Quantitative MRI of the brain in children with sickle cell disease reveals abnormalities unseen by conventional MRI

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.     

Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease

Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16–17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSβ⁺ thalassaemia; n = 52 HbSS/HbSβ⁰ thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ⁺ thalassaemia; n = 8 HbSS/HbSβ⁰ thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ⁰ thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ⁰ thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ⁺ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ⁺ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ⁰ thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD.     

Comparison of anterior colporrhaphy and retropubic urethropexy for patients with genuine stress urinary incontinence

OBJECTIVE: Our purpose was to compare the efficacy of anterior colporrhaphy and retropubic urethropexy performed for genuine stress urinary incontinence.STUDY DESIGN: A retrospective analysis was performed on women who underwent either anterior colporrhaphy or retropubic urethropexy for genuine stress urinary incontinence. Patients were identified by a computer-assisted search, and these women were contacted by telephone. The interview was used to assess current continence status. Variables reviewed included demographic data, medications, hormonal status, current smoking history, significant medical and surgical history, and time to recurrence of incontinence. Operative procedure, prior or concomitant hysterectomy, history of previous incontinence procedures, concomitant surgery for repair of other pelvic floor defects, experience level of the primary surgeon, and duration of postoperative catheterization were also documented.RESULTS: Seventy-six women who had undergone surgery for genuine stress incontinence during a 4-year period were identified and evaluated by telephone interview. Fifty-six had undergone anterior colporrhaphy and 20 retropubic urethropexy. Both groups of patients were comparable in age, social status, race, parity, and weight. The duration of follow-up (mean ± SD) was 66.6 ± 14.2 months (range 48 to 96 months). Concurrent surgery to repair other pelvic floor defects was more common in patients undergoing anterior colporrhaphy than in patients undergoing retropubic urethropexy (p < 0.05). Of the 56 patients treated with anterior colporrhaphy, 26 (46%) were continent at the time of interview versus 15 of 20 (75%) treated with retropubic urethropexy (p < 0.05). Times to recurrence for anterior colporrhaphy and retropubic urethropexy were not significantly different. History of previous incontinence procedures, concomitant hysterectomy, previous hysterectomy, duration of postoperative catheterization, obesity, chronic lung disease, and smoking were not correlated with success for either procedure. Experience of the primary surgeon did have a significant effect on success, with attending staff having a better cure rate than resident surgeons (p < 0.05).CONCLUSION: Retropubic urethropexy was significantly more effective than anterior colporrhaphy for long-term cure of genuine stress urinary incontinence. We believe these conclusions should be tempered because of the complex nature of genuine stress incontinence. Patients having anterior colporrhaphy may represent a high-risk group because nearly all of them had associated pelvic floor defects. Experience of the surgeon seems to enhance the liklihood of success and may reflect subtle modifications of technique.     

Comparison of energy prediction equations with measured resting energy expenditure in children with sickle cell anemia

OBJECTIVE: To determine the accuracy of energy prediction equations when compared with measured resting energy expenditure (REE) in children with sickle cell anemia. To develop a modified equation that more accurately estimates the energy needs of children with sickle cell anemia and to cross-validate these on a different set of patients (test patients). DESIGN: REE was measured in children using indirect calorimetry and compared with predicted values using the Harris-Benedict and the Food and Agriculture Organization/World Health Organization/United Nations University equations (WHO). SUBJECTS/SETTING: Eighteen patients participated in the original sample that compared predicted with measured energy expenditure. The modified equations were developed using the original 18 patients. A test population of 20 different patients was used to validate the modified equations. STATISTICAL ANALYSIS: Wilcoxon signed-rank test was performed to compare measured with predicted REE. The correlation analysis method and multiple linear regression method were used to develop 2 modified versions for the Harris-Benedict and WHO prediction equations. RESULTS: When compared with the mean predicted REE using the Harris-Benedict and WHO equations, the mean measured REE was 14% and 12% greater than both (P=.005 and P=.014, respectively). Two modified equations were developed from the Harris-Benedict and WHO equations. Based on the data from the test patients, the mean measured REE was 15% greater than the mean predicted REE based on the Harris-Benedict and WHO equations (P=.0001 for both). When the modified Harris-Benedict and WHO equations were used, there was almost no difference in the mean measured REE and the mean predicted REE (mean difference using Harris-Benedict = 14, P = .9273; mean difference using WHO = -13, P = .6215). CONCLUSION: Both energy prediction equations underestimated REE in children with sickle cell anemia. The 2 modified versions of the energy prediction equations that we propose predicted the energy needs of these children much more accurately; however, the modified equations need to be validated through application to other children with sickle cell anemia.     

Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification

The incidence of acute humoral rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute rejection biopsies. The initial histologic diagnoses of the C4d(+) acute rejection cases were as follows: AHR only, 30%; acute cellular rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).     

Effect of long-term transfusion on growth in children with sickle cell anemia: results of the STOP trial

OBJECTIVE: To determine whether long-term transfusion improves growth in children with sickle cell anemia. STUDY DESIGN: In the Stroke Prevention Trial for Sickle Cell Anemia Study, patients were randomized to receive long-term transfusion (CTX) or standard care (STC). Transfusions were administered every 3 to 5 weeks, and hemoglobin S levels were maintained at 30% pretransfusion for an average of 2 years. Serial height and weight measurements (obtained every 3 months), body mass index (BMI) values, and growth z-scores were analyzed. RESULTS: Children in the CTX (n=53) and STC (n=41) groups were similar at baseline. After 24 months, the z-scores for height, weight, and BMI of those receiving CTX had improved significantly, whereas no changes occurred in the STC group. Patients in the CTX group approached normal height-for-age and weight-for-age z-scores. Patients from a large historical control group had significantly lower weight and height growth velocities than patients in the CTX group. CONCLUSIONS: Patients in the Stroke Prevention Trial for Sickle Cell Anemia Study who received CTX had improved height and weight and BMI over a 2-year period. Higher hemoglobin levels resulting from transfusion may improve growth by lowering energy expenditure. In addition to the prevention of vasoocclusive events, CTX results in significant improvement in the growth of children with sickle cell disease.