Paul Kraegel

Magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

BACKGROUND Magnetic resonance (MR) technology offers noninvasive methods for in vivo assessment of neuroabnormalities. METHODS A comprehensive neuropsychological/psychiatric battery, coupled with MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessments, were administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The 4 study groups included: (i) fetal alcohol syndrome (FAS)/partial FAS (PFAS); (ii) static encephalopathy/alcohol exposed (SE/AE); (iii) neurobehavioral disorder/alcohol exposed (ND/AE) as diagnosed with the FASD 4-Digit Code; and (iv) healthy peers with no prenatal alcohol exposure. Presented here are the MRI assessments that were used to compare the sizes of brain regions between the 4 groups. The neuropsychological/behavioral, MRS, and fMRI outcomes are reported separately. RESULTS Progressing across the 4 study groups from Controls to ND/AE to SE/AE to FAS/PFAS, the mean absolute size of the total brain, frontal lobe, caudate, putamen, hippocampus, cerebellar vermis, and corpus callosum length decreased incrementally and significantly. The FAS/PFAS group (the only group with the 4-Digit FAS facial phenotype) had disproportionately smaller frontal lobes relative to all other groups. The FAS/PFAS and SE/AE groups [the 2 groups with the most severe central nervous system (CNS) dysfunction] had disproportionately smaller caudate regions relative to the ND/AE and Control groups. The prevalence of subjects in the FAS/PFAS, SE/AE, and ND/AE groups that had 1 or more brain regions, 2 or more SDs below the mean size observed in the Control group was 78, 58, and 43%, respectively. Significant correlations were observed between size of brain regions and level of prenatal alcohol exposure, magnitude of FAS facial phenotype, and level of CNS dysfunction. CONCLUSIONS Magnetic resonance imaging provided further validation that ND/AE, SE/AE, and FAS/PFAS as defined by the FASD 4-Digit Code are 3 clinically distinct and increasingly more affected diagnostic subclassifications under the umbrella of FASD. Neurostructural abnormalities are present across the spectrum. MRI could importantly augment diagnosis of conditions under the umbrella of FASD, once population-based norms for structural development of the human brain are established.

Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.

