S Constantini

Tel Aviv University, Tell Afif, Tel Aviv, Israel

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Publications (91)155.25 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P value<0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (P<0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (P<0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.European Journal of Human Genetics advance online publication, 10 October 2012; doi:10.1038/ejhg.2012.221.
    European journal of human genetics: EJHG 10/2012; · 3.56 Impact Factor
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    ABSTRACT: 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.
    Child s Nervous System 07/2012; 28(10):1679-86. · 1.24 Impact Factor
  • N Pencovich, L Ben-Sira, A Kesler, S Constantini
    Child s Nervous System 03/2012; 28(8):1269-71. · 1.24 Impact Factor
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    ABSTRACT: BACKGROUND: To determine the toxicity and efficacy of rapamycin and erlotinib for the treatment of recurrent pediatric low-grade gliomas (LGGs). METHODS: Patients <21 years of age with recurrent LGGs who had failed conventional treatment were eligible, including those with NF1. The treatment consisted of two phases, a feasibility portion which assessed the toxicity of erlotinib at 65 mg/m(2) /day once daily and rapamycin at 0.8 mg/m(2) /dose twice daily for 28 consecutive days. RESULTS: Nineteen (19) patients, median age of 8 years, with recurrent LGGs received the two-drug regimen. Eight (8) of the patients had NF1. The combination of erlotinib and rapamycin was well tolerated and no patient was removed from study due to toxicity. All 19 patients were evaluable for response and one child, with NF1, had a partial response to treatment. Six (6) patients received the planned 12 courses of treatment. The reasons for stoppage of therapy before 1 year of treatment were poor compliance (1), parental desire for withdrawal (1), persistent vomiting which pre-dated initiation of therapy (1), and radiographic progression (10). In those patients with stabilization of disease for 12 months or greater, 3 stayed on therapy and ultimately developed progressive disease, and one patient stopped therapy at 12 months and progressed. Two (2) patients, both with NF1, have had >1 year disease control. CONCLUSIONS: The combination of rapamycin and erlotinib is well tolerated in children with LGGs. Objective responses were infrequent, although there was prolonged disease stabilization in some patients with LGGs, especially in two children with NF1. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2012; · 2.35 Impact Factor
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    Acta Neurochirurgica 01/2012; 154(4):751-2. · 1.55 Impact Factor
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    ABSTRACT: IIH is a disorder associated with increased intracranial pressure with no clinical, laboratory, or radiologic evidence of an intracranial space-occupying lesion. The aim of this study was to establish ONSD standards of healthy pediatric subjects and compare the normal measurements with those of patients with IIH. One hundred fifteen MR imaging studies of children 4 months to 17 years of age were blinded and reviewed by a pediatric neuroradiologist. A total of 230 optic nerves were measured. Eighty-six MR imaging examinations were performed in apparently healthy subjects. This control group included subjects who underwent MR imaging for various reasons, and their MR imaging findings were interpreted as normal. Twenty-nine MR imaging examinations were performed in patients with documented IIH. The ONSD was measured 1 cm anterior to the optic foramina on an axial T2 sequence. For statistical analysis, both patients and controls were stratified into 4 age groups (I, 0-3 years; II, 3-6 years; III, 6-12 years; IV, 12-18 years). The mean ONSD of the control group in all age groups (I, 3.1 mm; II, 3.41 mm; III, 3.55 mm; IV, 3.56 mm) was significantly smaller than the mean ONSD of patients (I, 4.35 mm; II, 4.37 mm; III, 4.25 mm; IV, 4.69 mm). A positive correlation between age and ONSD (r = 0.414, P < .01) was found in the control group. According to our study, in pediatric patients with IIH, the ONSD is significantly larger than that in healthy controls regardless of age group and sex. This measurement might prove to be an auxiliary tool in the diagnosis of increased intracranial pressure in pediatric patients.
    American Journal of Neuroradiology 11/2011; 33(2):366-9. · 3.17 Impact Factor
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    ABSTRACT: This paper presents an automatic method for the segmentation, internal classification and follow-up of optic pathway gliomas (OPGs) from multi-sequence MRI datasets. Our method starts with the automatic localization of the OPG and its core with an anatomical atlas followed by a binary voxel classification with a probabilistic tissue model whose parameters are estimated from the MR images. The method effectively incorporates prior location, tissue characteristics, and intensity information for the delineation of the OPG boundaries in a consistent and repeatable manner. Internal classification of the segmented OPG volume is then obtained with a robust method that overcomes grey-level differences between learning and testing datasets. Experimental results on 25 datasets yield a mean surface distance error of 0.73 mm as compared to manual segmentation by experienced radiologists. Our method exhibits reliable performance in OPG growth follow-up MR studies, which are crucial for monitoring disease progression. To the best of our knowledge, this is the first method that addresses automatic segmentation, internal classification, and follow-up of OPG.
