Publications by authors named "Nitza Goldenberg-Cohen"

83 Publications

Optic Nerve Drusen Is Highly Prevalent Among Children With Pseudotumor Cerebri Syndrome.

Front Neurol 2021 13;12:789673. Epub 2021 Dec 13.

Bruce Rappaport Faulty of Medicine, Technion, Haifa, Israel.

The clinical presentation of pseudotumor cerebri syndrome (PTCS) usually includes headache, nausea, and vomiting with normal physical examination apart from papilledema and diplopia. However, pseudopapilledema, which can be caused by optic nerve drusen, may lead to misdiagnosis. The prevalence of optic nerve drusen in the general population is 0.5-2%. The purpose of our study was to evaluate the prevalence and risk factors of optic nerve drusen among patients with PTCS. Medical records of children evaluated in the pediatric department at Bnai Zion Medical Center due to PTCS between 2008 and 2020 were assessed. Inclusion criteria were children age under 18 years with a PTCS diagnosis and ophthalmic B-mode ultrasonography (US). Exclusion criteria were secondary intracranial hypertension. Thirty-four children were included with a mean age 10.1 years which included 50% boys. A majority of the patients, 24 (72.4%), complained of headaches, while 15 (45.5%) complained of transient visual obscuration, and 9 (26.5%) of vomiting. Visual acuity on presentation was normal (20/20-20/30) in 23 of the children (67%), moderately diminished (20/40-20/80) in 9 (26%), and showing profound loss (20/200) in 2 (7%). Five patients (14.7%) were diagnosed with optic nerve drusen via B-mode ophthalmic ultrasonography (US). However, they still fulfilled the diagnostic criteria for PTCS, and disc swelling improved after treatment. There were no statistically significant differences between the group with optic nerve drusen and the rest of the patients. Optic nerve drusen are common among pediatric patients with PTCS. Diagnosis of optic nerve drusen should not rule out the presence of increased intracranial pressure.
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http://dx.doi.org/10.3389/fneur.2021.789673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710470PMC
December 2021

The Management of Congenital Microphthalmia With Orbital Cyst: A Case Series.

J Pediatr Ophthalmol Strabismus 2021 Dec 20:1-8. Epub 2021 Dec 20.

Purpose: To describe a series of patients treated for congenital microphthalmia associated with orbital cyst and recommend a management protocol.

Methods: This retrospective case series comprised 6 patients (7 eyes) who attended an oculoplastic tertiary medical center from 2001 to 2018. Clinical, treatment, and outcome data were collected from the electronic files. Main outcome measures were preservation of vision and cosmetic appearance.

Results: Four patients were diagnosed at birth. Six cysts were located inferiorly and one superiorly. Two patients had a visual potential of light perception or better in the affected eye. In 4 eyes, the cyst was initially retained and the eye was fitted with a custom-made conformer. In 1 eye, the fornices were too shallow for a conformer, warranting fornix reconstruction and cyst excision. Early surgery was required in 1 eye for an expanded cyst and large orbit volume, and in another eye the cyst had overgrown the orbit, causing bone erosion and remodeling. Cosmetic results were good in 3 of the eyes in which the cyst was retained in early childhood, stimulating orbital growth.

Conclusions: Congenital microphthalmia with orbital cyst is rare. Management should focus on preserving visual potential, especially in unilateral cyst cases when the other eye is also microphthalmic. Otherwise cosmetic symmetry is the main concern; cyst retention combined with ocular conformers may stimulate socket expansion. The authors found that, in most cases, if treated early, enucleation was avoidable during cyst excision. Early assessment, meticulous follow-up, and individually tailored treatment are warranted. .
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http://dx.doi.org/10.3928/01913913-20210929-01DOI Listing
December 2021

Classifying Medulloblastoma Subgroups Based on Small, Clinically Achievable Gene Sets.

Front Oncol 2021 10;11:637482. Epub 2021 Jun 10.

Department of Molecular Biology, Ariel University, Ariel, Israel.

As treatment protocols for medulloblastoma (MB) are becoming subgroup-specific, means for reliably distinguishing between its subgroups are a timely need. Currently available methods include immunohistochemical stains, which are subjective and often inconclusive, and molecular techniques-e.g., NanoString, microarrays, or DNA methylation assays-which are time-consuming, expensive and not widely available. Quantitative PCR (qPCR) provides a good alternative for these methods, but the current NanoString panel which includes 22 genes is impractical for qPCR. Here, we applied machine-learning-based classifiers to extract reliable, concise gene sets for distinguishing between the four MB subgroups, and we compared the accuracy of these gene sets to that of the known NanoString 22-gene set. We validated our results using an independent microarray-based dataset of 92 samples of all four subgroups. In addition, we performed a qPCR validation on a cohort of 18 patients diagnosed with SHH, Group 3 and Group 4 MB. We found that the 22-gene set can be reduced to only six genes (, , , , , and ) without compromising accuracy. The identified gene set is sufficiently small to make a qPCR-based MB subgroup classification easily accessible to clinicians, even in developing, poorly equipped countries.
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http://dx.doi.org/10.3389/fonc.2021.637482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223061PMC
June 2021

Differences in RNA and microRNA Expression Between PTCH1- and SUFU-mutated Medulloblastoma.

Cancer Genomics Proteomics 2021 May-Jun;18(3):335-347

Department of Molecular Biology, Ariel University, Ariel, Israel;

Background/aim: Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions.

Patients And Methods: We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways.

Results: Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups).

Conclusion: Our results help towards finding new treatable molecular targets for these types of medulloblastomas.
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http://dx.doi.org/10.21873/cgp.20264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126327PMC
December 2021

High Myopia and Strabismus Induced by a Deep Intronic Mutation in .

Curr Eye Res 2021 07 9;46(7):1051-1055. Epub 2020 Dec 9.

The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.

