Impaired cerebellar learning in children with prenatal alcohol exposure: a comparative study of eyeblink conditioning in children with ADHD and dyslexia.

Neuroanatomical and behavioral evidence indicate that the cerebellum is particularly vulnerable to the toxic effects of prenatal alcohol exposure. Recent research has shown impairments in eyeblink conditioning in rats following binge-like neonatal ethanol exposure. The neural substrates of eyeblink conditioning have been localized to the cerebellum and related brainstem mechanisms. The present study considered whether heavy prenatal alcohol exposure would result in similar impairments in eyeblink conditioning in children. A related purpose was to determine if eyeblink conditioning could discriminate between children with prenatal alcohol exposure and children diagnosed with attention deficit hyperactive disorder or developmental dyslexia. Fifty-three age-matched children [10 prenatal alcohol exposure (FAE), 16 attention deficit hyperactive disordered (ADHD), 14 children with dyslexia (DYS), 13 normal controls] were assessed on eyeblink conditioning in the delay paradigm. Children in the FAE and DYS groups failed to learn the conditioned response, producing longer latencies and poorly timed responses to the conditioning stimulus. Children with ADHD were impaired on measures of adaptively timed responses, although conditioned responses matched normal controls. The results suggest that children prenatally exposed to alcohol have deficits in cerebellar processing similar to those with dyslexia, and that these functional deficits are related to disabilities in learning.

"Do I know what I need to do?" A social communication intervention for children with complex clinical profiles.

PURPOSE: Speech-language pathologists frequently address social communication difficulties in children with diverse clinical profiles. The purpose of this study was to investigate the feasibility of a social communication intervention for a school-age child with a complex cognitive and behavioral profile secondary to diagnosis of a fetal alcohol spectrum disorder. METHOD: A case study is presented to describe the implementation of the intervention targeting mental state verb production and social cognitive skills. The intervention included group role play of social scripts and a checklist to elicit the participant's statements about others' perspectives and strategies for completing the social script. Treatment data monitored the participant's responses to the checklist questions. Probe sessions, consisting of theory of mind false belief tasks, were used to examine mental state verb use. RESULTS: Treatment data demonstrated that the participant stated more strategies in response to checklist questions. The participant did not produce any mental state verbs during baseline probes, but did produce mental state verbs during the treatment phase. CLINICAL IMPLICATIONS: The results support use of this intervention to change children's linguistic and social cognitive skills. Suggestions for extending this intervention to include a generalization plan targeting classroom social communication interactions are provided.

Spatial locations gone awry: object and spatial memory deficits in children with fetal alcohol syndrome.

Hippocampus vulnerability following gestational alcohol exposure has been demonstrated neuroanatomically and behaviorally in animal models of fetal alcohol syndrome (FAS). There has been no similar demonstrations in humans. The Smith and Milner (1981) Memory for 16 Objects task has been used to explore the effects of right vs left temporal lobectomy with varying degrees of damage to the hippocampus. In the present experiment, this same task was administered to 15 children with FAS (mean age 10.03, S.D. = 2.33) and 15 control children (mean age 10.02, S.D. = 2.31). Similar to patients with right temporal lobectomies and a large excision to the hippocampus, children with FAS were able to perform immediate but not delayed object recall, had a general spatial memory deficit (P < 0.05), and significantly distorted the spatial array (P < 0.05). Although these results are consistent with an interpretation of hippocampal dysfunction, gestational alcohol exposure is known to result in a wide-ranging spectrum of neuropsychological deficits that vary in both extent and severity. Visuospatial deficits on the Beery test of Visuomotor Integration and Clock Drawing are suggestive of the other neural regions that may be involved in producing the behavioral deficits in children with FAS.

Ganglioneuroblastoma and fetal hydantoin-alcohol syndromes.

A ganglioneuroblastoma developed in a 35-month-old boy with both the fetal hydantoin and fetal alcohol syndromes. Our case, plus two recent reports in the literature, would very likely establish the relationship between fetal hydantoin syndrome and the development of neural crest tumors. Infants exposed in utero to hydantoins should be closely observed for the development of these tumors.

Developmental language disability as a consequence of prenatal exposure to ethanol.