    Medical image analysis 07/2011; 16(1):177-88. · 3.09 Impact Factor
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    ABSTRACT: Plexiform Neurofibroma (PN) is a major complication of NeuroFibromatosis-1 (NF1), a common genetic disease that involving the nervous system. PNs are peripheral nerve sheath tumors extending along the length of the nerve in various parts of the body. Treatment decision is based on tumor volume assessment using MRI, which is currently time consuming and error prone, with limited semi-automatic segmentation support. We present in this paper a new method for the segmentation and tumor mass quantification of PN from STIR MRI scans. The method starts with a user-based delineation of the tumor area in a single slice and automatically detects the PN lesions in the entire image based on the tumor connectivity. Experimental results on seven datasets yield a mean volume overlap difference of 25% as compared to manual segmentation by expert radiologist with a mean computation and interaction time of 12 minutes vs. over an hour for manual annotation. Since the user interaction in the segmentation process is minimal, our method has the potential to successfully become part of the clinical workflow.
    Proc SPIE 03/2011;
  • Childs Nerv Syst. 01/2011; Mar 27:429-38.
  • Michal Yalon, L Ben-Sira, S Constantini, A Toren
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    ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes and characterized by slow-growing tumors in multiple organs. Of the affected individuals, 10% display subependymal giant cell astrocytomas (SEGAs), which can lead to substantial neurological morbidity. The TSC1/TSC2 protein complex is a negative regulator of the mTOR pathway. Hence, mutations in these genes in preclinical models are associated with increased mTOR pathway activation and heightened sensitivity to mTOR inhibitors. We hereby report our experience with RAD001 (Everolimus) therapy, a novel mTOR inhibitor, in inducing a dramatic regression of SEGAs. A patient with TSC and SEGAs was treated with 10 mg/day oral RAD001. MRIs and neuro-ophthalmological exams were performed before and at regular intervals following the initiation of therapy. The lesions exhibited significant regression in several tumor locations and stabilization in others, accompanied with an improvement of his visual status. Treatment was well tolerated for 11 months but was than discontinued due to hypertension and elevated CPK, without evidence for rhabdomyolysis. Yet, during 9 months following the interruption of therapy, SEGAs remained unchanged. Oral RAD001 demonstrated preliminary encouraging results as treatment of astrocytomas associated with TSC. These preliminary results were recently supported by the Novartis announcement of the phase II study of RAD001 for SEGAs, which was not published yet. According to their statement, 75% of the patients showed reduction of SEGAs' volume following treatment with RAD001. Based on these results, RAD001 may be an alternative to surgery in selected patients with TSC and SEGAs.
    Child s Nervous System 01/2011; 27(1):179-81. · 1.24 Impact Factor
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    ABSTRACT: The objective of this manuscript is to discuss current management strategies regarding pediatric patients with intramedullary spinal cord ependymomas. Spinal ependymoma is the second most common spinal cord tumor in children. The clinical evaluation of these patients, operative techniques, postoperative management considerations, and long-term outcomes are discussed. The gold standard for the treatment of spinal ependymoma continues to be gross total resection. Patients with residual tumor postoperatively may benefit from adjuvant radiation therapy. Intraoperative monitoring is critical to minimize permanent postoperative neurologic deficit. Patients requiring multilevel laminectomy may benefit from concomitant laminoplasty or instrumented fusion to avoid progressive spinal column deformity.
