Aristotelis S. Filippidis

Cerebral venous sinus thrombosis: review of the demographics, pathophysiology, current diagnosis, and treatment

Cerebral venous sinus thrombosis (CVST) is a rare clinicopathological entity. The incidence of CVST in children and neonates has been reported to be as high as 7 cases per million people, whereas in adults the incidence is 3-4 cases per million. The predisposing factors to this condition are mainly genetic and acquired prothrombotic states and infection. The clinical picture of CVST is nonspecific, highly variable, and can mimic several other clinical conditions. Diagnosis of CVST is established with the implementation of neuroimaging studies, especially MR imaging and venography. Identification and elimination of the underlying cause, anticoagulation, proper management of intracranial hypertension, and anticonvulsant prophylaxis constitute cornerstones of CVST treatment. Newer treatment strategies such as endovascular thrombolysis and decompressive craniectomy have been recently used in the treatment of patients with CVST with variable success rates. Further clinical research must be performed to delineate the exact role of these newer treatments in the management of severe cases of CVST. The recent advances in the diagnosis and treatment of patients with CVST have significantly lowered the associated mortality and morbidity and have improved the outcome of these patients.

Hydrocephalus and aquaporins: lessons learned from the bench

PurposeHydrocephalus is a common disorder of defective cerebrospinal fluid (CSF) turnover. The identification of the aquaporin water channels (AQPs) led to the study of their role in the composition of biological fluids including CSF. The purpose of this study is to review the potential role of aquaporins in the pathogenesis, compensation, and possibly treatment of hydrocephalus.MethodsWe performed a MEDLINE search using the terms “aquaporin AND hydrocephalus.” The search returned a total of 20 titles. Eleven studies fulfilled the criteria for this review.ResultsMost studies were performed in animal models. The expression of AQPs in hydrocephalus is significantly altered. Aquaporin-1 levels at the choroid plexus are decreased in most models of hydrocephalus while CSF production and intracranial pressure are reduced in AQP1 knockout mice. In contrast, the expression of AQP4 in hydrocephalus is increased at its sites of expression. Aquaporin-4 knockout mice show a decreased clearance of brain edema via blood–CSF and blood–brain barrier (BBB) pathways and decreased survival in hydrocephalus models.ConclusionsAquaporin-1 is highly expressed at the choroid plexus and is related to CSF production. Aquaporin-4 is expressed at the ependyma, glia limitans, and at the perivascular end feet processes of astrocytes of the BBB, facilitating the water movement across these tissue interfaces. The observations obtained from animal studies and few cases in humans indicate an adaptive and protective role of AQPs in hydrocephalus by decreasing CSF production and increasing edema clearance. Aquaporins are attractive targets for the pharmaceutical treatment of hydrocephalus.

Selective Vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury

A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm(2)) versus sham groups (78.3±0.1%; 9.5±0.9 µm(2)), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8µm(2)). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03±0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema.

Negative-pressure and low-pressure hydrocephalus: the role of cerebrospinal fluid leaks resulting from surgical approaches to the cranial base

OBJECT Negative-pressure and low-pressure hydrocephalus are rare clinical entities that are frequently misdiagnosed. They are characterized by recurrent episodes of shunt failure because the intracranial pressure is lower than the opening pressure of the valve. In this report the authors discuss iatrogenic CSF leaks as a cause of low- or negative-pressure hydrocephalus after approaches to the cranial base. METHODS The authors retrospectively reviewed cases of low-pressure or negative-pressure hydrocephalus presenting after cranial approaches complicated with a CSF leak at their institution. RESULTS Three patients were identified. Symptoms of high intracranial pressure and ventriculomegaly were present, although the measured pressures were low or negative. A blocked communication between the ventricles and the subarachnoid space was documented in 2 of the cases and presumed in the third. Shunt revisions failed repeatedly. In all cases, temporary clinical and radiographic improvement resulted from external ventricular drainage at subatmospheric pressures. The CSF leaks were sealed and CSF communication was reestablished operatively. In 1 case, neck wrapping was used with temporary success. CONCLUSIONS Negative-pressure or low-pressure hydrocephalus associated with CSF leaks, especially after cranial base approaches, is difficult to treat. The solution often requires the utilization of subatmospheric external ventricular drains to establish a lower ventricular drainage pressure than the drainage pressure created in the subarachnoid space, where the pressure is artificially lowered by the CSF leak. Treatment involves correction of the CSF leak, neck wrapping to increase brain turgor and allow the pressure in the ventricles to rise to the level of the opening pressure of the valve, and reestablishing the CSF route.

