Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex.

OBJECTIVE: The purpose of this study was to assess the prevalence of and to identify epidemiologic, genetic, electrophysiologic, and neuroanatomic risk factors for autism spectrum disorders (ASD) in a cohort of patients with tuberous sclerosis complex (TSC). METHODS: A total of 103 patients with TSC were evaluated for ASD. A retrospective review of patients' records was performed, including mutational analysis. EEG reports were analyzed for the presence of ictal and interictal epileptiform features. Brain MRI scans were evaluated for TSC neuropathology, including tuber burden. RESULTS: Of the 103 patients with TSC, 40%were diagnosed with an ASD. On univariate analysis, patients with ASD were less likely to have mutations in the TSC1 gene. Patients with ASD also had an earlier age at seizure onset and more frequent seizures. On EEG, those with ASD had a significantly greater amount of interictal epileptiform features in the left temporal lobe only. On MRI, there were no differences in the regional distribution of tuber burden, although those with TSC2 and ASD had a higher prevalence of cyst-like tubers. CONCLUSIONS: The development of ASD in TSC is not well understood. Given our findings, ASD may be associated with persistent seizure activity early in development in particular brain regions, such as those responsible for social perception and communication in the left temporal lobe. The presence of cyst-like tubers on MRI could provide a structural basis or marker for ASD pathology in TSC, although studies assessing their effect on cortical function are needed.

Effectiveness of a home intervention for perceived child behavioral problems and parenting stress in children with in utero drug exposure.

OBJECTIVE: To determine if a home-based nurse intervention (INT), focusing on parenting education/skills and caregiver emotional support, reduces child behavioral problems and parenting stress in caregivers of in utero drug-exposed children. DESIGN: Randomized clinical trial of a home-based INT. SETTINGS: Two urban hospital newborn nurseries; homes of infants (the term infant is used interchangeably in this study with the term child to denote those from birth to the age of 36 months); and a research clinic in Baltimore, Md. PARTICIPANTS: In utero drug-exposed children and their caregivers (N = 100) were examined when the child was between the ages of 2 and 3 years. Two groups were studied: standard care (SC) (n = 51) and INT (n = 49). INTERVENTION: A home nurse INT consisting of 16 home visits from birth to the age of 18 months to provide caregivers with emotional support and parenting education and to provide health monitoring for the infant. MAIN OUTCOME MEASURES: Scores on the Child Behavior Checklist and the Parenting Stress Index. RESULTS: Significantly more drug-exposed children in the SC group earned t scores indicative of significant emotional or behavioral problems than did children in the INT group on the Child Behavior Checklist Total (16 [31%] vs 7 [14%]; P =.04), Externalizing (19 [37%] vs 8 [16%]; P =.02), and Internalizing (14 [27%] vs. 6 [12%]; P =.05) scales and on the anxiety-depression subscale (16 [31%] vs. 5 [10%]; P =.009). There was a trend (P =.06) in more caregivers of children in the SC group reporting higher parenting distress than caregivers of children in the INT group. CONCLUSIONS: In utero drug-exposed children receiving a home-based nurse INT had significantly fewer behavioral problems than did in utero drug-exposed children receiving SC (P =.04). Furthermore, those caregivers receiving the home-based INT reported a trend toward lower total parenting distress compared with caregivers of children who received SC with no home visits.

Effects of ketogenic diet on development and behavior: preliminary report of a prospective study.

The ketogenic diet is increasingly used for the management of difficult-to-control seizures in children. Here, we describe the first prospective study of the effects of the diet on development, behavior, and parenting stress. Participants were 65 children (36 males, 29 females) with intractable seizures, ages 18 months to 14 years 6 months, enrolled in a prospective study at the Johns Hopkins Hospital, Baltimore, MD, USA, to study the diet's efficacy. Children were assessed before diet initiation and at 1-year follow-up. At follow-up, 52% (34 of 65) children remained on the diet. Mean seizure frequency decreased from 25 per day before diet initiation to less than two per day 1 year later. At follow-up, mean developmental quotient showed statistically significant improvement (p<0.05), with significant behavioral improvements in attention and social functioning. Parental stress was essentially unchanged. No baseline factor examined predicted diet adherence, and the primary reason for diet discontinuation was insufficient seizure control. These preliminary results support prior anecdotal reports of the beneficial effects of the diet on cognition and behavior.

Language recovery after left hemispherectomy in children with late-onset seizures.