    Child s Nervous System 05/2009; 25(10):1253-9. · 1.24 Impact Factor
  • Matthew J McGirt, Shlomi Constantini, George I Jallo
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    ABSTRACT: Postoperative progressive spinal deformity often complicates functional outcome after resection of pediatric intramedullary spinal cord tumors (IMSCTs). The authors propose a preoperative grading scale that correlates with the postoperative development of progressive spinal deformity requiring subsequent fusion. The data obtained in 164 patients who underwent resection of an IMSCT at a single institution were retrospectively collected and analyzed to determine the development of progressive spinal deformity requiring fusion. A grading scale (range of scores I-V) was created based on the presence or absence of 4 preoperative variables: preoperative scoliosis, involvement of the thorocolumbar junction, age<13 years, and number of surgeries for an IMSCT. The grading scale was then retrospectively applied to this series of 164 children to assess the correlation of variables with subsequent spinal deformity. Nine patients presented with Grade I status, 41 patients with Grade II, 58 patients with Grade III, 44 patients with Grade IV, and 12 patients with Grade V. Overall, 44 patients (27%) developed progressive spinal deformity requiring fusion at a mean follow-up of 5 years after surgery. A higher preoperative grade was associated with an increasing need for subsequent fusion for progressive spinal deformity (Grade I [0%], Grade II [5%], Grade III [26%], Grade IV [40%], and Grade V status [75%]). Application of this grading scheme to a series of resected pediatric IMSCTs has demonstrated its correlation with the incidence of postoperative progressive spinal deformity requiring fusion. The application of a standardized grading scheme will assist in the process of surgical decision making and postoperative evaluation.
    Journal of Neurosurgery Pediatrics 10/2008; 2(4):277-81. · 1.63 Impact Factor
  • J Roth, S Constantini, D T Blumenthal, Z Ram
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    ABSTRACT: Patients with an advanced-stage glioblastoma multiforme (GBM) often show general motor, gait, and cognitive deterioration. Some have radiological evidence of ventriculomegaly, but the relevance of this to their symptoms may be unclear. Distinction between tumour patients who have dilated fluid spaces as a consequence of tissue loss from surgery or treatment, and those who have a symptomatic hydrocephalic process, one who may gain benefit from insertion of a ventriculo-peritoneal shunt, is an important clinical challenge. From a series of 530 GBM patients treated by a single surgeon (ZR), we retrospectively reviewed 16 patients with advanced-stage GBM who had presented with non-obstructive ventriculomegaly and clinical deterioration not explained by progressive disease. Each had been treated by insertion of a ventriculo- peritoneal shunt (VPS). Assessments included clinical features, Karnofsky Performance Scale, motor and cognitive findings, complications and survival. Ten patients benefited from insertion of the shunt, with moderate to significant cognitive improvement. Of seven patients who presented with motor symptoms, such as gait instability, general weakness, and slowness, four patients showed significant motor improvement in addition to major cognitive improvement. Early infectious complication occurred in five patients; a late shunt infection in one; one patient had symptoms related to overdrainage; and in another a mechanical shunt malfunction occurred. Three patients died from shunt-related complications. Insertion of a ventriculo-peritoneal shunt can improve cognitive and motor function in a small subset of patients with advanced-stage glioblastoma multiforme and ventriculomegaly. Infection is a major risk in this patient population.
    Acta Neurochirurgica 02/2008; 150(1):41-6; discussion 46-7. · 1.55 Impact Factor
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    ABSTRACT: Gross-total resection of pediatric intramedullary spinal cord tumors (IMSCTs) can be achieved in the majority of cases, with preservation of long-term neurological function. However, progressive spinal deformity requiring subsequent fusion occurs in many cases. It remains unknown which subgroups of patients have the greatest risk for progressive spinal deformity. Data for 161 patients undergoing resection of IMSCTs at a single institution were retrospectively collected and analyzed with regard to the development of progressive spinal deformity requiring fusion and patient functional status (based on the modified McCormick Scale [mMS] and Karnofsky Performance Scale [KPS]) by conducting telephone interviews corroborated by medical records. The independent association of all clinical, radiographic, and operative variables to subsequent progressive spinal deformity was assessed using multivariate logistic regression analysis. Patients were a mean of 8.6 +/- 5.7 years old at the time of surgery. The tumor spanned a mean of six +/- three spinal levels. Preoperative scoliotic deformity was present in 56 cases (35%). Seventy-six patients (47%) had undergone a previous biopsy procedure, and 28 (17%) a prior resection. Gross-total resection (> 95%) was achieved in 122 cases (76%). A median of 9 years (range 1-21) after surgery, progressive spinal deformity requiring fusion developed in 43 patients (27%). The median functional scores at the last follow-up were worse in patients who required fusion compared with those who did not (mMS: 3 compared with 2, p = 0.006; KPS: 80 compared with 90, p = 0.04) despite similar mMS scores between the groups at 3 months postoperatively. An age less than 13 years, preoperative scoliotic deformity (Cobb angle > 10 degrees), involvement of the thoracolumbar junction, and tumor-associated syrinx independently increased the odds of a postoperative progressive deformity requiring fusion 4.4-, 3.2-, 2.6-, and 3.4-fold, respectively (p < 0.05). Each subsequent resection increased the odds of a progressive deformity 1.8-fold (p < 0.05). Symptoms lasting less than 1 month before resection decreased the odds of spinal deformity requiring fusion ninefold (p < 0.05). Progressive spinal deformity requiring fusion occurred in 27% of children undergoing resection of an IMSCT and was associated with a decreased functional status. Preoperative scoliotic deformity, an increasing number of resections, an age less than 13 years, tumor-associated syrinx, and surgery spanning the thoracolumbar junction increased the risk for progressive spinal deformity. Patients possessing one or more of these characteristics should be monitored closely for progressive spinal deformity following surgery.