Low back pain is one of the most frequently encountered conditions in clinical practice (1, 2). The most commonly prescribed medications for low back pain are nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal muscle relaxants, antidepressants, and opioids (35); benzodiazepines, systemic corticosteroids, and antiseizure medications are also prescribed (3). Patients often use over-the-counter acetaminophen and NSAIDs. A 2007 guideline (6) and associated systematic review (7) from the American College of Physicians (ACP) and American Pain Society (APS) found evidence to support the use of acetaminophen and NSAIDs as first-line pharmacologic options for low back pain; secondary options were skeletal muscle relaxants, benzodiazepines, and antidepressants. New evidence and medications are now available. Here, we review the current evidence on benefits and harms of medications for low back pain. This article has been used by ACP to update a clinical practice guideline, also in this issue. Methods Detailed methods and data for our review, including the analytic framework, additional medications (topical capsaicin and lidocaine), nonpharmacologic therapies (addressed in a separate article) (8), search strategies, inclusion criteria, data extraction and quality-rating methods, and additional outcomes (for example, quality of life, global improvement, and patient satisfaction), are available in the full report (9). The protocol was developed by using a standardized process (10) with input from experts and the public and is registered in the PROSPERO database (11). This article addresses the key question, what are the comparative benefits and harms of different systemic pharmacologic therapies for acute or chronic nonradicular low back pain, radicular low back pain, or spinal stenosis? Data Sources and Searches A research librarian searched Ovid MEDLINE (January 2007 through April 2015), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (through April 2015). We used the prior ACP/APS review (12) to identify earlier studies. Updated searches were performed through November 2016. We also reviewed reference lists and searched ClinicalTrials.gov. Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. The population was adults with nonradicular or radicular low back pain of any duration (categorized as acute [<4 weeks], subacute [4 to 12 weeks], and chronic [12 weeks]). Excluded conditions were low back pain due to cancer, infection, inflammatory arthropathy, high-velocity trauma, or fracture; low back pain during pregnancy; and presence of severe or progressive neurologic deficits. We evaluated acetaminophen, NSAIDs, opioids, tramadol and tapentadol, antidepressants, skeletal muscle relaxants, benzodiazepines, corticosteroids, and antiseizure medications versus placebo, no treatment, or other therapies. We also evaluated the combination of 2 medications versus 1 medication alone. Outcomes were long-term (1 year) or short-term (6 months) pain or function, mood (for antidepressants), risk for surgery (for corticosteroids), and harms. Given the large number of medications addressed, we included systematic reviews of randomized trials (13, 14). For each medication, we selected the most recent, most relevant, and highest-quality comprehensive systematic review based on a validated assessment tool (14, 15). If more than 1 good-quality systematic review was available, we preferentially selected updates of those used in the ACP/APS review. We supplemented systematic reviews with additional trials. Although we did not include systematic reviews identified in update searches, we checked reference lists for additional studies. We excluded nonEnglish-language articles and abstract-only publications. Data Extraction and Quality Assessment One investigator extracted study data, and a second verified accuracy. For systematic reviews, we abstracted details about inclusion criteria, search strategy, databases searched, search dates, number and characteristics of included studies, quality assessment methods and ratings, synthesis methods, and results. For randomized trials, we abstracted details about the setting, sample size, eligibility criteria, population characteristics, treatment characteristics, results, and funding source. Two investigators independently assessed the quality of each study as good, fair, or poor using criteria developed by the U.S. Preventive Services Task Force (for randomized trials) (16) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) (14). For primary studies included in systematic reviews, we used both the quality ratings and the overall grade (for example, good, fair, or poor, or high or low) as determined in the reviews. We classified the magnitude of effects as small/slight, moderate, or large/substantial based on the definitions in the ACP/APS review (Table 1) (6, 17). We also reported risk estimates based on the proportion of patients achieving successful pain or function outcomes (for example, >30% or >50% improvement). Table 1. Definitions for Magnitude of Effects, Based on Mean Between-Group Differences Data Synthesis and Analysis We synthesized data qualitatively for each medication, stratified according to the duration of symptoms (acute, subacute, or chronic) and presence or absence of radicular symptoms. We reported meta-analysis results from systematic reviews. When statistical heterogeneity was present, we examined the degree of inconsistency and evaluated subgroup and sensitivity analyses. We did not conduct an updated meta-analysis; rather, we qualitatively examined whether results of new studies were consistent with pooled or qualitative findings from prior systematic reviews. Qualitative assessments were based on whether the findings from the new studies were in the same direction as the prior systematic reviews and whether the magnitude of effects was similar; when prior meta-analyses were available, we analyzed whether the estimates and CIs from new studies were encompassed in the CIs from pooled estimates. We assessed the strength of evidence (SOE) for each body of evidence as high, moderate, low, or insufficient based on aggregate study quality, precision, consistency, and directness (18). Role of the Funding Source The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services funded this review. AHRQ staff assisted in developing the scope and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Results Literature Search The search and selection of articles are summarized in the Figure. Database searches found 2847 potentially relevant articles. After dual review of abstracts and titles, we selected 746 articles for full-text dual review; 46 publications met inclusion criteria. Quality ratings are summarized in Supplement Tables 1 and 2. Supplement. Data Supplement. Figure. Summary of evidence search and selection. ACP = American College of Physicians; AHRQ = Agency for Healthcare Research and Quality; APS = American Pain Society; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized, controlled trial; SR = systematic review. * Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Other sources include prior reports, reference lists of relevant articles, and systematic reviews. Publications may be included or excluded for multiple reasons. Acetaminophen Ten trials evaluated acetaminophen; 9 of these (sample sizes, 39 to 456) were included in the ACP/APS review (19). We identified 1 additional large (n= 1643), good-quality, placebo-controlled trial (20). Six trials compared acetaminophen with NSAIDs and were included in a systematic review of NSAIDs (Supplement Table 3) (21, 22). Along with the new trial, 3 others (2325) were rated good- or high-quality. For acute low back pain, 1 new trial found no differences between 4 weeks or less of scheduled or as-needed acetaminophen (about 4 g/d) and placebo in pain (differences, 0.20 point on a 0- to 10-point scale), function (differences, 0.60 point on the 0- to 24-point RolandMorris Disability Questionnaire [RDQ]), or risk for serious adverse events (about 1% in each group) after 12 weeks (Supplement Table 4) (20). One trial of acetaminophen versus no treatment included in the ACP/APS review (26) also found no differences. We found no difference between acetaminophen and NSAIDs in pain intensity (standardized mean difference [SMD], 0.21 [95% CI, 0.02 to 0.43]) at 3 weeks or less based on 3 low-quality trials, although estimates favored NSAIDs (22). Acetaminophen had a lower risk for adverse events than NSAIDs (relative risk [RR], 0.57 [CI, 0.36 to 0.89]). Evidence was insufficient to determine the effects of acetaminophen versus various nonpharmacologic therapies (24, 27, 28) or amitriptyline (25); each comparison was evaluated in 1 trial with methodological shortcomings. No study evaluated acetaminophen for chronic or radicular low back pain. NSAIDs Seventy trials evaluated NSAIDs; 57 were in the ACP/APS review. Sixty-five trials (total n= 11237; sample sizes, 20 to 690), 28 of which were high-quality, were included in a systematic review (Supplement Table 3) (22). We identified 5 additional trials (n= 54 to 525) (Supplement Table 5) (2933). One trial was rated good-quality (31), and 4 were rated fair-quality (29, 30). For acute back pain, 1 systematic review (22) found that NSAIDs were associated with greater mean improvements in pain intensity than placebo (4 trials: weighted mean difference, 8.39 points on a 0- to 100-point scale [CI, 12.68 to 4.10 points]; chi-square test, 3.47 points; P> 0.10) (3437). One additional trial (n= 171) reported consistent findings (29). Three trials in this review found no differences between an NSAID and placeb

