GLYOXALASE I A111E, PARAOXONASE 1 Q192R AND L55M POLYMORPHISMS IN ITALIAN PATIENTS WITH SPORADIC CEREBRAL CAVERNOUS MALFORMATIONS: A PILOT STUDY.

It is already known that the conditions of increased oxidative stress are associated to a greater susceptibility to vascular malformations including cerebral cavernous malformations (CCMs). These are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1(Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Polymorphisms in the genes encoding for enzymes involved in the antioxidant systems such as glyoxalase I (GLO I) and paraoxonase I (PON I) could influence individual susceptibility to the vascular malformations. A single nucleotide polymorphism was identified in the exon 4 of GLO 1 gene that causes an amino acid substitution of Ala for Glu (Ala111Glu). Two common polymorphisms have been described in the coding region of PON1, which lead to glutamine → arginine substitution at 192 (Q192R) and a leucine → methionine substitution at 55 (L55M). The polymorphisms were characterized in 59 patients without mutations in the CCM genes versus 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that the frequency of patients carrying the GLO1 A/E genotype among the case group (56%) was four-fold higher than among the controls (14.1%). In the cohort of CCM patients, an increase in the frequency of PON192 Q/R genotype was observed (39% in the CCM group versus 3.7% in the healthy controls). Similarly, an increase was observed in the proportion of individuals with the genotype R/R in the disease group (5%) in respect to the normal healthy cohort (0.5%). Finally, the frequency of the PON55 heterozygotes L/M genotype was 29% in patients with CCMs and 4% in the healthy controls. The same trend was observed in PON55 homozygous M/M genotype frequency (CCMs 20% vs controls 10%). The present study aimed to investigate the possible association of GLO1 A111E, PON1 Q192R and L55M polymorphisms with the risk of CCMs. We found that individuals with the GLO1 A /E genotype, PON192/QR-RR genotypes and PON55/LM-MM genotypes had a significantly higher risk of CCMs compared with the other genotypes. However, because CCM is a heterogeneous disease, other additional factors might be involved in the initiation and progression of CCM disease.

Genealogy of centenarians and their relatives: a study of 12 families.

The longevity is a complex phenomenon in which specific genetic properties seem to play a role. The present study intended to reconstruct the genealogical tree of 12 subjects, being residents of one Northern and one Southern province of Italy, in order to establish the longevity of the ancestors. Detailed studies have been performed in the registry offices and the historic archives. The research method started from the identification of the centenarians on the basis of the documentation of the relevant birth document, it was continued by identifying the documents of birth, marriages and death of the parents of the centenarians. This way we proceeded systematically backwards in time. In addition, we verified the medium life span of the Italian population in the given periods of time, when the centenarians and their ascending lines had lived. These results offer clear historic-statistical evidences for the genetic basis of longevity.

MRI Tractography of Corticospinal Tract and Arcuate Fasciculus in High-Grade Gliomas Performed by Constrained Spherical Deconvolution: Qualitative and Quantitative Analysis.

BACKGROUND AND PURPOSE: MR imaging tractography is increasingly used to perform noninvasive presurgical planning for brain gliomas. Recently, constrained spherical deconvolution tractography was shown to overcome several limitations of commonly used DTI tractography. The purpose of our study was to evaluate WM tract alterations of both the corticospinal tract and arcuate fasciculus in patients with high-grade gliomas, through qualitative and quantitative analysis of probabilistic constrained spherical deconvolution tractography, to perform reliable presurgical planning. MATERIALS AND METHODS: Twenty patients with frontoparietal high-grade gliomas were recruited and evaluated by using a 3T MR imaging scanner with both morphologic and diffusion sequences (60 diffusion directions). We performed probabilistic constrained spherical deconvolution tractography and tract quantification following diffusion tensor parameters: fractional anisotropy; mean diffusivity; linear, planar, and spherical coefficients. RESULTS: In all patients, we obtained tractographic reconstructions of the medial and lateral portions of the corticospinal tract and arcuate fasciculus, both on the glioma-affected and nonaffected sides of the brain. The affected lateral corticospinal tract and the arcuate fasciculus showed decreased fractional anisotropy (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) and linear coefficient (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) along with increased spherical coefficient (z = -2.51, n = 20, P = .006; z = -2.52, n = 20, P = .006). Mean diffusivity values were increased only in the lateral corticospinal tract (z = -2.53, n = 20, P = .006). CONCLUSIONS: In this study, we demonstrated that probabilistic constrained spherical deconvolution can provide essential qualitative and quantitative information in presurgical planning, which was not otherwise achievable with DTI. These findings can have important implications for the surgical approach and postoperative outcome in patients with glioma.