Two pre-school-aged patients with a history of prenatal exposure to ethanol had abnormal head size and developmental delay. Both children were strikingly similar in physical appearance, behavior, and cognitive dysfunction. Facial features were typical of fetal alcohol syndrome. Head circumference greater than 97th percentile without hydrocephalus and no evidence of prenatal or postnatal growth failure were unusual for ethanol teratogenicity. Each child had a similar pattern of verbal and behavioral dysfunctions characterized by (1) marked hypervigilence, (2) distractability, and (3) cognitive confusion manifested as anxiety and behavioral disorganization. It is suggested that a history of prenatal exposure to ethanol associated with (1) large head circumference, (2) facial features of fetal alcohol syndrome, and (3) early developmental delay, particularly in language acquisition, and impaired modulation of attention and arousal may represent a possible new effect of alcohol teratogenicity.

Fetal alcohol syndrome--an ophthalmological and socioeducational prospective study.

BACKGROUND: The eye is a sensitive indicator of adverse effects of prenatal alcohol exposure. Anomalies of the eyes and their adnexa are known to be associated with the fetal alcohol syndrome (FAS), although long-term effects of these malformations are unknown. DESIGN: A prospective ophthalmologic follow-up (median, 11 years; range, 4 to 19 years) was performed in 25 children with FAS. Their social situation and educational status were also investigated. RESULTS: All but one of the children had ophthalmologic abnormalities. Fundus anomalies were observed in 23 children, of whom 19 had optic nerve hypoplasia. Thirteen children had concomitant strabismus. Microphthalmos, buphthalmos, phthisis, microcornea, coloboma of the iris and uvea, blepharoptosis, cataract, persistent hyperplastic primary vitreous, and nystagmus were observed in single cases. The dysmorphology of the eyes remained unchanged during the follow-up period. In 2 children with severe mental retardation and, initially, very poor vision, the severe visual handicap persisted. Seventeen children had an initial visual activity > or = 20/70, which remained unchanged in 10 children and improved in 7 children, despite the presence of optic nerve hypoplasia in 14 of the children. Ten mothers died, 8 of them because of alcohol-related diseases, and only 4 of the mothers were able to take care of their children. Sixteen children went to schools for the mentally retarded, and only 3 children had a normal school education without extra teaching assistance. CONCLUSIONS: In children with FAS, the major sequela, ie, brain, damage, remains despite extensive medical, educational, and social support. The presence of ophthalmic signs, which persisted but did not deteriorate during the follow-up period, strengthens the diagnosis of FAS, and the high frequency of ocular involvement indicates the importance of a complete ophthalmologic evaluation in children with FAS.

Hearing disorders in children with fetal alcohol syndrome: findings from case reports.

Fourteen children with the fetal alcohol syndrome were evaluated by standard audiologic procedures. Thirteen of the 14 children had childhood histories of hearing disorders. All 13 of these children (93%) had clinically significant histories of bilateral recurrent serous otitis media (ie, they were otitis prone), and at least four children (29%) had bilateral sensorineural hearing losses in addition to being otitis prone. Many of the children with recurrent serous otitis media required repeated myringotomies with placement of ventilation tubes, and those with sensorineural hearing losses required sound amplification during childhood. Recurrent respiratory infections (secondary to immune deficiencies) and eustachian tube dysfunction (secondary to embryonic malformations of the first and second branchial arches) are discussed as possible etiologic factors in the presence of the recurrent serous otitis media. An alcohol-induced neuroectoderm syndrome and alcohol ototoxicity are discussed as possible etiologic factors in the occurrence of sensorineural hearing loss. The findings suggest that hearing disorders are a heretofore unrecognized characteristic of the fetal alcohol syndrome. Such hearing disorders may contribute to the speech and language and learning difficulties seen in children with fetal alcohol syndrome. The present study also provided confirmatory evidence of visual, health, and speech and language disorders in children with this syndrome.

Renal anomalies in fetal alcohol syndrome.