Magnetic resonance spectroscopy outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

Magnetic resonance (MR) technology offers noninvasive methods for in vivo assessment of neuroabnormalities. A comprehensive neuropsychological/behavioral, MR imaging (MRI), MR spectroscopy (MRS) and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine whether global and/or focal abnormalities could be identified and to distinguish diagnostic subclassifications across the spectrum. The four study groups included (1) FAS/partial FAS; (2) static encephalopathy/alcohol exposed (SE/AE); (3) neurobehavioral disorder/alcohol exposed (ND/AE) as diagnosed with the FASD 4-Digit Code; and (4) healthy peers with no prenatal alcohol exposure. Results are presented in four separate reports: MRS (reported here) and neuropsychological/behavioral, MRI and fMRI outcomes (reported separately). MRS was used to compare neurometabolite concentrations [choline (Cho), n-acetyl-aspartate (NAA) and creatine (Cre)] in a white matter region and a hippocampal region between the four study groups. Choline concentration in the frontal/parietal white matter region, lateral to the midsection of the corpus callosum, was significantly lower in FAS/PFAS relative to all other study groups. Choline decreased significantly with decreasing frontal white matter volume and corpus callosum length. These outcomes suggest low choline concentrations may reflect white matter deficits among FAS/PFAS. Choline also decreased significantly with increasing severity of the 4-Digit FAS facial phenotype, increasing impairment in psychological performance and increasing alcohol exposure. NAA and Cre concentrations did not vary significantly. This study provides further evidence of the vulnerability of the cholinergic system in FASD.

Functional magnetic resonance imaging outcomes from a comprehensive magnetic resonance study of children with fetal alcohol spectrum disorders

A comprehensive neuropsychological/psychiatric, MR imaging, (MRI), MR spectroscopy (MRS), and functional MRI (fMRI) assessment was administered to children with fetal alcohol spectrum disorders (FASD) to determine if global and/or focal abnormalities could be identified, and distinguish diagnostic subclassifications across the spectrum. The four study groups included: 1. FAS/Partial FAS; 2. Static Encephalopathy/Alcohol Exposed (SE/AE); 3. Neurobehavioral Disorder/Alcohol Exposed (ND/AE); and 4. healthy peers with no prenatal alcohol exposure. fMRI outcomes are reported here. The neuropsychological/psychiatric, MRI, and MRS outcomes are reported separately. fMRI was used to assess activation in seven brain regions during performance of N-back working memory tasks. Children across the full spectrum of FASD exhibited significant working memory deficits and altered activation patterns in brain regions that are known to be involved in working memory. These results demonstrate the potential research and diagnostic value of this non-invasive MR tool in the field of FASD.