: To characterize a genetic mutation causing Stickler syndrome in a previously undiagnosed family.: Five generations of a single family suspected of having Stickler syndrome were evaluated clinically and genetically.: The demographic and clinical data yielded specific clinical phenotypes of Stickler syndrome in 13 family members; 7 had more than one clinical feature. Four family members underwent genetic analysis: the proband (index patient) and his mother, maternal grandfather, and healthy father. No relevant mutation was detected in the proband on whole exome analysis, but subsequent extension of the analysis to intronic areas yielded a deep intronic mutation, NM_001844.5:c.1527 + 135 G > A. Sanger sequencing was used to validate the results in the family members.: Stickler syndrome has several subtypes with variable clinical features. Therefore, predicting the genetic locus of the disease based on clinical characteristics is challenging. We present a rarely described intronic mutation in . Genetic testing may aid in the early diagnosis of Stickler syndrome, which is important for genetic counselling, proper clinical management, and improved prognosis.
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http://dx.doi.org/10.1080/02713683.2020.1855661DOI Listing
July 2021

Association of pediatric idiopathic intracranial hypertension with olfactory performance.

Eur J Paediatr Neurol 2021 Jan 3;30:162-169. Epub 2020 Oct 3.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel; Neurology Institute, Schneider Children's Medical Center of Israel, Petach Tikva, 4920235, Israel. Electronic address:

Objective: To assess the association between pediatric Idiopathic intracranial hypertension (IIH) and olfactory performance.

Methods: A cross-sectional comparative study was conducted including 17 patients under 18 years diagnosed with IIH at a tertiary hospital and 17 healthy age- and sex-matched subjects. All participants underwent the semi-objective chemosensory Sniffin' Sticks test for evaluation of odor threshold (OT), indicative of peripheral olfactory function, and odor identification (OI), reflecting higher cognitive olfactory processing. Scores were compared and referred to the updated normative values. Demographic, clinical, and neuroimaging data were collected from the medical files. The patients with IIH were reassessed for olfactory function and clinical state at the subsequent follow-up, under treatment.

Results: Compared to controls, the IIH group had a significantly lower mean OT score (6.41 ± 3.43 vs 10.21 ± 2.79, p = 0.001) and higher rate of OT score below the 10th percentile for age and sex according to the normative values (47.1% vs 0%, p = 0.001). There was no significant between-group difference in mean OI scores (9.82 ± 1.63, vs 10.59 ± 1.84, p = 0.290). OT scores were not associated with sex, age, body mass index, neuroimaging abnormalities, or lumbar puncture opening pressure. At the follow-up assessment, the OT scores were improved (9.36 ± 4.17 vs 6.7 ± 3.32, p = 0.027) whereas the OI scores were unchanged (9.88 ± 2.5 vs 9.69 ± 1.58, p = 0.432).

Conclusions: As reported in adults, children and adolescents with IIH appear to have a selective reversible deficit in olfactory detection threshold, which may imply a reduction in peripheral olfactory perceptual ability. Future studies should examine the predictive value of olfactory function for IIH.
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http://dx.doi.org/10.1016/j.ejpn.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532354PMC
January 2021

The Need to Look for Visual Deficit After Stroke in Children.

Front Neurol 2020 2;11:617. Epub 2020 Jul 2.

Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel.

To evaluate the role of the ophthalmologist in the management of children with arterial stroke, at presentation and during follow-up. This retrospective case series comprised children with arterial stroke who were followed for at least 12 months in a tertiary pediatric medical center in 2005-2016. Demographic data and findings on radiological neuroimaging and ophthalmological and neurological examination were retrieved from the medical files. The cohort included 26 children with stroke. Underlying disorders included metabolic syndrome ( = 5, 19.2%), cardiac anomaly or Fontan repair ( = 3 each, 11.5%), vascular anomaly ( = 3, 11.5%), head trauma with traumatic dissection ( = 3, 11.5%), and hypercoagulability ( = 1, 3.8%); in eight patients (30.8%), no apparent cause was found. Eleven patients (42.3%) had a non-ophthalmological neurological deficit as a result of the stroke. Eye examination was performed in nine patients (34.6%) during follow-up. Ophthalmological manifestations included hemianopic visual field defect in seven patients (7.7%) and complete blindness and poor visual acuity in one patient each (3.8%). At the last visit, no change in visual function was detected. The variable etiology and presentation of pediatric stroke may mask specific visual signs. Children with arterial stroke should be referred for early ophthalmological evaluation and visual rehabilitation.
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http://dx.doi.org/10.3389/fneur.2020.00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343911PMC
July 2020

Proptosis due to intraorbital space-occupying lesions in children.

Graefes Arch Clin Exp Ophthalmol 2020 Nov 16;258(11):2541-2550. Epub 2020 Jul 16.

Krieger Eye Research Laboratory, Felsenstein Medical Research Center, 4941492, Petah Tikva, Israel.

Purpose: To report the 10-year experience of two tertiary medical centers with children presenting with proptosis due to an intraorbital space-occupying lesion.

Methods: Patients were identified by file review. Data were collected on demographics, findings on ophthalmologic and imaging evaluations, etiology, treatment, and outcome.

Results: Nineteen children (7 male) were included. Eleven patients had optic nerve glioma, including 9 with substantially decreased visual acuity. Treatment consisted of chemotherapy alone or with radiation, resection or anti-VEGF agents, MEK inhibitor, or observation only (n = 1). Visual and cosmetic outcomes were poor in all cases. Outcome for arteriovenous malformations was good following corticosteroid treatment (n = 1), but catheterization led to persistent proptosis and fluctuating visual acuity (n = 1). Compound capillary hemangioma (n = 1) was treated with laser and systemic beta blockers with satisfactory results. Rhabdomyosarcoma had a good prognosis in one patient treated with resection and radiation but was fatal in another even after chemotherapy. Juvenile xanthogranuloma, frontal bone osteoma, and localized hypertrophic neuropathy of the supraorbital nerve (n = 1 each) were treated by resection with good visual and cosmetic outcomes.

Conclusions: Proptosis accompanied by visual loss is an uncommon presentation in children and suggests an orbital tumor. We found that visual outcome was better when the nerve was not involved by tumor. Optic nerve glioma was the most common cause and failed to respond to various treatments. Catheterization for arteriovenous malformation did not prevent proptosis, and final visual acuity fluctuated. Surgery for rhabdomyosarcoma and xanthogranuloma led to remission with preservation of vision in 2 of 3 cases.
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http://dx.doi.org/10.1007/s00417-020-04840-3DOI Listing
November 2020

Gene-Related Response of Basal Cell Carcinoma to Biologic Treatment with Vismodegib.