Six patients with fetal alcohol syndrome were found to have developmental abnormalities of the kidney. In only one patient was investigation for renal pathology made in the absence of clinical indication. Two had palpable masses in the left upper quadrant, one had pyelonephritis, one had painless hematuria, and the fifth patient had symptomatology suggestive of renal failure. Although the renal pathology was not of the same type in all cases, it is of interest that four patients had either unilateral or bilateral renal hypoplasia.

Two brothers with macrocephaly, progressive cerebral atrophy and abnormal white matter, severe mental retardation, and Lennox-Gastaut spectrum type epilepsy: an inherited encephalopathy of childhood?

Two brothers with severe mental retardation of unknown origin were found to share several physical anomalies, including large round head, small concave nose, downslanted palpebral fissures, and gingival hyperplasia. In addition to relative macrocephaly, magnetic resonance imaging (MRI) showed severe cerebral atrophy, especially fronto-temporally. The brothers also had a thin corpus callosum and atrophic caudate nuclei. The reduced white matter showed patchy periventricular signal intensity changes. The lateral and third ventricles were large, but the fourth ventricle was of normal size. The boys had large cisterna magna, communicating widely with the fourth ventricle, but no vermian hypoplasia. Both boys had Lennox-Gastaut spectrum type epilepsy. No chromosomal anomalies were found, despite the suggestive clinical picture. Some of the clinical findings resembled fetal alcohol effects/fetal alcohol syndrome (FAE/FAS), which was also suggested by history. Current diagnostic criteria for FAE/FAS, however, excluded full-blown FAS in these cases and failed to explain the entire clinical picture in the boys. We argue that these boys had an unidentified inherited syndrome, possibly modified by fetal alcohol exposure.

Fetal alcohol damage and schizophrenia.

The case of a 15 year old girl with fetal alcohol damage and schizophrenia is presented. Because fetal exposure to alcohol may produce brain damage, itself associated with increased vulnerability for schizophrenia, and because chronic exposure to alcohol may lead to a symptomatic schizophrenic illness, prospective study of children with fetal alcohol damage is needed to determine whether they are at greater risk for the later development of schizophrenia.

Fetal alcohol syndrome. Eye malformations in a mouse model.

Acute maternal ethanol administration on gestational day 7 (gastrulation stage) in C57Bl/6J mice results in a spectrum of ocular malformations. A deficiency in the anterior neural plate observable within 24 hours of exposure results in corresponding defects in the optic sulcus and subsequent optic vesicle. Deficiency in the size of the lens vesicle induced by a small optic vesicle is demonstrable as microphakia in older embryos. Delayed detachment of the lens vesicle from the surface ectoderm manifests in the live offspring as progressive corneal opacification and vascularization related to defects in corneal endothelium and Descemet's membrane. Anterior segment dysgenesis results in persistent iridocorneal adhesions, dyscoria, and abnormal formation of the anterior chamber. In contrast, ethanol exposure on day 8 of gestation did not result in eye malformations. Thus, it appears that many of the ocular abnormalities associated with fetal alcohol syndrome may result from an acute insult to the optic primordia during a very specific period that corresponds to the third week after fertilization in the human.

Ocular involvement in the fetal alcohol syndrome.

Maternal alcohol abuse during pregnancy causes malformations of the eyes with serious consequences to the vision of the affected children. A high percentage (up to 90%) of children suffering from the fetal alcohol syndrome have eye abnormalities, including malformation in the outer eye region, disorders of motility, and defects of different intraocular structures. Two kinds of malformations stand out as most typical--hypoplasia of the optic nervehead (up to 48%) and increased tortuosity of the retinal vessels, especially of the arteries (up to 49%). Visual acuity is often moderately or severely reduced. Considering the developmental timing of different tissues of the eye, one can presume that there is a risk for deleterious effects of alcohol on eye structures at any point of time from early gestation until development is completed.

Children with Fetal Alcohol Syndrome are impaired at place learning but not cued-navigation in a virtual Morris water task.

