Eric Levey

Sensory and motor deficits in children with cerebral palsy born preterm correlate with diffusion tensor imaging abnormalities in thalamocortical pathways

Aim  Cerebral palsy (CP) is frequently linked to white matter injury in children born preterm. Diffusion tensor imaging (DTI) is a powerful technique providing precise identification of white matter microstructure. We investigated the relationship between DTI‐observed thalamocortical (posterior thalamic radiation) injury, motor (corticospinal tract) injury, and sensorimotor function.

Diffusion Tensor Imaging in Children with Periventricular Leukomalacia: Variability of Injuries to White Matter Tracts

BACKGROUND AND PURPOSE: Conventional MR imaging shows evidence of brain injury and/or maldevelopment in 70%–90% of children with cerebral palsy (CP), though its capability to identify specific white matter tract injury is limited. The great variability of white matter lesions in CP already demonstrated by postmortem studies is thought to be one of the reasons why response to treatment is so variable. Our hypothesis is that diffusion tensor imaging (DTI) is a suitable technique to provide in vivo characterization of specific white matter tract lesions in children with CP associated with periventricular leukomalacia (PVL). MATERIALS AND METHODS: In this study, 24 children with CP associated with PVL and 35 healthy controls were evaluated with DTI. Criteria for identification of 26 white matter tracts on the basis of 2D DTI color-coded maps were established, and a qualitative scoring system, based on visual inspection of the tracts in comparison with age-matched controls, was used to grade the severity of abnormalities. An ordinal grading system (0 = normal, 1 = abnormal, 2 = severely abnormal or absent) was used to score each white matter tract. RESULTS: There was marked variability in white matter injury pattern in patients with PVL, with the most frequent injury to the retrolenticular part of the internal capsule, posterior thalamic radiation, superior corona radiata, and commissural fibers. CONCLUSION: DTI is a suitable technique for in vivo assessment of specific white matter lesions in patients with PVL and, thus, a potentially valuable diagnostic tool. The tract-specific evaluation revealed a family of tracts that are highly susceptible in PVL, important information that can potentially be used to tailor treatment options in the future.

Parent and self-report ratings of executive function in adolescents with myelomeningocele and hydrocephalus.

Parent and self-report ratings were obtained for 28 adolescents with myelomeningocele and congenital hydrocephalus using the Behavior Assessment System for Children (BASC; Reynolds & Kamphaus, 1998a, 1998b) and the Behavior Rating Inventory of Executive Function (BRIEF; Gioia, Isquith, Guy, & Kenworthy, 2000; Guy, Gioia, & Isquith, 1998). Parents rated their children as having significantly more problems, compared to published norms, on the BRIEF but not the BASC. Adolescents rated themselves as having significantly more problems, compared to parent ratings, on scales comprising the BRIEF Behavioral Regulation Index; but not on common scales of the BASC. Parents also reported more problems on the BRIEF Global Executive Composite than on all three primary BASC indices, and more problems on the BRIEF Metacognition Index than on the BRIEF Behavioral Regulation Index. We conclude that the BRIEF captures salient executive dysfunction among individuals with myelomeningocele and hydrocephalus, and may be useful in identifying needs for intervention that might not be identified by broad-band behavior rating scales alone.

Neuroanatomy of holoprosencephaly as predictor of function Beyond the face predicting the brain

BackgroundDespite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described. Objective To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function. Methods The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation. Results In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01). ConclusionsPatients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.

Middle interhemispheric variant of holoprosencephaly: A distinct cliniconeuroradiologic subtype

Background: The middle interhemispheric variant (MIH) is a subtype of holoprosencephaly (HPE) in which the posterior frontal and parietal areas lack midline separation, whereas more polar areas of the cerebrum are fully cleaved. While the neuroradiologic features of this subtype have been recently detailed, the clinical features are largely unknown. Objective: To present the clinical manifestations of MIH and to compare them with classic subtypes (alobar, semilobar, and lobar) of HPE. Methods: The authors evaluated 15 patients with MIH in a multicenter study. Neuroimaging and clinical data were collected and correlated. They compared the data with those of 68 patients who had classic HPE. Results: The frequency of endocrinopathy in MIH (0%) was lower compared with the classic subtypes (72%) (p < 0.0001). This correlated with the lack of hypothalamic abnormalities. The percentage of patients with seizures (40%) did not significantly differ from classic HPE. Spasticity was the most common motor abnormality, seen in 86% of MIH patients, similar to other subtypes. The frequency of choreoathetosis in MIH (0%) was lower than that for semilobar HPE (41%) (p < 0.0039). This correlated with the lack of caudate and lentiform nuclei abnormalities. Developmental functions, including mobility, upper-extremity function, and language, of the MIH group were similar to the least severe classic type, lobar HPE. Conclusion: MIH is a recognizable variant of HPE with differing clinical prognosis. Similar to the lobar subtype by functional measures, MIH differs from classic HPE by the absence of endocrine dysfunction and choreoathetosis.

