Faculty Bibliography

BACKGROUND: Diagnosis of adolescent polycystic ovary syndrome (PCOS) remains a challenge despite several existing criteria, and may be difficult to distinguish from pubertal changes. Different parameters to study ovarian function using ultrasonography have been proposed, but there is still no consensus about their diagnostic value. OBJECTIVE: To evaluate the role of ultrasonography in the diagnosis of adolescent PCOS by reviewing available studies that assessed the ovarian volume (OV) and other ovarian morphological features such as location and number of follicles, stromal area, and volume. METHODS: MEDLINE/PubMed database were searched to identify studies that assessed ovarian characteristics of adolescent PCOS patients by ultrasound. Studies on adults were also reviewed if study population included adolescents and stromal characteristics were assessed by three-dimensional (3D) sonogram. RESULTS: Five studies, including 262 PCOS adolescents (10-19 years of age) and two-dimensional (2D) ultrasound analysis, were identified. Mean OV was 9.29 cm3 for PCOS patients and 4.77 cm3 for controls. The morphology of ovarian follicles, when reported, showed multiple (>10) peripheral follicles in 83% of cases. Two studies, including 157 PCOS adolescents and young women (15-35 years of age) and 2D and 3D ultrasound analysis, were identified. Patients with PCOS patients had a MOV 13.1 cm3, multiple follicles (>15), and a statistically significant greater S/A ratio compared to controls. Stromal volume indices were positively correlated with hyperandrogenemia in PCOS patients. CONCLUSION: Pelvic ultrasound is an increasingly important aid in the diagnosis of PCOS in adolescents. Besides ovarian volume, ovarian morphology must be assessed with 2D ultrasound to look for peripherally located multiple follicles. Further studies are warranted to evaluate the utility of 3D ultrasonographic assessment in adolescents with PCOS.

OBJECTIVES: The rapid growth of computed tomography (CT) has resulted in increased concerns of ionizing radiation exposure and its subsequent risk of cancer development. We evaluated the impact of a new protocol using rapid sequence magnetic resonance imaging (rsMRI) instead of CT in children presenting with possible ventriculoperitoneal shunt (VPS) malfunction to promote patient safety. METHODS: This is a retrospective case series of pediatric patients who received a neuroimaging study for emergency evaluation of possible VPS malfunction at New York University's Tisch Hospital Emergency Department between January 2010 and July 2011. Radiology Charge Master was queried to identify the patient database. The trend in the use of rsMRI and CT was calculated for 3 patient age groups and compared across 3 chronological intervals. The effective dose of ionizing radiation per CT scan was calculated using the CT dose index and dose-length product for each patient. RESULTS: Total of 365 patients with the mean age of 8.87 years received either rsMRI or CT study during the study period. One hundred forty-four of these patients required the imaging studies because of VPS malfunction. Overall, 62% of all VPS malfunction cases used rsMRI instead of CT. The ratio of the number of patients receiving rsMRI divided by CT studies has progressively increased from 1.4:1 to 2.1:1 over 3 chronologic periods. CONCLUSIONS: Children with VPS are subject to multiple neuroimaging studies throughout their lifetime. Rapid sequence MRI is an effective alternative to CT while providing no ionizing radiation exposure or risk of developing radiation-induced cancer.

White matter microstructural changes during the first three years of healthy brain development are characterized using two different models developed for limited clinical diffusion data: White Matter Tract Integrity (WMTI) metrics from Diffusional Kurtosis Imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI). Both models reveal a non-linear increase in intra-axonal water fraction and in tortuosity of the extra-axonal space as a function of age, in the genu and splenium of the corpus callosum and the posterior limb of the internal capsule. The changes are consistent with expected behavior related to myelination and asynchrony of fiber development. The intra- and extracellular axial diffusivities as estimated with WMTI do not change appreciably in normal brain development. The quantitative differences in parameter estimates between models are examined and explained in the light of each model's assumptions and consequent biases, as highlighted in simulations. Finally, we discuss the feasibility of a model with fewer assumptions.

