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

Abstract

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.

Figure 1

A. FASD 4-Digit Diagnostic Code grid. FASD is defined by growth deficiency, specific FAS facial features, evidence of CNS damage and prenatal alcohol exposure. The 4-Digit Code ranks each of these areas on 4-point, case-defined, Likert scales. The 4-Digit Code (3444) inserted in the grid is 1 of 12 codes that meet the diagnostic criteria for FAS (Astley, 2004). B. FASD 4-Digit Code FAS facial phenotype. The Rank 4 FAS facial phenotype determined with the 4-Digit Diagnostic Code requires the presence of all 3 of the following anomalies: (1) palpebral fissure length 2 or more standard deviations below the norm; (2) smooth philtrum (Rank 4 or 5 on the Lip-Philtrum Guide), an (3) thin upper lip (Rank 4 or 5 on the Lip-Philtrum Guide). Examples of the Rank 4 FAS facial phenotype for Caucasian, Native American, African American, and Asian American children are shown.

Figure 2

Two subjects with (A) agenesis and (B) hypogenesis of the corpus callosum in the FAS/PFAS group. C. Variability in corpus callosum shape among Controls with no prenatal alcohol exposure.

Figure 3

The relative volume (cc) of the frontal lobe was significantly smaller in the FAS/PFAS group (after exclusion of the two subjects with ACC/HCC) compared to each of the other study groups. The FAS/PFAS group is the only group with the full FAS facial phenotype. Morphogenesis of the middle and upper face is heavily influenced by signals emanating from the forebrain to the frontonasal prominence (Marcucio et al., 2005). The frontonasal prominence is the purple region in the insert depicting a 5-week (left) and 10-week (right) fetus (Moore et al., 1994). C.I.: confidence interval.

Figure 4

A. Prevalence of subjects in each FASD study group that had one or more brain regions, two or more standard deviations below the mean size observed in the Control group. B. Mean (95% confidence interval) absolute caudate volume decreased as a global measure of brain function (4-Digit Code CNS Rank) increased in impairment. C.I.: confidence interval.

Figure 5

A. The relative volume of the frontal lobe decreased significantly with increasing maximum number of alcohol drinks per drinking occasion during pregnancy among subjects with FASD (Pearson Correlation Coefficient−.430, p .02). B. A significant linear decrease in the mean relative volume of the frontal lobe was also observed when the FASD study sample was divided into groups based on their duration of exposure (exposure through 1^st trimester only, (n = 10, mean .31, SD .03); through the 2^nd trimester only (n = 9, mean .29, SD .02); and through all 3 trimesters (n = 32, mean, .28, SD .02) (ANOVA overall F = 3.1; df 2,50; p = 0.05; unweighted linear trend, F = 6.1; df 1,50; p = 0.017). The unexposed Control group is plotted for visual comparison. Circle = FAS/PFAS, square = SE/AE, X = ND/AE, triangle = control.