Susan J. Astley

Efficacy of aerosolized tobramycin in patients with cystic fibrosis.

BACKGROUND Direct aerosol delivery of aminoglycosides such as tobramycin to the lower airways of patients with cystic fibrosis may control infection with Pseudomonas aeruginosa and improve pulmonary function, with low systemic toxicity. We conducted a randomized crossover study to evaluate the safety and efficacy of aerosolized tobramycin in patients with cystic fibrosis and P. aeruginosa infections. METHODS Seventy-one patients with stable pulmonary status were recruited from seven U.S. centers for the treatment of cystic fibrosis and randomly assigned to one of two crossover regimens. Group 1 received 600 mg of aerosolized tobramycin for 28 days, followed by half-strength physiologic saline (placebo) for two 28-day period. Group 2 received placebo for 28 days, followed by tobramycin for two 28-day periods. Pulmonary function, the density of P. aeruginosa in sputum, ototoxicity, nephrotoxicity, and the emergence of tobramycin-resistant P. aeruginosa were monitored. RESULTS In the first 28-day period, treatment with tobramycin was associated with an increase in the percentage of the value predicted for forced expiratory volume in one second (9.7 percentage points higher than the value for placebo; P < 0.001), forced vital capacity (6.2 percentage points higher than the value for placebo; P = 0.014), and forced expiratory flow at the midportion of the vital capacity (13.0 percentage points higher than the value for placebo; P < 0.001). A decrease in the density of P. aeruginosa in sputum by a factor of 100 (P < 0.001) was found during all periods of tobramycin administration. Neither ototoxicity nor nephrotoxicity was detected. The frequency of the emergence of tobramycin-resistant bacteria was similar during both tobramycin and placebo administration. CONCLUSIONS The short-term aerosol administration of a high dose of tobramycin in patients with clinically stable cystic fibrosis is an efficacious and safe treatment for endobronchial infection with P. aeruginosa.

Selective dorsal rhizotomy: efficacy and safety in an investigator‐masked randomized clinical trial

The objective of this single‐center investigator‐masked randomized clinical trial was to investigate the efficacy and safety of selective dorsal rhizotomy (SDR) in children with spastic diplegia. Forty‐three children with spastic diplegia were randomly assigned on an intention‐to‐treat basis to receive SDR plus physical therapy (PT), or PT alone. Thirty‐eight children completed follow‐up through 24 months. Twenty‐one children received SDR (SDR+PT group) and 17 received PT (PT Only group). SDR was guided with electrophysiological monitoring and performed by one experienced neurosurgeon. All subjects received equivalent PT. Spasticity was quantified with an electromechanical torque measurement device (spasticity measurement system [SMS]). The Gross Motor Function Measure (GMFM) was used to document changes in functional mobility. Primary outcome measures were collected at baseline, 6, 12, and 24 months by evaluators masked to treatment.

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.

A case definition and photographic screening tool for the facial phenotype of fetal alcohol syndrome.

OBJECTIVES The purpose of this study was to demonstrate that a quantitative, multivariate case definition of the fetal alcohol syndrome (FAS) facial phenotype could be derived from photographs of individuals with FAS and to demonstrate how this case definition and photographic approach could be used to develop efficient, accurate, and precise screening tools, diagnostic aids, and possibly surveillance tools. STUDY DESIGN Frontal facial photographs of 42 subjects (from birth to 27 years of age) with FAS were matched to 84 subjects without FAS. The study population was randomly divided in half. Group 1 was used to identify the facial features that best differentiated individuals with and without FAS. Group 2 was used for cross validation. RESULTS In group 1, stepwise discriminant analysis identified three facial features (reduced palpebral fissure length/inner canthal distance ratio, smooth philtrum, and thin upper lip) as the cluster of features that differentiated individuals with and without FAS in groups 1 and 2 with 100% accuracy. Sensitivity and specificity were unaffected by race, gender, and age. CONCLUSIONS The phenotypic case definition derived from photographs accurately distinguished between individuals with and without FAS, demonstrating the potential of this approach for developing screening, diagnostic, and surveillance tools. Further evaluation of the validity and generalizability of this method will be needed.

Maternal marijuana use during lactation and infant development at one year

Prenatal marijuana exposure is associated with adverse perinatal effects. Very little is known about the effect of postnatal marijuana exposure on infant development. Postnatal exposure can result from maternal use of marijuana during lactation. Delta-9-tetrahydrocannabinol (THC) transfers and concentrates in the mothers milk and is absorbed and metabolized by the nursing infant. The present study investigated the relationship between infant exposure to marijuana via the mothers milk and infant motor and mental development at one year of age. One hundred and thirty-six breast-fed infants were assessed at one year of age for motor and mental development. Sixty-eight infants were exposed to marijuana via the mothers milk. An additional 68 infants were matched to the marijuana-exposed infants on pre- and postpartum maternal alcohol and tobacco use. Marijuana exposure via the mothers milk during the first month postpartum appeared to be associated with a decrease in infant motor development at one year of age.

THE ROLE OF SELECTIVE DORSAL RHIZOTOMY IN cérébral PALSY: CRITICAL EVALUATION OF A PROSPECTIVE CLINICAL SERIES

This is a prospective observational study of a consecutive series of 34 children with spastic cérébral palsy treated at a single center. 10 had spastic quadriplegia and 24 had spastic diplegia. AH were followed for at least one year. After selective dorsal rhizotomy (SDR), all children received one month of physical therapy at the center and were prescribed a program of physical therapy in their community. The children were assessed before and one year after SDR and physical therapy, using the Ashworth Scale, deep tendon reflex response, range of motion and the Gross Motor Function Measure. The results show that there is often a decrease in lower‐extremity spasticity and functional improvement after SDR with physical therapy, but that there is considerable variability in outcome. Randomized prospective clinical trials with masked objective outcome measures are needed to determine the efficacy of SDR.

