Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspective.

INTRODUCTION: The implementation of early long-term, regular clotting factor concentrate (CFC) replacement therapy ('prophylaxis') has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short- and long-term results and benefits of prophylactic regimens. AIMS: This report presents a critical review of outcome measures for use in the assessment of musculoskeletal health in persons with haemophilia according to the International Classification of Functioning, Disability and Health (ICF). This framework considers structural and functional changes, activities and participation in a context of both personal and environmental factors. METHODS: Results were generated by a combination of a critical review of available literature plus expert opinion derived from a two day consensus conference between 48 health care experts from different disciplines involved in haemophilia assessment and care. Outcome tools used in haemophilia were reviewed for reliability and validity in different patient groups and for resources required. RESULTS AND CONCLUSION: Recommendations for choice of outcome tools were made according to the ICF domains, economic setting, and reason for use (clinical or research). The next step will be to identify a 'core' set of outcome measures for use in clinical care or studies evaluating treatment.

Inter-rater reliability of the radiographic assessment of simple bone cysts.

PURPOSE: To develop and evaluate the reliability of an explicit set of parameters and criteria for simple bone cysts (SBCs) and evaluate the reliability of single versus serial chronological reading methods. METHODS: Radiographic criteria were developed based on the literature and expert consensus. A single anteroposterior/lateral radiograph from 32 subjects with SBC were evaluated by three radiologists. A second reading was then conducted using revised criteria including a visual schematic. In the third reading the same images were assessed but radiologists had access to images from two additional time points. Inter-rater reliability was assessed after each reading using kappa (κ) and percentage agreement for categorical and binary parameters and intra-class correlation coefficient (ICC) for continuous parameters. RESULTS: Parameters that were revised with more explicit definitions including the visual schematic demonstrated consistent or improved inter-rater reliability with the exception of continuous cortical rim present and cyst location in the metaphysis and mid-diaphysis. Cortical rim displayed only slight reliability throughout (κ= -0.008 to 0.16). All other categorical parameters had a percentage agreement above 0.8 or a moderate (κ= 0.41 to 0.60), substantial (κ = 0.61 to 0.80) or almost perfect inter-rater reliability (κ = 0.81 to 1.0) in at least one reading. All continuous parameters demonstrated excellent inter-rater reliability (ICC > 0.75) in at least one reading with the exception of scalloping (ICC = 0.37 to 0.70). Inter-rater reliability values did not indicate an obviously superior method of assessment between single and serial chronological readings. CONCLUSION: Explicit criteria for SBC parameters used in their assessment demonstrated improved and substantial inter-rater reliability. Inter-rater reliability did not differ between single and serial chronological readings. LEVEL OF EVIDENCE: Not Applicable.

Reliability and construct validity of the compatible MRI scoring system for evaluation of elbows in haemophilic children.

We assessed the reliability and construct validity of the Compatible MRI scale for evaluation of elbows, and compared the diagnostic performance of MRI and radiographs for assessment of these joints. Twenty-nine MR examinations of elbows from 27 boys with haemophilia A and B [age range, 5-17 years (mean, 11.5)] were independently read by four blinded radiologists on two occasions. Three centres participated in the study: (Toronto, n = 24 examinations; Atlanta, n = 3; Cuiaba, n = 2). The number of previous joint bleeds and severity of haemophilia were reference standard measures. The inter-reader reliability of MRI scores was substantial (ICC = 0.73) for the additive (A)-scale and excellent (ICC = 0.83) for the progressive (P)-scale. The intrareader reliability was excellent for both P-scores (ICC = 0.91) and A-scores (ICC = 0.93). The total P- and A-scores correlated poorly (r = 0.36) or moderately (r = 0.54), but positively, with clinical-laboratory measurements. The total MRI scores demonstrated high accuracy for discrimination of presence or absence of arthropathy [P-scale, area-under-the-curve (AUC) = 0.94 +/- 0.05; A-scale, AUC = 0.89 +/- 0.06], as did the soft tissue scores of both scales (P-scale, AUC = 0.90 +/- 0.06; A-scale, AUC = 0.86 +/- 0.06). Areas-under-the-curve used to discriminate severe disease demonstrated high accuracy for both P-MRI scores (AUC = 0.83 +/- 0.09) and A-MRI scores (AUC = 0.87 +/- 0.09), but non-diagnostic ability to discriminate mild disease. Similar results were noted for radiographic scales. In conclusion, both MRI scales demonstrated substantial to excellent reliability and accuracy for discrimination of presence/absence of arthropathy, and severe/non-severe disease, but poor to moderate convergent validity for total scores and non-diagnostic discriminant validity for mild/non-mild disease. Compared with radiographic scores, MRI scales did not perform better for discrimination of severity of arthropathy.

Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study.

BACKGROUND: Prophylactic treatment for severe hemophilia A is likely to be more effective than treatment when bleeding occurs, however, prophylaxis is costly. We studied an inception cohort of 25 boys using a tailored prophylaxis approach to see if clotting factor use could be reduced with acceptable outcomes. METHODS: Ten Canadian centers enrolled subjects in this 5-year study. Children were followed every 3 months at a comprehensive care hemophilia clinic. They were initially treated with once-weekly clotting factor; the frequency was escalated in a stepwise fashion if unacceptable bleeding occurred. Bleeding frequency, target joint development, physiotherapy and radiographic outcomes, as well as resource utilization, were determined prospectively. RESULTS: The median follow-up time was 4.1 years (total 96.9 person-years). The median time to escalate to twice-weekly therapy was 3.42 years (lower 95% confidence limit 2.05 years). Nine subjects developed target joints at a rate of 0.09 per person-year. There was an average of 1.2 joint bleeds per person-year. The cohort consumed on average 3656 IU kg(-1)year(-1) of factor (F) VIII. Ten subjects required central venous catheters (three while on study); no complications of these devices were seen. One subject developed a transient FVIII inhibitor. End-of-study joint examination scores--both clinically and radiographically--were normal or near-normal. CONCLUSIONS: Most boys with severe hemophilia A will probably have little bleeding and good joint function with tailored prophylaxis, while infusing less FVIII than usually required for traditional prophylaxis.

Terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27-->qter)].

We report on a terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27-->qter)] in a female newborn infant who died 45 hours after delivery and had multiple congenital abnormalities including bilateral anophthalmia, congenital heart disease, and abnormal genitalia. The findings are compared to those of four previously reported cases with terminal del (3q).

Spontaneous pneumothorax in cystic adenomatoid malformation. Unusual clinical and histologic features.

Pneumothorax is a rare presentation of congenital cystic adenomatoid malformation (CCAM) in the newborn period and is presumed to be due to resuscitative measures. A previously well three-week-old baby presented with spontaneous tension pneumothorax due to CCAM. In the lung resection specimen, a malformation was seen, which in addition to the histologic changes of CCAM, showed diffuse vascular proliferation in the interstitium and lining of air space by type 2 pneumocytes. We propose that this is a new variant of CCAM rather than one of the classic three types. The unusual clinical manifestation may be related to the unusual histologic features.

Reliability of the chest radiograph in the diagnosis of lower respiratory infections in young children.

OBJECTIVE: This study was conducted to determine the reliability of detecting features and making diagnoses of lower respiratory infections from chest radiograms in young infants. METHODS: Forty chest radiograms of infants younger than 6 months of age admitted with lower respiratory tract infection to a tertiary care pediatric hospital were independently reviewed on two separate occasions by three pediatric radiologists blinded to the patients' clinical diagnoses. For each radiograph the radiologists noted whether a feature was present, absent or equivocal on a standardized form. The features examined were hyperinflation, peribronchial thickening, perihilar linear opacities, atelectasis and consolidation. On the same form each radiologist indicated whether the radiograph was normal or showed airways and/or airspace disease. Within and between observer agreement were calculated by the average weighted kappa statistic. RESULTS: Within observer agreement for the radiologic features of hyperinflation, peribronchial wall thickening, perihilar linear opacities, atelectasis and consolidation were 0.85, 0.76, 0.87, 0.86 and 0.91, respectively. The between observer kappa results for these features were 0.83, 0.55, 0.82, 0.78 and 0.79, respectively. The within and between observer kappa statistics for interpretation of the radiographic features were best for airspace disease (within, 0.92; between, 0.91), and lower for normal (within, 0.80; between, 0.66) radiogram and for airways disease (within, 0.68; between, 0.48). The presence of consolidation was highly correlated with a diagnosis of airspace disease by all three radiologists. CONCLUSIONS: Clinicians basing the diagnosis of lower respiratory infections in young infants on radiographic diagnosis should be aware that there is variation in intraobserver and interobserver agreement among radiologists on the radiographic features used for diagnosis. There is also variation in how specific radiologic features are used in interpreting the radiogram. However, the cardial finding of consolidation for the diagnosis of pneumonia appears to be highly reliable.

