Macular ganglion cell complex thinning in children with visual field defects due to central nervous system pathology.

PURPOSE: To study the relationship between macular ganglion cell complex (GCC) thickness and visual field defects (VFD) caused by central nervous system (CNS) lesions in children and evaluate the possibility of predicting VFD according to GCC maps. METHODS: The GCC maps of a group of children with VFD due to CNS lesions with respect of the vertical meridian in at least one eye (study group), as well as of children with other neuro-ophthalmological problems and healthy children were presented to two masked evaluators, who were asked to predict the patients' VFD on the basis of GCC damage: the evaluators classified VFD as normal, hemianopia (homonymous or heteronymous) or diffuse. RESULTS: Seventeen patients were included in the study group, with a median age of 12 years. Fifteen had brain tumours and two epilepsy. The mean MD of the affected hemifields was -26.00 dB (SD 7.89 dB) versus -5.51 dB (SD 3.52 dB) for the nonaffected hemifields, p < 0.001. The mean GCC thickness was of 56.04 µm (SD 11.95 µm) in the affected hemiretinas versus 74.31 µm (SD 10.64 µm) for the non-affected, p < 0.001. Kappa coefficients between VFD and those estimated by the evaluators were 0.705 and 0.658 (p < 0.001) for evaluators 1 and 2. CONCLUSIONS: GCC thickness can reflect damage to the visual pathway and GCC maps may be useful to identify chiasmal and retrochiasmal lesions, since GCC atrophy in most of these cases respects the vertical meridian. GCC maps might be used as a surrogate marker for visual damage in patients unable to perform perimetry.

[Transformation of myelodysplastic syndrome to acute lymphoblastic leukemia: 2 new cases]. / Transformación de síndrome mielodisplásico a leucemia linfoblástica aguda: 2 casos nuevos.

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells, with a variable risk of transformation to acute myeloid leukemia. Progression into acute lymphoblastic leukemia (ALL) is an extremely rare event, with very few cases published in children. In this report, we describe two cases of myelodysplastic syndromes that progressed to ALL. Moreover, we review previously reported cases of MDS transformation to acute lymphoblastic leukemia in the pediatric population whose prognosis seems to be similar to that for adults.

Experience with coflex interspinous implant.

A first generation of Coflex implant for non-rigid stabilization of lumbar spine was presented by Samani (Study of a semi-rigid interspinous U fixation system. Spinal Surgery, Child Orthopaedics: 1707, 2000).We started to treat patients with this Coflex device in 2004 and since then more than 600 patients have been operated in our Neurosurgical Department. We are reporting 156 patients treated between December 2004 and 2006 with complete follow-up. The clinical trials of this and other implants provide evidence that this interspinous non-rigid stabilization is useful against low-back pain due to degenerative instability and without serious complications.

[Subependymal giant cell astrocytoma in tuberous sclerosis complex. A presentation of eight paediatric patients]. / Astrocitoma subependimario de células gigantes en el complejo de esclerosis tuberosa. Presentación de ocho pacientes infantiles.

OBJECTIVE: Presentation of 8 patients with subependymal giant-cell astrocytomas (SGCA) associated with tuberous sclerosis complex (TSC). MATERIAL AND METHODS: There are 8 patients, 6 males and 2 females with TSC, who presented with the tumour between the neonatal period and 24 years. RESULTS: All patients showed bilateral hypersignalised areas in zones close to the foramen of Monro. Three of the patients were admitted urgently due to blindness and increased intracranial pressure. Incomplete removal of the tumour has always been bad solution as it resulted in the death of the patient (in one case) or further surgery operation in the short term. Only one patient developed the tumour suddenly from pre-existing subependymal nodules from the childhood and they had to be removed at 24 years of age. By contrast, 32 patients with TSC and images of subependymal nodules whose CT or MR progress was followed up for between 10 and 30 years did not develop a tumour. One patient had to be operated four times over 20 years. CONCLUSIONS: SGCA associated with TSC is a severe complication which as likely to develop and careful monitoring is required from neonatal age with periodicclinical and imaging studies in order to avoid its irreversible complications. Hydrocephaly, blindness and even the death can be the main consequences. Reintervention of the recurrent tumour is often necessary.