Sci Rep 2020 01 27;10(1):1244. Epub 2020 Jan 27.

The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel.

We aimed to characterise the response of locally advanced basal cell carcinoma (BCC) to systemic treatment with Vismodegib, a Hedgehog pathway inhibitor, by changes in the expression levels of Hedgehog pathway genes. Data were collected prospectively on 12 patients treated systemically for locally advanced BCC. Biopsy samples taken on admission and after treatment cessation were analysed pathologically and with the NanoString nCounter system to quantify the expression of 40 Hedgehog signaling pathway genes. Findings were compared before and after treatment, between complete and partial responders, and with localised BCC samples from 22 patients. Sixteen Hedgehog pathway genes changed significantly from before to after treatment. GAS1 was the only gene with a significantly different expression at baseline between complete responders (6 patients) and partial responders (4 patients) to Vismodegib (P = 0.014). GAS, GLIS2 and PRKACG1 showed different expression before treatment between the locally advanced and localised BCCs. The baseline expression level of GAS1 appears to be predictive of the response of locally advanced BCC to systemic Vismodegib treatment. A change in expression of many Hedgehog pathway genes, albeit expected by the known activity of Vismodegib, may nevertheless serve as an indicator of the response potential of the tumour.
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http://dx.doi.org/10.1038/s41598-020-58117-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985141PMC
January 2020

Diffusion Reflection Measurements of Antibodies Conjugated to Gold Nanoparticles as a Method to Identify Cutaneous Squamous Cell Carcinoma Borders.

Materials (Basel) 2020 Jan 17;13(2). Epub 2020 Jan 17.

Faculty of Engineering and Institute of Nanotechnology and Advanced Materials, Bar Ilan University, Ramat Gan 5290002, Israel.

Diffusion reflectance spectroscopy measurements targeted with gold nanoparticles (GNPs) can identify residual cutaneous squamous cell carcinoma (SCC) in excision borders. Human SCC specimens were stained with hematoxylin and eosin to identify tumor borders, and reflected onto an unstained deparaffinized section. Diffusion reflection of three sites (normal and SCC) were measured before and after GNPs targeting. Hyperspectral imaging showed a mean of 2.5 sites with tumor per specimen and 1.2 tumor-free ( < 0.05, -test). GNPs were detected in 25/30 tumor sites (sensitivity 83.3%, false-negative rate 16.6%) and 12/30 non-tumor sites (specificity 60%, false-positive rate 40%). This study verifies the use of nanotechnology in identifying SCC tumor margins. Diffusion reflection scanning has high sensitivity for detecting the residual tumor.
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http://dx.doi.org/10.3390/ma13020447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014005PMC
January 2020

The co-occurrence of rare non-ocular phenotypes in patients with inherited retinal degenerations.

Mol Vis 2019 14;25:691-702. Epub 2019 Nov 14.

The Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Purpose: To describe the coexistence of additional non-ocular genetic diseases in patients diagnosed with inherited retinal degenerations (IRDs).

Methods: The study was based on a retrospective chart review of patients diagnosed with IRD and additional rare systemic diseases. The chart review included the ophthalmic and genetic aspects of each patient. The ophthalmic examination included best-corrected visual acuity, biomicroscopic examination, cycloplegic refraction, retinal imaging (fundus photos, optical coherence tomography, and fundus autofluorescence), and electroretinography. Genetic testing included homozygosity mapping, whole exome sequencing, and Sanger sequencing.

Results: Fifteen index cases diagnosed with IRDs and one or more rare systemic diseases were identified. Six of the families were consanguineous. Of six patients with complete molecular diagnosis, four (66%) had pathogenic variants in two autosomal recessive (AR) disease genes, and of the total pathogenic variants identified, AR mutations were the most common (16/22, 72%). One patient was diagnosed with mutations in three different genes, underlying three distinct genetic conditions. Nine patients could have had an incorrect clinical diagnosis based on the clinical evaluation only (e.g., retinitis pigmentosa and hearing loss could have been diagnosed as Usher syndrome).

Conclusions: The common working paradigm for the ophthalmologist is combining the different symptoms observed in a patient into one unifying diagnosis. However, IRD is a strikingly heterogeneous condition, and may coincide with other genetic (and non-genetic) rare conditions. Establishing a correct diagnosis is important for the patients and their family members, as it enables prediction of disease prognosis, aids in tailoring the correct follow-up and treatment, and allows patients to pursue prenatal counseling and reproductive planning.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857777PMC
June 2020

Long-Term Follow-up of Pseudotumor Cerebri Syndrome in Prepubertal Children, Adolescents, and Adults.

Pediatr Neurol 2019 12 27;101:57-63. Epub 2019 Apr 27.

Department of Ophthalmology, Kaplan Medical Center, Rehovot, Israel; The Hebrew University of Jerusalem, Jerusalem, Israel.

Purpose: Pseudotumor cerebri syndrome can have a recurrent course. We compared the long-term disease course, recurrences, and final visual outcomes in prepubertal children, adolescents, and adults.

Methods: In this retrospective observational study, patients were divided into prepubertal children (group A) adolescents (group B), and adults (group C).

Results: Sixty-five patients (56 females, nine males) were included, 26.2% in group A, 24.6% in group B, and 49.2% in group C. Age at diagnosis was 8.6 ± 2.0 years, 14.3 ± 1.5 years, and 31.9 ± 9.7 years for the prepubertal children, adolescents, and adults, respectively. Medical treatment duration was similar (2.4 to 3.3 years, P > 0.05). Recurrences were observed in 23.5% of prepubertal children, 50% of adolescents, and 28.1% of adults. Recurrences occurred within 1.3 ± 0.6 years from treatment cessation in the prepubertal group compared with 3.8 ± 5.1 years in adolescents and 2.7 ± 2.0 years in adults (P = 0.267). Optic neuropathy was evident in 41% of group A, 31% of group B, and 87.5% of group C (P < 0.001). Obesity and cerebrospinal fluid opening pressures were unassociated with either relapsing rates or final visual outcomes in all groups.