Preoperative chemotherapy in hepatoblastoma.

Since January 1986, 15 children with hepatoblastoma received three to six cycles of chemotherapy with cisplatin (20 mg/m2/day x 5 days) and doxorubicin hydrochloride (25 mg2/m2/day x 3 days) every 3 weeks before surgery. The extent of the tumor was defined by computerized tomography scan of abdomen and chest and diagnosis confirmed by percutaneous liver biopsy before therapy was started. Tumors in 10 children were considered unresectable at diagnosis because of pulmonary metastases, extensive bilobar involvement, or venous involvement. Volume of tumor reduction ranged from 35% to 95% and was independent of tumor histologic findings. After a minimum of three chemotherapy cycles, excision was undertaken when tumor volume decreased to a size at which hepatic resection was feasible and safe. Chemotherapy complications that were not serious did not delay surgery or result in tumor growth during treatment. Complete surgical excision was possible in 13 children, including 10 who had had unresectable tumors and five with pulmonary metastases. Only three resections of more than one liver lobe were required, and partial lobectomy was possible in four children. One operative death and three postoperative complications, one severe, occurred. Cyclic chemotherapy was restarted 4 to 6 weeks after surgery until a total of six courses were given. Twelve children (eight whose tumors were originally unresectable) completed treatment 3 to 56 (median, 21) months ago and have no evidence of disease. Two other children currently undergoing therapy may have residual disease. The results to date far surpass historic survival rates, which ranged about 25%.

Imaging patients with Wilms tumor.

Imaging plays a significant role in the management of Wilms tumor. Appropriate imaging continually must undergo refinement related to improvements in therapy and imaging modalities. We must recognize the need to demonstrate effectiveness in all phases of patient management and address the contentious issue of maximizing yield and minimizing cost.

Imaging of immature articular cartilage using ultrasound backscatter microscopy at 50 MHz.

A high frequency sonographic technique-ultrasound backscatter microscopy-was used to visualize the subsurface structure of immature porcine articular cartilage from the knee joint. In 20-week-old pigs, all parts that were scanned, except the weight-bearing regions of the femoral condyles, demonstrated heterogeneous ultrasound backscatter characteristics within the articular cartilage. A trilaminar pattern consisting of hypoechoic, hyperechoic, and anechoic layers ranging from superficial to deep generally was observed, except in the weight-bearing regions of the femoral condyles, where a homogeneous anechoic pattern was seen. In the younger pigs (6 and 10 weeks old), the trilaminar backscatter pattern was not observed. Small, highly echogenic structures that correlated with vascular channels in histologic assessment were observed frequently in the cartilage of younger pigs, but they were seldom present in the cartilage of 20-week-old pigs. Structural details, such as disruption of the subchondral bone and presence of a thickened fibrous layer on the articular surface at the chondrosynovial junction, also were detected with the ultrasound backscatter microscope. We concluded that high frequency ultrasound can be used to visualize the subsurface structure of immature articular cartilage and some of its developmental changes. Further research is required to explain the mechanism underlying the observed backscatter characteristics of immature articular cartilage and to study its potential for the imaging of pathologic changes.

Fatal ethibloc embolization of vertebrobasilar system following percutaneous injection into aneurysmal bone cyst of the second cervical vertebra.

A 4-year-old boy developed progressive neck pain and an expansile osteogenic lesion of C2; the diagnosis was an aneurysmal bone cyst. An image-guided biopsy with 3D CT planning was performed followed by Ethibloc injection into the aneurysmal bone cyst. Subsequent CT and MR images demonstrated embolization material in the vertebrobasilar system, and the patient died of brain stem and cerebellar infarction 23 hours after the intervention. The course of events and technical considerations are discussed.

Primary meningeal tumors in children: correlation of clinical and CT findings with histologic type and prognosis.

