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ADHD Diagnosis and Treatment in Children and Adolescents

Author/s: 
Peterson, BS, Trampush, J, Maglione, M, Bolshakova, M, Brown, M., Rozelle, M

Objective. The systematic review assessed evidence on the diagnosis, treatment, and monitoring of attention deficit hyperactivity disorder (ADHD) in children and adolescents to inform a planned update of the American Academy of Pediatrics (AAP) guidelines.

Data sources. We searched PubMed®, Embase®, PsycINFO®, ERIC, clinicaltrials.gov, and prior reviews for primary studies published since 1980. The report includes studies published to June 15, 2023.

Review methods. The review followed a detailed protocol and was supported by a Technical Expert Panel. Citation screening was facilitated by machine learning; two independent reviewers screened full text citations for eligibility. We abstracted data using software designed for systematic reviews. Risk of bias assessments focused on key sources of bias for diagnostic and intervention studies. We conducted strength of evidence (SoE) and applicability assessments for key outcomes. The protocol for the review has been registered in PROSPERO (CRD42022312656).

Results. Searches identified 23,139 citations, and 7,534 were obtained as full text. We included 550 studies reported in 1,097 publications (231 studies addressed diagnosis, 312 studies addressed treatment, and 10 studies addressed monitoring). Diagnostic studies reported on the diagnostic performance of numerous parental ratings, teacher rating scales, teen/child self-reports, clinician tools, neuropsychological tests, EEG approaches, imaging, and biomarkers. Multiple approaches showed promising diagnostic performance (e.g., using parental rating scales), although estimates of performance varied considerably across studies and the SoE was generally low. Few studies reported estimates for children under the age of 7. Treatment studies evaluated combined pharmacological and behavior approaches, medication approved by the Food and Drug Administration, other pharmacologic treatment, psychological/behavioral approaches, cognitive training, neurofeedback, neurostimulation, physical exercise, nutrition and supplements, integrative medicine, parent support, school interventions, and provider or model-of-care interventions. Medication treatment was associated with improved broadband scale scores and ADHD symptoms (high SoE) as well as function (moderate SoE), but also appetite suppression and adverse events (high SoE). Psychosocial interventions also showed improvement in ADHD symptoms based on moderate SoE. Few studies have evaluated combinations of pharmacological and youth-directed psychosocial interventions, and we did not find combinations that were systematically superior to monotherapy (low SoE). Published monitoring approaches for ADHD were limited and the SoE is insufficient.

Conclusion. Many diagnostic tools are available to aid the diagnosis of ADHD, but few monitoring strategies have been studied. Medication therapies remain important treatment options, although with a risk of side effects, as the evidence base for psychosocial therapies strengthens and other nondrug treatment approaches emerge.

Hematuria as a Marker of Occult Urinary Tract Cancer: Advice for High-Value Care From the American College of Physicians

Author/s: 
Nielsen, Matthew, Qaseem, Amir, High Value Care Task Force of the American College of Physicians

Background: The presence of blood in the urine, or hematuria, is a common finding in clinical practice and can sometimes be a sign of occult cancer. This article describes the clinical epidemiology of hematuria and the current state of practice and science in this context and provides suggestions for clinicians evaluating patients with hematuria.

Methods: A narrative review of available clinical guidelines and other relevant studies on the evaluation of hematuria was conducted, with particular emphasis on considerations for urologic referral.

High-value care advice 1: Clinicians should include gross hematuria in their routine review of systems and specifically ask all patients with microscopic hematuria about any history of gross hematuria.

High-value care advice 2: Clinicians should not use screening urinalysis for cancer detection in asymptomatic adults.

High-value care advice 3: Clinicians should confirm heme-positive results of dipstick testing with microscopic urinalysis that demonstrates 3 or more erythrocytes per high-powered field before initiating further evaluation in all asymptomatic adults.

High-value care advice 4: Clinicians should refer for further urologic evaluation in all adults with gross hematuria, even if self-limited.

High-value care advice 5: Clinicians should consider urology referral for cystoscopy and imaging in adults with microscopically confirmed hematuria in the absence of some demonstrable benign cause.

High-value care advice 6: Clinicians should pursue evaluation of hematuria even if the patient is receiving antiplatelet or anticoagulant therapy.

