Holoprosencephaly--topologic variations in a liveborn series: a general model based upon MRI analysis.

We present an MRI-based anatomic analysis of a series of 9 human brains, representing lobar, semilobar and alobar forms of holoprosencephaly. The analysis of these variable forms of the malformation is based upon a topologic systematics established in a prior analysis of a homogeneous set of semilobar malformations. This systematics has the dual advantage that it serves both as a uniform reference for qualitative description and as a quantitative descriptive base for mathematical correlations between parameters of topology and of growth and development. Within this systematics, the prosencephalic midline is divided from caudal to rostral into diencephalic (DD-right and left, subthalamus through suprachiasmatic junction with telencephalon), telencephalic (TT-right and left, suprachiasmatic border of telencephalon midline to hippocampal commissure) and diencephalic-telencephalic (DT-right and left-hippocampal commissure through temporal limb of choroid fissure) segments. The topologic abnormality of the initial semilobar series was expressed in an orderly rostral to caudal gradient along the TT segment. In each malformation, normal midline topology began with a small posterior corpus callosum. Although the topologic anomaly in the present series invariably also involved the TT segment, this involvement was not continuous and was variably associated with anomalies of the DD in 6 and unilaterally of the DT in 1 brain. In the present as well as with the earlier series of HPE malformations but not in "normative brains," total telencephalic growth is strongly correlated with the length of the midline telencephalic segment. We propose that this system of analysis will be sensitive to the developmental stage and locus of expression of genetic and non-genetic determinants of the formal origin of HPE. For all of the present series, karyotype anlyses were normal. Mutations in the Shh and Zic2 genes were excluded in 2 cases.

Semilobar holoprosencephaly with midline 'seam': a topologic and morphogenetic model based upon MRI analysis.

We present an MRI-based anatomic analysis of a series of seven human brains with the semilobar form of holoprosencephaly. The analysis defines a set of common descriptors for a pattern of topological anomaly which is uniform for the set of seven brains. The core of the anomaly is a rostro-caudally aligned midline gray matter 'seam' that extends from the telencephalic-suprachiasmatic junctional region to abut the posterior aspect of the callosal commissure. The seam forms the ventricular roof throughout its extent. Rostrally it is formed by the conjoined heads of caudate/accumbens nuclei. It continues caudally as a gray matter bridge in the fundus of the interhemispheric fissure, where it bridges right and left neocortex. Fornix, septal nuclei and septal limb of the choroid plexus are absent, and the telencephalic ventricles communicate with the diencephalic via open septal limbs of the choroid fissures. By contrast, the temporal limb of hippocampal formation and the choroid plexus are normal and the temporal limb of the choroid fissure is closed. This topological anomaly of conjoined left and right cortical and nuclear gray matter into a midline seam and absent septal structures is thus confined to the region of the midline telencephalic hemisphere evagination. Total telencephalic growth is strongly correlated with the length of this topologically abnormal midline telencephalic segment. The set of findings is consistent with graded failure of induction of rostral to caudal specification in the midline rostral telencephalic zone.

MRI shows abnormal white matter maturation in classical holoprosencephaly.

In an attempt to assess white matter maturation in holoprosencephaly (HPE), MRI scans of 47 patients with HPE were retrospectively reviewed. White matter maturation was delayed in 25/47 patients, including 24/29 patients with classic HPE who were

Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain.

BACKGROUND: Despite 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). CONCLUSIONS: Patients 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.

Chiari-II malformation: a biometric analysis.

