Treatment of Attention-Deficit/Hyperactivity Disorder in AdolescentsA Systematic Review

Original article can be found here: http://jama.jamanetwork.com/article.aspx?articleID=2520634

Eugenia Chan, MD, MPH1,3; Jason M. Fogler, PhD1,2,3; Paul G. Hammerness, MD2,3
JAMA. 2016;315(18):1997-2008. doi:10.1001/jama.2016.5453.
 ABSTRACT

Importance  Although attention-deficit/hyperactivity disorder (ADHD) is highly prevalent in adolescents and often persists into adulthood, most studies about treatment were performed in children. Less is known about ADHD treatment in adolescents.

Objective  To review the evidence for pharmacological and psychosocial treatment of ADHD in adolescents.

Evidence Review  The databases of CINAHL Plus, MEDLINE, PsycINFO, ERIC, and the Cochrane Database of Systematic Reviews were searched for articles published between January 1, 1999, and January 31, 2016, on ADHD treatment in adolescents. Additional studies were identified by hand-searching reference lists of retrieved articles. Study quality was rated using McMaster University Effective Public Health Practice Project criteria. The evidence level for treatment recommendations was based on Oxford Centre for Evidence-Based Medicine criteria.

Findings  Sixteen randomized clinical trials and 1 meta-analysis, involving 2668 participants, of pharmacological and psychosocial treatments for ADHD in adolescents aged 12 years to 18 years were included. Evidence of efficacy was stronger for the extended-release methylphenidate and amphetamine class stimulant medications (level 1B based on Oxford Centre for Evidence-Based Medicine criteria) and atomoxetine than for the extended-release α2-adrenergic agonists guanfacine or clonidine (no studies). For the primary efficacy measure of total symptom score on the ADHD Rating Scale (score range, 0 [least symptomatic] to 54 [most symptomatic]), both stimulant and nonstimulant medications led to clinically significant reductions of 14.93 to 24.60 absolute points. The psychosocial treatments combining behavioral, cognitive behavioral, and skills training techniques demonstrated small- to medium-sized improvements (range for mean SD difference in Cohen d, 0.30-0.69) for parent-rated ADHD symptoms, co-occurring emotional or behavioral symptoms, and interpersonal functioning. Psychosocial treatments were associated with more robust (Cohen d range, 0.51-5.15) improvements in academic and organizational skills, such as homework completion and planner use.

Conclusions and Relevance  Evidence supports the use of extended-release methylphenidate and amphetamine formulations, atomoxetine, and extended-release guanfacine to improve symptoms of ADHD in adolescents. Psychosocial treatments incorporating behavior contingency management, motivational enhancement, and academic, organizational, and social skills training techniques were associated with inconsistent effects on ADHD symptoms and greater benefit for academic and organizational skills. Additional treatment studies in adolescents, including combined pharmacological and psychosocial treatments, are needed.

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Effect of Dilute Apple Juice and Preferred Fluids vs Electrolyte Maintenance Solution on Treatment Failure Among Children With Mild Gastroenteritis

Original article an be found at http://jama.jamanetwork.com/article.aspx?articleID=2518402

Stephen B. Freedman, MDCM, MSc1; Andrew R. Willan, PhD2; Kathy Boutis, MD3,4; Suzanne Schuh, MD3,4 JAMA. 2016;315(18):1966-1974. doi:10.1001/jama.2016.5352.
ABSTRACT

Importance  Gastroenteritis is a common pediatric illness. Electrolyte maintenance solution is recommended to treat and prevent dehydration. Its advantage in minimally dehydrated children is unproven.

Objective  To determine if oral hydration with dilute apple juice/preferred fluids is noninferior to electrolyte maintenance solution in children with mild gastroenteritis.

Design, Setting, and Participants  Randomized, single-blind noninferiority trial conducted between the months of October and April during the years 2010 to 2015 in a tertiary care pediatric emergency department in Toronto, Ontario, Canada. Study participants were children aged 6 to 60 months with gastroenteritis and minimal dehydration.

Interventions  Participants were randomly assigned to receive color-matched half-strength apple juice/preferred fluids (n=323) or apple-flavored electrolyte maintenance solution (n=324). Oral rehydration therapy followed institutional protocols. After discharge, the half-strength apple juice/preferred fluids group was administered fluids as desired; the electrolyte maintenance solution group replaced losses with electrolyte maintenance solution.