High-value care advice 7: Clinicians should not obtain urinary cytology or other urine-based molecular markers for bladder cancer detection in the initial evaluation of hematuria.

Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia

Author/s: 
Hemmy, L.S, Fink, H.A., Linskens, E.J., Silverman, P.G., MacDonald, R., McCarten, J.R., Talley, K.M.C., Desai, P.J., Forte, M.L., Miller, M.A., Brasure, M., Nelson, V.A., Taylor, B.C., Ng, W., Ouellette, J.M., Greer, N.L., Sheets, K.M., Wilt, T.J., Butler, M.

Objective. To summarize evidence on: (1) the accuracy of brief cognitive tests for identifying clinical Alzheimer’s-type dementia (CATD) in individuals with suspected cognitive impairment; (2) the accuracy of biomarkers for identifying Alzheimer’s disease (AD) in individuals with dementia; and (3) the benefits and harms of prescription drugs and supplements for cognition, function, and behavioral and psychological symptoms of dementia (BPSD) in patients with CATD.

Data sources. Electronic bibliographic databases to March 2019, ClinicalTrials.gov, systematic review bibliographies.

Review methods. Cognitive test accuracy studies must have used explicit CATD diagnostic criteria and a non-CATD control group. Biomarker accuracy studies must have used neuropathologic criteria to define AD cases and non-AD controls. All treatment trials must have enrolled participants with CATD; those evaluating BPSD enrolled individuals with CATD and BPSD. Minimum trial duration was 2 weeks for agitation, aggression, psychosis, and disinhibited sexual behavior, and 24 weeks for other outcomes. Two reviewers rated risk of bias (ROB) and strength of evidence. One reviewer extracted data; a second checked accuracy. We analyzed English-language studies with low or medium ROB.

Results. We analyzed 56 unique studies on the accuracy of brief cognitive tests for CATD, 24 on accuracy of biomarkers for AD (15 brain imaging, nine cerebrospinal fluid [CSF] testing), and 67 trials of CATD treatment (54 reporting cognition or function, 13 reporting BPSD). Multiple brief cognitive tests were highly sensitive and specific (>0.8) for distinguishing CATD from normal cognition, but less so for distinguishing mild CATD from normal cognition or CATD from mild cognitive impairment (MCI). Based on few studies, compared with clinical evaluation alone, amyloid positron emission tomography (PET), fluorodeoxyglucose (FDG)-PET, and combinations of CSF tests added to clinical evaluation may improve accuracy for distinguishing AD from non-AD dementia. Regardless of CATD severity, cholinesterase-inhibitors produced small improvements in cognition and function compared with placebo but may increase serious adverse events and withdrawals due to adverse events. For moderate to severe CATD, memantine plus a cholinesterase inhibitor slightly improved global change and inconsistently improved cognition, but not function, compared with a cholinesterase inhibitor alone. Evidence was mostly insufficient about the effects of prescription drugs and supplements on agitation, aggression, psychosis, or disinhibited sexual behavior.

Conclusion. Brief cognitive tests accurately distinguished CATD from normal cognition, but were less accurate distinguishing smaller clinical differences. Whether biomarkers improve diagnostic accuracy when added to clinical evaluation needs further verification, but potential benefits of testing are limited by lack of effective treatments for AD and non-AD dementias. Cholinesterase-inhibitors slightly outperformed placebo for cognition and function, but evidence of whether any drug treatments improved BPSD was largely insufficient.

Keywords 
cognitive screening tests alzheimer's disease treatment

Ameliorative Effects Of N-Acetylcysteine As Adjunct Therapy On Symptoms Of Painful Diabetic Neuropathy

Author/s: 
Heidari, N., Sajedi, F., Mohammadi, Y., Mirjalili, M., Mehrpooya, M.

PURPOSE:

Painful diabetic neuropathy (PDN) is a variant of diabetic peripheral neuropathy which is highly prevalent and distressing in diabetic patients. Despite its high burden, the optimal treatment of PDN has remained a clinical challenge. To explain the emergence and maintenance of PDN, increasing attention has been focused on dimensions of inflammation and oxidative toxic stress (OTS). Accordingly, the aim of this study was to investigate the effects of oral N-acetylcysteine (NAC), an agent with known anti-oxidant and anti-inflammatory effects, as an adjunct therapy in patients suffering from PDN.