    Journal of Neurosurgery 01/2008; 107(6 Suppl):463-8. · 3.15 Impact Factor
  • N Biyani, A Silbiger, J Ben-Ari, S Constantini
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    ABSTRACT: The incidence of pneumocephalus after supratentorial craniotomy has been reported to be as high as 100%. However, transformation of postoperative pneumocephalus into tension pneumocephalus (symptomatic intracranial air) is a rather rare phenomenon. Tension pneumocephalus after posterior fossa surgery is reported mainly when the surgery is performed in a sitting position. We hereby report on a patient who developed brain-stem tension pneumocephalus in the early postoperative period after posterior fossa craniotomy for an exophytic brainstem astrocytoma, operated in the prone position. A complete locked-in syndrome resolved following surgical relief of the trapped air.
    Pediatric Neurosurgery 02/2007; 43(5):414-7. · 0.42 Impact Factor
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    ABSTRACT: The optimal antibiotic prophylaxis for pediatric shunt-related procedures is not clear. There is much inconsistency among different medical centers. This paper summarizes and analyzes the various prophylactic antibiotic regiments used for shunt-related surgeries at different pediatric neurosurgery centers in the world. A survey questionnaire was distributed through the Pediatric Neurosurgery list-server (an e-mail-based special interest group in pediatric neurosurgery). Forty-five completed questionnaires were received, one per medical center, primarily from pediatric neurosurgeons with the following geographic breakdown: 25 from North America, 13 from Europe, and 7 from Asia and other countries. All centers routinely administered prophylactic antibiotics for shunt-related procedures. The drugs of choice were first-generation cephalosporins (23), second-generation cephalosporins (10), naficillin/oxacillin (4), vancomycin (3), clindamycin (1), amoxicillin (1), and mixed protocols in three centers. The initial drug administration ("first dose") was: in the department before transfer to operating room (5), upon arrival to operating room (11), at induction of anesthesia (13), and at initial skin incision (16). The duration of antibiotic dosage also varied: single dose (13), 24-h administration (26), 48-h administration (2), and longer than 48 h in four centers. Two general tendencies were noted, common to the majority of participating centers. There was a general trend to modify antibiotic treatment protocol in "high-risk" populations. The second common theme noted in more than half of responding centers was the use of long-term antibiotic treatment for externalized devices (such as externalized shunts, external ventricular drains or lumbar drains), usually till the device was in place.
    Child s Nervous System 12/2006; 22(11):1465-71. · 1.24 Impact Factor
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    ABSTRACT: Diffusion tensor imaging (DTI) is an MR imaging-based technique that provides an in vivo tool for visualization of white matter tracts. In this preliminary study, we used this technique to investigate the diffusion characteristics of white matter tracts in patients with hydrocephalus before and after surgery and compared them with age-matched volunteers. Seven patients with different types of acute hydrocephalus (defined by acute clinical signs of increased intracranial pressure and imaging evidence of enlarged ventricles) underwent MR imaging including a DTI protocol before and after surgery for shunt placement/revision or ventriculostomy. Eight age-matched healthy subjects served as a control group. The DTI was acquired in a clinical setting that included 6 gradient directions with a b value of 1000 s/mm(2). Before surgery, in fiber systems lateral to the ventricles (corona radiata), the diffusion parallel to the fibers was increased (+10%) and the diffusion perpendicular to the fibers was decreased (-25%) in all patients, resulting in an overall increase in the fractional diffusion anisotropy (FA, +28%). Following surgery, the FA values approached those of control values in all except 1 patient. In the corpus callosum, the presurgery FA values in patients with hydrocephalus (HCP) were lower than those of control values, and no significant changes were seen following surgery. DTI can distinguish the compression characteristics of white matter before and after surgery in patients with HCP. At the acute stage of the disease, DTI characteristics point to white matter compression as a possible cause of the observed changes.
