-year postoperative period than gastric band.

Acute Myocardial Infarction in Young Adults Who Abuse Amphetamines

BACKGROUND Case reports suggest a link between methamphetamine abuse and acute myocardial infarction (AMI), but no epidemiologic studies have examined this link. Our objective was to test the hypothesis that young adults who abuse amphetamines are at higher risk for AMI. METHODS In this study of 3,148,165 discharges from Texas hospitals in a quality indicators database during 2000-2003, among persons aged 18-44 years we identified 11,011 AMIs, defined according to the Agency for Healthcare Research and Qualitys AMI mortality inpatient quality indicator. RESULTS In a multiple logistic regression analysis - while controlling for cocaine abuse, alcohol abuse, tobacco use, hypertension, diabetes mellitus, lipid disorders, obesity, congenital defects, and coagulation defects - amphetamine abuse was significantly associated with AMI (adjusted odds ratio=1.61; 95% CI=1.24-2.04, p=0.0004). The rate of AMIs among amphetamine abusers increased significantly from 2000 to 2003. The population attributable risk suggests that amphetamine abuse is responsible for 0.2% of AMIs in the state of Texas. The geographical distribution of amphetamine abuse varied by region, with the prevalence being highest in the North Texas and Panhandle regions of Texas. CONCLUSIONS This modest, though statistically robust, association suggests that amphetamine abuse may play a role in AMI.

Brain Activity in Adolescent Major Depressive Disorder Before and After Fluoxetine Treatment

OBJECTIVE Major depression in adolescents is a significant public health concern because of its frequency and severity. To examine the neurobiological basis of depression in this population, the authors studied functional activation characteristics of the brain before and after antidepressant treatment in antidepressant-naive depressed adolescents and healthy comparison subjects. METHOD Depressed (N=19) and healthy (N=21) adolescents, ages 11 to 18 years, underwent functional MRI assessment while viewing fearful and neutral facial expressions at baseline and again 8 weeks later. The depressed adolescents received 8 weeks of open-label fluoxetine treatment after their baseline scan. RESULTS Voxel-wise whole brain analyses showed that depressed youths have exaggerated brain activation compared with healthy comparison subjects in multiple regions, including the frontal, temporal, and limbic cortices. The 8 weeks of fluoxetine treatment normalized most of these regions of hyperactivity in the depressed group. Region-of-interest analyses of the areas involved in emotion processing indicated that before treatment, depressed youths had significantly greater activations to fearful relative to neutral facial expressions than did healthy comparison subjects in the amygdala, orbitofrontal cortex, and subgenual anterior cingulate cortex bilaterally. Fluoxetine treatment decreased activations in all three regions, as compared with the repeat scans of healthy comparison subjects. CONCLUSIONS While effective treatments are available, the impact of depression and its treatment on the brain in adolescents is understudied. This study confirms increases in brain activation in untreated depressed adolescents and demonstrates reductions in these aberrant activations with treatment.

A randomized, double-blinded, placebo-controlled pilot trial of anticoagulation in low-risk traumatic brain injury: The Delayed Versus Early Enoxaparin Prophylaxis I (DEEP I) study.

BACKGROUND Our group has created an algorithm for venous thromboembolism prophylaxis after traumatic brain injury (TBI), which stratifies patients into low, moderate, and high risk for spontaneous injury progression and tailors a prophylaxis regimen to each arm. We present the results of the Delayed Versus Early Enoxaparin Prophylaxis I study, a double-blind, placebo-controlled, randomized pilot trial on the low-risk arm. METHODS In this two-institution study, patients presenting within 6 hours of injury with prespecified small TBI patterns and stable scans at 24 hours after injury were randomized to receive enoxaparin 30 mg bid or placebo from 24 to 96 hours after injury in a double-blind fashion. An additional computed tomography scan was obtained on all subjects 24 hours after starting treatment (and therefore 48 hours after injury). The primary end point was the radiographic worsening of TBI; secondary end points were venous thromboembolism occurrence and extracranial hemorrhagic complications. RESULTS A total of 683 consecutive patients with TBI were screened during the 28 center months. The most common exclusions were for injuries larger than the prespecified criteria (n = 199) and preinjury anticoagulant use (n = 138). Sixty-two patients were randomized to enoxaparin (n = 34) or placebo (n = 28). Subclinical, radiographic TBI progression rates on the scans performed 48 hours after injury and 24 hours after start of treatment were 5.9% (95% confidence interval [CI], 0.7–19.7%) for enoxaparin and 3.6% (95% CI, 0.1–18.3%) for placebo, a treatment effect difference of 2.3% (95% CI, −14.42–16.5%). No clinical TBI progressions occurred. One deep vein thrombosis occurred in the placebo arm. CONCLUSION TBI progression rates after starting enoxaparin in small, stable injuries 24 hours after injury are similar to those of placebo and are subclinical. The next Delayed Versus Early Enoxaparin Prophylaxis studies will assess efficacy of this practice in a powered study on the low-risk arm and a pilot trial of safety of a 72-hour time point in the moderate-risk arm. LEVEL OF EVIDENCE Therapeutic study, level II.

Attention Training for School-Aged Children with ADHD: Results of an Open Trial.

Objective: The article discusses a feasibility study conducted to examine whether Pay Attention!, an intervention training sustained, selective, alternating, and divided attention, could be utilized in a clinical setting with children diagnosed with ADHD, and whether children who received the intervention made attention and executive functioning gains. Method: After a diagnostic and baseline evaluation, 23 school-aged children with ADHD participate in up to 16 sessions of Pay Attention! and the outcomes are evaluated. Results: Results show the intervention is feasible to administer and acceptable to participants. Parents and clinicians rate fewer ADHD symptoms following the intervention and report improvements in executive function. Child performance on neuropsychological tests showed improvements in fluid reasoning and cognitive flexibility and working memory. Conclusion: The findings suggest that a randomized clinical trial of Pay Attention! is warranted to investigate its viability as a treatment for attention and executive functioning deficits in ADHD. (J. of Att. Dis. 2010; 14(1) 86-94)