Main Outcomes and Measures  The primary outcome was a composite of treatment failure defined by any of the following occurring within 7 days of enrollment: intravenous rehydration, hospitalization, subsequent unscheduled physician encounter, protracted symptoms, crossover, and 3% or more weight loss or significant dehydration at in-person follow-up. Secondary outcomes included intravenous rehydration, hospitalization, and frequency of diarrhea and vomiting. The noninferiority margin was defined as a difference between groups of 7.5% for the primary outcome and was assessed with a 1-sided α=.025. If noninferiority was established, a 1-sided test for superiority was conducted.

Results  Among 647 randomized children (mean age, 28.3 months; 331 boys [51.1%]; 441 (68.2%) without evidence of dehydration), 644 (99.5%) completed follow-up. Children who were administered dilute apple juice experienced treatment failure less often than those given electrolyte maintenance solution (16.7% vs 25.0%; difference, −8.3%; 97.5% CI, −∞ to −2.0%; P < .001 for inferiority and P = .006 for superiority). Fewer children administered apple juice/preferred fluids received intravenous rehydration (2.5% vs 9.0%; difference, −6.5%; 99% CI, −11.6% to −1.8%). Hospitalization rates and diarrhea and vomiting frequency were not significantly different between groups.

Conclusions and Relevance  Among children with mild gastroenteritis and minimal dehydration, initial oral hydration with dilute apple juice followed by their preferred fluids, compared with electrolyte maintenance solution, resulted in fewer treatment failures. In many high-income countries, the use of dilute apple juice and preferred fluids as desired may be an appropriate alternative to electrolyte maintenance fluids in children with mild gastroenteritis and minimal dehydration.

Trial Registration  clinicaltrials.gov Identifier: NCT01185054

Cannabidiol May Reduce Seizures in Children and Young Adults with Treatment-Resistant Epilepsy

Reference – Lancet Neurol 2015 Dec 23 early online (level 3 [lacking direct] evidence)

  • Anecdotal reports suggest medical marijuana or marijuana-derived compounds might benefit patients with intractable epilepsy, though evidence from clinical studies supporting this claim is extremely limited.
  • A recent uncontrolled trial including 214 children and young adults with treatment-resistant, intractable epilepsy reported a median 36.5% reduction in motor seizures and 34.6% reduction in total seizures after 12 weeks of cannabidiol treatment.
  • Cannabidiol was well tolerated, with most patients reporting only mild-to-moderate, transient adverse events including somnolence, decreased appetite, diarrhea, fatigue, and convulsion.

Up to one third of patients with epilepsy are resistant to medical therapy and are at an increased risk of injury, poor quality of life, and premature death (Lancet 2015 Mar 7;385(9971):884, N Engl J Med 2011 Sep 8;365(10):919).  Anecdotal evidence suggests cannabidiol, 1 of the 2 main cannabinoids found in marijuana, might reduce seizures in drug-resistant patients (Epilepsy Behav 2013 Dec;29(3):574, Lancet 2015 Oct 24;386(10004):1615).  This limited evidence has generated great interest in the potential use of this compound as an add-on therapy to antiepileptic drugs, particularly in rare pediatric epilepsies such as Dravet syndrome, Lennox-Gastaut syndrome, and Doose syndrome.  In response, many states have approved medical marijuana (or cannabidiol extracts) specifically for children and adults with intractable epilepsy.  However, the efficacy and safety of using cannabinoids for treating patients with epilepsy, especially children, remains unknown.  To further examine this issue, a recent study evaluated oral cannabidiol in 214 children and young adults aged 1-30 years (mean age 11 years) with treatment-resistant, intractable, childhood onset epilepsy.  All patients had ≥ 4 countable seizures with a motor component in a 4-week period and were receiving stable treatment for at least 4 weeks before enrollment.  Cannabidiol dosing began at 2-5 mg/kg/day and was titrated up weekly until it was no longer tolerated or the maximum dose (25 mg/kg/day or 50 mg/kg/day depending on study site) was achieved.

Only 64% of patients were assessed in the efficacy analysis, which included patients with ≥ 12 weeks follow-up, but excluded patients who had no motor seizures during a 4-week pretreatment baseline period.  The most common epilepsy syndromes in this group were Dravet syndrome (23%) and Lennox-Gastaut syndrome (22%).  The mean cannabidiol dose was 22.7 mg/kg at 12 weeks and 30% of patients were eventually titrated to the maximum 50 mg/kg daily dose.  At the 12-week follow-up, the median number of monthly motor seizures had decreased from 30 at baseline to 15.8, with a median 36.5% decrease in monthly motor seizures.  During weeks 8-12 of treatment, 11% of patients were free from motor seizures and 7% were free from all seizures.  Efficacy of cannabidiol appears to be influenced by seizure type, with the greatest reduction seen in patients with focal seizures (55% reduction) or atonic seizures (54.3% reduction).  Overall, cannabidiol reduced total seizures by 34.6%.