Comparison of the 4-Digit Diagnostic Code and the Hoyme Diagnostic Guidelines for Fetal Alcohol Spectrum Disorders

OBJECTIVE. The 4-Digit Diagnostic Code for fetal alcohol spectrum disorders and the Hoyme fetal alcohol spectrum disorders diagnostic guidelines differ markedly. The performances of the 2 diagnostic systems were compared. METHODS. The fetal alcohol syndrome diagnostic criteria from the 4-Digit Code and Hoyme guidelines were applied to 952 patients who had received an interdisciplinary, fetal alcohol spectrum disorders, diagnostic evaluation at the University of Washington with the 4-Digit Diagnostic Code and 16 children with confirmed absence of prenatal alcohol exposure. RESULTS. The prevalence of fetal alcohol syndrome was 3.7% with the 4-Digit Code and 4.1% with the Hoyme guidelines. Although the prevalences were similar, the patients identified were not. Only 17 individuals met the fetal alcohol syndrome criteria for both systems. An extraordinary number of patients (35%) met the Hoyme criteria for the fetal alcohol syndrome facial phenotype, but only 39 of those 330 patients met the Hoyme criteria for fetal alcohol syndrome. Even some children with no alcohol exposure (25%) had the Hoyme fetal alcohol syndrome face. The specificities of the Hoyme fetal alcohol syndrome face for the Hoyme fetal alcohol syndrome diagnosis and prenatal alcohol exposure were low in these populations. CONCLUSIONS. Without a specific facial phenotype, a valid diagnosis of fetal alcohol syndrome cannot be rendered for patients with prenatal alcohol exposure, because a causal link between their outcomes and exposure cannot be established, and a valid diagnosis of fetal alcohol syndrome cannot be rendered for patients with unknown alcohol exposure, because the face cannot serve as a valid proxy measure for alcohol exposure. Diagnostic guidelines must confirm the specificity of their fetal alcohol syndrome facial criteria to validate their diagnostic criteria.

Cognitive and behavioral deficits in nonhuman primates associated with very early embryonic binge exposures to ethanol

This study was undertaken to evaluate teratogenesis associated with early weekly ethanol exposure followed by later gestational abstinence. Ethanol, 1.8 gm/kg, was orally administered weekly to gravid nonhuman primates (Macaca nemestrina) for the first 3, 6, or the entire 24 weeks of pregnancy. Control animals received weekly sucrose solution as did the 3- and 6-week cohort animals in subsequent weeks. Thirty-five viable infants were assessed for growth, malformations, and behavioral and cognitive dysfunction. Animals in the 6-week and 24-week cohorts were uniformly abnormal in behavior and inconsistently abnormal in physical development relative to the control animals. Animals in the 3-week cohort were equivocally normal. These results demonstrate ethanols capacity to produce behavioral teratogenesis (brain dysfunction) in isolation from physical anomalies in the rest of the body. The results strongly suggest that binge drinking in the first 6 to 8 weeks of pregnancy (a period when women may not know that they are pregnant), followed by later gestational abstinence, is as dangerous to the fetus as exposure throughout gestation.

Fetal alcohol syndrome : Changes in craniofacial form with age, cognition, and timing of ethanol exposure in the macaque

One component of the fetal alcohol syndrome (FAS) facial phenotype is a frontonasal anomaly characterized by a thin upper lip and a smooth philtrum. The expression of this anomaly can diminish with age and occurs infrequently in prenatal alcohol-exposed individuals. This study sought to explain these observations. Standardized craniofacial cephalograms of 18 nonhuman primates exposed weekly to ethanol or sucrose solution in utero were measured at ages 1, 6, 12, and 24 months to assess skeletal changes in craniofacial form with age, cognition, and timing of ethanol exposure. The data suggest that there may be a critical period for induction of alcohol-induced craniofacial alterations that occurs very early in gestation and is very short in duration (gestational days 19 or 20). The alterations were scarcely detectable at age 1 month, were most prominent at 6 months, and diminished progressively at 12 and 24 months in the macaque. The appearance and disappearance of the thin upper lip and smooth philtrum may be explained by underlying changes in skeletal structure with age. The infrequent occurrence of the FAS frontonasal anomaly may be explained, in part, by its short critical period of induction.

Responding to the Challenge of Early Intervention for Fetal Alcohol Spectrum Disorders

Prenatal alcohol exposure can lead to significant neurodevelopmental disabilities, now recognized as fetal alcohol spectrum disorders (FASD). This includes both fetal alcohol syndrome, a lifelong birth defect, and a wider range of enduring learning and behavior deficits often called alcohol-related neurodevelopmental disorder (ARND). Diagnostic classification systems have been developed to identify children with FASD, and early interventionists from multiple disciplines can be central in identification and referral for diagnosis, and in providing the known protective influence of intervention early in life. With the recent federal mandates to better address needs of children born prenatally affected by substances, or those impacted by abuse and/or neglect, by referring them for screening and possible early intervention services, there is heightened need for providers to understand FASD. There is a growing body of research data describing the teratogenic effects of alcohol on central nervous system function and physical development, the diversity of children with prenatal alcohol exposure and their families, and the developmental and behavioral characteristics of this clinical population. This article reviews the latest research evidence, bearing in mind what is important to early intervention. This article also gives practical guidance on FASD prevention, methods for early screening, and referral of young children for diagnosis of FASD (and referral for needed services once diagnosed), and how to provide education, support, advocacy assistance, and anticipatory guidance for families raising children with FASD.