PURPOSE: To identify the radiologic features that might help in preoperative differentiation of the meningiomas from the remaining primary meningeal tumors, in particular the malignant tumors. METHODS: The clinical and computed tomographic features of 21 children with histologically proved primary meningeal tumors were analyzed. FINDINGS: Benign tumors (meningiomas) are more likely to occur in older children, to have longer symptom duration, and to have CT appearances similar to the "typical" adult meningioma. Atypical CT features suggest a malignant meningeal tumor, such as meningeal sarcoma, melanoma, or meningeal primitive neuroectodermal tumor. The recent identification of a new subtype of meningioma (a "sclerosing" group) is discussed. This is common in children and the CT and clinical features are similar to those seen in other meningiomas. It is frequently mistaken histologically for an intraaxial tumor, or for an atypical or malignant meningioma. These sclerosing meningiomas may also show brain invasion but despite this, in the short term, the prognosis is no different from other meningiomas. CONCLUSION: The bad reputation previously ascribed to childhood primary meningeal tumors should be confined to that small group that are malignant. Meningiomas have a more favorable outlook.

Complications of use of the Ilizarov technique in the correction of limb deformities in children.

We reviewed the records of the first forty patients who had been managed at our institution with the Ilizarov technique for the correction of limb deformities, including limb-length inequality, to delineate the complications of this method of treatment. The duration of follow-up ranged from two and one-half to four years. A complication was defined as any untoward occurrence to a patient either during the course of treatment or after removal of the fixator. A major complication was considered one that necessitated an additional operative procedure; caused lasting sequelae, such as malunion, deformation of new bone, joint contracture or stiffness, or nerve palsy; or prolonged the treatment. A minor complication was regarded as one that responded to non-operative treatment and did not cause lasting sequelae, such as transient decreased motion of the joint, paresthesia, or pin-track infection. There were eighty-eight complications--thirty-eight, major, and the remaining fifty, minor--in the sixty-one segments of the limb that were treated; this represented an average of almost one and one-half complications for each segment. Twenty-nine unplanned operative procedures were performed either during treatment with the Ilizarov technique or after removal of the fixator. As anticipated, the prevalence of major complications was highest in the patients who had had more complex and prolonged treatment. Such complications were encountered less often as the surgeons gained experience with the procedure, but the rate of minor complications remained relatively constant, despite the increased experience.(ABSTRACT TRUNCATED AT 250 WORDS)

New concepts in imaging of the gastrointestinal tract in children.

This article highlights some of the significant recent advances in imaging of the pediatric gastrointestinal tract that have occurred over the last decade. The current roles of the newer imaging modalities, including ultrasound, computed tomography, and magnetic resonance imaging, are discussed and illustrated. Particular emphasis is given to antenatal evaluation, suspected gastric outlet obstruction, inflammation, and other causes of the acute abdomen. Enhancements in fluoroscopic techniques are outlined, including the use of the newer contrast agents as well as air reduction of intussusception. Continued good communication between the pediatric radiologist and pediatric surgeon is vital to improve the care to children with disorders of the gastrointestinal tract.

Infantile myositis presenting in the neonatal period.

Infantile myositis, observed in the neonatal period, is rare and may be confused with congenital muscular dystrophy. The patient presented here showed evidence of a myopathy with in utero onset with intrauterine growth retardation and decreased fetal movements. A muscle biopsy demonstrated characteristic perifascicular atrophy and inflammatory infiltrates. Initial magnetic resonance (MR) examination revealed high signal intensity in several proximal muscle groups. With subsequent corticosteroid treatment, the patient's symptoms, clinical course and MR findings have gradually improved. The diagnosis of infantile myositis should be established as early as possible, since proper treatment can lead to resolution of clinical symptomatology and MR findings.

Spinal cord birth injury: value of computed tomographic myelography.

The value of myelography in the assessment of spinal cord injury in the early neonatal period has not been documented, although this study has been recommended frequently in the literature. Eight neonates are reviewed who presented with the clinical features of spinal cord injury and who had myelography performed. Clinical features included difficult delivery, absent respiration, flaccid paralysis, sensory level, and neurogenic bladder. Myelography revealed that 7 patients had the early changes of swollen cord and 1 patient had the late changes of cord atrophy. None of the neonates had surgical intervention. One neonate died at 3 days of age, while 2 others died after prolonged ventilation. Of the 5 infants who survived, 3 still require ventilation and have spastic quadriparesis, 1 has almost recovered completely and 1 had spontaneous respiration and limb movement but brisk deep tendon reflexes when last examined at 1 month of age. Myelography, which was performed in the early neonatal period in our infants, was abnormal in all patients. Myelography is useful in confirming the diagnosis, outlining the level and extent of the lesion, and excluding extramedullary compression. Myelography may assist in the assessment of prognosis but did not alter management in our patients.

Normal bone marrow: signal characteristics and fatty conversion.