Clinical Spectrum of SIX3-Associated Mutations in Holoprosencephaly: Correlation between Genotype, Phenotype, and Function.

Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective: To characterise genetic and clinical findings in patients with SIX3 mutations. Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype–phenotype correlation, as shown by functional studies using animal models.

Fractures in children with cerebral palsy.

Introduction: We studied the fracture history in a large population of patients with cerebral palsy to determine which children were at the highest risk for fracture. Methods: The International Classification of Diseases (Ninth Revision) coding identified 763 children with cerebral palsy. Patients and caregivers were contacted for information about fracture history and risk factors for low bone density. Of the 763 children identified, 418 children (54.8%) were available for this study; 243 (58%) had quadriplegia, 120 (29%) diplegia, and 55 (13%) hemiplegia. Three hundred sixty-six children were spastic, 23 mixed tone, 13 athetoid, and 16 classified as others. We identified 50 children (12%) who fractured; 15 of these same children had, over time, multiple fractures. Results: The number of fractures showed a normal distribution by age, with a mean of 8.6 (SD, 4.0). Children with cerebral palsy with mixed tone had a higher rate of fracture (&khgr;2 = 14.7, P < 0.01); &khgr;2 analysis indicated that the children who fractured were, as a group, more likely to use a feeding tube, have a seizure disorder, take valproic acid (VPA), and use standing equipment in therapy. Multiple regression analysis demonstrated older age and VPA use as predictive of fracture and gave the following equation: fracture = −0.01 + (VPA × 0.17) + (age × 0.15). The subgroup that sustained multiple fractures were older at the time of first fracture than the children who had only one reported fracture (t = −2.3, P < 0.05). Conclusions: The main finding of our article is that older age at first fracture and use of VPA are predictive of fractures and define a group of children with cerebral palsy who may benefit from treatment interventions to increase bone density.

Mutations in ZIC2 in Human Holoprosencephaly: Description of a Novel ZIC2-Specific Phenotype and Comprehensive Analysis of 157 Individuals

Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE. Objective To characterise genetic and clinical findings in patients with ZIC2 mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search. Results By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4% (49/582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears. Conclusions HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.

Correlates of Depressive and Anxiety Symptoms in Young Adults with Spina Bifida

Objective Based on social ecological theory, this study was designed to examine the unique relationships between multi-level ecological factors and psychological symptoms in young adults with spina bifida (SB). Method A sample of 61 individuals with SB, 18–25 years of age, completed standardized self-report measures of attitude toward SB, satisfaction with family functioning, Chronic Care Model (CCM) services, and depressive and anxiety symptoms. A chart review yielded SB clinical data. Results High rates of depressive and anxiety symptoms were found. Hierarchical regression analysis identified the proximal individual (attitude toward SB) and family (satisfaction with family functioning) factors as more strongly related to depressive symptoms than the distal healthcare system factor (CCM services). Self-reported pain was the only ecological factor associated with anxiety symptoms. Conclusions Study findings provide a potential foundation for multi-factor screening of young adults with SB at risk for psychological symptoms.

A retrospective survey of perinatal risk factors of 104 living children with holoprosencephaly

Holoprosencephaly (HPE) is a brain malformation resulting from a primary defect in development of the basal forebrain during early gestation. Prenatal genetic and environmental factors and birth outcomes were described in a population of 104 children with holoprosencephaly referred to three clinical centers from 1998 through 2002. The mean child age was 4 years. Of cases karyotyped, 9% presented with a chromosomal abnormality. This study of living children with holoprosencephaly, the majority of whom are cytogenetically normal, provides new information on the subsample of children with a less severe phenotype. Most children were born at term; about 51% were microcephalic at birth. Consistent with previous research, the association between HPE and maternal history of diabetes merits further investigation. Several findings have important implications for future research. Only 22% of the children in this study sample were diagnosed with holoprosencephaly prenatally. The vast majority of children (72%) were diagnosed with HPE between birth and 1 year of age. Also, 19% of the cases referred to the Carter Centers with HPE were not confirmed on scan review. When possible, future population‐based epidemiological studies should emphasize mechanisms that identify children with HPE outside of the newborn period and confirm the diagnosis by review of MRI or high quality CT brain scan.