[Cranial lesions due to forceps delivery]. / Lesiones craneales secundarias a parto asistido con forceps.

Deliveries with forceps or vacuum-extraction increase the incidence of perinatal craneoencephalic lesions, for which reason cesarean sections are performed more frequently. We report 3 cases of cranial lesions due to forceps deliveries, 2 with depressed skull fractures and 1 with a depressed fracture and an associated epidural hematoma. Diagnosis is made on clinical and radiological founds with CT scan or MRI. Treatment is surgical and consists of elevation of the depressed fracture and evacuation of the hematoma. The correct use of forceps is very important to avoid this kind of lesions in the newborn, especially in cases of difficult delivery.

Brain malformations in the sheep model of myelomeningocele are similar to those found in human disease: preliminary report.

PURPOSE: To examine if brain malformations, similar to those which account for cognitive disorders seen in human disease, are present in an ovine model of myelomeningocele (MMC). METHODS: An MMC-like lesion was surgically created in 16 fetal lambs between 60 and 80 days of gestation. Ten did not undergo fetal repair (group A), 2 were repaired with an open two-layer closure (group B), 2 with open bioglue coverage (group C) and 2 with fetoscopic coverage (group D). Lambs were killed and their brains were examined. Two brains from normal unoperated lambs served as controls. RESULTS: Thirteen lambs died in utero (81%). Two lambs in group A and 1 in group B were delivered at term. Group A brains showed hydrocephalus and extensive areas of polymicrogyria. There was also an extensive denudation of the ependymal lining under the polymicrogyric areas and the corpus callosum was thinner than normal. No hindbrain herniation was observed. Brains from group B and the control did not show any of these abnormalities. CONCLUSIONS: Some of the central nervous system abnormalities associated to MMC in human patients are also found in the uncorrected fetal lamb model of MMC but not in the only survivor to intrauterine coverage. Further studies are necessary to ascertain if these abnormalities can be prevented by coverage of the defect.

Thrombolysis and neuroprotection in cerebral ischemia.

Stroke is a major cause of death and disability worldwide. The resulting burden on society grows with the increase in the incidence of stroke. The term brain attack was introduced to describe the acute presentation of stroke and emphasize the need for urgent action to remedy the situation. Though a large number of therapeutic agents, like thrombolytics, NMDA receptor antagonists, calcium channel blockers and antioxidants, have been used or are being evaluated, there is still a large gap between the benefits of these agents and the properties of an ideal drug for stroke. So far, only thrombolysis with rtPA within a 3-hour time window has been shown to improve the outcome of patients with ischemic stroke. Understanding the mechanisms of injury and neuroprotection in these diseases is important to target news sites for treating ischemia. Better evaluation of the drugs and increased similarity between the results of animal experimentation and in the clinical setting requires critical assessment of the selection of animal models and the parameters to be evaluated. Our laboratory has employed a rat embolic stroke model to investigate the combination of rtPA with citicoline as compared to monotherapy alone and investigated whether neuroprotection should be provided before or after thrombolysis in order to achieve a greater reduction of ischemic brain damage.

Cerebral fluid edema: an unusual complication of ventriculoperitoneal shunts.

INTRODUCTION: A case of accumulation of CSF into the brain parenchyma simulating a brain tumor, secondary to an obstructed ventriculoperitoneal shunt, is presented. Until now, only seven cases of this rare complication have been described. CASE REPORT: Magnetic resonance showed an expansive, low-density intracranial lesion on the right frontal and parietal lobe. This mass was biopsied, but no tumor was found and the diagnosis was brain edema. CONCLUSION: The mistake in the diagnosis was due to the clinical symptoms and to the MR images.