Understanding the dynamic MR appearance of normal bone marrow during childhood is essential. This article reviews normal bone marrow structure and development, especially the process of fatty conversion, laying the cornerstone for accurate interpretation of marrow MR imaging.

Diagnosis and management of duodenal injuries in children.

Traumatic duodenal perforations in children pose a diagnostic and therapeutic challenge. To identify specific diagnostic criteria and define an optimal therapeutic protocol, we reviewed all duodenal injuries treated at our institution in the past 10 years. There were 14 hematomas and 13 perforations. The diagnosis was confirmed by computed tomography (CT), ultrasound scan (US), upper gastrointestinal contrast studies (UGI), or at laparotomy. The clinical findings and CT findings of the two groups were compared. Children with suspected duodenal hematomas were treated expectantly, and children with duodenal perforations were treated surgically. Twenty-five associated injuries (10 pancreatic) occurred in 19 children. Children with perforations had higher injury severity scores (ISS) (25 v 9), but the two groups could not be differentiated based on presenting signs, symptoms, or laboratory findings. CT findings of retroperitoneal air or contrast were seen in 9 of 9 perforations and in 0 of 10 hematomas. CT findings of intraabdominal or retroperitoneal fluid, mesenteric enhancement, and thickened duodenal wall did not differentiate the two groups. Duodenojejunostomy was performed in one patient, and primary repair was performed in 11 children who had perforation. In five children, duodenostomy tube drainage with feeding jejunostomy or gastrojejunostomy were added. Complications occurred in three of four children in the first 5 years of the study and in two of nine children in the last 5 years. The decreased morbidity rate correlated with reduced time to definitive therapy (28 v 7.8 hours). Duodenal fistulae resulted in three of seven children treated without duodenostomy tube drainage and zero of five treated with drainage. Enteral feeds resumed faster (average, 12 v 27 days) if repair of perforation was combined with feeding jejunostomy or pyloric exclusion and gastrojejunostomy. Children with duodenal hematoma resumed eating an average of 16 days after injury. Only one child required surgery for persistent obstruction. The findings of retroperitoneal air and contrast extravasation on CT accurately distinguish duodenal perforation from hematoma. Conservative management of hematoma is safe and effective. Primary repair of perforation with duodenal drainage results in fewer postoperative complications, and gastrojejunostomy or feeding jejunostomy shorten the time to resumption of feeds.

What have we learned about traumatic diaphragmatic hernias in children?

BACKGROUND/PURPOSE: Diaphragmatic injuries have been reported to be a predictor of serious associated injuries in trauma and a marker of severity. The aim of this retrospective study was to identify pitfalls in the diagnosis and treatment of these injuries in children. METHODS: Data were collected from all patients admitted to the trauma service with traumatic diaphragmatic hernias for the period of January 1977 to August 1998. The authors evaluated 15 cases of traumatic diaphragmatic rupture (6 girls and 9 boys). RESULTS: Mean age was 7.5 years (range, 3 weeks to 15 years). Thirteen patients suffered from blunt trauma, and 2 patients suffered from penetrating trauma. The right and left hemidiaphragms were injured equally (7 patients each), with 1 additional patient suffering from bilateral injuries. All but 1 patient had laparotomies for trauma (n = 14). The diagnosis was made preoperatively in 8 patients (53%) with just a chest radiograph. Computed tomography (CT) scan, magnetic resonance imaging (MRI), and oral contrast studies were used as ancillary tests to diagnose traumatic diaphragmatic rupture. There were 3 missed injuries. Associated injuries included liver lacerations (47%), pelvic fractures (47%), major vessels tear (40%), bowel perforations (33%), long bone fractures (20%), renal lacerations (20%), splenic lacerations (13%), and closed head injuries (13%). The mean hospital stay was 20 days (range, 7 to 60 days). Complications were observed most commonly in those patients with multiple injuries and included postoperative ileus (40%), pneumonia (30%), pancreatitis (20%), wound infection (20%), intestinal obstruction (20%), cholestasis (10%), and renal failure (6%). Five deaths (33%) were caused by hemorrhagic shock, respiratory failure, coagulopathy, and refractory acidosis. CONCLUSIONS: Traumatic diaphragmatic hernias usually are associated with serious injuries in children. It is important to combine a high index of suspicion with radiological diagnostic tests in patients at risk. Palpation and/or visualization of both diaphragms at laparotomy is extremely important in detecting these injuries when they are not suspected preoperatively.