MR Imaging Characteristics and ADC Histogram Metrics for Differentiating Molecular Subgroups of Pediatric Low-Grade Gliomas.

BACKGROUND AND PURPOSE: BRAF and type 1 neurofibromatosis status are distinctive features in pediatric low-grade gliomas with prognostic and therapeutic implications. We hypothesized that DWI metrics obtained through volumetric ADC histogram analyses of pediatric low-grade gliomas at baseline would enable early detection of BRAF and type 1 neurofibromatosis status. MATERIALS AND METHODS: We retrospectively evaluated 40 pediatric patients with histologically proved pilocytic astrocytoma (n = 33), ganglioglioma (n = 4), pleomorphic xanthoastrocytoma (n = 2), and diffuse astrocytoma grade 2 (n = 1). Apart from 1 patient with type 1 neurofibromatosis who had a biopsy, 11 patients with type 1 neurofibromatosis underwent conventional MR imaging to diagnose a low-grade tumor without a biopsy. BRAF molecular analysis was performed for patients without type 1 neurofibromatosis. Eleven patients presented with BRAF V600E-mutant, 20 had BRAF-KIAA rearrangement, and 8 had BRAF wild-type tumors. Imaging studies were reviewed for location, margins, hemorrhage or calcifications, cystic components, and contrast enhancement. Histogram analysis of tumoral diffusivity was performed. RESULTS: Diffusion histogram metrics (mean, median, and 10th and 90th percentiles) but not kurtosis or skewness were different among pediatric low-grade glioma subgroups (P < .05). Diffusivity was lowest in BRAF V600E-mutant tumors (the 10th percentile reached an area under the curve of 0.9 on receiver operating characteristic analysis). There were significant differences between evaluated pediatric low-grade glioma margins and cystic components (P = .03 and P = .001, respectively). Well-defined margins were characteristic of BRAF-KIAA or wild-type BRAF rather than BRAF V600E-mutant or type 1 neurofibromatosis tumors. None of the type 1 neurofibromatosis tumors showed a cystic component. CONCLUSIONS: Imaging features of pediatric low-grade gliomas, including quantitative diffusion metrics, may assist in predicting BRAF and type 1 neurofibromatosis status, suggesting a radiologic-genetic correlation, and might enable early genetic signature characterization.

Neuroimaging Findings in Children with Constitutional Mismatch Repair Deficiency Syndrome.

BACKGROUND AND PURPOSE: Constitutional mismatch repair deficiency is a hereditary childhood cancer predisposition syndrome characterized by brain tumors and colorectal and hematologic malignancies. Our objective was to describe the neuroimaging findings in patients with constitutional mismatch repair deficiency. MATERIALS AND METHODS: This retrospective study included 14 children with genetically confirmed constitutional mismatch repair deficiency who were referred to 2 tertiary pediatric oncology centers. RESULTS: Fourteen patients from 11 different families had diagnosed constitutional mismatch repair deficiency. The mean age at presentation was 9.3 years (range, 5-14 years). The most common clinical presentation was brain malignancy, diagnosed in 13 of the 14 patients. The most common brain tumors were glioblastoma (n = 7 patients), anaplastic astrocytoma (n = 3 patients), and diffuse astrocytoma (n = 3 patients). Nonspecific subcortical white matter T2 hyperintensities were noted in 10 patients (71%). Subcortical hyperintensities transformed into overt brain tumors on follow-up imaging in 3 patients. Additional non-neoplastic brain MR imaging findings included developmental venous anomalies in 12 patients (85%) and nontherapy-induced cavernous hemangiomas in 3 patients (21%). CONCLUSIONS: On brain MR imaging, these patients have both highly characteristic intra-axial tumors (typically multifocal high-grade gliomas) and nonspecific findings, some of which might represent early stages of neoplastic transformation. The incidence of developmental venous anomalies is high in these patients for unclear reasons. Awareness of these imaging findings, especially in combination, is important to raise the suspicion of constitutional mismatch repair deficiency in routine diagnostic imaging evaluation or surveillance imaging studies of asymptomatic carriers because early identification of the phenotypic "gestalt" might improve outcomes.