Twenty-five additional patients (12%), most of whom had been excluded for lack of motor seizures during the baseline period, were included in the safety analysis.  Adverse events were reported in 79% of patients, though most were mild-to-moderate and transient.  The most commonly reported adverse events were somnolence, decreased appetite, diarrhea, fatigue, and convulsion.  Only 12% of patients reported serious adverse events that were possibly related to treatment, most frequently status epilepticus.

The results of this study are promising, showing a large reduction in seizures in children and young adults with treatment-resistant epilepsy with minimal adverse effects.  With 137 patients included in the efficacy analysis and 162 patients included in the safety analysis, this is the largest study to date on the effects of cannabidiol in this population.  Even though this drug is not yet available, this study still informs the discussion about the potential benefit of marijuana in this group of patients.  There are a number of potential sources of bias to consider, however.  There was no control group to truly determine efficacy or assess the potential for a placebo effect.  This is especially important in epilepsy where there is a natural variation in seizure frequency.  In addition, the 12-week follow-up period only allows for the assessment of immediate treatment effect, but long-term efficacy and safety remain unknown.  Finally, 24% of patients were excluded from all analyses because they did not have 12 weeks of follow-up.  Overall, the results of this study suggest that cannabidiol may help reduce seizures for severe, drug-resistant epilepsy, but randomized controlled trials are clearly needed.

For more information, see the Medical uses of cannabinoids and Epilepsy in children topics in DynaMed Plus. DynaMed users click here and here.

Antibiotics in Women with Uncomplicated Urinary Tract Infections May Not Be Necessary

Reference – BMJ 2015 Dec 23;351:h6544 (level 1 [likely reliable] evidence)

  • Immediate antibiotic therapy is currently recommended for women with uncomplicated urinary tract infections (UTI), although a portion of these infections may be self-limited.
  • In women not immediately treated with antibiotics, 65% had symptom resolution with ibuprofen alone and 35% required antibiotic treatment.
  • The time to symptom resolution was significantly longer with ibuprofen.

Increasing rates of antibiotic resistance have strengthened the need for judicious antibiotic use and antimicrobial stewardship.  Current recommendations support immediate antibiotic therapy for uncomplicated urinary tract infections (UTIs) (Clin Infect Dis 2011 Mar 1;52(5):e103, EAU 2015 Mar PDF), even though some data suggests that many uncomplicated UTIs are self-limited (Curr Infect Dis Rep 2013 Apr;15(2):124).  To assess the potential to treat UTI symptoms without antibiotics, a recent randomized trial compared ibuprofen 400 mg 3 times daily vs. single dose fosfomycin 3 g in 494 women aged 18-65 years with symptoms of uncomplicated UTI.  UTI symptoms considered for trial inclusion were dysuria or frequency/urgency of micturition, with or without lower abdominal pain.  Women were excluded for symptoms of upper urinary tract infection including fever or loin tenderness.  Both groups received placebo pills for the corresponding active treatment given to the other group to maintain blinding. Urine cultures and dipstick tests were performed, but the results did not inform eligibility.  All women were advised to consult their general practitioner if symptoms persisted or worsened, at which point antibiotic treatment was prescribed at the discretion of the practitioner based on the initial urine culture results.

Ten women were incorrectly screened and excluded from the trial after randomization.  Among the 484 women included in the intention-to-treat analysis, 92% (446 women) completed the 28 day follow-up.  Urine culture results were available for 471 women, with a positive urine culture (> 100 colony forming units/mL) in 76% (360 women).  Comparing ibuprofen vs. fosfomycin at day 28, antibiotics were prescribed to 35% vs. 100% (p < 0.001).  The total number of antibiotic courses prescribed within 28 days was 94 in the 222 women treated with ibuprofen vs. 283 in the 224 women treated with fosfomycin (p < 0.001).  This corresponds to an overall 66.5% incidence rate reduction in antibiotic use in the ibuprofen group.  In a subgroup analysis of women with a positive urine culture, ibuprofen was associated with a 58.5% reduction in antibiotic use.  However, ibuprofen was associated with an increased time to symptom resolution.  Only 39% of women treated with ibuprofen had symptom resolution at day 4 compared to 56% treated with fosfomycin (p < 0.001).  At day 7, symptom resolution occurred in 70% with ibuprofen vs. 82% with fosfomycin (p = 0.004).  Although there was no significant difference in symptom worsening within 7 days, there was a nonsignificant increase in the rate of pyelonephritis in the ibuprofen group (5 cases vs. 1 case).