PATIENTS AND METHODS:

113 eligible patients with type 2 diabetes suffering from PDN were randomly assigned to either the pregabalin + placebo or pregabalin + NAC group for 8 weeks (pregabalin at a dose of 150 mg per day, NAC and matched placebo at doses of 600 mg twice a day). Mean pain score was evaluated at baseline, week 1, 2, 4, 6, and 8 of the study based on the mean 24 hr average pain score, using an 11-point numeric rating scale (NRS). As secondary efficacy measures, mean sleep interference score (SIS) resulting from PDN, responder rates, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety were also assessed. Additionally, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.

RESULTS:

Ninety patients completed the eight-week course of the study. The decrease in mean pain scores and mean sleep interference score in pregabalin + NAC group was greater in comparison with pregabalin + placebo group (p value<0.001 in both conditions). Moreover, more responders (defined as ≥50% reduction in mean pain score from baseline to end-point) were observed in the pregabalin + NAC group, in comparison with pregabalin + placebo group (72.1% vs 46.8%). More improvement in PGIC and CGIC from baseline to the end of the study was reported in pregabalin + NAC group. Oral NAC had minimal adverse effects and was well tolerated in almost all patients. Furthermore, in respect to OTS biomarkers, adjuvant NAC significantly decreased serum level of MDA and significantly increased serum levels of SOD, GPx, TAC, and TTG.

CONCLUSION:

The pattern of results suggests that compared to placebo and over a time period of 8 weeks, adjuvant NAC is more efficacious in improving neuropathic pain associated with diabetic neuropathy than placebo. Ameliorative effects of NAC on OTS biomarkers demonstrated that NAC may alleviate painful symptoms of diabetic neuropathy, at least in part by its antioxidant effects.

Keywords 
N-acetylcysteine oxidative stress painful diabetic neuropathy pregabalin

Preoperative Cardiac Risk Assessment

Author/s: 
Raslau, D, Bierle, DM, Stephenson, CR, Mikhail, MA, Kebede, EB, Mauck, KF

Major adverse cardiac events are common causes of perioperative mortality and major morbidity. Preventing these complications requires thorough preoperative risk assessment and postoperative monitoring of at-risk patients. Major guidelines recommend assessment based on a validated risk calculator that incorporates patient- and procedure-specific factors. American and European guidelines define when stress testing is needed on the basis of functional capacity assessment. Favoring cost-effectiveness, Canadian guidelines instead recommend obtaining brain natriuretic peptide or N-terminal prohormone of brain natriuretic peptide levels to guide postoperative screening for myocardial injury or infarction. When conditions such as acute coronary syndrome, severe pulmonary hypertension, and decompensated heart failure are identified, nonemergent surgery should be postponed until the condition is appropriately managed. There is an evolving role of biomarkers and myocardial injury after noncardiac surgery to enhance risk stratification, but the effect of interventions guided by these strategies is unclear.

Keywords 
cardiac preoperative assessment risk factors heart failure

Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial

Author/s: 
Ordi-Ros, J, Sáez-Comet, L., Pérez-Conesa, M., Vidal, X., Riera-Mestre, A., Castro-Salomó, A., Cuquet-Pedragosa, J., Ortiz-Santamaria, V., Mauri-Plana, M., Solé, C., Cortés-Hernández, J.

BACKGROUND:

The potential role of new oral anticoagulants in antiphospholipid antibody syndrome (APS) remains uncertain.

OBJECTIVE:

To determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS.

DESIGN:

3-year, open-label, randomized noninferiority trial. (EU Clinical Trials Register: EUDRA [European Union Drug Regulatory Authorities] code 2010-019764-36).

SETTING:

6 university hospitals in Spain.

PARTICIPANTS:

190 adults (aged 18 to 75 years) with thrombotic APS.

INTERVENTION:

Rivaroxaban (20 mg/d or 15 mg/d, according to renal function) versus dose-adjusted VKAs (target international normalized ratio, 2.0 to 3.0, or 3.1 to 4.0 in patients with a history of recurrent thrombosis).