Conclusions: Pseudotumor cerebri syndrome exhibits a relapsing course in a third of cases. Recurrences tend to occur within one year after treatment cessation in prepubertal children, and within three years in older patients, revealing the importance of longer follow-up, especially in adults. Optic neuropathy was more common in adults along with a tendency for visual decline. Longer treatment times were associated with fewer recurrences.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.04.018DOI Listing
December 2019

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Hum Mutat 2020 01 15;41(1):140-149. Epub 2019 Sep 15.

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.
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http://dx.doi.org/10.1002/humu.23903DOI Listing
January 2020

Ocular Effects of Sildenafil in Naïve Mice and a Mouse Model of Optic Nerve Crush.

Invest Ophthalmol Vis Sci 2019 05;60(6):1987-1995

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: To investigate the potential neuroprotective effect of sildenafil on the ocular circulation in mice with/without optic nerve crush (ONC).

Methods: Male adult mice (n = 63) were treated with intravitreal (IVT) sildenafil 24 μg/3 μL, intraperitoneal (IP) sildenafil 24 μg/300 μL, or IP saline immediately before right ONC induction (ONC group). A second group (n = 123) received the same treatments without ONC induction (naïve group). Evaluations included fluorescein angiography (naïve group; day 0), molecular studies (days 1 and 3), and retinal and optic nerve histology (day 21).

Results: Maximal retinal vessel dilatation and increased choroidal effusion were detected within 30 minutes of sildenafil injection. In the ONC group, moderate retinal ganglion cell (RGC) loss was noted at 21 days. However, molecular studies showed increased stress induced gene expression (IP superoxide dismutase [SOD]-1: 3.1-fold; heme oxygenase [HO]-1: 5.8-fold; IVT SOD-1: 1.47-fold), proapoptotic gene expression (IP BAX/B-cell lymphoma [BCL]-2 10.8-/2.3-fold), and glial gene expression (IP glial fibrillary acidic protein [GFAP]: 2.8- and myelin basic protein [MBP]: 2.5-fold). In the naïve group, IVT sildenafil was not associated with RGC loss or optic nerve stroke on histology, although in two samples, molecular parameters were compatible with stroke, showing increased gene expression of HO-1 (3.8-fold) and BCL-2 (2.5-fold). In the IP sildenafil subgroup, optic neuropathy was observed in 6/120 optic nerves, including 3 cyan fluorescence protein (CFP)-Thy-1 mice. Levels of antiapoptosis and anti-ischemia genes were decreased (<0.5-fold) except for three outliers.

Conclusions: Sildenafil affects retinal and choroidal perfusion in mice. When injected immediately before ONC, molecular parameters showed a preconditioning neuroprotective effect while histologic studies did not. In the absence of ONC, it is associated with neuropathy, possibly dose-dependent.
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http://dx.doi.org/10.1167/iovs.18-26333DOI Listing
May 2019

Likelihood of Diagnosing Neuroblastoma in Isolated Horner Syndrome.

J Neuroophthalmol 2019 09;39(3):308-312

Department of Ophthalmology (NG-C), Bnai Zion Medical Center, Haifa, Israel; Krieger Eye Research Laboratory (NG-C), Felsenstein Medical Research Center, Beilinson Hospital, Petach Tikva, Israel; The Ruth and Bruce Rappaport Faculty of Medicine (NG-C), Technion, Haifa, Israel; Sackler Faculty of Medicine (ABS, HT, SA), Tel Aviv University, Tel Aviv, Israel; Department of Radiology (JL), Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; Department of Pediatric Oncology (HT, SA), Schneider Children's Medical Center of Israel, Petach Tikva; Israel.

Background: The need for an extensive evaluation for neuroblastoma in children with Horner syndrome is controversial.

Methods: A retrospective study design was used. The cohort included 47 children with anisocoria who were diagnosed with Horner syndrome and 135 children with neuroblastoma evaluated at a pediatric medical center between 2007 and 2015. To detect neuroblastoma, patients with Horner syndrome underwent brain and cervical MRI, abdominal ultrasound, and/or measurement of urinary vanillylmandelic acid (VMA). The neuroblastoma group was evaluated for signs/symptoms of Horner syndrome at the time of diagnosis.

Results: Seven patients with Horner syndrome were lost to follow-up, and the findings of the remaining 40 were categorized according to the age of the patient. Horner syndrome most frequently was idiopathic (58%), and in only 1 patient did the discovery of neuroblastoma precede the appearance of Horner syndrome. In the 21 patients aged 1-18 years, Horner syndrome was acquired in 15 patients and congenital in 6. The most common etiology was trauma (62%). Imaging was performed in 14 patients and VMA testing in 13. Neuroblastoma was diagnosed in 5 patients; in none was it related to Horner syndrome. In the 135 patients with neuroblastoma, most of the tumors were diagnosed at Stage 4 (60%) or Stage 3 (30%) with 53% originating in the abdomen. In one patient (0.74%) with signs/symptoms of Horner syndrome at diagnosis of neuroblastoma, the tumor had been identified prenatally and the diagnosis confirmed by imaging postnatally.

Conclusions: The absence of occult neuroblastoma in children with Horner syndrome and of signs/symptoms of Horner syndrome in the children diagnosed with neuroblastoma suggests that Horner syndrome might not be as frequent a cause of neuroblastoma as previously thought. We recommend that full investigation for neuroblastoma be reserved for suspicious cases associated with additional systemic signs or symptoms.
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http://dx.doi.org/10.1097/WNO.0000000000000764DOI Listing
September 2019

[THE ISRAELI INHERITED RETINAL DISEASES CONSORTIUM (IIRDC)- CLINICAL-GENETIC MAPPING AND FUTURE PERSPECTIVES].

Harefuah 2019 Feb;158(2):91-95

Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.

Introduction: The sense of vision is highly important for humans and its loss markedly affects function and quality of life. Many inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptor cells. These diseases show clinical and genetic heterogeneity.

Aims: The Israeli IRD consortium (IIRDC) was established with the goal of performing clinical and genetic mapping of IRDs in the Israeli population.