We investigated the language capabilities of the isolated right hemisphere in 6 children (age, 7-14 years) after left hemidecorticectomy for treatment of Rasmussen's syndrome. Patients were right-handed before surgery and had at least 5 years of normal language development before the onset of seizures. Language testing included speech sound (phoneme) discrimination, single word and phrasal comprehension, repetition, and naming. Within 4 to 16 days after surgery, patients showed improved phoneme discrimination compared with their performance shortly before surgery. Other language functions remained severely impaired until at least 6 months after surgery. By 1 year after surgery, receptive functions were comparable with, or surpassed, patient presurgery performance. Although word repetition was intact by 1 year after surgery, naming remained impaired, and patient speech was limited largely to production of single words. These results suggest that the right hemisphere is innately capable of supporting multiple aspects of phoneme processing. Recovery of higher level receptive and, to a lesser extent, expressive language functions is attributed to plasticity of the right hemisphere, which appears to persist beyond the proposed critical period for language acquisition and lateralization.

Sequential neuromotor examination in children with intrauterine cocaine/polydrug exposure.

Data are presented on 157 newborn infants followed sequentially in a randomized home-based nursing-intervention trial for drug-exposed infants with follow up at 3 (N=118), 6 (N=124), and 12 months (N=77). The objectives of this study were to describe the longitudinal neurodevelopmental status of a cohort of children with intrauterine exposure to illicit drugs during their gestation, characterize the evolution of early tone abnormalities in a polydrug-exposed cohort, and determine whether neuromotor outcome is associated with drug-exposure patterns. For analysis, infants were grouped based on maternal drug-use pattern and the presence of drug metabolites in the neonatal drug screen. The sequential neuromotor examination was used at each age to define the neuromotor status of six domains and define categorical classifications as either normal, suspect, or abnormal. Multiple patterns of neuromotor abnormalities were observed during the neonatal period; most resolved over time. Axial hypotonia was a prominent finding in the neonatal period; however, it was infrequent in abnormal examinations at 12 months. Increased lower-extremity tone was a less frequent finding during the neonatal period. Infants whose neonatal urine drug screen was positive for both cocaine and opiates, were more likely than infants with negative urine drug screens, cocaine only, or opiate only drug screen results to have abnormal neuromotor examinations; while positive maternal drug screens for concurrent cocaine and opiate use were associated with peripheral hypertonia. Persistence of increased leg-extensor tone was found in 67% of the abnormal examinations at 12 months. Acquisition of rolling and walking was delayed in the drug-exposed cohort.

MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia.

OBJECTIVE: This study sought to determine whether volumes of the hippocampus and amygdala are disproportionately smaller in subjects with Down's syndrome than in normal comparison subjects and whether volume reduction is greater in Down's syndrome subjects with dementia. METHOD: The subjects were 25 adults with Down's syndrome (eight with dementia) and 25 cognitively normal adults who were individually matched on age, sex, and race. Magnetic resonance imaging measures included volumes of the hippocampus, amygdala, and total brain. Nineteen of the Down's syndrome subjects had follow-up scans (interscan interval = 9-41 months). RESULTS: Nondemented Down's syndrome subjects had significantly smaller volumes of the hippocampus, but not the amygdala, than their comparison subjects, even when total brain volume was controlled for. Volumes of both the hippocampus and the amygdala were smaller in the demented Down's syndrome subjects than in their comparison subjects, even when total brain volume was controlled for. Age was not correlated with volume of the hippocampus or amygdala among the nondemented Down's syndrome subjects and the comparison subjects; age was correlated with volume of the amygdala, but not the hippocampus, among the Down's syndrome subjects with dementia. Changes in volume over time were not statistically significant for either the demented or the nondemented subjects. CONCLUSIONS: Hippocampal volume, while disproportionately small for brain size in individuals with Down's syndrome, remains fairly constant through the fifth decade of life in those without dementia. All subjects over age 50 who had Down's syndrome demonstrated volume reduction in the hippocampus as well as clinical signs of dementia. Dementia was also associated with volume reductions in the amygdala that exceeded reductions in total brain volume.

MRI brain changes in subjects with Down syndrome with and without dementia.