Behavioral deficits following experimental subarachnoid hemorrhage in the rat.

To characterize some of the short-term and long-term functional consequences of subarachnoid hemorrhage (SAH) in rats, we employed a battery of well-characterized tests for assessment of acute and chronic behavioral and neurologic performances. Three groups of 10 rats (blood injected, mock CSF injected and sham-operated controls) were studied. During the acute stage, simple nonpostural somatomotor reflexes (pinna and corneal reflexes), simple postural responses (paw flexion, tail flexion, and head support), startle response, and postural functions (righting reflex) did not differ significantly between the experimental groups. Assessments of body weight, beam walking ability, and beam balancing revealed significant disturbances in blood-injected rats. This work demonstrates that this single-hemorrhage rodent model of SAH is associated with the induction of enduring neurologic and behavioral deficits. Because of the significant interspecies difference, a direct extrapolation of our results to humans may not be appropriate. However, we suggest that the observed behavioral and neurologic changes may parallel those seen in humans after SAH. Results reported here further confirm the rat model of SAH as a viable laboratory instrument for the study of the pathophysiology of SAH and provide normative values for the evaluation of new treatment modalities.

Effect of experimental subarachnoid hemorrhage on CSF eicosanoids in the rat.

A simple and inexpensive experimental model of subarachnoid hemorrhage (SAH) was developed in the rat. Based on accumulating data indicating the important role of arachidonic acid metabolites in the etiology of delayed cerebral vasospasm, we investigated changes induced by SAH on cerebrospinal fluid (CSF) levels of prostaglandin E2 (PGE2), F2 alpha (PGF2 alpha), and thromboxane B2 (TXB2). SAH was produced by the cisternal injection of blood via percutaneous suboccipital puncture. SAH rats (n = 200) were injected with 300 microliters of fresh autologous arterial blood; Control rats (n = 100) received the same volume of mock CSF. In 60 additional animals, no injections were made. To follow the changes induced by SAH on both the spectrum and time course of CSF eicosanoids, cisternal CSF samples were collected under basal conditions, 6, 12, and 36 after cisternal injection. PGE2, PGF2 alpha, and TXB2 were assayed in aliquots of CSF obtained by pooling samples from each experimental group. Eicosanoids were assayed using radioimmunoassay techniques. Arterial spasm was verified in parallel groups of SAH and control rats by comparison of the angiographic diameters of the basilar arteries (BA) and middle cerebral arteries (MCA) to that of the stapedial artery. CSF levels of all three eicosanoids were significantly higher in the SAH groups compared to both noninjected and mock-CSF injected control rats. These increases in concentrations of eicosanoids were accompanied by a decrease in the mean vascular diameter (77.5-82.0% of control) on day 2 following cisternal injection. We conclude that marked elevations of spasmogenic eicosanoids in the CSF are associated with experimental SAH.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage.