Methods: Clinical evaluation is carried out at electroretinography (ERG) centers and ophthalmology departments, where the patients undergo a comprehensive eye exam, including testing of visual acuity, refractive error, imaging techniques and ERG tests. Genetic analysis is performed using Sanger sequencing, analysis of founder mutations, and whole exome sequencing.

Results: We recruited over 2,000 families including more than 3,000 individuals with IRDs. The most common inheritance pattern is autosomal recessive (65% of families). The most common retinal phenotype is retinitis pigmentosa (RP- 45% of families), followed by cone/cone-rod dystrophy, Stargardt Disease and Usher syndrome. We identified the cause of disease in 51% of families, mainly due to mutations in ABCA4, USH2A, FAM161A, CNGA3, and EYS. IIRDC researchers were involved in the identification of 16 novel IRD genes. In parallel, IIRDC members are involved in the development of therapeutic modalities for these currently incurable diseases.

Conclusions: IIRDC works in close collaborative efforts aiming to continue and recruit for the genotype - phenotype study from the vast majority of Israeli IRD families, to identify all disease-causing mutations, and to tailor therapeutic interventions to each IRD patient.
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February 2019

Use of Optical Coherence Tomography to Detect Retinal Nerve Fiber Loss in Children With Optic Pathway Glioma.

Front Neurol 2018 20;9:1102. Epub 2018 Dec 20.

Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Petah Tikva, Israel.

Optic pathway glioma (OPG) presents in childhood and can cause significant morbidity and visual loss. Magnetic resonance imaging (MRI) is the current imaging modality of choice for evaluation of OPG progression, but it is a relatively limited resource often requiring sedation in the pediatric age group. Additionally, OPG progression on MRI does not always correlate with clinical progression. As a result, several other modalities for evaluating OPG are being investigated, including optical coherence tomography (OCT), a readily available imaging technique in ophthalmic practice. The purpose of the present study was to examine the association between retinal nerve fiber layer (RNFL) thickness measured using OCT and optic nerve function in children with OPG with and without neurofibromatosis-1 (NF-1). A retrospective chart review was conducted to identify children diagnosed with OPG from 2001 to 2015 at a tertiary pediatric medical center. The correlation between OCT measurements and clinical visual parameters was statistically analyzed. Included were 23 children with imaging-confirmed OPG and spectral domain OCT: 10 with NF-1 (mean age at diagnosis 5.8 years) and 13 without (mean age at diagnosis 5.9 years). The glioma involved the chiasma-hypothalamus in 19 patients, optic nerve in 11, and optic tract in 7; more than one anatomic site was affected in 15. Symptoms were reported in 2 patients with NF-1 and most patients without NF-1. Visual field defects included monocular, bitemporal, nasal, and homonymous hemianopia. Initial mean RNFL was 85.4 μm in the NF-1 group and 65 μm in the non-NF-1 group. Visual acuity deteriorated in 1/10 patients and 5/13 patients, respectively. Repeated OCT showed continued RNFL thinning in 3 patients (5 eyes) in the NF-1 group and in 8 patients (11 eyes) in the non-NF-1 group, often associated with a decrease in optic nerve function. In conclusion, visual function in children with OPG is correlated with repeated OCT measurements and weakly with neuroimaging. Children without NF-1 are usually symptomatic and have a worse clinical outcome. These findings may have important implications when considering initiating, continuing or stopping chemotherapy for OPG. The application of OCT in the assessment of OPG and the correlation of the findings to clinical progression can have a significant impact on OPG patient management.
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http://dx.doi.org/10.3389/fneur.2018.01102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306407PMC
December 2018

Late diagnosis of Alstrom syndrome in a Yemenite-Jewish child.

Ophthalmic Genet 2019 02 2;40(1):7-11. Epub 2019 Jan 2.

a The Krieger Eye Research Laboratory , Felsenstein Medical Research Center , Petach Tikva , Israel.

Background: We describe the ophthalmologic, clinical, and genetic findings in a patient of Yemenite-Jewish origin diagnosed with Alstrom syndrome due to a novel splice-site mutation 10 years after a clinical misdiagnosis of Leber congenital amaurosis.

Methods: Ophthalmological evaluations included visual acuity, cycloplegic refraction, slit-lamp, and optical coherent tomography. Genetic analyses included whole exome sequencing followed by bioinformatics analysis and segregation analysis. An in vitro splicing assay was used to evaluate the effect of the identified mutation on splicing. Taqman assay was used to determine the need for population screening for the identified mutation.

Results: Ophthalmologic findings at age 6 were impaired vision, nystagmus, and hyperopia. At age 16 years, the patient presented with obesity, hypothyroidism, and elevated transaminase levels in addition to reduced vision, wandering nystagmus, disc pallor, and degenerative retinal changes. Targeted genetic analysis of ALMS1 revealed a homozygous transversion, c.11544 + 3A>T, suggesting a novel splicing mutation, with elimination of the donor splice site and insertion of 73 nucleotides at the end of exon 16. These changes were validated by Sanger sequencing and co-segregation on family members.

Conclusions: Ophthalmologists should be alert to the differential diagnosis of inherited retinal degeneration in young patients who present with impaired vision, especially if systemic symptoms are mild and there is no known family history. In the present case, targeted genetic analysis of a child with a syndromic cone-rod dystrophy yielded a novel splicing mutation in ALMS1 causing Alstrom syndrome.
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http://dx.doi.org/10.1080/13816810.2018.1561900DOI Listing
February 2019

Protective Effect of TLR4 Ablation against Corneal Neovascularization following Chemical Burn in a Mouse Model.

Curr Eye Res 2019 05 24;44(5):505-513. Epub 2019 Jan 24.

a Krieger Eye Research Laboratory, Felsenstein Medical Research Center , Beilinson Hospital , Petach Tikva , Israel.

Purpose: To determine whether Toll-like receptor 4 knockout protects mice from corneal neovascularization following chemical injury compared to wild-type (WT) mice.

Methods: A chemical burn (75% silver nitrate, 25% potassium nitrate) was created under anesthesia in the central right cornea of 32 WT and 31 Toll-like receptor 4 knockout mice. Corneal neovascularization was evaluated at 3, 4, 6, 8, 10, and 35 days after injury using digital photography, fluorescein angiography, gelatin perfusion with fluorescence vascular imaging, immunofluorescence staining, and molecular analysis.