We employed a computerized (virtual) Morris water task (VMWT) to measure place learning and cued-navigation in eight adolescent males (9.5-16.5 years old) diagnosed with Fetal Alcohol Syndrome (FAS). Eight adolescent males matched for age and ethnicity with no history of prenatal alcohol exposure served as controls. Participants were trained to navigate to a hidden platform in a fixed location relative to a set of four conspicuous extramaze cues. After 20 hidden platform trials, a single no-platform probe trial was conducted, followed by 8 trials during which the platform was visible (cued-navigation). The FAS group traveled further than controls to navigate to the hidden platform during training. During the probe trial, controls navigated more directly to the platform region and persisted in searching where the platform had been more than the FAS group. Cued-navigation was comparable in both groups, suggesting that group differences in place learning were not attributable to visual-motor or motivational deficits in the FAS subjects. This pattern of impaired place learning and spared cued-navigation is similar to that reported in rats exposed to ethanol during periods of prenatal or early postnatal brain growth, as well as in animals with hippocampal damage.

Fetal alcohol syndrome and mental retardation: spine distribution of pyramidal cells in prenatal alcohol-exposed rat cerebral cortex; a Golgi study.

Among the various possible effects of the fetal alcohol-syndrome (FAS), mental retardation can be considered the most deleterious. In animal studies, prenatal alcohol exposure has been shown to result in increased neonatal mortality, retarded cerebellar development and a significant decrease in neonatal brain weight. In a Golgi study on Wistar rats that were prenatally exposed to alcohol the spine distribution in proximal apical dendrites of layer V pyramidal cells of the parietal cortex was examined. As compared with controls, a distinct spine abnormality could be demonstrated at 12 days and at 40 days of postnatal age: a persistent predominance of long, thin and entangled spines, and a decreased number of normal stubby and mushroom-shaped spines. These abnormal dendritic patterns show a striking resemblance to those described by Purpura in mentally retarded children of normal karyotype.

Deficiency of neuronal nitric oxide synthase (nNOS) worsens alcohol-induced microencephaly and neuronal loss in developing mice.

Previous work conducted in vitro suggests that nitric oxide (NO) protects developing neurons against the toxic effects of alcohol. We tested the hypothesis that neonatal mice carrying a null mutation for neuronal nitric oxide synthase (nNOS), the enzyme which synthesizes NO in neurons, have increased vulnerability to alcohol-induced microencephaly and neuronal loss. Wild-type mice and mutant (nNOS(-/-)) mice received a single intraperitoneal injection of ethanol (0.0, 2.2, 3.3, or 4.4 g/kg) daily over postnatal days (PD) 4-9 and were sacrificed on PD 10. Peak blood alcohol concentrations were approximately 170, 280, and 385 mg/dl for the 2.2, 3.3 and 4.4 g/kg/day treatment groups, respectively, and did not differ significantly between wild-type and nNOS(-/-) strains. Exposure to alcohol induced dose-dependent reductions in total brain weight, forebrain weight and cerebellum weight in both strains of mice. However, the reductions in brain weight were significantly more severe in the nNOS(-/-) mice than in wild type. Quantification of cerebellar neurons revealed that alcohol-induced losses of Purkinje cells and granule cells were both significantly greater in the nNOS(-/-) mice than in wild type. The increased vulnerability of nNOS-deficient neurons to alcohol-induced cell death was confirmed in vitro. Cerebellar granule cell cultures derived from nNOS(-/-) and wild-type mice were exposed for 24 h to 0, 100, 200 or 400 mg/dl ethanol. At each alcohol concentration, the nNOS(-/-) neurons had a significantly greater cell loss than did the wild-type neurons. The results demonstrate that deficiency of nNOS decreases the ability of developing neurons to survive the toxic effects of alcohol. Because NO upregulates intracellular cGMP, which can activate cGMP-dependent protein kinase (PKG), we hypothesize that the NO-cGMP-PKG pathway has a neuroprotective role against alcohol toxicity within the developing brain.

Ocular manifestations in fetal alcohol syndrome.

Eight children with the fetal alcohol syndrome are described with ocular anomalies. They all had a strong history of maternal alcohol abuse throughout pregnancy, especially in the first trimester. All the children had eye abnormalities. These included external eye lesions, Peters' anomaly, lens opacification, ocular motility disorders, and optic nerve hypoplasia.

Fetal alcohol syndrome: a review.