Individuals with Down syndrome (DS), a disorder of known genetic etiology (trisomy of chromosome 21), exhibit several types of structural brain abnormalities that are detectable pathologically and by MRI. In addition, in middle age, individuals with DS develop histological and, in some cases, clinical features of Alzheimer's disease (AD). Abnormalities in MRI scans of 50 adults with DS, 11 of whom had clinical dementia, are described and compared with those of 23 cognitively normal, healthy subjects who were matched for age, sex, and race. Qualitative visual analogue scale (VAS) ratings on MRI hard copies for all subjects and computer-aided volume measures for a subsample of subjects were carried out. On VAS, subjects with DS had larger lateral ventricles, a higher frequency of posterior fossa arachnoid cysts/megacisterna magna and fewer scans rated as normal compared with controls. Quantitatively, total brain and gray-matter volumes were reduced in DS, as were the volumes of the left hippocampus and amygdala; ventricle volumes were larger. Post hoc comparisons of subjects with DS with and without dementia revealed that on VAS the former had more generalized atrophy for age, mesial temporal shrinkage, and third ventricular enlargement. Similarly, total brain, left hippocampus, and left amygdala volumes were reduced quantitatively in subjects with DS with dementia, while ventricular volumes were increased.

Why would you remove half a brain? The outcome of 58 children after hemispherectomy-the Johns Hopkins experience: 1968 to 1996.

PURPOSE: To report the outcomes of the 58 hemispherectomies performed at Johns Hopkins between 1968 and January 1996. METHODS: Charts were reviewed of the 58 hemispherectomies performed at Johns Hopkins Medical Institutions by the Pediatric Epilepsy Group during the years 1968 to 1996. Twenty-seven operations were done for Rasmussen's syndrome, 24 operations for cortical dysplasias/hemimegalencephalies, and 7 for Sturge-Weber syndrome or other congenital vascular problems. Seizure control alone did not seem to adequately describe the outcomes of the procedure. Therefore, a score was constructed that included seizure frequency, motor disability, and intellectual handicap. This burden of illness score better described the child's handicap before and after surgery. RESULTS: Perioperative death occurred in 4 out of 58 children. Of the 54 surviving children, 54% (29/54) are seizure-free, 24% (13/54) have nonhandicapping seizures, and 23% (12/54) have residual seizures that interfere to some extent with function. Reduction in seizures was related to the etiology of the unilateral epilepsy. Eighty-nine percent of children with Rasmussen's, 67% of those with dysplasias, and 67% of the vascular group are seizure-free, or have occasional, nonhandicapping seizures. All operations were considered by the parents and the physicians to have been successful in decreasing the burden of illness. In 44 the procedure was very successful, in 7 it was moderately successful, and in 3 it was minimally successful. Success was related to the etiology, and early surgery was preferable. CONCLUSION: Hemispherectomy can be a valuable procedure for relieving the burden of seizures, the burden of medication, and the general dysfunction in children with severe or progressive unilateral cortical disease. Early hemispherectomy, although increasing the hemiparesis in children with Rasmussen's syndrome, relieves the burden of constant seizures and allows the child to return to a more normal life. In children with dysplasias, early surgery can allow the resumption of more normal development.

Basal ganglia volume in adults with Down syndrome.

This study was designed to determine the effects of aging on the volume of the basal ganglia in individuals with Down syndrome (DS) and to examine the relationship between basal ganglia volumes, neuropsychological test performance, and dementia status in this population. Subjects were 32 adults with DS. Basal ganglia volumes from 22 of these subjects were compared with those of 22 cognitively-normal individuals, who were individually matched on age, sex, and race. Performance on neuropsychological tests was correlated with basal ganglia volumes for 32 individuals with DS, and basal ganglia volumes of five demented DS subjects were compared with those of 14 non-demented DS subjects. Results indicated larger putamen volumes in the DS subjects, despite significantly smaller total brain volumes. Volumes of caudate and globus pallidus did not differ between DS and control subjects. Although there were some significant correlations between basal ganglia volumes and age, neuropsychological test performance, and dementia status in the DS subjects, these associations appeared to be a reflection of neurodevelopmental or atrophic reductions in overall brain volume rather than a reflection of specific basal ganglia abnormality. Correlations between age and volumes of basal ganglia and total brain were not significantly greater in non-demented DS subjects than in control subjects. Results suggest that volume reductions of the basal ganglia are not a salient feature of aging or of the dementia associated with DS.

Cerebellar volume in adults with Down syndrome.

