Charles W. McCluggage

Multi‐disciplinary clinical study of Smith‐Magenis syndrome (deletion 17p11.2)

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic, neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65%, brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter.

Paranasal sinus development in chronic sinusitis, cystic fibrosis, and normal comparison population: a computerized tomography correlation study.

Chronic sinus disease in patients with and without cystic fibrosis may have an impact on the pattern of paranasal sinus pneumatization. Arrest of pneumatization has been reported in both of these conditions. To assess the development of the paranasal sinuses in relationship to chronic sinusitis and cystic fibrosis (CF), a retrospective review of coronal CT scans of the age-matched patients with no previous sinus disease, patients with chronic sinusitis, and cystic fibrosis patients was conducted. The patients’ ages ranged from 4 to 17 years. The maxillary sinus volume, anteroposterior diameter, and greatest transverse diameter and height were determined using image analysis software after the coronal CT scans were scanned into Macintosh computer. The size of the maxillary sinus increased with advancing age in the control and chronic sinusitis group, but not in the patients with cystic fibrosis. The patients with cystic fibrosis had a statistically significant smaller maxillary sinus size. Approximately 50% of the patients with chronic sinusitis had anatomic anomalies, the most common being paradoxical middle turbinates. The CT scans of CF patients were characterized by uncinate process demineralization and medial displacement of the lateral nasal wall in the middle meatus, and decreased maxillary sinus pneumatization.

Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237

Idarubicin (IDA), the 4-demethoxy analog of daunomycin, has had significant cytotoxicity in many malignancies. In previous reports, the alcohol metabolite of IDA, 4-demethoxydaunorubicinol (idarubicinol, or IDOL), had cytotoxic activity and the ability to penetrate the blood-brain barrier. For this reason, the Pediatric Oncology Group conducted a Phase 2 trial of IDA for children with recurrent or progressive brain tumors. Ninety-one eligible children were entered on this study, with ages ranging from 3 months to 19 years. Patients were stratified by tumor types into 6 categories: stratum 1, low-grade astrocytoma; stratum 2, malignant glioma (glioblastoma multiforme and anaplastic astrocytoma); stratum 3, medulloblastoma; stratum 4, brainstem glioma; stratum 5, ependymoma; and stratum 6, miscellaneous malignant tumors not included in the previous diagnoses. IDA(18 mg/m2) was infused over 4 h and followed by granulocyte colony-stimulating factor (G-CSF) beginning day 5 after infusion of IDA. G-CSF was continued until blood cell count recovery. Cycles were repeated at approximately 21-day intervals until patients developed progressive disease or had completed 6 cycles with stable or improved disease. Pharmacokinetic plasma and cerebrospinal fluid (CSF) samples were collected from a subset of these patients. Response was poor in all strata. Most patients developed progressive disease; however, in 21 patients with medulloblastoma there was 1 partial response, and 6 patients had stable disease (SD) that in 4 patients lasted more than 20 weeks. Grades 3/4 hematopoietic toxicities were the most common toxic events, and 14 infection-related events resulted in hospitalization of patients. Only 1 patient developed reduced cardiac function. The systemic clearance data for IDA and IDOL were nearly identical to those published on patients with leukemia, and the plasma elimination of the IDOL metabolite was substantially longer than that of the parent drug IDA. The peak CSF:plasma ratios of IDA and IDOL were very low. The overall response rates to IDA were disappointing despite periods of prolonged SD in nearly a fourth of the patients. We conclude from this data and from that in nonhuman primates that it is unlikely that IDA, daunomycin, or other related anthracyclines will be useful for treating primary CNS tumors.

A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group.

SummaryThe role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent studies did not show similar favorable contribution of chemotherapy to the outcome of these children. Further efforts to identify active chemotherapy agents in children include use of agents that have shown efficacy in adult patients with high-grade glioma and agents that have shown promise in mice bearing human xenografts of brain tumors. A Pediatric Oncology Group (POG 9431) trial tested the activity of two such agents, procarbazine and topotecan in newly diagnosed patients with high-grade glioma who had measurable disease after diagnostic surgery. Neither agent showed efficacy within the confines of the statistical design of the study. This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT). Future trials should consider strategies to overcome the resistance mechanisms in children with high-grade glioma.

Spinal Metastasis in Primitive Neuroectodermal Tumors (Medulloblastoma) of the Posterior Fossa: Evaluation with CT Myelography and Correlation with Patient Age and Tumor Differentiation

Twelve consecutive children with primitive neuroectodermal tumors of the posterior fossa (PNET-PF) were evaluated for spinal metastases with CT metrizamide myelography (CTMM) in the early postoperative period. Metastases were identified in 5 children (42%) and all were noted to have deposits in the thoracic region. All children with metastases were less than 3 years old and had differentiated PNET-PF.

Tethered-cord syndrome after repair of meningomyelocele

The occurrence of tethered-cord syndrome is one of the delayed consequences of the repair of meningomyclocele. The existing neurological deficit worsens, or a new deficit is superimposed on the existing one. In addition, urological and orthopedic symptoms are also frequently encountered. Although radiological studies may be suggestive of tethering of the cord, not all children are symptomatic. Magnetic resonance imaging is the best radiologic study available. Ultrasonography, although economical and easy to perform, does not yield an optimal image. It appears that a careful periodic clinical evaluation is the best way to evaluate the patients for surgery.