MEASUREMENTS:

The primary efficacy outcome was the proportion of patients with new thrombotic events; the primary safety outcome was major bleeding. The prespecified noninferiority margin for risk ratio (RR) was 1.40. Secondary outcomes included time to thrombosis, type of thrombosis, changes in biomarker levels, cardiovascular death, and nonmajor bleeding.

RESULTS:

After 3 years of follow-up, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group (RR in the rivaroxaban group, 1.83 [95% CI, 0.71 to 4.76]). Stroke occurred more commonly in patients receiving rivaroxaban (9 events) than in those receiving VKAs (0 events) (corrected RR, 19.00 [CI, 1.12 to 321.9]). Major bleeding occurred in 6 patients (6.3%) in the rivaroxaban group and 7 (7.4%) in the VKA group (RR, 0.86 [CI, 0.30 to 2.46]). Post hoc analysis suggested an increased risk for recurrent thrombosis in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease.

LIMITATION:

Anticoagulation intensity was not measured in the rivaroxaban group.

CONCLUSION:

Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non-statistically significant near doubling of the risk for recurrent thrombosis.

PRIMARY FUNDING SOURCE:

Bayer Hispania.

Keywords 
rivaroxaban thrombosis wafarin

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma

Author/s: 
Wechsler, ME, Szefler, SJ, Ortega, VE, Pongracic, JA, Chinchili, V, Lima, JJ, Krishnan, JA, Kunselman, SJ, Mauger, D, Bleecker, ER, Bacharier, LB, Beigelman, A, Benson, M, Blake, KV, Cabana, MD, Cardet, JC, Castro, M, Chmiel, JF, Covar, R, Denlinger, L, DiMango, E, Fitzpatrick, AM, Gentile, D, Grossman, N, Holguin, F, Jackson, DJ, Kumar, H, Kraft, M, LaForce, CF, Lang, J, Lazarus, SC, Lemanske, RF Jr, Long, D, Lugogo, N, Martinez, F, Meyers, DA, Moore, WC, Moy, J, Naureckas, E, Olin, JT, Peters, SP, Phipatanakul, W, Que, L, Raissy, H, Robison, RG, Ross, K, Sheehan, W, Smith, LJ, Solway, J, Sorkness, CA, Sullivan-Vedder, L, Wenzel, S, Israel, E, NHLBI AsthmaNet

BACKGROUND:

Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.

METHODS:

We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry.

RESULTS:

When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age.

CONCLUSIONS:

In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Keywords 
asthma African Americans glucocorticoids randomized control trial

The Many Faces of Cobalamin (Vitamin B12) Deficiency

Author/s: 
Wolffenbuttel, Bruce, Wouters, Hanneke J.C.M., Heiner-Fokkema, Rebecca, van der Klauw, Melanie M.

Although cobalamin (vitamin B12) deficiency was described over a century ago, it is still difficult toestablish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B12 deficiency may present with the classic megaloblastic anemia.
In clinical practice, many cases of vitamin B12 deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe the heterogeneous disease spectrum of patients with vitamin B12 deficiency in whom the diagnosis was either based on low serum B12 levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B12 therapy. We discuss the possible clinical signs and symptoms of patients with B12 deficiency and the various pitfalls of diagnosis and treatment.

Keywords 
Vitamin B 12 Biomarkers diagnosis

The Many Faces of Cobalamin (Vitamin B12) Deficiency

Author/s: 
Wolffenbuttel, Bruce, Wouters, Hanneke J.C.M., Heiner-Fokkema, Rebecca, van der Klauw, Melanie M.

Although cobalamin (vitamin B12) deficiency was described over a century ago, it is still difficult toestablish the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin B12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals with vitamin B12 deficiency may present with the classic megaloblastic anemia.
In clinical practice, many cases of vitamin B12 deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe the heterogeneous disease spectrum of patients with vitamin B12 deficiency in whom the diagnosis was either based on low serum B12 levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement of clinical symptoms after the institution of parenteral vitamin B12 therapy. We discuss the possible clinical signs and symptoms of patients with B12 deficiency and the various pitfalls of diagnosis and treatment.

Keywords 
Vitamin B 12 Biomarkers diagnosis
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