OBJECTIVES: To determine the effects of aging on cerebellar volume in individuals with Down syndrome (DS). To determine whether volume of cerebellum is associated with dementia or with age-related decline in fine-motor control. DESIGN: Case-control study involving comparison of cerebellar volumes in adults with DS and matched control subjects; survey study involving correlations between cerebellar volume and subjects' age and performance on a test of fine motor control; and longitudinal study assessing change in cerebellar volume in adults with DS. SETTING: The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 40 adults with DS. Thirty of them were matched on age, sex, and race with cognitively normal subjects. A diagnosis of probable dementia was made for 5 of the subjects with DS. Longitudinal data were available for 23 of the 40 subjects with DS, with a mean interscan interval of 2 years. MAIN OUTCOME MEASURES: Volumes of cerebellum, total brain, and intracranial region were measured on magnetic resonance imaging scans. The Purdue Pegboard, a test of fine-motor control, was administered to 38 of the subjects with DS. RESULTS: Subjects with DS had significantly smaller cerebellar volumes than matched controls, even after adjusting for total brain volume or total intracranial volume. Volume of cerebellum did not correlate significantly with age for either the subjects with DS or controls. Longitudinal change in cerebellar volume in subjects with DS was not significant. Volume of total brain, but not cerebellum, correlated significantly with performance on the Purdue Pegboard. CONCLUSIONS: Although cerebellar volumes are disproportionately small in individuals with DS, they do not diminish significantly with age and do not undergo age-related atrophy that is different from that of normal controls. Volume reduction in the cerebellum does not appear to be specifically responsible for the age-related decline in fine-motor control that is observed in adults with DS.

Reduced survival of apolipoprotein E4 homozygotes in Down's syndrome?

An increased frequency of apolipoprotein E (ApoE) allele epsilon 4 has been established in Alzheimer's disease (AD) subjects. Based on the observation that all individuals with Down's syndrome (DS) develop the neuropathology of AD by the age of 40 years we sought to determine whether ApoE genotype affected the clinical symptoms of AD. Unexpectedly, we failed to find any epsilon 4 homozygotes, as have other published studies: this is highly significant statistically. We suggest this is due to decreased survival or, less likely, embryonic lethality of epsilon 4 homozygotes in DS.

The neuropsychology of mental retardation.

This critical review examines mental retardation (MR) from a neuropsychological perspective. Competing definitions of MR are discussed and the prevalence is estimated. Descriptions are given of idiopathic MR and the five major identifiable prenatal causes of MR: fetal alcohol syndrome, Down's syndrome, fragile X syndrome, Prader-Willi syndrome, and Angelman syndrome. Similarities and differences among syndromes are examined. Cognitive deficits common to all disorders were in attention, short-term memory, and sequential information processing, whereas language and visuospatial abilities were varied. Neuroanatomical abnormalities common to all disorders were in the hippocampus and cerebellum; individual disorders typically showed a unique pattern of other neurological abnormalities. Both knowledge of individual MR-related disorders and comparative research between disorders are important for researchers and clinicians. Further research is called for in both areas.

Maternal estimates of developmental age in preschool children.

OBJECTIVE: To investigate the accuracy of maternal estimates of developmental age in preschool children with suspected developmental delay. METHODS: In a sample of 139 preschool children, aged 5 to 60 months, mothers were asked before evaluation to estimate the developmental age of their child. Maternal estimates were converted to a developmental quotient (DQ) and compared with results from standardized tests of cognitive functioning, adaptive abilities, expressive and receptive language, and visual-motor skills. RESULTS: A high correlation was found (r = 0.82; p < 0.0001) between maternal-estimate DQ and actual DQ (mean of test scores). Most mothers estimated within 15% of their child's actual functioning, and 84% of mothers estimated within +/- 5 months of actual functioning. Multiple regression found no factors that would identify mothers who were more or less accurate in estimating developmental age. Maternal-estimate DQ was sensitive (83%) and specific (83%) for mental retardation. CONCLUSION: Maternal estimates provide an accurate measure of developmental functioning and could be successfully incorporated into routine developmental surveillance of preschool children.

Clinical Adaptive Test/Clinical Linguistic Auditory Milestone Scale in early cognitive assessment.

Correlations between the Clinical Adaptive Test/Clinical Linguistic Auditory Milestone Scale (CAT/CLAMS) and the Bayley Scales of Infant Development--Mental Scale (BSID) were examined in 61 infants and toddlers with suspected developmental delay. Highly significant correlations were found between the two instruments. Gender, race, and gestational age did not influence the relationship between CAT/CLAMS and BSID scores. The CAT/CLAMS was both sensitive (88%) and specific (67%) for mental retardation (BSID < 70). The CAT/CLAMS correlates with the BSID and can be used as an instrument for detecting cognitive delay.