Shalom Michowiz

High incidence of meningioma in cranial irradiated survivors of childhood acute lymphoblastic leukemia

Most survivors of childhood acute lymphoblastic leukemia (ALL) and T‐cell lymphoma (T‐NHL) treated before 1990 received cranial radiation. This study assessed the occurrence of second tumors in irradiated and non‐irradiated survivors.

Task Switching After Cerebellar Damage

The authors of this study investigated task switching following cerebellar damage. The study group consisted of 7 children and adolescents (M age=13.8 years) who underwent surgical removal of a benign posterior fossa tumor. They were tested at a sufficient interval after surgery (M lag=6.13 years) for restoration of normal cognitive skills and intelligence. Although all showed normal learning of the task compared with control participants, when rapid behavioral changes were required (short preparation time), they exhibited behavioral rigidity manifested by enhanced switching cost. These results are in line with another study on serial reaction time with the same patients (A. Berger et al., in press). They have important implications for our understanding of the cognitive sequelae of early cerebellar damage as well as the involvement of the cerebellum in task switching.

Spinal anesthesia in infants with ventriculoperitoneal shunt: report of five cases and review of literature

We describe five cases of children with ventriculoperitoneal shunt who underwent abdominal and perineal procedures under spinal anesthesia. Four of them had been born prematurely, and all had suffered from severe neonatal complications. All of our patients suffered from severe respiratory impairment, that had required mechanical ventilation, and three of them suffered additionally from apnea of prematurity. Four patients had ventriculoperitoneal shunt inserted because of obstructive hydrocephalus and one because of congenital central nervous system anomalies. Two underwent subsequently shunt revision. The benefits of spinal anesthesia in this high‐risk population are described. The risks of spinal anesthesia in the presence of a ventricular shunt device, especially infection and dural leakage, are discussed, and the literature about this topic briefly reviewed.

Motor and non-motor sequence learning in children and adolescents with cerebellar damage

Cerebellar involvement in motor and non-motor sequence learning was examined with serial reaction time tasks (SRT). Our sample consisted of 8 children and adolescents who had undergone surgical removal of a benign posterior fossa tumor (PFT) during childhood. None of them had undergone chemotherapy or cranial radiation therapy (CRT). Ages ranged from 1-11 years at surgery and 9-17 years at testing. The children were tested not earlier than 2.5 years after surgery (M = 5.9 years), enabling brain plasticity and recovery of functions. Their performance was compared with a matched control sample. The PFT group was not impaired in the implicit learning of sequences, as reflected in their performance in blocks with a repeated sequence, both before and after a random block. However, in the perceptual task, their performance deteriorated more than that of the control group when a random block was introduced, suggesting that it was more difficult for the patients to respond flexibly or change their response set when encountering changing task demands. These results are in line with another study by our group on task switching with the same patients.

Retinal NFL thinning on OCT correlates with visual field loss in pediatric craniopharyngioma.

OBJECTIVE To investigate the use of peripapillary optical coherence tomography for monitoring optic neuropathy in pediatric craniopharyngioma. DESIGN Retrospective, consecutive-cohort, single-centre chart analysis. PARTICIPANTS Twenty children with craniopharyngioma treated at a pediatric medical centre from 1999 to 2011. METHODS The medical files were reviewed for demographics and optic nerve function. Findings for visual acuity and visual fields were analyzed against repeated optical coherence tomography (OCT) measurements of peripapillary nerve fibre layer thickness (using either time-domain Stratus OCT or spectral-domain Cirrus OCT). RESULTS Average age at diagnosis was 6.5 ± 3.88 years. The most common presenting symptom was headache; only 1 child complained of visual loss. Mean best corrected visual acuity (logMAR) was 0.036 ± 0.06 in the 17 healthy eyes and 1.05 ± 1.45 in the 23 eyes with optic neuropathy. Positive signs included relative afferent pupillary defect (8/20), visual acuity loss (7/20), temporal visual field loss (bilateral 4/15, unilateral 4/15), papilledema (3/20), and unilateral/bilateral optic disc pallor (14/20). RNFL thickness was significantly lower in eyes with optic neuropathy than in healthy eyes (65 ± 22 µm vs 86.2 ± 29 µm; p = 0.000) and correlated with visual acuity (r = -0.43 to -0.17, p = 0.0001) and presence or absence of a visual field defect (mean difference, 26.1 ± 5.8 µm, p = 0.003). Ten children showed no change in RNFL thickness over time (mean 18 ± 14.2 months). CONCLUSIONS A thinner RNFL on ocular coherence tomography is correlated with poorer visual acuity and visual field loss. Ocular coherence tomography may serve as an objective method to quantify axonal loss caused by craniopharyngioma. Further investigation is needed to determine its use for evaluating progressive axonal loss over time.