Erythropoietin exerts a neuroprotective effect during cerebral ischemia. We investigated the effect of systemic administration of recombinant human erythropoietin in a rabbit model of subarachnoid hemorrhage-induced acute cerebral ischemia. The animals were divided into three groups: group 1, subarachnoid hemorrhage; group 2, subarachnoid hemorrhage plus placebo; group 3, subarachnoid hemorrhage plus recombinant human erythropoietin (each group, n=8). Experimental subarachnoid hemorrhage was produced by injecting autologous blood into the cisterna magna. Treatment with recombinant human erythropoietin and placebo was started 5 min after subarachnoid hemorrhage and was continued every 8 h for 24 h. Before the animals were killed, erythropoietin concentration was measured in the cerebrospinal fluid. The rabbits were killed 24 h after subarachnoid hemorrhage and ischemic brain injury was histologically evaluated. In group 3, the concentration of erythropoietin in the cerebrospinal fluid was significantly increased and a significant reduction in cortical necrotic neuron count was also observed. These findings may encourage the use of erythropoietin in the treatment of cerebral ischemia that often occurs in the early stage of subarachnoid hemorrhage.

In vivo evidence that erythropoietin has a neuroprotective effect during subarachnoid hemorrhage.

To ascertain in vivo whether recombinant human erythropoietin has a neuroprotective effect on the cortex during subarachnoid hemorrhage, 56 rabbits were divided into the following groups: Group 1 control sham operated plus placebo (n=14; saline solution - NaCl 0.9%); Group 2 control sham operated plus recombinant human erythropoietin (n=14); Group 3 subarachnoid hemorrhage plus placebo (n=14); Group 4 subarachnoid hemorrhage plus recombinant human erythropoietin (n=14; intraperitoneal administration of recombinant human erythropoietin immediately after inducing subarachnoid hemorrhage). In none of the Groups 1 and 2 animals was subarachnoid hemorrhage induced. In Group 3 rabbits, an increase in locomotor activity (open field apparatus) was observed 24, 48 and 72 h after surgery, and the mortality rate was 42.9% within 72 h after surgery, and, no increase in locomotor activity was observed in Group 4 rabbits, which survived for at least 72 h. Our findings suggest that recombinant human erythropoietin may be of benefit in the treatment of subarachnoid hemorrhage.

Multiloculated hydrocephalus in infants.

The clinical features and the neuroradiological appearance of multiloculated hydrocephalus that followed meningitis and ventriculitis in five newborn infants are presented. Several factors probably involved in the pathogenesis are discussed. Computed tomography is particularly helpful in the recognition of this entity and in the evaluation of its course. However, ventriculograms are advised to document the communication of the septated cavities. Of four infants treated by ventriculoatrial shunting, two died and two are mentally and neurologically disabled. Another infant, who underwent craniotomy and fenestration of the ventricular membranes, died accidentally 3 months after operation. In light of similar cases reported in the literature, the prognosis seems very poor. Craniotomy with fenestration of the ventricular septa seems a promising procedure, although further supportive evidence is needed.

Monitoring of brain tissue pressure with a fiberoptic device.

Continuous monitoring of brain tissue pressure can now be achieved with intracerebral placement of fiberoptic microtransducers. This study was undertaken to test the safety, accuracy, and reliability of this relatively new type of intracranial pressure (ICP) monitoring. Initially, the fiberoptic device was compared with a concurrently functioning intraventricular catheter in 18 patients. The results from the two methods corresponded closely over a wide range of pressures, and the correlation coefficient approached 1.0. Subsequently, this monitor was used for routine measurement of ICP in a series of almost 200 neurosurgical patients at risk of intracranial hypertension. The tracings showed good wave forms and consistent absolute values of ICP. No instances of hemorrhage, mechanical failure, or other complications were associated with this monitor, except one case of infection, which was not directly attributable to the device per se. When bilateral intraparenchymal pressures were recorded in patients with unilateral mass lesions, significant transitory pressure differentials between the ipsilateral and contralateral sides were documented. It is concluded that monitoring intraparenchymal pressure with the fiberoptic device offers safe and reliable ICP recordings for routine neurosurgical practice. In patients with unilateral masses, ICP should be measured in close proximity to the lesion.

Does lamina terminalis fenestration reduce the incidence of chronic hydrocephalus after subarachnoid hemorrhage?