INTRODUCTION: Chiari-II malformation is a complex set of anatomic abnormalities of the posterior fossa, brainstem, and cerebellum seen in myelomeningocele. Previous studies have tried to understand this condition and its clinical consequences by studying a few fixed anatomic landmarks as dependent variables and clinical symptoms as outcome variables. These studies have led to conflicting and limited results. As a first step towards a more comprehensive study of the structural-functional relationships in Chiari-II malformation, we undertook a biometric case-series analysis of a group of individuals with MMC, using both traditional methods to study size, and thin-plate spline methodology to study shape. MATERIALS AND METHODS: The traditional analysis was a retrospective, randomly obtained case-series of 25 individuals with myelomeningocele and Chiari-II malformation. MRIs were digitized for biometric analysis of the component structures and compared to 25 controls. Landmarks on the digitized images were measured using Scion Image. Data were statistically analyzed using SPSS. The thin-plate spline analysis used a subset of these individuals (n = 14). Landmarks on digitized MRIs were identified and marked with TPSDig software. Landmark data was then imported into Splus to generate a series of shape variables. Statistical analysis using Splus was then undertaken. RESULTS: Traditional analysis revealed relationships between vermian herniation and pontomedullary junction position (p < 0.05) as well as between the height (and overall size) of the posterior fossa and degree of vermian herniation (p < 0.05). The degree of brainstem herniation/elongation did not correlate with the degree of vermian herniation. The shape analysis revealed that there is as much shape variability within the group of Chiari-II patients as there is between this group and unaffected controls. Thin-plate spline analysis shows that the position of the caudal-most aspect of the vermis is the point of greatest brain rearrangement; likewise, the opisthion is the point of greatest bony rearrangement. Partial least-squares analysis shows that in Chiari-II patients, a strong correlation (r = 0.821) exists between the extent to which the brain is warped (specifically, in regard to vermian descent) and the extent to which the bone is warped (specifically, in regard to the displacement of the opisthion) (p < 0.05). CONCLUSION: Traditional biometric analysis of size confirms that the degree of vermian herniation and cervicomedullary junction herniation are independent variables in Chiari-II malformation. Posterior fossa size is an important factor in explaining the variability of vermian herniation. The relationship between IPN position and vermian herniation suggests the possibility of a common etiology. The phenomenon of cervicomedullary junction descent appears to be independent, suggesting a different etiology. Analysis of shape indicated that shape changes in bone and brain are related, and that the Chiari-II-associated abnormalities vary greatly in their degree of abnormality. The extreme morphological variability argues against the use of mean differences as a statistical technique in analyzing morphological abnormalities in the structures we investigated.

The dorsal cyst in holoprosencephaly and the role of the thalamus in its formation.

The dorsal cyst is poorly understood, although it is commonly encountered in holoprosencephaly. We endeavor to establish the role of diencephalic malformations in the formation of the dorsal cyst and speculate on the developmental factors responsible. We reviewed the imaging of 70 patients with holoprosencephaly (MRI of 50 and high-quality CT of 20). The presence or absence of a dorsal cyst, thalamic noncleavage and abnormal thalamic orientation were assessed for statistical association, using Fisher's Exact Test and logistical regression. The presence of a dorsal cyst correlated strongly with the presence of noncleavage of the thalamus (P = 0.0007) and with its degree (P < 0.00005). There was a trend toward an association between abnormalities in the orientation of the thalamus and the dorsal cyst, but this was not statistically significant (P = 0.07). We speculate that the unseparated thalamus physically blocks egress of cerebrospinal fluid from the third ventricle, resulting in expansion of the posterodorsal portion of the ventricle to form the cyst.

Between two worlds medical student perceptions of humor and slang in the hospital setting.

OBJECTIVE: Residents frequently use humor and slang at the expense of patients on the clinical wards. We studied how medical students react to and interpret the "appropriateness" of derogatory and cynical humor and slang in a clinical setting. DESIGN: Semistructured, in-depth interviews. SETTING: Informal meeting spaces. PARTICIPANTS: Thirty-three medical students. MEASUREMENTS: Qualitative content analysis of interview transcriptions. MAIN RESULTS: Students' descriptions of the humorous stories and their responses reveal that students are able to take the perspective of both outsiders and insiders in the medical culture. Students' responses to these stories show that they can identify the outsider's perspective both by seeing themselves in the outsider's role and by identifying with patients. Students can also see the insider's perspective, in that they identify with residents' frustrations and disappointments and therefore try to explain why residents use this kind of humor. Their participation in the humor and slang--often with reservations--further reveals their ability to identify with the perspective of an insider. CONCLUSIONS: Medical students describe a number of conflicting reactions to hospital humor that may enhance and exacerbate tensions that are already an inevitable part of training for many students. This phenomenon requires greater attention by medical educators.

Assessment of the deep gray nuclei in holoprosencephaly.