Multiple Brain Developmental Venous Anomalies as a Marker for Constitutional Mismatch Repair Deficiency Syndrome.

BACKGROUND AND PURPOSE: Biallelic constitutional mutations in DNA mismatch repair genes cause a distinct syndrome, constitutional mismatch repair deficiency syndrome (CMMRD), characterized by cancers from multiple organs, most commonly brain tumors, during childhood. Surveillance protocols include total and brain MR imaging among other modalities to enable early detection of tumors. Brain surveillance scans revealed prominent brain developmental venous anomalies (DVAs) in some patients. DVAs are benign vascular anomalies, and their incidence in the general population is 2.6%-6.4%. Most developmental venous anomalies are asymptomatic and are found incidentally. Our purpose was to assess the prevalence of DVAs in CMMRD patients and describe their phenotype. MATERIALS AND METHODS: A retrospective descriptive analysis of brain MR imaging studies from 10 patients from 3 families with CMMRD was performed. Analysis included the number of developmental venous anomalies, location, draining vessels, and associated vascular anomalies (ie, cavernomas), with clinical correlation of symptoms and tumors. RESULTS: All 10 patients had ≥2 developmental venous anomalies, and 2 had, in addition, non-therapy-induced cavernomas. There was no clinically symptomatic intracranial bleeding from developmental venous anomalies. Six patients had malignant brain tumors. The location of brain tumors was not adjacent to the developmental venous anomalies. No new developmental venous anomalies developed during follow-up. CONCLUSIONS: The occurrence of multiple developmental venous anomalies in all our patients with CMMRD suggests that developmental venous anomalies may be a characteristic of this syndrome that has not been previously described. If confirmed, this quantifiable feature can be added to the current scoring system and could result in early implementation of genetic testing and surveillance protocols, which can be life-saving for these patients.

Malignant transformation in pediatric spinal intramedullary tumors: case-based update.

BACKGROUND: In children, intramedullary spinal cord neoplasms are rare. These are typically low-grade neuroepithelial tumors, most commonly astrocytomas, ependymomas, and gangliogliomas. Malignant transformation, while common in recurrent adult low-grade gliomas, is an unusual event in pediatric low-grade neoplasms, specifically in intramedullary spinal cord tumors. ILLUSTRATIVE CASES: We report two cases of malignant transformation in low-grade neuroepithelial tumors of the pediatric intramedullary spinal cord. Two children with intramedullary tumors, one with a WHO grade I ganglioglioma and one with a low-grade astrocytoma, were treated surgically, diagnosed histologically, and followed through the course of their disease. Both patients' tumors transformed to higher grades without prior irradiation or chemotherapy, and without a genetic predisposition to tumorigenesis. DISCUSSION: Malignant transformation can occur in low-grade intramedullary neoplasms in children. This is a novel documented event for pediatric intramedullary spinal cord tumors and a rare event for all pediatric low-grade neuroepithelial tumors without induction by irradiation. A survey of the relevant literature reveals an underwhelming number of studies focusing on malignant transformation in children's CNS tumors relative to adults. Further investigation into molecular mechanisms of pediatric low-grade neoplasms may reveal more aggressive tumor sub-variants predisposed to malignant degeneration.

Predisposition to the fragile X syndrome in Jews of Tunisian descent is due to the absence of AGG interruptions on a rare Mediterranean haplotype.