    American Journal of Neuroradiology 10/2006; 27(8):1717-24. · 3.17 Impact Factor
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    S Sgouros, A V Kulkharni, S Constantini
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    ABSTRACT: During the recent meetings of the International Study Group on Neuroendoscopy and the International Society for Pediatric Neurosurgery, the consensus view emerged that there is a need to assess the value and efficacy of neuroendoscopic procedures against shunting in a scientific manner, to resolve long-lasting debates on the subject. A prospective randomized, controlled trial of endoscopic third ventriculostomy vs shunting in children presenting under the age of 2 years with pure aqueduct stenosis is been proposed and organized (the International Infant Hydrocephalus Study, IIHS). The participating surgeons must adhere to the philosophy of randomization and be suitably experienced in endoscopic techniques in infants. The primary outcome of the trial will be the overall health-related quality of life of these children at 5 years of age. Hence, the study is focusing on the effect of surgery on neurodevelopment, rather than the less important issue of shunt or stoma survival, that has been debated extensively with no conclusion so far. Intention-to-treat analysis will be performed according to the first surgery. Secondary outcomes such as complication and reoperation rate, total hospitalization time and cost, need for repeat imaging, and others will be analyzed as well. Pure aqueduct stenosis is relatively rare, making recruitment problematic, but has been chosen to avoid other confounding factors that could influence outcome. More than 25 centers worldwide have committed already to patient recruitment to the study. It is anticipated that recruitment will last for 2 years, aiming for 91 patients per arm. The study has started recruiting patients already in some countries. It is hoped that the trial will not only provide answers to unsettled debates on the value of neuroendoscopy but also create a network of collaborating pediatric neurosurgeons for future initiatives.
    Child s Nervous System 05/2006; 22(4):338-45. · 1.24 Impact Factor
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    B Sade, L Beni-Adani, L Ben-Sira, S Constantini
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    ABSTRACT: The association of spinal dysraphism and terminal syringomyelia is a well-known entity, and untethering with or without syrinx drainage is usually the surgery of choice. However, progression of the previously existing syrinx after an untethering procedure is an uncommon course. The objective of this study was to discuss the diagnostic, surgical, and follow-up consequences of such an occurrence. Four children with occult spina bifida associated with terminal syrinx at the time of initial presentation are included in this study. After the primary releasing procedure, all developed enlargement of the syrinx. Two of them were operated on for placement of a syringo-subarachnoid shunt, while the other two were followed up conservatively. One of the shunted patients also had a second releasing procedure. Progression of the pre-existing terminal syrinx after the primary untethering procedure should be kept in mind even in the absence of overt neurological progression.
    Child s Nervous System 03/2003; 19(2):106-8. · 1.24 Impact Factor
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    01/2003;

Publication Stats

1k Citations
155.25 Total Impact Points

Institutions

  • 2001–2012
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 1993–2012
    • Tel Aviv Sourasky Medical Center
      • • Neurosurgery (Pediatrics)
      • • Division of Internal Medicine
      Tel Aviv, Tel Aviv, Israel
  • 2009
    • Johns Hopkins University
      • Department of Neurosurgery
      Baltimore, MD, United States
  • 2008
    • Johns Hopkins Medicine
      • Department of Neurosurgery
      Baltimore, MD, United States
    • Tufts Medical Center
      • Department of Neurosurgery
      Boston, MA, United States
  • 2006
    • Birmingham Children's Hospital NHS Foundation Trust
      Birmingham, England, United Kingdom
  • 1986–2002
    • Hadassah Medical Center
      • • Department of Neurology
      • • Department of Neurosurgery
      Jerusalem, Jerusalem District, Israel
  • 2000
    • Beth Israel Medical Center
      New York City, New York, United States
    • Ben-Gurion University of the Negev
      • Faculty of Health Sciences
      Beersheba, Southern District, Israel
  • 1995–1997
    • Michigan State University
      • Department of Pediatrics
      East Lansing, MI, United States
    • NYU Langone Medical Center
      • Division of Pediatric Surgery
      New York City, NY, United States
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
  • 1994–1997
    • State University of New York Downstate Medical Center
      • Department of Neurosurgery
      Brooklyn, NY, United States