[Usefulness of tranexamic acid in cranial remodeling surgery]. / Utilidad del ácido tranexámico en la cirugía de remodelación craneal.

OBJECTIVES: To assess the usefulness of tranexamic acid (TA) in pediatric cranial remodeling surgery, by analyzing its effects on bleeding and transfusion requirements, number of days of cranial drainage required, and time spent in the postoperative recovery unit. MATERIAL AND METHOD: A single-blind, controlled study was designed with 20 patients (10 cases and 10 controls) randomly assigned to receive or not receive 15 mg/kg of intravenous TA upon anesthetic induction, every 4 hours during surgery, and every 8 hours throughout the 48 hours after surgery. Variables analyzed were results of blood tests, blood loss, volume transfused, time in the recovery unit, and complications related to TA infusion. RESULTS: The group treated with TA experienced less bleeding during surgery than did the controls (199 +/- 60 vs 290 +/- 43 mL) and had less need of intraoperative (176 +/- 104 vs 206 +/- 70 mL) and postoperative transfusion (9 +/- 28 vs 52 +/- 72 mL) 24 hours after surgery. TA group patients also spent less time in the recovery unit (60 +/- 14 vs 72 +/- 11 hours). Blood test variables in TA-treated children were also better 24 hours after surgery with regard to hemoglobin (12.1 +/- 2 vs 11.6 +/- 1.3 mg/dL) and platelet (261 +/- 68.5 vs 181.6 +/- 58.1 platelets/mm3) concentrations, and cephalin time (33 +/- 12 vs 49 +/- 16 seconds). No complications related to TA treatment were observed. CONCLUSIONS: TA can reduce perioperative bleeding in the context of pediatric cranial remodeling surgery. TA-treated patients have less need of transfusion and this may reduce the rate of related complications as well a make care more efficient.

Combined nimodipine and citicoline reduce infarct size, attenuate apoptosis and increase bcl-2 expression after focal cerebral ischemia.

Cerebral ischemia triggers a multitude of pathophysiological and biochemical events that separately affect the evolution of focal ischemia and, therefore, stroke treatment should logically employ all known neuroprotective agents. We hypothesized that a treatment combining nimodipine and citicoline might have a potential neuroprotective effect. To assess this idea, Sprague-Dawley rats underwent transient bilateral common carotid artery ligation with simultaneous middle cerebral artery occlusion for 60 min. Four treatment groups were established. Animals received either: a) saline (control group); b) intracarotid nimodipine infusion during 30 min in the ischemia-reperfusion (nimodipine group); c) i.p. postischemic citicoline injections once daily for 7 days (citicoline group); or d) intracarotid nimodipine bolus during ischemia-reperfusion plus i.p. postichemic citicoline injections (combination group). They were killed after either 7 or 3 days after reperfusion. In the first case, the volume of the infarcted tissue was studied by a stereological procedure and in the second case, in situ end-labeling of nuclear DNA fragmentation (TUNEL) and Bcl-2 expression were employed to determine the level of apoptosis. The infarct volume was significantly reduced in both the nimodipine and the citicoline treatment groups after 7 days of reperfusion; combination of both drugs produced an additive effect. After 3 days of reperfusion, the number of Bcl-2-positive neurons was significantly increased while that of TUNEL-positive cells significantly decreased at the infarct border in the combined-treatment animals. Our findings demonstrate a neuroprotective effect from an acute single dose of nimodipine during ischemia-reperfusion and prolonged post-ischemic treatment with citicoline in a model of focal cerebral ischemia. These results suggest that a possible mechanism of neuroprotective action would be mediated by increased Bcl-2 expression and decreased apoptosis within the boundary zone of the infarct together with neutralization of the ischemia-reperfusion injury.

Abolished angiogenicity and tumorigenicity of rat glioma by 1-naphthalenemonosulfonate.