Hydrocephalus and Aquaporins: The Role of Aquaporin-1

INTRODUCTION Aquaporins (AQPs) are membrane proteins that facilitate water and small solute movement in tissues. Hydrocephalus is a major central nervous system disorder associated with defective cerebrospinal fluid (CSF) turnover. Aquaporin-1 (AQP1) is a water channel located mainly at the choroid plexus epithelium and plays an active role in CSF production. The aim of this study is to review the pertinent literature concerning the role of aquaporin-1 in the pathophysiology of hydrocephalus. METHODS We performed a MEDLINE search using the terms aquaporin AND hydrocephalus. The results of the search were further refined to exclude studies not related to aquaporin-1. RESULTS Five studies were identified. Three of these studies utilized an animal model, while only two studies referred to a few human cases of hydrocephalus. Most of the studies indicate that there is a down-regulation of AQP1 expression in choroid plexus in models of hydrocephalus. A small series of human choroid plexus tumors showed that AQP1 expression is up-regulated. In cases of human choroid plexus tumors, there are indications that AQP1 may have alternative physiologic roles, but it is not clear whether this is associated with a specific type of hydrocephalus or the genetic burden of the tumor. CONCLUSION There has been a paucity of research on the link between aquaporins and hydrocephalus. Most studies have relied on animal models. An adaptive and protective role of AQP1 as a regulator of CSF production is proposed in the pathophysiology of hydrocephalus. Further research is needed to clarify if this association exists in humans.

Propranolol Treatment of Cavernous Malformations with Symptomatic Hemorrhage

BACKGROUND Cerebral cavernous malformations are more common than generally thought, affecting approximately 1 in every 250 adults. Most of these lesions are asymptomatic or have a relatively benign course, but a small minority behave aggressively and present with recurrent episodes of symptomatic hemorrhage. A safe and effective medical treatment option for the management of this latter group would be useful. Propranolol has recently been shown to be effective in the treatment of infantile hemangioma, a close pathologic counterpart of cavernous malformations. These results suggest a potential role for propranolol treatment in the management of patients with symptomatic cavernous malformations. METHODS Low-dose propranolol (20 mg, three times daily) was used to treat 2 adult female patients in their mid- to late fifties, both of whom had symptomatic cavernous malformations and a history of repeated hemorrhage. Serial magnetic resonance imaging studies after the initiation of propranolol demonstrated regression of the lesions and no evidence of recurrent hemorrhage. CONCLUSIONS Propranolol may offer a safe and effective treatment for patients who have cavernous malformations with symptomatic hemorrhage. Additional studies are needed to confirm these findings.

Real-Time Monitoring of Changes in Brain Extracellular Sodium and Potassium Concentrations and Intracranial Pressure after Selective Vasopressin-1a Receptor Inhibition following Focal Traumatic Brain Injury in Rats