Results: There was no significant between-group difference in relative corneal burn area at 10 days after injury (39.0 ± 2.4% vs. 38.8 ± 9.8%, respectively). Neovascularization was detected in all corneas in vivo and perfusion was detected by fluorescence vascular imaging, reaching maximum area on day 10. The relative area of neovascularization was significantly smaller in the knockout than the WT mice on days 6 (33.3 ± 4.2% vs. 46.8 ± 7.4%, respectively, p = 0.005) and 8 (36.6 ± 1.1% vs. 52.2 ± 6.4%, respectively, p = 0.027), although neovascularization was intensive in both groups. In line with the immunostaining findings of angiogenesis and inflammatory infiltration of damaged corneas, molecular analysis (performed on day 3) revealed elevated expression levels of angiogenesis-related genes (vascular endothelial growth factor, VEGFR2, VEGFR1) and inflammation-related genes (CD45 and TGFβ1) in the WT mice. The knockout mice had higher TNF-α expression than the WT mice.

Conclusion: In a mouse corneal chemical burn model, lack of Toll-like receptor 4 expression did not completely inhibit angiogenesis, but did have a relative effect to reduce neovascularization as compared to the WT.
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http://dx.doi.org/10.1080/02713683.2018.1564833DOI Listing
May 2019

Pathogen Detection Using Frequency Domain Fluorescent Lifetime Measurements.

IEEE Trans Biomed Eng 2018 12 9;65(12):2731-2741. Epub 2018 Mar 9.

Objective: Inflammation of the meninges is a source of severe morbidity and therefore is an important health concerns worldwide. The conventional clinical microbiology approaches used today to identify pathogens suffer from several drawbacks and frequently provide false results. This research describes a fast method to detect the presence of pathogens using the frequency domain (FD) fluorescence lifetime (FLT) imaging microscopy (FLIM) system.

Methods: The study included 43 individuals divided into 4 groups: 9 diagnosed with different types of bacteria; 16 diagnosed with different types of viruses; 5 healthy samples served as a control; and 12 samples were negative to any pathogen, although presenting related symptoms. All samples contained leukocytes that were extracted from the cerebrospinal fluid (CSF) and were subjected to nuclear staining by 4', 6-diamidino-2-phenylindole (DAPI) and FLT analyses based on phase and amplitude crossing point (CRPO).

Results: Using notched boxplots, we found differences in 95% probability between the first three groups through different notch ranges (NR). Pathogen samples presented a longer median FLT (3.28 ns with NR of 3.24-3.32 ns in bacteria and 3.18 ns with NR of 3.16-3.21 ns in viruses) compared to the control median FLT (2.65 ns with NR of 2.63-2.67 ns). Furthermore, we found that the undetected forth group was divided into two types: a relatively normal median FLT (2.72 ns with NR of 2.68-2.76 ns) and a prolonged FLT (3.22 ns with NR of 3.17-3.27 ns).

Conclusion: FLT measurements can differentiate between control and pathogen by the CRPO method.

Significance: The FD-FLIM system can provide a high throughput diagnostic technique that does not require a physician.
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http://dx.doi.org/10.1109/TBME.2018.2814597DOI Listing
December 2018

Single-Nucleotide Polymorphisms in IL23R-IL12RB2 (rs1495965) Are Highly Prevalent in Patients with Behcet's Uveitis and Vary Between Populations.

Ocul Immunol Inflamm 2019 24;27(5):766-773. Epub 2018 May 24.

b Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv , Israel.

: To test the frequency of single-nucleotide polymorphisms in the genes in patients with Behcet's uveitis. : Blood samples were collected from 89 Israeli and Turkish patients, and from healthy control subjects of different origins. Genomic DNA was extracted from peripheral blood leukocytes and genotyped. : The risk allele, A, in rs1800871, of gene was highly prevalent in Behcet's uveitis and healthy control samples alike; highest among the Turkish groups. Prevalence of G allele, in rs1495965, in the gene was high in Behcet's uveitis patients, and among healthy Turkish and Israelis of Middle Eastern origin, while lower among the other Israeli control group (77.9%, 78.9%, 27.8%, respectively, < 0.001). : Our findings highlight the differences between populations and may account for the increased prevalence of the disease among Turkish and Israelis of Middle Eastern origin. Further studies are required to map other healthy and affected populations.
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http://dx.doi.org/10.1080/09273948.2018.1467463DOI Listing
January 2020

MicroRNA-mRNA expression profiles associated with medulloblastoma subgroup 4.

Cancer Manag Res 2018 16;10:339-352. Epub 2018 Feb 16.

Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel.

Purpose: Medulloblastoma (MB), the most common malignant brain tumor in children, is divided into four tumor subgroups: wingless-type (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Ideally, clinical practice and treatment design should be subgroup specific. While WNT and SHH subgroups have well-defined biomarkers, distinguishing Group 3 from Group 4 is not straightforward. MicroRNAs (miRNAs), which regulate posttranscriptional gene expression, are involved in MB tumorigenesis. However, the miRNA-messenger RNA (mRNA) regulatory network in MB is far from being fully understood. Our aims were to investigate miRNA expression regulation in MB subgroups, to assess miRNA target relationships, and to identify miRNAs that can distinguish Group 3 from Group 4.

Patients And Methods: With these aims, integrated transcriptome mRNA and miRNA expression analysis was performed on primary tumor samples collected from 18 children with MB, using miRNA sequencing (miRNA-seq), RNA sequencing (RNA-seq), and quantitative PCR.

Results: Of all the expressed miRNAs, 19 appeared to be significantly differentially expressed (DE) between Group 4 and non-Group 4 subgroups (false discovery rate [FDR] <0.05), including 10 miRNAs, which, for the first time, are reported to be in conjunction with MB. RNA-seq analysis identified 165 genes that were DE between Group 4 and the other subgroups (FDR <0.05), among which seven are predicted targets of five DE miRNAs and exhibit inverse expression pattern.

