Clinical features and outcome of pediatric Wegener's granulomatosis.

OBJECTIVE: Wegener's granulomatosis (WG) is a predominantly small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs). There are few reports describing its clinical features and outcome in children. We report on the experience at a single tertiary referral center over 21 years. METHODS: We conducted a retrospective chart review of all patients diagnosed with WG at The Hospital for Sick Children between 1984 and 2005. RESULTS: Twenty-five patients were identified. Median age at diagnosis and median followup were 14.5 years and 32.7 months, respectively. Male-to-female ratio was 1:4. Median duration of symptoms before diagnosis was 2 months. Of 22 patients, 21 were ANCA positive during their disease course (classic ANCA 78.9%). Constitutional symptoms were the most common clinical feature at presentation (24 of 25). Glomerulonephritis was present in 22 patients at presentation. Only 1 of 11 patients who presented with or developed renal impairment had normalization of serum creatinine. Upper airway involvement occurred in 21 patients at presentation and 24 over followup; only 1 had subglottic stenosis. Twenty patients had initial pulmonary involvement, most commonly nodules (44%) and pulmonary hemorrhage (44%). Five patients required ventilation for pulmonary hemorrhage. Four patients (16%) had venous thrombotic events (VTEs). Treatment included prednisone (100%), cyclophosphamide (76%), azathioprine (40%), and methotrexate (32%). CONCLUSION: Pediatric WG typically presents in adolescence and has a female predominance. Glomerulonephritis and pulmonary disease are common at diagnosis and frequently present as a pulmonary-renal syndrome. Loss of renal function is common and rarely completely reversible. As in adults, children with WG are at risk of VTEs.

Home nocturnal hemodialysis in children.

OBJECTIVE: To describe the effect of home nocturnal hemodialysis (NHD) in North American children. STUDY DESIGN: Four teenagers underwent NHD for 8 hours, 6 to 7 nights/week, using either central venous lines or fistulae for periods of 6 to 12 months. Blood flow approximated 200 mL/min, and dialysate flow was 300 mL/min; the dialysate contained potassium and phosphate. The procedure was remotely monitored. RESULTS: The children had unrestricted diets and fluid allowance and did not require phosphate binders. Persistent relative hypotension developed in 2 of 4 children. Weekly Kt/V urea values were consistently >10; other biochemical measures varied. Quality of life and school attendance improved in 3 of 4 children. The workload and reported emotional burden of NHD was substantial. No significant complications occurred. Dialysate losses of calcium, phosphate and carnitine required supplementation. The annual cost per patient was dollar 64,000 Canadian, which represented a 27% savings compared with thrice weekly in-center hemodialysis. CONCLUSIONS: NHD is feasible in selected children, allows free dietary and fluid intake, and improves patient wellbeing. The burden on the family is substantial, and NHD requires support of a dedicated multidisciplinary team.

The teratogenicity of anticonvulsant drugs.

BACKGROUND: The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as the anticonvulsant embryopathy, is increased in infants exposed to anticonvulsant drugs in utero. However, whether the abnormalities are caused by the maternal epilepsy itself or by exposure to anticonvulsant drugs is not known. METHODS: We screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. RESULTS: The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants. CONCLUSIONS: A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

Peritoneal access in children.

Catheter-related infections continue to be the most common complication of CPD, and the most frequent cause of catheter removal. Available evidence supports the superiority of double-cuff catheters and a downward-facing tunnel for preventing peritonitis in children. The Swan-neck double-cuff catheter seems best suited to achieving those objectives, while still reducing the problems of external cuff extrusion and catheter migration. Clearly further pediatric experience with that catheter is desirable. Analysis of the literature confirms that excellent catheter survival and a reduced rate of infectious complications can be achieved with a variety of catheter designs and implantation techniques. The most crucial aspect of catheter success and survival appears to be the commitment and expertise of the team involved in catheter insertion and postoperative catheter management.

Anticonvulsant teratogenesis 4: inter-rater agreement in assessing minor physical features related to anticonvulsant therapy.