Suramins and suradistas, an important group of potential anti-cancer agents, inhibit fibroblast growth factor (FGF) mitogenic activity. It has been shown that naphthalenesulfonates, with a common chemical function to the family of suramins and suradistas, mimic their inhibitory activity, abolishing FGF-induced angiogenesis in vivo, and inducing apoptosis of C6 glioma cells in culture. In the present report, we show that intratumoral administration of 1-naphthalenemonosulfonate induces a considerable regression of gliomas in rats, significantly enhances apoptosis, and attenuates tumor angiogenesis. These findings may lead to new approaches for the treatment of glioblastoma, a most common primary malignant brain tumor of very poor prognosis, as well as of other angiogenesis-dependent malignancies.

Therapeutic implications of fibroblast growth factors in traumatic spinal cord injury.

Neurological damage after acute traumatic spinal cord injury (SCI) results from both the primary mechanical injury as well as the subsequent activation of cell death cascades mediating delayed tissue damage. Since secondary injury following traumatic SCI is a tightly regulated process in which several neurotrophic factors seem to be implicated, administration of these proteins has a clinical interest. Fibroblast growth factor may be one of the agents to be used for the treatment of traumatic SCI.

Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms.

We undertook a series of systematic studies to address the role of fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) activity in tumor growth and angiogenesis. We expressed dominant-negative FGFR2 (FGFR2-DN) or FGFR1 (FGFR1-DN) in glioma C6 cells by using constitutive or tetracycline-regulated expression systems. Anchorage-dependent or independent growth was inhibited in FGFR-DN-expressing cells. Tumor development after xenografting FGFR-DN-expressing cells in immunodeficient mice or after transplantation in rat brain was strongly inhibited. Quantification of microvessels demonstrated a significant decrease in vessel density in tumors derived from FGFR-DN-expressing cells. Furthermore, in a rabbit corneal assay, the angiogenic response after implantation of FGFR-DN-expressing cells was decreased. In tumors expressing FGFR-DN, vascular endothelial growth factor expression was strongly inhibited as compared with control tumor. These results indicate that inhibition of FGF activity may constitute a dominant therapeutic strategy in the treatment of FGF-producing cerebral malignancies and may disrupt both angiogenesis-dependent and -independent signals required for glioma growth and invasion.

Cerebral ischemia: from animal studies to clinical practice. Should the methods be reviewed?

The development of experimental models of focal cerebral ischemia has allowed for a better knowledge of its pathophysiology and for testing therapeutic strategies. However, most neuroprotective substances giving favorable results in these models have later not been shown to be clinically effective. This could be explained by several reasons. First, the homogeneity obtained in animal models in order to achieve results is not seen in clinical practice in humans, in whom a given pathological condition may show a high variability depending on several parameters. This makes it difficult to achieve groups of patients sufficiently large and homogeneous to obtain valid conclusions in the clinical trials. The lack of agreement between the experimental studies and the clinical practice can also be explained by other reasons, such as the methods of the experimental model itself; by the fact that the methods to assess results in these models are not comparable to those used in clinical practice; by pathophysiological differences between experimental animals and man, and even by the fact that the substances tested have different pharmacological properties in the different species. These disadvantages must not invalidate preclinical neuroprotection studies. Rather, the knowledge of the reasons for divergences with the clinical situation can help to optimize experimental models so that both become actually comparable, and the laboratory results can be confirmed by clinical studies.

Fibroblast growth factors in myocardial ischemia / reperfusion injury and ischemic preconditioning.

Angiogenic growth factors such as fibroblast growth factors (FGFs) are currently in clinical trials for accelerating blood vessel formation in myocardial and limb ischemic conditions. However, recent experimental evidence suggests that FGFs can also participate as endogenous cardioprotective agents. In this report, the current knowledge for FGFs implication in myocardial ischemic tolerance will be summarized. Pharmacologic preconditioning with drugs as FGFs that mimic the beneficial effects of ischemic preconditioning could lead to novel therapeutic approaches for the treatment of ischemic disorders including myocardial infarction and stroke.