Conclusion: This study identified miRNA molecules that may be involved in Group 4 etiology, in general, and can distinguish between Group 3 and Group 4, in particular. In addition, understanding the involvement of miRNAs and their targets in MB may improve diagnosis and advance the development of targeted treatment for MB.
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http://dx.doi.org/10.2147/CMAR.S156709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818864PMC
February 2018

Long-term follow-up of benign positional vertical opsoclonus in infants: retrospective cohort.

Br J Ophthalmol 2018 06 13;102(6):757-760. Epub 2017 Sep 13.

Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel.

Background/aims: Benign positional vertical opsoclonus in infants, also described as paroxysmal tonic downgaze, is an unsettling phenomenon that leads to extensive work-up, although benign course has been reported in sporadic cases. We describe long-term follow-up of a series of infants with the phenomenon.

Methods: This retrospective cohort included all infants diagnosed with rapid downgaze eye movement in 2012-2015 and followed until 2016. The databases of two medical centres were retrospectively reviewed. Benign positional vertical opsoclonus was diagnosed based on clinical findings of experienced neuro-ophthalmologists. Data were collected on demographics, symptoms and signs, neuro-ophthalmological and neurological evaluations, and outcome. Imaging studies were reviewed. Main outcome measures were long-term outcome and findings of the thorough investigation.

Results: The cohort included six infants. All infants were born at term. Age at presentation was several days to 12 weeks. Episodes lasted a few seconds and varied in frequency from <10 to dozens per day. In five infants, symptoms occurred in the supine position. There was a wide variability in the work-up without any pathological findings. Follow-up ranged from 1 to 2.5 years. Ocular symptoms gradually decreased until resolution. Infants reached normal developmental milestones.

Conclusions: Our identification of six patients in only 3 years suggests benign positional vertical opsoclonus may be more prevalent than previously described. In our experience, it affects otherwise healthy infants and resolves spontaneously. In view of the good long-term outcome, a comprehensive clinical investigation may not be necessary.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310893DOI Listing
June 2018

Fluorescence Lifetime Imaging Microscopy, a Novel Diagnostic Tool for Metastatic Cell Detection in the Cerebrospinal Fluid of Children with Medulloblastoma.

Sci Rep 2017 06 16;7(1):3648. Epub 2017 Jun 16.

The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Beilinson Hospital, Petach Tikva 4941492, affiliated to Tel Aviv University, Tel Aviv, 6997801, Israel.

In pediatric brain tumours, dissemination of malignant cells within the central nervous system confers poor prognosis and determines treatment intensity, but is often undetectable by imaging or cytology. This study describes the use of fluorescence lifetime (FLT) imaging microscopy (FLIM), a novel diagnostic tool, for detection of metastatic spread. The study group included 15 children with medulloblastoma and 2 with atypical teratoid/rhabdoid tumour. Cells extracted from the tumour and the cerebrospinal fluid (CSF) 2 weeks postoperatively and repeatedly during chemo/radiotherapy were subjected to nuclear staining followed by FLT measurement and cytological study. Control CSF samples were collected from patients with infectious/inflammatory disease attending the same hospital. Median FLT was prolonged in tumour cells (4.27 ± 0.28 ns; P < 2.2*10) and CSF metastatic cells obtained before chemo/radiotherapy (6.28 ± 0.22 ns; P < 2.2*10); normal in inflammatory control cells (2.6 ± 0.04 ns) and cells from children without metastasis before chemo/radiotherapy (2.62 ± 0.23 ns; P = 0.858) and following treatment (2.62 ± 0.21 ns; P = 0.053); and short in CSF metastatic cells obtained after chemo/radiotherapy (2.40 ± 0.2 ns; P < 2.2*10). FLIM is a simple test that can potentially identify CSF spread of brain tumours. FLT changes in accordance with treatment, with significant prolonged median values in tumours and metastases. More accurate detection of metastatic cells may guide personalised treatment and improve the therapeutic outcome.
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http://dx.doi.org/10.1038/s41598-017-03892-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473849PMC
June 2017

The promise of stem cell-based therapeutics in ophthalmology.

Neural Regen Res 2017 Feb;12(2):173-180

The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel.

The promising role of cellular therapies in the preservation and restoration of visual function has prompted intensive efforts to characterize embryonic, adult, and induced pluripotent stem cells for regenerative purposes. Three main approaches to the use of stem cells have been described: sustained drug delivery, immunomodulation, and differentiation into various ocular structures. Studies of the differentiation capacity of all three types of stem cells into epithelial, neural, glial and vascular phenotypes have reached proof-of-concept in culture, but the correction of vision is still in the early developmental stages, and the requirements for effective implementation are still unclear. We present an overview of some of the preclinical findings on stem-cell rescue and regeneration of the cornea and retina in acute injury and degenerative disorders.
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http://dx.doi.org/10.4103/1673-5374.200793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361491PMC
February 2017

Comparison of Neuroprotective Effect of Bevacizumab and Sildenafil following Induction of Stroke in a Mouse Model.

Biomed Res Int 2016 29;2016:3938523. Epub 2016 May 29.

Department of Neurosurgery, Rabin Medical Center-Beilinson Hospital, 49100 Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel.

To evaluate the effect of bevacizumab and sildenafil on stroke parameters in a mouse model, middle cerebral artery occlusion was induced in male C57Bl/6 mice using an intra-arterial filament method. The filament was removed after 60 minutes, and the mice were immediately given a single intraperitoneal injection of saline, bevacizumab, or sildenafil. An additional group of mice (n = 7) received bevacizumab 6 h after MCAO induction. The mice were euthanized 24 hours later and evaluated for infarct area and brain edema using triphenyltetrazolium chloride staining and ImageJ. In the saline-treated mice (n = 16), total stroke volume was 19.20 ± 6.38 mm(3), mean penumbra area was 4.5 ± 2.03 mm(3), and hemispheric asymmetry was 106.5%. Corresponding values in the bevacizumab group (n = 19) were 17.79 ± 5.80 mm(3), 7.3 ± 3.5 mm(3), and 108.6%; in the delayed (6 h) bevacizumab injected mice (n = 7) they were 9.80 ± 8.00 mm(3), 2.4 ± 2.0 mm(3), and 98.2%; and in the sildenafil group (n = 16) they were 18.42 ± 5.41 mm(3), 5.7 ± 2.02 mm(3), and 109.9%. The bevacizumab group had a significantly larger mean penumbra area when given immediately and smaller total stroke area in both groups than the saline- (p = 0.03) and sildenafil-treated (p = 0.003) groups. Only delayed bevacizumab group had reduced edema. Bevacizumab, injected immediately or delayed after injury, exerts a neuroprotective/salvage effect, whereas immediate treatment with sildenafil does not. Inflammation may play a role in the neuroprotective effect.
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http://dx.doi.org/10.1155/2016/3938523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903133PMC
February 2017

Exome sequencing identified a novel de novo OPA1 mutation in a consanguineous family presenting with optic atrophy.