Presented is a review of the clinical manifestations of fetal alcohol syndrome (FAS), the mode of action in this syndrome, the maternal malnutrition that may occur, and consideration that may prevent the development of FAS in the fetus. Several factors are discussed that may help explain the abnormalities noted in infants with FAS. Education regarding the dangers of alcohol abuse for pregnant women is essential in prevent the development of fetal alcohol syndrome and other alcohol-related birth defects.

Effectiveness of methylphenidate in Native American children with fetal alcohol syndrome and attention deficit/hyperactivity disorder: a controlled pilot study.

This pilot study was designed to assess the short-term effectiveness and side effects of methylphenidate in treating symptoms of attention deficit hyperactivity disorder (ADHD) in Native American children (5 to 12 years old) with documented fetal alcohol syndrome (FAS) or partial fetal alcohol syndrome. Using strict criteria for the diagnosis of FAS and ADHD, a randomized double-blind cross-over study of two placebos and a fixed dose of methylphenidate was completed in 4 Native American children in a residential school. Each treatment condition lasted 5 days, and daily observational outcome measures, the Conners Parent Rating Scale (CPRS-48), and the Conners Teacher Rating Scale (CTRS-39), were employed. Methylphenidate significantly improved scores of the Hyperactivity Index Scale on the CPRS-48 and the CTRS-39 but not the Daydreaming-Attention score on the CTRS-39. Side effects were similar to those traditionally found in other populations. The promising preliminary results suggest that a more definitive study of methylphenidate in Native and non-Native children with FAS and ADHD is warranted.

Prevention possibility for brain dysfunction in rat with the fetal alcohol syndrome--low-zinc-status and hypoglycemia.

As a treatable cause of CNS dysfunctions in the fetal alcohol syndrome (FAS), low-zinc-status in addition to hypoglycemia has been investigated in experimental rat models. During the premating period female rats of an ethanol group and a control group received 30% ethanol (E) and water (W), respectively. During pregnancy, some of both groups received zinc or nicotinamide-adenine dinucleotide (NAD) or nicotinamide throughout pregnancy and glucose for gestational day (gd) 15 to 19 with E or W. Independent of maternal blood glucose levels, maternal insulin levels were lower on gd 15 and 18 in the ethanol group than in the control one. A decrease in the activity of carbonic anhydrase in the hippocampal area on postnatal day (pd) 1 was observed in the ethanol group. Administration of zinc with E resulted in a better effect on fetal total body weight and on preventing resorption, mean fetal body weight and protein content in the cerebrum than administration of E alone. Administration of glucose only in the late gestational period resulted in a better effect on fetal cerebral weight than administration of E alone, with a decrease in the litter size. Administration of zinc with E during pregnancy resulted in higher maternal serum zinc levels, without an increase in fetal cerebral zinc content, than administration without zinc with E. There was a positive correlation between fetal body ethanol levels and maternal blood ethanol levels, and a negative correlation between fetal body ethanol levels and fetal total body weight. The beneficial effect of supplementary zinc on fetal growth may possibly help preventing the CNS dysfunctions of FAS, but it is important that the effect was not good compared to the control without E.

The spectrum of arthrogryposis in 33 chinese children.

The clinical profile of 33 children (19 boys, 14 girls) with multiple congenital contractures has been studied. The majority (54%) belong to arthrogryposis multiplex congenita with a static clinical course. Children were classified into three groups: group I (limb involvement only; n = 21) having arthrogryposis multiplex congenita (n = 18), distal arthrogryposis syndrome (n = 2) and Streeter syndrome (n = 1); group II (limb involvement with other malformation or anomalies; n = 7) having congenital contractural arachnodactyly (n = 3), Larsen syndrome (n = 1), multiple pterygium syndrome (n = 1), craniocarpotarsal dystrophy (n = 1), and Schwartz Jampel syndrome (n = 1); and group III (limb involvement with central nervous system dysfunction or mental retardation; n = 5) having myotonia dystrophica (n = 2), congenital muscular dystrophy (n = 1), foetal alcohol syndrome (n = 1) and Pena-Shokeir syndrome (n = 1). Three children died, one each of arthrogryposis multiplex congenita, congenital contractural arachnodactyly and myotonia dystrophica. The majority had a good prognosis with independent function and mobility.