We have studied the ethnic distribution of the fragile X syndrome in Israel and have found that 36/136 (26.5%) of apparently unrelated pedigrees were of Tunisian Jewish descent. The Tunisian Jews, however, constitute only 2%-3% of the general Israeli population, identifying the first ethnic group significantly (P < .001) predisposed to the development of this disease. Associated with this increase in disease prevalence, we have found an unusually high incidence of FMR1 CGG repeats devoid of AGG interruptions among the normal Tunisian Jewish population (30/150, or 20.0%). Furthermore, the proportion of these alleles beyond the FMR1 CGG repeat instability threshold (>35 repeats) (8/150, or 5.3%) was significantly greater (P < .04) than that proportion found among non-Tunisian Jewish controls in Israel (1/136). Haplotype analysis has indicated that these large uninterrupted CGG repeat alleles are present on a previously unreported (DXS548-FRAXAC1-FRAXAC2) haplotype that accounts for all observed cases of disease among Tunisian Jewish X chromosomes. The high prevalence of disease among Tunisian Jews, we suggest, is due to a founder effect of this rare haplotype, which is completely devoid of AGG interruptions in the Jewish population of Tunisia.

Exchange of IOGEL hydrogel one-piece foldable intraocular lens for bag-fixated J-loop poly(methyl methacrylate) intraocular lens.

In 1990, IOGEL lenses placed in the capsular bag were reported to displace into the vitreous after neodymium:YAG (Nd:YAG) laser capsulotomy. We exchanged a bag-placed IOGEL lens in one patient after erroneous biometry and capsular opacification. The technique and results of lens explantation, aspiration of Elschnig pearls, and in-the-bag implantation of a modified J-loop poly(methyl methacrylate) (PMMA) lens are demonstrated. Removal of the soft and nonadhesive IOGEL lens was easy. The capsule pockets held patent by the flanges of the taco-style IOGEL lens allowed for easy insertion and bag fixation of the J-style loops. Visual acuity improved from 20/60 to 20/20. Centration of the exchange IOL was satisfactory. In a series of 61 Nd:YAG laser posterior capsulotomies, we did not observe the reported tendency of IOGEL lenses to luxate posteriorly. Therefore, we recommend Nd:YAG discission of the posterior capsule as the preferred approach to posterior capsule opacification with IOGEL lenses. However, the technical ease of the technique makes the explantation and replacement of IOGEL lenses by a bag-fixated PMMA IOL a valid option to correct an erroneous biometry.

Improved procedure for surface analysis of explanted intraocular lenses by combined light microscopy and scanning electron microscopy.

An improved surface characterization procedure for evaluating explanted intraocular lens (IOL) biocompatibility was developed. The technique combines aqueous hematoxylin-eosin staining for characterizing adherent cells and tissue with subsequent scanning electron microscopy of the same IOL.

In vitro evaluation of iris chafe protection afforded by hydrophilic surface modification of polymethylmethacrylate intraocular lenses.

An in vitro iris chafe test was developed to evaluate possible differences in abrasive interaction of various intraocular lens (IOL) materials with the posterior surface of the iris. The materials that were compared in initial tests with rabbit irides were high molecular weight polymethylmethacrylate (PMMA), the primary IOL material in current use, and surface-modified PMMA, which had a permanent, chemically bound, hydrophilic, polymer surface. Scanning electron microscopy, light microscopy, and examination of histological sections were used to assess tissue damage. A "window defect" type of abrasive damage was observed by light microscopy for PMMA lenses and is very similar in appearance to that seen for iris abrasion by human implants when viewed in vivo in slitlamp examinations. Results for both pigmented and albino rabbit irides indicate a reduction in abrasive insult to the external iris basement membrane and underlying pigment epithelium by the hydrophilic surface modification of PMMA. These results are consistent with our observation of a major reduction in corneal endothelium damage on contact with the hydrophilic surface-modified PMMA as compared with PMMA itself. This in vitro iris abrasion test, therefore, appears to be a useful technique for future evaluation of IOL surface properties.

Polycarbonate intraocular lenses.