Nonhistological diagnosis of human cerebral tumors by 1H magnetic resonance spectroscopy and amino acid analysis.

We describe a multivariate analysis procedure to classify human cerebral tumors nonhistologically in vitro, combining the use of 1H magnetic resonance spectroscopy (MRS) with automatic amino acid analysis of biopsy extracts. Eighty-one biopsies were obtained surgically and classified histologically in eight classes: high-grade astrocytomas (class 1, n = 19), low-grade astrocytomas (class 2, n = 10), normal brain (class 3, n = 9), medulloblastomas (class 4, n = 4), meningiomas (class 5, n = 18), metastases (class 6, n = 8), neurinomas (class 7, n = 9), and oligodendrogliomas (class 8, n = 4). Perchloric acid extracts were prepared from every biopsy and analyzed by high resolution 1H MRS and automatic amino acid analysis by ionic exchange chromatography. Intensities of 27 resonances and ratios of resonances were measured in the 1H MRS spectra, and 17 amino acid concentrations were determined in the chromatograms. Linear discriminant analysis provided the most adequate combination of these variables for binary classifications of a biopsy between any two possible classes and in multiple choice comparisons, involving the eight possible classes considered. Correct diagnosis was obtained when the class selected by the computer matched the histological diagnosis. In binary comparisons, consideration of the amino acid profile increased the percentage of correct classifications, being always higher than 75% and reaching 100% in many cases. In multilateral comparisons, scores were: high-grade astrocytomas, 80%; low-grade astrocytomas, 74%; normal brain, 100%; medulloblastomas, 100%; meningiomas, 94.5%; metastases, 86%; neurinomas, 100%; and oligodendrogliomas, 75%. These results indicate that statistical multivariate procedures, combining 1H MRS and amino acid analysis of tissue extracts, provide a valuable classifier for the nonhistological diagnosis of biopsies from brain tumors in vitro.

Fibroblast growth factor cardioprotection against ischemia-reperfusion injury may involve K+ ATP channels.

We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K+ATP) channel that was implicated in the ischemic preconditioning (I-PC) phenomenon, has a role in the cardioprotective effects of fibroblast growth factors (FGFs). For this purpose, we administered glibenclamide, a specific K+ATP channel blocker, before acidic fibroblast growth factor (aFGF, FGF-1) treatment, in rat heart subjected to left ventricular ischemia for 20 minutes followed by reperfusion for 24 hours. Creatine kinase (CK) activity was analyzed in myocardial tissue to assess the degree of cardiac injury. FGF-1 treatment markedly maintains CK activity. This cardioprotective effect of FGF-1 was blocked by glibenclamide. As shown by ultrastructural data, Ca2+ overload and associated cardiomyocyte alterations shown in glibenclamide-treated rats were not observed in specimens from the FGF-1 group. These findings suggest that FGF serves as an effector in I-PC and support a clinical interest of these proteins for increasing myocardial ischemic tolerance.

Fibroblast growth factor-1 inhibits medial smooth muscle cells apoptosis after balloon injury.

We performed balloon injury in the rat common carotid artery and identified apoptosis of vascular smooth muscle cells (VSMCs) by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, 2 h after injury. Balloon injury induces apoptosis and loss of bcl-X protein in the innermost layers of the media of the common carotid artery. Treatment with acidic fibroblast growth factor (aFGF, FGF-1) attenuated by 56% the balloon angioplasty-induced apoptosis. In addition, FGF-1 treatment also induces expression of the bcl-X anti-apoptotic protein in the same site of the media showing VSMC apoptosis. These data suggest that the anti-apoptotic effect of FGF in injured vascular wall was mediated by a bcl-X pathway and identified FGF as an important factor in vascular remodeling.