We present the first case of pediatric intracranial M abscessus infection in a 16-month-old female with neurofibromatosis type-1. We describe a successful treatment regimen including excisional biopsy combined with high dose steroids and 16 weeks of triple antimicrobial therapy that resulted in clinical cure and an excellent neurologic outcome.

BACKGROUND: Patients with polycystic ovary syndrome (PCOS) often suffer from comorbidities associated with chronic inflammation characterized by elevations in pro-inflammatory cytokines. There is limited data on markers of chronic inflammation, in particular Tumor Necrosis Factor-alpha (TNF-alpha), in adolescents with PCOS. OBJECTIVES: To compare serum levels of TNF-alpha in overweight or obese adolescents with PCOS and obese controls. In the PCOS group, to correlate serum TNF-alpha levels with body mass index (BMI) z-score, severity of hyperandrogenism, degree of insulin resistance, and ovarian ultrasonographic characteristics. METHODS: We performed a cross-sectional retrospective analysis of clinical and biochemical findings in 23 overweight or obese adolescent females with PCOS (mean BMI z-score 2, mean age 15.2 yrs) and 12 obese age- and sex-matched controls (mean BMI z-score 2, mean age 14.1 y). All subjects were post-menarchal. Serum TNF-alpha levels were compared between groups. In the PCOS group, cytokine levels were correlated with BMI z-score, androgen levels, fasting insulin and glucose levels as well as ovarian ultrasonographic features. RESULTS: Both groups were comparable in age, BMI z-score, fasting glucose, and fasting insulin. Mean free testosterone was 9.76 +/- 5.13 pg/mL in the PCOS group versus 5 +/- 2.02 pg/mL in the control group (P = .0092). Serum TNF-alpha was 7.4 +/- 4 pg/mL in the PCOS group versus 4.8 +/- 3.16 pg/mL in the control group (P = .0468). There was no significant correlation between serum TNF-alpha and BMI z-score, free testosterone, fasting insulin, or fasting glucose. No correlation existed between serum TNF-alpha and ovarian follicle number, distribution, or volume. CONCLUSIONS: Serum TNF-alpha is elevated in overweight/obese adolescents with PCOS. Chronic inflammation in adolescents with PCOS render them at a potential increased risk for the development of atherosclerosis, type 2 diabetes, cancer, infertility, and other comorbidities. Every effort should be made to identify adolescents with PCOS early and initiate aggressive therapy to prevent future complications.

This report describes a 6-year-old boy with disseminated low-grade astrocytoma and ventriculo-peritoneal shunt, who developed recurrent ascites while receiving sorafenib on a clinical trial. Laboratory analysis of the peritoneal fluid showed no elevation of protein content and no evidence of underlying infection or tumor dissemination. This report highlights ascites as a previously unrecognized adverse reaction to sorafenib in a patient with a ventriculo-peritoneal shunt. We conclude that such patients should be closely monitored for this complication when treated with sorafenib.

Bilateral symmetric bone nodules were observed in the anterolateral first ribs of an infant with shaking injuries at autopsy. The location prompted diagnostic considerations of healing fractures versus anomalous articulations with pseudarthroses. The forensic pathologist worked with forensic anthropologists and pediatric radiologists to evaluate autopsy findings and compare premortem and postmortem X-rays. Gross examination of the bones by the pathologist and anthropologists confirmed bilateral, callus-like bone nodules in first-rib locations associated with pseudarthroses. Histologic examination of one of the bones further showed features most consistent with pseudarthrosis, not a healing fracture. Radiologists then compared multiple premortem and postmortem radiographs that showed no remodeling of the bone over a 2-week interval between the time of injury and death, which would be unexpected for a healing fracture in an infant. This multidisciplinary approach resulted in the appropriate diagnosis of pseudarthroses due to anomalous articulations, an uncommon finding in forensic pathology.