Evaluation of commercial PC-based DICOM image viewer

ConclusionWhile each software product incorporated some excellent features, none included the full repertoire of needed functions. Depending on the specific clinical practice setting, absence of a function could constitute an inconvenience or preclude use of the software. For a referring physician inside the hospital, another software application affords access to the radiologist report, but remote access may not be available. When the primary practice involves plain radiography, the lack of sophisticated tools for managing complex cross-sectional images is a minor inconvenience, but for a neuroradiologist it is a major inconvenience. Comparisons with prior exams and measurement tools are often used to assess changes in patient status, but these tools are primitive stage of development. Although we concluded that our staff could use these products to evaluate patient exams, we will continue to search for a product that provides full support for clinical operations.There is apparently no technological limitation precluding inclusion of these tools of PC viewer software, rather it seems to be the result of incomplete requirement definition, inadequate software development, or deliberate decisions to limit product development. Development activity seems to have shifted from PC-based viewers to Web-based products.

Puncture-proof picture archiving and communication system

As we become increasingly dependent on our picture archiving and communications system (PACS) for the clinical practice of medicine, the demand for improved reliability becomes urgent. Borrowing principles from the discipline of Reliability Engineering, we have identified components of our system that constitute single points of failure and have endeavored to eliminate these through redundant components and manual work-around procedures. To assess the adequacy of our preparations, we have identified a set of plausible events that could interfere with the function of one or more of our PACS components. These events could be as simple as the loss of the network connection to a single component or as broad as the loss of our central data center. We have identified the need to continue to operate during adverse conditions, as well as the requirement to recover rapidly from major disruptions in service. This assessment led us to modify the physical locations of central PACS components within our physical plant. We are also taking advantage of actual disruptive events coincident with a major expansion of our facility to test our recovery procedures. Based on our recognition of the vital nature of our electronic images for patient care, we are now recording electronic images in two copies on disparate media. The image database is critical to both continued operations and recovery. Restoration of the database from periodic tape backups with a 24-hour cycle time may not support our clinical scenario: acquisition modalities have a limited local storage capacity, some of which will not contain the daily workload. Restoration of the database from the archived media is an exceedingly slow process, that will likely not meet our requirement to restore clinical operations without significant delay. Our PACS vendor is working on concurrent image databases that would be capable of nearly immediate switchover and recovery.

What Causes Mental Retardation and Cerebral Palsy

Mental retardation is present in approximately 780,000 school age children. Cerebral palsy affects 750,000 Americans, and nearly 2,000,000 individuals have epilepsy. Countless individuals suffer combinations of these neurologic disabilities. In an effort to assess our current state of knowledge about the pre-and perinatal factors associated with these brain disorders and to set research goals for the coming decade, the National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS), appointed a task force to survey current knowledge about pregnancyand birth-related events that account for the continued incidence of neurologic handicap among infants and children. This report, titled Prenatal and Perinatal Factors Associated with Brain Disorders, represents a watershed in our thinking about the causes of mental retardation and cerebral palsy and epilepsy. Despite major advances in obstetric and neonatal medicine, physicians, patients, and attorneys still believe that the major causes of these brain disorders are related to birth trauma and the problems of labor. The committee found that only cerebral palsy could be related to perinatal insults. Only when mental retardation or epilepsy were found in association with cerebral palsy, could ischemia or hypoxia be causally related. The committee stated ‘although it was once simple to say that a specific event such as birth trauma or asphyxia caused these brain disorders, it is not usually possible to pinpoint a single cause and its effect’. Cerebral Palsy Cerebral palsy was found to be associated with prematurity, growth retardation and asphyxia at birth. The asphyxiated infant, documented by an Apgar score of less than 3 at 10–15 min, neurologic abnormalities in the newborn period and neonatal seizures, had a dramatically increased risk of later cerebral palsy. However, the majority of children with these risk factors had no evidence of neurologic dysfunction. More than 75% of children who had later cerebral palsy did not demonstrate these risk factors in the neonatal period. Mental Retardation Severe mental retardation is primarily genetic, biochemical, viral and developmental and not related to birth events. Only when it was associated with cerebral palsy, did severe mental retardation possibly link to asphyxia. Mild retardation, the most common degree of retardation, appears not to be related to pregnancy or birth events, but rather to social and environmental conditions. Associated factors, including maternal life styles, poor nutrition, cigarette smoking, alcohol and drug abuse, increase the likelihood of mild retardation. Prematurity and intrauterine growth retardation are commonly linked to these life styles. The risk of these problems was also correlated with the risk of being raised in an impoverished environment with less opportunity for optimal neurologic and intellectual development. Epilepsy Epilepsy did not appear to be related to preor perinatal events except when associated with cerebral palsy. Current Challenges and Directions for Research The committee noted that major challenges for the future included identifying women at high risk for bearing a neurologically handicapped child. For some such women, lowering the risk may begin before pregnancy, by management of conditions leading to risk and changes in life style. During pregnancy identification of the fetus with growth retardation may be an important area for reducing risk. The amount of damage due to hypoxia or ischemia depends both on its duration and severity, and on the infant’s biologic reserve and repair capabilities. Most infants who experience difficult labors do not develop later neurologic handicaps; most infants who demonstrate later brain disorders had no evidence of problems during the perinatal period. Premature infants are subject to the additional stress of hypoxia, respiratory distress and intraventricular hemorrhage. Prematurity was found to be the salient birth-related risk factor for later cerebral palsy. Understanding premature labor, and prevention of prematurity are the most important challenges in preventing later brain disorders. Major challenges now lie in detecting asphyxia earlier and knowing both its severity and duration. Neurologic damage to the fetus from asphyxia depends on the duration of the asphyxia, its severity, and on the gestational age of the fetus. Criteria which take into account these factors need to be developed for intervention. 176 Richardson