BACKGROUND: We report on inter-rater agreement in the assessment of newborn infants with respect to a range of minor physical features in a cohort study of the fetal effects of maternal anticonvulsant use during pregnancy. METHODS: Infants from three groups (exposed to anticonvulsants, seizure history but no medication exposure, and unexposed controls) were examined by both a pediatrician/teratologist, who was blinded with respect to the mother's exposure status, and an unblinded research assistant. Agreement on assessments for selected anomalies associated with anticonvulsant therapy was measured by kappa-statistics, as well as by more sensitive log-linear modeling techniques, which allow examination of possible covariate effects on the strength of agreement. Although the physician and research assistant agreed on a high proportion of cases (80-90%), kappa values were modest (0.2-0. 5), partly because of the low prevalence of the anomalies considered. To explore how agreement varies within subgroups, we used recently developed methods for studying agreement based on log-linear models. RESULTS: Log-linear modeling indicated that there was substantial variation in pattern of agreement between different individual research assistants but that other factors (e.g., exposure category, sex, and birthweight) did not appear to be related to agreement. Our results suggest that research assistants with more experience showed the highest degree of agreement with the physicians. CONCLUSIONS: Our results have implications for both clinical practice and epidemiologic research and underline the importance of thorough training of staff in the definitions to be used and also the need for multiple independent assessments of these subtle anomalies.

Can the DOQI guidelines be met by peritoneal dialysis alone in pediatric patients? Dialysis Outcomes Quality Initiative.

DOQI guidelines recommend minimal standards for automated peritoneal dialysis (APD), with a weekly Kt/V of 2.1 and creatinine clearance (Ccr) of 63 l/1.73 m2. The purpose of this study was to assess if the DOQI guidelines could be met by dialysis alone in children on PD. Dialysis clearance studies were retrospectively analyzed in 20 pediatric patients on APD, all with a dwell volume of at least 1,000 ml/m2. Mean dialytic Kt/V was 2.0; only 45% had a Kt/V above the recommended 2.1. Mean dialytic Ccr was 43.5 l/week per 1.73 m2; only 10% achieved a Ccr above the recommended 63 l/week per 1.73 m2. Despite the significant correlation between total therapy volume (TTV) and both Kt/V and Ccr, only 2 of 10 patients with a TTV over 10 l/m2 per day reached the target Ccr. All patients had currently recommended dwell volumes, therapy times, and nocturnal cycles, but DOQI guidelines were difficult to achieve with dialysis alone. Strict adherence to DOQI guidelines in anephric pediatric PD patients may result in changing dialysis modality. However, without evidence of a correlation between delivered dose of dialysis and improved outcome, adequate dialysis should not be assessed by only measuring Kt/V and Ccr.

Intelligence and physical features of children of women with epilepsy.

The teratogenicity of maternal epilepsy has been attributed to several factors, including the antiepileptic drugs taken to prevent seizures during pregnancy, the occurrence of seizures during pregnancy, and the factors in the mother that caused her to have epilepsy. We have addressed the hypothesis that the children of women who have a history of epilepsy (seizure history), but who took no antiepileptic drugs (AED) and had no tonic-clonic seizures in pregnancy, have an increased risk of malformations and diminished intelligence. The frequency of cognitive dysfunction was determined in 57 seizure history and 57 matched control children aged 6-l6 years. The masked evaluation of the children included a physical and neurologic examination and testing with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and a systematic physical examination for the features of the fetal AED syndrome. The evaluation of both parents of each child included a test of reasoning (Ravens Progressive Matrix) and a physical examination. There were no differences between the two groups of children in either IQ scores or physical features; none of the seizure history children was judged to have the "anticonvulsant face" or digit hypoplasia. This study had 80% power to rule out a difference of seven or more IQ points between the two groups, based on a two-sided test at a 5% level of significance. Our confidence in concluding that there was no difference between seizure history and control infants was strengthened by the fact that no statistically significant differences were observed with respect to multiple outcomes, including eight related measures of intelligence. Thirty (53%) of the seizure history mothers resumed taking AED after the birth of the child we evaluated. Additional studies are needed to address the teratogenicity of the antiepileptic drugs as monotherapy.