BACKGROUND AND PURPOSE: Although holoprosencephaly has been known for many years, few detailed analyses have been performed in a large series of patients to outline the range of morphology in this disorder, particularly regarding the deep gray nuclear structures. We reviewed a large patient cohort to elucidate the combinations of morphologic aberrations of the deep gray nuclei and to correlate those findings with recent discoveries in embryology and developmental neurogenetics. METHODS: A retrospective review of the imaging records of 57 patients (43 MR studies and 14 high-quality CT studies) to categorize the spectrum of deep gray nuclear malformations. The hypothalami, caudate nuclei, lentiform nuclei, thalami, and mesencephalon were graded as to their degree of noncleavage. Spatial orientation was also evaluated, as was the relationship of the basal ganglia to the diencephalic structures and mesencephalon. The extent of noncleavage of the various nuclei was then assessed for statistical association. RESULTS: In every study on which it could be accurately assessed, we found some degree of hypothalamic noncleavage. Noncleavage was also common in the caudate nuclei (96%), lentiform nuclei (85%), and thalami (67%). Complete and partial noncleavage were more common in the caudate nuclei than in the lentiform nuclei. The degree of thalamic noncleavage was uniformly less than that in the caudate and lentiform nuclei. Abnormalities in alignment of the long axis of the thalamus were seen in 71% of cases, and were associated with degree of thalamic noncleavage; 27% of patients had some degree of mesencephalic noncleavage. CONCLUSION: The hypothalamus and caudate nuclei are the most severely affected structures in holoprosencephaly, and the mesencephalic structures are more commonly involved than previously thought in this "prosencephalic disorder." These findings suggest the lack of induction of the most rostral aspects of the embryonic floor plate as the cause of this disorder.

Holoprosencephaly: recent advances and new insights.

Holoprosencephaly is a relatively common brain malformation occurring in 5-12/100,000 live births. The astonishing growth in molecular genetic medicine has provided the field of developmental nervous system malformations with new perspectives and tools for unraveling its mysteries and offering better information for clinicians and families. This is particularly evident in the group of complex midline malformations known as holoprosencephaly. Although new molecular findings have shed light on some of the causes and manifestations of this malformation, there remains a need to build on the existing clinical knowledge so that we may develop more effective treatments and improve the quality of life of these patients.

Laparoscopic surgery in patients with ventriculoperitoneal shunts: safety and monitoring.

PURPOSE: It was suggested that patients with a ventriculoperitoneal shunt are at risk for increased intracranial pressure during pneumoperitoneum. Shunt pressure monitoring and ventricular drainage to maintain normal pressure were recommended. We evaluated a series of patients with a ventriculoperitoneal shunt who underwent laparoscopic surgery to determine the clinical indications of increased intracranial pressure. MATERIALS AND METHODS: We reviewed the anesthesia records of 12 females and 6 males with a mean age of 13.2 years who had a ventriculoperitoneal shunt and underwent a total of 19 consecutive laparoscopic operations. Data on operative time, carbon dioxide level, pulse, blood pressure and any untoward anesthetic events were obtained. Postoperative records were assessed for evidence of neurological change. RESULTS: Mean operative time was 7 hours 13 minutes and estimated mean laparoscopic time was 2 hours 52 minutes. Average insufflation pressure was 16 mm. Hg (range 12 to 20). There was no evidence of a trend to combined bradycardia and hypertension or surgically related neurological deterioration and no untoward anesthetic events. Ventriculoperitoneal shunt revision was done in 3 cases, a rate consistent with that in the literature. Mean followup was 23.4 months (range 1 to 58). CONCLUSIONS: There was no evidence of clinically significant increased intracranial pressure in our series or in the literature in patients with a ventriculoperitoneal shunt who undergo laparoscopy. Invasive methods for shunt monitoring are not without risk. Routine anesthetic monitoring should remain the standard of care in the absence of clear evidence to the contrary.

Young women with physical disabilities: risk factors for symptoms of eating disorders.

Women with disabilities are at risk for poor psychological adjustment and unhealthy weight-control practices. This study was conducted to determine the prevalence of symptoms of eating disorders in a clinic-based sample of women who had two disabling conditions and to identify condition-related risk factors that were linked to these symptoms. A cross-sectional survey of 71 women (mean age = 23 yr) with spina bifida or rheumatologically related illnesses was conducted to assess the symptoms of eating disorders, condition-related characteristics, and weight-control practices. Symptoms of eating disorders were measured by the Eating Disorders Inventory (EDI). Eight percent of the respondents reported a sufficient number of symptoms of eating disorders to indicate a possible clinical disorder. More than 20% of the respondents scored at or above the clinical cut-point on at least one of the eight EDI subscales. Selected condition-related characteristics (multiple conditions, condition-affected driving, and uncertainty of illness course) were associated with EDI scores after adjusting for demographic variables, family factors, and weight-control practices.

Beyond multidisciplinary care: a new conceptual model for spina bifida services.