In this trial, 65% of women with an uncomplicated UTI initially treated with ibuprofen recovered without antibiotic treatment.  While treatment with ibuprofen was associated with an increased total symptom burden within the first 7 days, the mean duration of symptoms was only 1 day longer with ibuprofen compared to fosfomycin.  The number of pyelonephritis cases was higher in women receiving ibuprofen, but the overall rate was low and the difference did not reach statistical significance. This potential for reducing antibiotic use is analogous to the current treatment of otitis media. For many children with nonsevere otitis media, the recommended approach is shared decision making with the parents regarding the choice between antibiotics or observation with close follow-up.  The results of this trial suggest that for women with mild uncomplicated UTIs, it may be reasonable to counsel about the potential for infection resolution without antibiotics and give the option to forgo antibiotics unless symptoms persist or worsen. One option is to empower the patient by giving a prescription that can be filled at the patient’s discretion, which has been shown to reduce the use of antibiotics in patients presenting with respiratory tract infections.

For more information, please see the Uncomplicated urinary tract infection (UTI) (pyelonephritis and cystitis) topic in DynaMed Plus.

Exercise With or Without Education May Prevent Low Back Pain

Reference – JAMA Intern Med 2016 Feb 1;176(2):199 (level 2 [mid-level] evidence)

  • Most people will experience a low back pain episode in their lifetime and recurrence is extremely common within 1 year of the episode.
  • A systematic review of 21 randomized trials assessing measures to prevent low back pain in 30,850 persons currently without low back pain found exercise with or without education significantly reduced episodes of low back pain.
  • Other interventions including education alone, back belt, and shoe insoles were not effective for preventing low back pain episodes or sick leave due to low back pain.

Low back pain is very common, with 49-70% of the population experiencing at least 1 episode of acute low back pain in their lifetime (BMJ 2006 Jun 17;332(7555):1430).  Approximately 70% of patients with an acute low back pain episode will have a recurrence within 1 year, and identifying interventions that can effectively prevent low back pain episodes could significantly reduce this healthcare burden (ICSI 2012 Nov PDF, Best Pract Res Clin Rheumatol 2010 Apr;24(2):155).  To help identify effective interventions, a recent systematic review analyzed 21 randomized trials assessing interventions to prevent low back pain in 30,850 persons currently without low back pain.  Trials examining both primary prevention of back pain and secondary prevention were included in the analysis.

The interventions were categorized as exercise, education, exercise plus education, back belt, shoe insoles, or other.  Control groups included no intervention, minimal intervention, or placebo.  Low back pain episodes and sick leave due to low back pain were assessed as both short-term (evaluations at ≤ 12 months) and long-term (> 12 month follow-up) outcomes.  All trials included in the analysis were of low to moderate quality and the duration of interventions as well as the specifics of each intervention group varied widely.  Interventions associated with a significant reduction in low back pain episodes or sick leave are presented in the table below.  There were no significant differences in short or long-term outcomes with education alone, back belts, or shoe insoles.

Interventions associated with reduced low back pain outcomes

The results of this systematic review suggest that exercise, either alone or in combination with educational interventions, is an effective intervention for preventing low back pain.  However, these results are limited by the low quality of evidence and the heterogeneity of exercise interventions included in the trials.  The type of exercise, number of sessions, and duration of the intervention varied widely, making it impossible to determine if one type of exercise may be more effective than another.  On the other hand, this heterogeneity also suggests that multiple forms of exercise may be beneficial, allowing programs to be tailored more towards individual needs and desires.  Though exercise alone significantly reduced short-term episodes of low back pain, the addition of education to exercise further reduced both short and long-term low back pain episodes.  These results indicate that education may be important in preventing low back pain episodes, but the small number of trials investigating long-term outcomes limit the ability to determine the magnitude of its role.  Equally important to identifying effective preventative measures, this systematic review also identified interventions that are not effective.  The results indicate that back belts, shoe insoles, and education alone may not be effective for preventing low back pain.

For more information, see the Acute low back pain topic in DynaMed Plus. DynaMed users click here.

Smartphone-Based Visual Acuity Measurement for Screening and Clinical Assessment

Christopher J. Brady, MD1; Allen O. Eghrari, MD1; Alain B. Labrique, PhD, MHS, MS2

Commentary discusses a study describes the accuracy of a smartphone-based visual acuity test for detecting visual impairment in rural Kenya.