The predictive power of combined neuropsychological measures for attention-deficit/hyperactivity disorder in children.

The present study explores the predictive power of seven neuropsychological assessment tools used in combination in classifying children with attention-deficit/hyperactivity disorder (ADHD). Twenty-one ADHD boys and 22 community control children participated. Group differences were significant on the continuous performance test only; however, battery analysis did increase overall predictive power, which was moderate. This study highlights the difficulty in identifying consistent mean differences on tests of frontal/executive functioning across studies, as well as the need to assess the predictive validity of these tests in classifying children with ADHD. The study suggests that these tests may provide greater predictive validity when used in combination. Inconsistencies in the literature are discussed, with consideration of research methodology, the heterogeneity of the ADHD population, and comorbid diagnoses.

Data monitoring: a hypothesis-testing approach for treatment-outcome research.

Traditional inferential statistics require that hypotheses be evaluated at only 1 sample size. That is, researchers must choose how many participants will be included in a study before conducting analyses; they are not allowed to add data if initial results are not significant. This requirement forces researchers to choose among including more participants than necessary, risking inconclusive results, or violating the requirement by adding participants. This study presents a more flexible approach, called data monitoring, that allows repeating an analysis as the sample increases. First, the cost of the uncorrected data monitoring that researchers sometimes do is estimated. Second, the correction that is needed to allow data monitoring while holding an overall alpha at a desired level is estimated. Third, the power of data monitoring is compared with traditional approaches. This study also provides an example of the use of data monitoring. At least in some circumstances, data monitoring can reduce Type II error or the number of participants needed without sacrificing Type I error.

Lessons on objectivity in clinical studies.

Clinical assessments made with measuring devices are generally considered "objective" and "accurate" and are, therefore, more discriminating than subjective assessments. We show that the choice of measuring devices or non-standardized landmarks to be used with the measuring devices affect the "accuracy" of the "objective" findings.

Anticonvulsant teratogenesis: 2. Statistical methods for multiple birth outcomes.

The purpose of this paper is to demonstrate the application of generalized estimating equations to assess an exposure effect using multiple birth outcomes. This multivariate approach provides the flexibility of regression modeling and improved power, as compared to series of univariate analyses or collapsing the multiple end-points to a single indicator of affectedness. Motivating the discussion will be a large cohort study designed to assess the effects of anticonvulsant medications on a variety of birth outcomes, including major malformations, and growth and weight parameters, as well as a broad spectrum of minor physical anomalies. Because the study is still in progress, the aim here is not to present a definitive analysis, but to present and describe the application of these recently developed statistical methods to analyze studies with multiple outcomes. For simplicity, we will focus on the control and drug-exposed groups only from that study (ignoring the seizure history group), and we will concentrate on an analysis of minor physical anomalies.

Anticonvulsant teratogenesis: I. A study design for newborn infants.

The basis for the apparent teratogenicity of maternal epilepsy is controversial. Is the critical factor the anticonvulsant drugs taken by the pregnant woman, or the genes which cause the mother's epilepsy? We describe a study design developed to assess these competing theories in a cohort study of newborn infants. We show the feasibility of ascertaining exposed and unexposed infants at several birthing hospitals in one urban area. Between 1986 and 1988, we identified 180 drug-exposed and 218 epilepsy-history infants among 49,403 infants. The rate of exposure to seizure medication was 0.36% and of maternal history of epilepsy was 0.44%. A significant number of infants could not be evaluated because they were missed, ineligible, or either the doctor, nurse or parent refused to participate. Overall, there was a significant increase in major malformations, microcephaly or growth retardation among the drug-exposed infants in comparison to both the epilepsy-history and the unexposed infants. The types of epilepsy and the apparent etiology were the same among women who took anticonvulsants and women with a history of epilepsy but no anti-convulsants during pregnancy. This study must be extended to include a sufficient number of infants exposed to each commonly used drug as monotherapy to allow for a comparison of the effect of each drug on pregnancy outcomes; to provide a comparison of infants whose mothers had a strong family history of epilepsy with infants whose mothers had trauma-induced epilepsy; and to assess the possible impact of the severity of the mothers' disease on the infants.