OBJECTIVE: The incidence of chronic hydrocephalus requiring cerebrospinal fluid shunting was analyzed for a prospective series of 52 consecutive patients with ruptured cerebral aneurysms who underwent fenestration of the lamina terminalis during early microsurgical aneurysm repair. We hypothesized that, by creating an anterior ventriculocisternostomy, fenestration of the lamina terminalis would facilitate cerebrospinal fluid dynamics and decrease the risk of subsequent hydrocephalus. METHODS: Patients were enrolled according to the following criteria: 1) age more than 40 years; 2) admission Hunt and Hess Grade 2 to 4; 3) initial subarachnoid hemorrhage severity of Fisher Grade 3 or 4; and 4) early microsurgical repair of an anterior circulation aneurysm. RESULTS: The mortality rate in this series was 9.6%. Of the 47 surviving patients, 32 (68%) were discharged with a Glasgow Outcome Scale score of 5, 10 (21%) with a Glasgow Outcome Scale score of 4, and 5 (11%) with a Glasgow Outcome Scale score of 3. The follow-up period ranged from 12 to 60 months. Chronic hydrocephalus was radiographically and clinically evident in 3.8% of the total population. Shunt surgery was performed for two patients who exhibited symptoms resulting from hydrocephalus, corresponding to 4.2% of the surviving patients. CONCLUSION: Estimates from the most recently published studies indicate that an incidence of chronic post-subarachnoid hemorrhage hydrocephalus (requiring shunt surgery) of 15 to 20% is representative for an average contemporary population of patients with aneurysmal subarachnoid hemorrhage. The lower incidence of chronic hydrocephalus observed in this series possibly reflects the favorable effect of lamina terminalis fenestration on cerebrospinal fluid dynamics.

Spasmodic torticollis due to neurovascular compression of the spinal accessory nerve by the anteroinferior cerebellar artery: case report.

OBJECTIVE AND IMPORTANCE: Spasmodic torticollis is a neuromuscular disorder characterized by uncontrollable clonic and intermittently tonic spasm of the neck muscles. We report a case of spasmodic torticollis attributable to neurovascular compression of the right XIth cranial nerve by the right anteroinferior cerebellar artery (AICA). CLINICAL PRESENTATION: A 72-year-old man with a 2-year history of right spasmodic torticollis underwent magnetic resonance imaging, which demonstrated compression of the right XIth cranial nerve by an abnormal descending loop of the right AICA. INTERVENTION: The patient underwent microvascular decompression surgery. During surgery, it was confirmed that an abnormal loop of the right AICA was compressing the right accessory nerve. Compression was released by the interposition of muscle between the artery and the nerve. CONCLUSION: The patient's postoperative course was uneventful, and his symptoms were fully relieved at the 2-year follow-up examination. This is the first reported case of spasmodic torticollis attributable to compression by the AICA; usually, the blood vessels involved are the vertebral artery and the posteroinferior cerebellar artery.

Chronic encapsulated intracerebral hematoma: contribution of thallium-201 single photon emission computed tomography in preoperative diagnosis: case report.

OBJECTIVE AND IMPORTANCE: Chronic encapsulated intracerebral hematoma is a fairly rare clinical entity. This unique lesion is peculiar for its clinical onset, formation of a capsule, and progressive enlargement. The mechanism for capsule formation and self-perpetuating expansion still remains uncertain, as well as the causal relationship with vascular malformations. Because of their pseudotumoral course and misleading neuroradiological features, these lesions can be misdiagnosed preoperatively as cerebral neoplasms. CLINICAL PRESENTATIONS: A 62-year-old man was referred with a 2-month history of generalized tonicoclonic seizures. There was no history of head injury or arterial hypertension. The results of a neurological examination were normal. Computed tomographic scans revealed a slightly hyperdense roundish area in the right parietotemporal region with ring-like enhancement after contrast medium injection, moderate mass effect, and perifocal low attenuation. With the provisional diagnosis of astrocytoma, the patient was admitted for a craniotomy. Before surgery, a thallium-201 single photon emission computed tomographic study was performed, which showed no abnormal uptake of the tracer, raising significant doubt regarding the presumptive diagnosis of a tumor. INTERVENTION: Intraoperative findings revealed a hematoma, with a well-demarcated, thick, fibrous-elastic capsule. There was evidence of repeated intracapsular hemorrhages. The lesion was totally removed, and the patient recovered fully. No other pathological findings, including vascular malformations, were noted. CONCLUSION: Chronic encapsulated intracerebral hematomas probably occur more frequently than the limited number of reported cases would indicate. This case represents a realistic clinical problem-solving setting in with thallium-201 single photon emission computed tomography was used because of its capacity for functional tumor detection and differential diagnosis.