JAMA Ophthalmology

Development and Validation of a Smartphone-Based Visual Acuity Test (Peek Acuity) for Clinical Practice and Community-Based Fieldwork

Andrew Bastawrous, MRCOphth; Hillary K. Rono, MBBS; Iain A. T. Livingstone, FRCOphth; Helen A. Weiss, PhD; Stewart Jordan, BSc; Hannah Kuper, ScD; Matthew J. Burton, PhD

Importance Visual acuity is the most frequently performed measure of visual function in clinical practice and most people worldwide living with visual impairment are living in low- and middle-income countries.

Objective To design and validate a smartphone-based visual acuity test that is not dependent on familiarity with symbols or letters commonly used in the English language.

Design, Setting, and Participants Validation study conducted from December 11, 2013, to March 4, 2014, comparing results from smartphone-based Peek Acuity to Snellen acuity (clinical normal) charts and the Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart (reference standard). This study was nested within the 6-year follow-up of the Nakuru Eye Disease Cohort in central Kenya and included 300 adults aged 55 years and older recruited consecutively.

Main Outcomes and Measures Outcome measures were monocular logMAR visual acuity scores for each test: ETDRS chart logMAR, Snellen acuity, and Peek Acuity. Peek Acuity was compared, in terms of test-retest variability and measurement time, with the Snellen acuity and ETDRS logMAR charts in participants’ homes and temporary clinic settings in rural Kenya in 2013 and 2014.

Results The 95% CI limits for test-retest variability of smartphone acuity data were ±0.029 logMAR. The mean differences between the smartphone-based test and the ETDRS chart and the smartphone-based test and Snellen acuity data were 0.07 (95% CI, 0.05-0.09) and 0.08 (95% CI, 0.06-0.10) logMAR, respectively, indicating that smartphone-based test acuities agreed well with those of the ETDRS and Snellen charts. The agreement of Peek Acuity and the ETDRS chart was greater than the Snellen chart with the ETDRS chart (95% CI, 0.05-0.10; P = .08). The local Kenyan community health care workers readily accepted the Peek Acuity smartphone test; it required minimal training and took no longer than the Snellen test (77 seconds vs 82 seconds; 95% CI, 71-84 seconds vs 73-91 seconds, respectively; P = .13).

Conclusions and Relevance The study demonstrated that the Peek Acuity smartphone test is capable of accurate and repeatable acuity measurements consistent with published data on the test-retest variability of acuities measured using 5-letter-per-line retroilluminated logMAR charts.

JAMA Ophthalmol. 2015;133(8):930-937. doi:10.1001/jamaophthalmol.2015.1468

Treatment for Intermittent Claudication

From The Journal of Family Practice

Treatment for Intermittent Claudication

Is combination therapy the answer?

December 1, 2015A combination therapy of endovascular revascularization followed by supervised exercise resulted in significantly greater improvement in walking distances and health-related quality-of-life scores compared with supervised exercise only for 212 patients with peripheral artery disease and intermittent claudication who were randomized 1:1 to the interventions. Researchers determined:

• Combination therapy was associated with significantly greater improvement in maximum walking distance (from 264 m to 1501 m for an improvement of 1237 m) compared with the supervised exercise only group (from 285 m to 1240 m for improvement of 955 m).

• The combination therapy group demonstrated significantly greater improvement in the disease-specific VascuQol score compared to the exercise group (1.34 vs 0.73) and in the score for the Short-Form Health Survey (SF-36) physical functioning (22.4 vs 12.6), respectively.

• No significant differences were found in the SF-36 domains of physical role functioning, bodily pain, and general health perceptions.

Citation: Fakhry F, Spronk S, van der Laan L, et al. Endovascular revascularization and supervised exercise for peripheral artery disease and intermittent claudication. JAMA. 2015;314(18):1936-1944. doi: 10.1001/jama.2015.14851.

Commentary:  While it is important to note that surgery plus exercise yielded greater improvement than exercise alone, it is equally important to note the impressive improvement in the exercise alone group. Improving from 285 meters walking to 1240 in the exercise alone group, a greater than fourfold increase in walking distance, is no small task.   In fact, the bulk of the improvement in walking distance occurred with exercise, so it is important to emphasize that if patients opt for surgery, then exercise should still be important as a part of treatment for peripheral vascular disease if optimal outcomes are to be achieved. —Neil Skolnik, MD

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