Medical care for people who are born with spina bifida (myelodysplasia) is complex and challenging, but the goal of such care is to optimize health and function for people with this condition. Despite years of expert agreement that multidisciplinary care is the medical standard for individuals with spina bifida, this model does not seem to go far enough towards accomplishing the goal of improved function as well as health for all people with spina bifida. Advances in the medical and surgical management of people with spina bifida and society's increased desire to include those with disabilities in family and community life has heightened our expectations for functional/participatory improvement for people with this condition. Some large spina bifida programs have added a separate rehabilitation component to the comprehensive package of services offered to people with spina bifida. The problem with adding further services to the traditional multidisciplinary spina bifida program is the increased complexity and potential for fragmentation that it presents, particularly for the patient and family. We performed a MEDLINE literature search to find information on integrating these services. Although several articles address the importance of either the multidisciplinary spina bifida clinic or a rehabilitation approach, there is little information about integration of medical and rehabilitation services. We propose a new model for spina bifida services throughout the lifespan that integrates the medical and functional/rehabilitative perspectives. Our model for conceptualizing spina bifida services builds on the WHO framework for coding disability (ICIDH-2). This framework includes not only health and functional perspectives, but a participation dimension as well. Furthermore, our new model emphasizes the importance of anticipatory guidance and transitional planning as an integrating dimension applicable across the lifespan. The model is based on three main conceptual dimensions--comprehensiveness, coordination and longitudinality. We are using the model to create standards of care, integrate services and improve their efficiency, and to develop policies regarding spina bifida services. Through this effort we hope to provide better medical and rehabilitation services to those with spina bifida and meet the complex challenge the condition presents throughout the lifespan.

Detection of adenocarcinoma by urinary microsatellite analysis after augmentation cystoplasty.

Augmentation cystoplasty is associated with an increased risk of bladder cancer development between 10 and 20 years after augmentation. Using microsatellite analysis, we analyzed urine obtained before surgical resection of the malignant lesion from a patient who developed invasive adenocarcinoma after augmentation cystoplasty. Loss of heterozygosity was identified in both urine and tumor samples from this patient. This observation suggests that microsatellite urine analysis may be useful as a monitoring tool for patients after augmentation cystoplasty.

Early sexual initiation: the role of peer norms.

OBJECTIVE: To elucidate which components of peer norms influence the process of sexual initiation for young adolescents. Design. Prospective cohort study. Setting. Fourteen elementary and middle schools in an urban public school district. Participants. The 1389 sixth-grade students who completed the questionnaire at the beginning (time 1) and at the end (time 2) of the school year comprise the study sample. Mean age at time 1 was 11.7 years. RESULTS: Of students entering the sixth grade, 30% (n = 416) reported having already initiated sexual intercourse, 5% (n = 74) reported initiating sexual intercourse during the sixth-grade school year (initiated group), and 63% (n = 873) reported not having initiated sexual intercourse by the end of the sixth-grade school year (never group). Demographic comparisons revealed that students in the initiated group were significantly more likely than students in the never group to be older (11.9 years vs 11.6 years), male (58% vs 37%), African-American (70% vs 51%), attending a poorer school (87% vs 85%), and living in an area with a high proportion of single-parent families (45% vs 41%). Self-reports and reports of peers' participation in nonsexual risk behaviors were more common for students in the initiated group. Students in the initiated group were more likely than students in the never group to perceive: 1) a high prevalence of sexual initiation among peers; 2) social gains associated with early sexual intercourse; and 3) younger age of peers' sexual initiation. Students in the never group were more likely to believe that sexually-experienced 12-year-old boys would be negatively stigmatized compared with students in the initiated group. Three predictive models were developed to test the relationship between peer norms and the process of initiation. These models demonstrate that the strongest predictor of sexual initiation in sixth grade is having high intention to do so at the beginning of sixth grade. The strongest predictor of high intention is belief that most friends have already had sexual intercourse. Perceptions of social gain and stigma for sexually-experienced 12-year-old boys act independently of intention to decrease risk of early sexual initiation. CONCLUSION: Early sexual intercourse is not an unplanned experience for many teens. Decisions about initiation are strongly bound to social context with peers playing an important role in creating a sense of normative behavior. Specific components of peer norms impact the process of sexual initiation in both positive and negative ways. Interventions aimed at delaying the onset of sexual initiation need to focus on cohort norms as well as on an individual's perceptions and behaviors.