Mass transfer area coefficients in children.

OBJECTIVE: Measurement of mass transfer area coefficients (MTAC) in children of different sizes to determine if solute transport varies with age and to compare with published adult values. DESIGN: Mass transfer area coefficients calculated from prospectively collected data in 28 selected patients. PARTICIPANTS: All children starting maintenance peritoneal dialysis at the Hospital for Sick Children. Selected patients were also studied if hospitalized for unrelated reasons. RESULTS: Mean MTAC values for creatinine and glucose were 4.0 and 4.5 mL/min, respectively, both considerably lower than adult values. When scaled per 70 kg body weight, these results were greater, and when scaled per 1.73 m2 surface area, they were lower than reported adult values. The MTAC/kg body weight was inversely correlated to age. CONCLUSIONS: Solute transport in children is directly related to age and does not approach adult values until later childhood. However, more rapid transport per unit body weight is observed in children and may reflect an increased effective peritoneal surface area.

The effects of prenatal exposure to phenytoin and other anticonvulsants on intellectual function at 4 to 8 years of age.

Twenty phenytoin exposed children between 48 and 99 months of age had an evaluation of behavior and intelligence by a single examiner who was unaware of exposure status. The controls were 98 children identified at birth as having three or more minor anomalies. None of the children evaluated were mentally retarded. In both, a case-by-case comparison and a comparison of the two entire groups, the phenytoin-exposed children had significantly lower scores for both Performance IQ (PIQ), Full Scale IQ (FSIQ), and Visual Motor Integration Test (VMIT). Similar abnormalities have been found in studies of animals exposed to phenytoin in utero. These results suggest that the teratogenic effects of phenytoin may include an effect on cognitive function.

The peritoneal equilibration test in children.

The peritoneal equilibration test (PET) has been recommended in adults as a standardized means of estimating solute transport. Based on results of the PET, adult peritoneal permeability has been classified as high, high average, low average, and low. We performed a PET on 32 children aged 0.8 to 17.8 years (mean 9.3) using a dwell volume of 32 +/- 5 ml/kg of 2.5% dialysate. Dialysate to plasma (D/P) ratios for creatinine, urea, and sodium were calculated at two and four hours as were the ratios of dialysate glucose at two and four hours to the dialysate glucose at time 0 (D/Do). Stepwise logistic regression identified only the patients' age and D/Do glucose values at two hours as significant predictors of ultrafiltration. Net ultrafiltration after a four hour dwell could be predicted for 75% of children above 9.3 years, or whose D/Do glucose value at two hours was greater than 0.45. The mean and standard deviation values for D/Do glucose and D/P creatinine at four hours were 0.31 +/- 0.17 and 0.71 +/- 0.12, respectively. When children are characterized according to adult standards, at least 70% fall into the high or high average permeability categories.

Inflammatory effects of prostaglandin D2 in rat and human skin.

1 Intradermal injection of prostaglandin (PG) D1 and D2 in the human forearm produced a long-lasting dose-related erythema. When compared with prostaglandin E1 or E2 the order of potency for erythema production was PGE1 greater than PGE2 greater than PGD2 greater than PGD1. 2 In rat skin, prostaglandin D2 but not D1 caused an increase in vascular permeability as quantitated by the Evans blue method and the 125I-albumin extravasation technique. Prostaglandin E2 was 3-5 times more potent than prostaglandin D2. 3 Prostaglandin D2 (10 ng) potentiated the increase in vascular permeability in rat skin produced by histamine, but not that produced by bradykinin. 4 Prostaglandin D2 (10, 20 and 50 ng) did not elicit oedema or hyperalgesia in the rat paw oedema test, but potentiated carrageenan-induced oedema; hyperalgesia was potentiated by doses of 100 ng and above.

Are platelets important in inflammation?

The participation of platelets in acute inflammation was tested by three different traumas in rats rendered thrombocytopenic with anti-platelet serum. Thrombocytopenic rats showed normal oedema response to carrageenin, anti-platelet serum and passive cutaneous anaphylaxis.