Peritumoral edema in meningiomas: microsurgical observations of different brain tumor interfaces related to computed tomography.

Although generally benign tumors, meningiomas may be associated with extensive peritumoral brain edema as seen on computed tomographic scans. Fifty-two patients with intracranial meningiomas were studied, and the hypodense areas on computed tomographic scans were related to the intraoperative microsurgical findings and to the sizes of the tumors. We have identified three kinds of tumor-brain interfaces characterized by different difficulties in microsurgical dissection: smooth type, transitional type, and invasive type. These different microsurgical interfaces seem to correlate very precisely with computed tomographic images of halo-like and finger-like hypodense areas, allowing prediction of the microsurgical effort to be made in the surgery of meningiomas. The size of the tumor seems to be important in our subjects in determining the amount of edema produced. Indeed, a positive correlation (P < 0.001) was found between the sizes of the tumors and the extent of peritumoral hypodensity. A positive correlation (P < 0.002) also has been found between grade of edema and cortical penetration. Cerebral cortex disruption was systematically observed by us in invasive-type meningiomas and in 3 of 21 cases (14.3%) in transitional-type meningiomas. No penetration was observed in smooth-type meningiomas.

Blood-brain barrier permeability changes after experimental subarachnoid hemorrhage.

Basic mechanisms underlying cerebrovascular permeability responses to subarachnoid hemorrhage (SAH) are still to be defined in detail. Previous investigations examining the occurrence of blood-brain barrier (BBB) breakdown after SAH in the experimental setting have yielded conflicting results. In a rat model of SAH, we assessed BBB changes by means of the quantitative [14C]-alpha-aminoisobutyric acid technique. Experiments were carried out on the second day post-SAH. In blood-injected rats [14C]-alpha-aminoisobutyric acid transport across the BBB increased significantly in cerebral cortices and cerebellar gray matter, averaging 1.3 to 1.5 times control values. The present data indicate that SAH induces well-defined changes in BBB function, possibly involved in the pathogenesis of post-SAH cerebral dysfunction in humans. Results reported here have also potential clinical implications for the management of aneurysm patients.

Do spinal meningiomas penetrate the pial layer? Correlation between magnetic resonance imaging and microsurgical findings and intracranial tumor interfaces.

OBJECTIVE: To study the relationships between spinal dura-arachnoid and tumor-cord interfaces in spinal meningiomas and to investigate whether a disruption of the pial layer and penetration of the tumor in the spinal cord occurs. METHODS: Fifteen patients with histologically proven meningiomas underwent magnetic resonance imaging (MRI) preoperatively. All patients underwent microsurgery. The histological characteristics of the tumors were compared with MRI and microsurgical findings. RESULTS: At surgery, the peritumoral hypointense rim revealed by MRI in 10 of 15 patients corresponded to a well-defined cerebrospinal fluid-containing space confined between the outer arachnoidal layer and the inner leptomeningeal layer. In those patients in whom the hypointense peritumoral rim was absent, the inner layer was either difficult to identify or clearly absent, and the blood vessels were extremely adherent to the tumor, requiring a more cautious dissection. Penetration of the tumors through disruption of the pial surface was not documented. CONCLUSION: Previous anatomic and electron microscopy studies demonstrated, in human spinal meninges, the presence of an intermediate layer attached to the inner aspect of the arachnoid, extending laterally over the dorsal surface of the spinal cord and arborizing over the nerve roots and blood vessels. The intermediate layer is not present in human cerebral leptomeninges. The presence/absence of this layer might explain the hypointense rim detected by MRI and might also explain why no penetration and no peritumoral edema is observed in spinal meningiomas as compared with intracranial meningiomas.