Bisphenol-A polycarbonate has been investigated as an improved polymer for ocular implants, especially for intraocular lenses (IOLs). Polycarbonate properties afford special opportunities for development of tougher, stronger, one-piece IOLs. Autoclave or gamma sterilizability and a higher refractive index may provide additional IOL advantages over polymethylmethacrylate. Implant studies in rabbits have shown polycarbonate IOLs to be well tolerated in the anterior chamber for 2.5 years. Polycarbonate appears promising for new IOLs and other ocular implant applications.

Intraocular-lens-endothelial interface: adhesive force measurements.

An instrument for measuring the force of adhesion between intraocular lens materials and the endothelium of excised rabbit corneas was constructed. The adhesion force was measured for polymethylmethacrylate (PMMA), polyhydroxyethylmethacrylate (PHEMA), Duragel (amino-polyamide hydrogel), PMMA surface grafted with polyvinylpyrrolidone, and PMMA surface treated with sodium hyaluronate (Healon). The force of adhesion was reduced considerably when the PMMA surface was modified with a hydrophilic polymer coating. This is consistent with previous studies showing reduced endothelium cell damage for hydrophilic polymer coated intraocular lenses. Adhesive forces were also decreased by addition of polyvinyl alcohol or gelatin to the saline solution in which the corneas were immersed. Extension of this type of measurement to pericardium, vascular endothelium, and peritoneum surfaces may also be important to understand tissue damage problems in general surgery.

Preliminary study of hydrophilic hydrogel intraocular lens implants in cats.

Soft hydrophilic intraocular lenses (IOLs) made of an aminopolyamide (Duragel) and a hydroxyethylmethylmethacrylate (HEMA) hydrogel polymer were implanted in cats and followed for six weeks. During surgery, a 45-second purposeful contact between the lens surface and the corneal endothelium was made. During the course of the experiment, all implanted eyes maintained clear IOLs and manifested a continuing mild iritis. Scanning electron microscopy of the corneas revealed numerous microvilli but no damage to cell membranes. Scanning electron microscopy of the aminopolyamide IOLs revealed fibroblast growth on the surface. No fibroblast growth was noted on the surface of the HEMA IOLs. These experiments suggest that soft hydrogel IOLs may be better than conventional hydrophobic acrylic IOLs in minimizing endothelial contact damage. However, the observation of corneal microvilli may indicate a mild adverse reaction to the hydrogels, possibly from impurities. Fibroblast growth on the aminopolyamide may also be due to an ocular inflammatory response to the material or impurities. Hydrogel IOLs may be of interest because of their semirigid physical properties and greater safety on contacting the endothelium. However, considerable attention must be given to polymer composition and polymer purification.

The prevalence of diabetic retinopathy: effect of sex, age, duration of disease and mode of therapy.

Studying 445 diabetic patients, we investigated the effects of sex, age, duration of disease, and mode of diabetes therapy on the prevalence of diabetic retinopathy. Of the study participants, 193 were treated with insulin injections, 164 took oral antidiabetic medications, and 88 were managed on diet alone. The prevalence of diabetic retinopathy was highest among insulin-treated patients (64%), while in the oral medication and diet groups, it was 36% and 12%, respectively. Diabetic retinopathy was more prevalent among patients with prolonged duration of disease. Sex and age did not seem to affect the prevalence of diabetic retinopathy when adjustments were made for the duration of disease.

Intraocular pressure reduction induced by hornet venom in the normal eye.

Intravenous injection into rabbits and cats of an aqueous extract of hornet venom sac, produced a significant reduction in the intraocular pressure. The mean reduction of the ocular pressure was between 7 and 15 mm Hg within one hour past injection and it lasted 6-12 h or in several instances even more than 24 h. The effect is produced by some thermolabile high-molecular-weight fraction(s), is dose-dependent and is reproducible by repetitive injections. Side effects may include diarrhea, micturition and lethargy, but usually there is no marked effect on the size of the pupil.