BACKGROUND: Activation of the RAS-RAF-MEK-ERK signaling pathway is thought to be the key driver of pediatric low-grade astrocytoma (PLGA) growth. Sorafenib is a multikinase inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This multicenter phase II study was conducted to determine the response rate to sorafenib in patients with recurrent or progressive PLGA. METHODS: Key eligibility criteria included age >/=2 years, progressive PLGA evaluable on MRI, and at least one prior chemotherapy treatment. Sorafenib was administered twice daily at 200 mg/m2/dose (maximum of 400 mg/dose) in continuous 28-day cycles. MRI, including 3-dimensional volumetric tumor analysis, was performed every 12 weeks. BRAF molecular testing was performed on tumor tissue when available. RESULTS: Eleven patients, including 3 with neurofibromatosis type 1 (NF1), were evaluable for response; 5 tested positive for BRAF duplication. Nine patients (82%) came off trial due to radiological tumor progression after 2 or 3 cycles, including 3 patients with confirmed BRAF duplication. Median time to progression was 2.8 months (95% CI, 2.1-31.0 months). Enrollment was terminated early due to this rapid and unexpectedly high progression rate. Tumor tissue obtained from 4 patients after termination of the study showed viable pilocytic or pilomyxoid astrocytoma. CONCLUSIONS: Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to paradoxical ERK activation. Close monitoring for early tumor progression should be included in trials of novel agents that modulate signal transduction.

BACKGROUND AND PURPOSE: Diffusional kurtosis imaging is an extension of DTI but includes non-Gaussian diffusion effects, allowing more comprehensive characterization of microstructural changes during brain development. Our purpose was to use diffusional kurtosis imaging to measure age-related microstructural changes in both the WM and GM of the developing human brain. MATERIALS AND METHODS: Diffusional kurtosis imaging was performed in 59 subjects ranging from birth to 4 years 7 months of age. Diffusion metrics, fractional anisotropy, and mean kurtosis were collected from VOIs within multiple WM and GM structures and subsequently analyzed with respect to age. Diffusional kurtosis tractography images at various stages of development were also generated. RESULTS: Fractional anisotropy and mean kurtosis both showed age-related increases in all WM regions, reflecting progression of diffusional anisotropy throughout development, predominantly in the first 2 years of life (eg, 70% and 157% increase in fractional anisotropy and mean kurtosis, respectively, from birth to 2 years for the splenium). However, mean kurtosis detected continued microstructural changes in WM past the fractional anisotropy plateau, accounting for more delayed isotropic changes (eg, 90% of maximum fractional anisotropy was reached at 5 months, whereas 90% of maximum mean kurtosis occurred at 18 months for the external capsule). Mean kurtosis may also provide greater characterization of GM maturation (eg, the putamen showed no change in fractional anisotropy but an 81% change in mean kurtosis from birth to 4 years 7 months). CONCLUSIONS: Mean kurtosis detects significant microstructural changes consistent with known patterns of brain maturation. In comparison with fractional anisotropy, mean kurtosis may offer a more comprehensive evaluation of age-related microstructural changes in both WM and GM and is potentially a valuable technique for studying brain development.

Acute lymphoblastic leukemia (ALL) in infants below 1 year of age accounts for 2.5% to 5% of childhood ALL. Most children with ALL present with fever, bruising, mucosal bleeding, bone pain, pallor, hepatosplenomegaly, and lymphadenopathy. Common sites of extramedullary involvement at diagnosis include liver, spleen, lymph nodes, brain, and testes. Nephromegaly has also been reported. We present a novel case of bilateral parotid enlargement along with bilateral palpable nephromegaly in a patient with newly diagnosed infant ALL. This unique presentation highlights the importance of considering ALL in the differential diagnosis of parotid enlargement especially when associated with abnormal blood counts.