Quantitative study of blood-brain barrier permeability changes after experimental whole-brain radiation.

Basic mechanisms underlying the tolerance and reaction of the central nervous system to ionizing radiation are not known precisely. We investigated the possibility of a change in blood-brain barrier (BBB) function as a causative factor for early delayed whole-brain radiation-induced cerebral dysfunction. Rats were exposed to conventional fractionation (200 cGy/d, 5 d/wk; total dose, 4000 cGy). BBB changes were assessed by means of the quantitative 14C-alpha-aminoisobutyric acid technique and electron microscopy. Studies of the passage of horseradish peroxidase across the BBB permitted comparative quantitative isotopical and qualitative morphological data. Experiments were carried out 2 to 3 weeks after the completion of the radiation exposure. The transport of 14C-alpha-aminoisobutyric acid across the BBB increased significantly in cerebral cortex and cerebellar gray matter, averaging 1.3 to 1.5 times over the normal values. Electron microscopy disclosed an intense vesicular response of the cortical microvascular endothelium that occurred without the opening of the tight junctions and resulted in an intense transport of HRP across the intact endothelium. The present data indicate that moderate doses of whole-brain radiation induce well-defined changes in BBB function, which possibly are involved in the pathogenesis of radiation-induced cerebral dysfunction in humans.

Time-related ultrastructural changes in an experimental model of whole brain irradiation.

To stimulate therapeutic irradiation, we exposed rats to conventional fractionation (200 +/- 4 cGy/d, 5 d/wk; total dose, 4000 cGy). The effects of this regimen were assessed by electron microscopic examinations of brain microvascular and parenchymal cells 15 and 90 days after irradiation. Studies of the transendothelial passage of horseradish peroxidase provided information about the functional status of the blood-brain barrier. At 15 days after irradiation, there was an increased vesicular transport of horseradish peroxidase across the intact endothelium without opening of the tight junctions, and without evidence of structural alterations of neuropil, neuronal bodies, and astrocytes. Ninety days after irradiation, well-defined ultrastructural alterations were observed, involving the microvasculature, the neuropil, the neuronal bodies, and astrocytes. The main ultrastructural feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Altered neurons and reactive activated astrocytes were also noticeable. These data suggest a possible association, not necessarily causal, between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain toxicity.

SEM evaluation of endothelial changes following end-to-side microvascular anastomoses in rats.

A scanning electron microscopic (SEM) study was carried out to evaluate the endothelial changes in carotid end-to-side microsurgical anastomoses. This procedure, associated with occlusion of the brachiocephalic trunk, was performed in 24 Sprague-Dawley rats. The animals were sacrificed at time intervals ranging between 15 minutes and 14 days after surgery. The specimens were collected after perfusion-fixation in vivo and treated for SEM observations. The findings show that the first 45 minutes are the most critical time for thrombus formation. Reendothelialization could be detected at 3 days after the microsurgical procedure. Endothelial regeneration occurred earlier on the suture line than on the stitches, documented by the migration and morphological changes of the endothelial cells advancing from the normal endothelium to cover the defect and the suture material. The repair was usually completed within 14 days. Damage of the inner vascular wall, related to minor failures of the microsurgical technique, appears to be a cause of delayed reendothelialization.

Supratentorial hemangioblastoma in a child. Case report.

Hemangioblastomas are rarely seen in the supratentorial region, especially in childhood. The case of a 10-year-old boy with left parieto-occipital cystic hemangioblastoma is reported. The neoplasm was not attached to the dura, nor was it associated with von Hippel-Lindau syndrome or with erythrocythemia. Cerebral angiography showed no evidence of a vascularized tumor, whereas computerized tomography gave more accurate information. The gross and microscopic appearance of the lesion is described, and a review of similar cases previously reported in the literature is presented.