Genet Res (Camb) 2016 06 6;98:e10. Epub 2016 Jun 6.

Sackler School of Medicine,Tel Aviv University,Israel.

Inherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Leber's hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in the OPA1 gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novel de novo OPA1 mutation in the proband. We conclude, that though de novo OPA1 mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations and OPA1 gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent.
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http://dx.doi.org/10.1017/S0016672316000070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865152PMC
June 2016

Gold Nanorods Based Air Scanning Electron Microscopy and Diffusion Reflection Imaging for Mapping Tumor Margins in Squamous Cell Carcinoma.

ACS Nano 2016 Feb 20;10(2):2349-56. Epub 2016 Jan 20.

Department of Oral Pathology and Oral Medicine, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University , Tel Aviv 6423906, Israel.

A critical challenge arising during a surgical procedure for tumor removal is the determination of tumor margins. Gold nanorods (GNRs) conjugated to epidermal growth factor receptors (EGFR) (GNRs-EGFR) have long been used in the detection of cancerous cells as the expression of EGFR dramatically increases once the tissue becomes cancerous. Optical techniques for the identification of these GNRs-EGFR in tumor are intensively developed based on the unique scattering and absorption properties of the GNRs. In this study, we investigate the distribution of the GNRs in tissue sections presenting squamous cell carcinoma (SCC) to evaluate the SCC margins. Air scanning electron microscopy (airSEM), a novel, high resolution microscopy is used, enabling to localize and actually visualize nanoparticles on the tissue. The airSEM pictures presented a gradient of GNRs from the tumor to normal epithelium, spread in an area of 1 mm, suggesting tumor margins of 1 mm. Diffusion reflection (DR) measurements, performed in a resolution of 1 mm, of human oral SCC have shown a clear difference between the DR profiles of the healthy epithelium and the tumor itself.
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http://dx.doi.org/10.1021/acsnano.5b07114DOI Listing
February 2016

Difficulty in Distinguishing Posterior Reversible Encephalopathy Syndrome, Hypoxic-Ischemic Insult, and Acute Toxic Leukoencephalopathy in Children.

Neuropediatrics 2016 Jan 8;47(1):33-8. Epub 2015 Dec 8.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Aim: This study aims to describe our experience of unique pediatric neurological cases and associated difficulty in differentiating posterior reversible encephalopathy syndrome (PRES) from hypoxic-ischemic insult (HII), and acute toxic leukoencephalopathy (ATL).

Methods: The study included three children with a clinical picture suggestive of PRES, HII, and ATL of different etiologies who were diagnosed and treated at a tertiary pediatric medical center in 2011 to 2014.

Results: All patients presented with blindness following seizures with asphyxia/aspiration in a syndromatic child, too-rapid lipid infusion in a child with acute lymphoblastic leukemia, and repeated vomiting in a child with cerebral palsy, hydrocephalus, and malfunction of ventriculoperitoneal shunt. All patients had cortical blindness and high-signal foci in the cortical and subcortical regions on magnetic resonance imaging. All children improved.

Conclusions: Familiarity with the clinical and radiological characteristics of neurological conditions leading to reversible cortical blindness is essential for diagnosis and management. Distinguishing PRES from HII and ATL can be challenging. Our cases most likely combined these etiologies, with the first patient diagnosed with PRES with HII, the second with PRES with ATL, and the third with focal HII. Given the diversity of the findings and the unclear prognostic significance, studies of the pathophysiology of PRES are warranted.
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http://dx.doi.org/10.1055/s-0035-1569154DOI Listing
January 2016

Acquired nystagmus as the initial presenting sign of chiasmal glioma in young children.

Eur J Paediatr Neurol 2015 Nov 9;19(6):694-700. Epub 2015 Jul 9.

Unit of Pediatric Neurosurgery, Schneider Children's Medical Center of Israel, Petach Tikva 49202, Israel.

Background/purpose: The aim of the study was to investigate the incidence of nystagmus at diagnosis in children with optic pathway glioma involving the chiasm and hypothalamus.

Methods: Twenty-two patients with a measurable optic pathway/hypothalamic glioma (without neurofibromatosis-1) were followed in our center from 2001 to 2013. The medical files were retrospectively reviewed for demographic and clinical findings, and the imaging scans, for tumor characteristics.

Results: There were 9 boys and 13 girls of mean age 3.5 ± 4.4 years at diagnosis; 15 were aged <2 years. Tumor size ranged from 10 × 6 mm to 62 × 29 mm. Mean duration of follow-up was 8.3 ± 5.4 years. Nystagmus was detected at diagnosis in 10 children (45%), all <2 years old (66.6% of the younger group); no child older than 2 years presented with nystagmus. Nystagmus, once present, did not resolve and continued throughout follow-up. There were no cases of new onset of nystagmus during follow-up in the children in whom it was not detected at diagnosis. Treatment consisted of partial resection/biopsy with/without shunting (n = 13) and chemotherapy (n = 19) with (n = 2) or without adjuvant radiation. Of the 22 children, 6 had a radiographic response to treatment, 8 remained stable, and 8 (all of whom received chemotherapy) showed disease progression despite treatment.

Conclusion: In conclusion, monocular nystagmus is a more common presenting sign of optic pathway/hypothalamic glioma in children <2 years old than previously estimated. Although subtle, nystagmus has a very narrow differential diagnosis, and its presence should raise suspicions of a chiasmal tumor with prompt referral for imaging. The visual prognosis is moderate to poor.
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http://dx.doi.org/10.1016/j.ejpn.2015.06.007DOI Listing
November 2015
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