Preoperative Visual Loss is the Main Cause of Irreversible Poor Vision in Children with a Brain Tumor

The purpose of this study was to characterize the severe postoperative irreversible visual loss induced by optic neuropathy in some children with a brain tumor. The computerized database (2003–2008) of a neuro-ophthalmology service of a major pediatric tertiary center was reviewed for all children with severe irreversible visual loss (counting fingers or less) due to brain-tumor-related optic neuropathy at their last follow-up examination. Data on age, gender, etiology, initial symptoms, and signs, visual acuity before and after surgery and at last examination, neuroimaging findings, and treatment were collected. Of 240 children, 198 were operated. Of those, 10 (5%, 5 boys and 5 girls) met the study criteria. Data for the initial visual examination were available for eight children: one had binocular blindness (uncertain light perception, counting fingers); three had monocular blindness already at diagnosis (no light perception, counting fingers, no fixation); three had 6/60 vision in the worse eye; and one had good vision bilaterally (6/10). Four children had direct optic nerve compression, four papilledema, and three gliomas. Four children (40%; with craniopharyngioma, pineal germinoma, or posterior fossa tumor) exhibited a rapid deterioration in vision after tumor depression (one direct optic nerve compression and three increased intracranial pressure); two had monocular visual loss postoperatively; vision remained stable in four (after ≥5 follow-up visits), but did not improve. This study shows that tumor-related optic neuropathy may be associated with marked visual loss inspite of successful tumor resection; in 40% of children, the deterioration occurs perioperatively. Direct compression is the main cause of visual loss, while papilledema usually resolved without visual sequelae. However, autoregulatory changes may be responsible for rapid visual loss following decompression for chronic papilledema. Clinicians need reminding about the problem of postoperative visual loss and we speculate on how it can be avoided.

Long-Term Ophthalmological Follow-Up of Children with Parinaud Syndrome

BACKGROUND AND OBJECTIVE To assess the long-term ophthalmological outcome of Parinaud syndrome. PATIENTS AND METHODS The files of 6 children with tumor-related Parinaud syndrome diagnosed and observed from 2000 to 2007 were reviewed. All had papilledema indicating increased intracranial pressure. RESULTS Mean presentation-to-diagnosis delay was 3.6 weeks. Treatment consisted of surgical shunting and complete or partial resection with adjuvant chemotherapy (n = 4) and radiation (n = 3). Visual acuity remained stable or improved in 8 of 9 eyes with 20/30 visual acuity at diagnosis; improved bilaterally in 1 patient from 20/100 to 20/25; and deteriorated bilaterally in 1 patient from 20/30 and 20/200 to counting fingers and hand motions, respectively. The most improvement was achieved within 4 months. Findings at follow-up (mean: 4.2 years) included up gaze limitation (minimal in 2 patients), abnormal convergence, convergence retraction nystagmus, and light-near dissociation. One child had bilateral optic atrophy. CONCLUSION Children with tumor-related Parinaud syndrome tend to have subtle but measurable residual ophthalmological findings years after diagnosis and treatment.

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

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 mm3, mean penumbra area was 4.5 ± 2.03 mm3, and hemispheric asymmetry was 106.5%. Corresponding values in the bevacizumab group (n = 19) were 17.79 ± 5.80 mm3, 7.3 ± 3.5 mm3, and 108.6%; in the delayed (6 h) bevacizumab injected mice (n = 7) they were 9.80 ± 8.00 mm3, 2.4 ± 2.0 mm3, and 98.2%; and in the sildenafil group (n = 16) they were 18.42 ± 5.41 mm3, 5.7 ± 2.02 mm3, 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.

BRAF, GNAQ, and GNA11 mutations and copy number in pediatric low‐grade glioma

Fifty‐two samples of pediatric low‐grade glioma (48 primary, 4 recurrent) were analyzed for BRAF copy number variation (digital PCR analysis, CopyCaller) and point mutations of BRAF V600E, and exon 5 Q209 in GNAQ, and GNA11, using the MALDI‐TOF mass spectrometer with validation by direct sequencing. An increased BRAF copy number was found in 18/47 primary samples tested; 15 of them (83.3%) were pilocytic astrocytomas. A BRAF mutation was found in 3/48 primary tumors, all with a normal BRAF copy number and no GNAQ mutation. One sample had a GNAQ209 mutation (Q209P626) with a normal BRAF gene; none of the tumors had a GNA11Q209 mutation. Recurrent or progressive tumors, analyzed in four patients, had the same molecular genotype as their primary. Increased BRAF copy number and activating BRAF mutations may be involved in the development of low‐grade glioma via overactivation of the Ras/Raf pathway. This is the first report of a mutation in GNAQ209 in pediatric low‐grade glioma. Understanding the molecular mechanisms underlying glioma initiation and growth may assist in the development of targeted therapies.

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

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*10−16) and CSF metastatic cells obtained before chemo/radiotherapy (6.28 ± 0.22 ns; P < 2.2*10−16); 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*10−16). 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.