Brain swelling and increased intracranial pressure (ICP) following traumatic brain injury (TBI) contribute to poor outcome. Vasopressin-1a receptors (V1aR) and aquaporin-4 (AQP4) regulate water transport and brain edema formation, perhaps in part by modulating cation fluxes. After focal TBI, V1aR inhibitors diminish V1aR and AQP4, reduce astrocytic swelling and brain edema. We determined whether V1aR inhibition with SR49059 after lateral controlled-cortical-impact (CCI) injury affects extracellular Na(+) and K(+) concentrations ([Na(+)]e; [K(+)]e). Ion-selective Na(+) and K(+) electrodes (ISE) and an ICP probe were implanted in rat parietal cortex, and [Na(+)]e, [K(+)]e, and physiological parameters were monitored for 5 h post-CCI. Sham-vehicle-ISE, CCI-vehicle-ISE and CCI-SR49059-ISE groups were studied, and SR49059 was administered 5 min to 5 h post-injury. We found a significant injury-induced decrease in [Na(+)]e to 80.1 ± 15 and 87.9 ± 7.9 mM and increase in [K(+)]e to 20.9 ± 3.8 and 13.4 ± 3.4 mM at 5 min post-CCI in CCI-vehicle-ISE and CCI-SR49059-ISE groups, respectively (p<0.001 vs. baseline; ns between groups). Importantly, [Na(+)]e in CCI-SR49059-ISE was reduced 5-20 min post-injury and increased to baseline at 25 min, whereas recovery in CCI-vehicle-ISE required more than 1 hr, suggesting SR49059 accelerated [Na(+)]e recovery. In contrast, [K(+)]e recovery took 45 min in both groups. Further, ICP was lower in the CCI-SR49059-ISE group. Thus, selective V1aR inhibition allowed faster [Na(+)]e recovery and reduced ICP. By augmenting the [Na(+)]e recovery rate, SR49059 may reduce trauma-induced ionic imbalance, blunting cellular water influx and edema after TBI. These findings suggest SR49059 and V1aR inhibitors are potential tools for treating cellular edema post-TBI.

Aquaporins in Brain Edema and Neuropathological Conditions

The aquaporin (AQP) family of water channels are a group of small, membrane-spanning proteins that are vital for the rapid transport of water across the plasma membrane. These proteins are widely expressed, from tissues such as the renal epithelium and erythrocytes to the various cells of the central nervous system. This review will elucidate the basic structure and distribution of aquaporins and discuss the role of aquaporins in various neuropathologies. AQP1 and AQP4, the two primary aquaporin molecules of the central nervous system, regulate brain water and CSF movement and contribute to cytotoxic and vasogenic edema, where they control the size of the intracellular and extracellular fluid volumes, respectively. AQP4 expression is vital to the cellular migration and angiogenesis at the heart of tumor growth; AQP4 is central to dysfunctions in glutamate metabolism, synaptogenesis, and memory consolidation; and AQP1 and AQP4 adaptations have been seen in obstructive and non-obstructive hydrocephalus and may be therapeutic targets.

Ruptured Anterior Spinal Artery Aneurysm Associated with Bilateral Vertebral Artery Occlusion Treated by Surgical Clipping

BACKGROUND Spinal artery aneurysms are rare lesions that can occur in isolation or may be attributed to a variety of secondary causes. Chronic bilateral vertebral artery occlusion is an exceedingly rare cause of anterior spinal artery aneurysm, with only one previous case reported in the literature. Surgical treatment of ventrally located anterior spinal artery aneurysms situated at the craniocervical junction presents particular challenges related to the operative approach, which may entail high cervical anterior exposure, posterolateral complete facetectomy/pediculectomy, or far lateral skull base approaches, among others. CASE DESCRIPTION We present the case of a patient who presented with a ruptured anterior spinal artery aneurysm at the level of C2, associated with a hypertrophied anterior spinal artery due to chronic bilateral vertebral artery occlusion; the second such case reported in the literature. A posterior approach with spinal cord rotation was employed to expose and clip the aneurysm. The patient made an uneventful recovery. CONCLUSION This report highlights an exceedingly rare cause of anterior spinal artery aneurysm and emphasizes the utility and technical aspects of the posterior approach with spinal cord rotation.

Assessment of locomotion in chlorine exposed mice by computer vision and neural networks

Assessment of locomotion following exposure of animals to noxious or painful stimuli can offer significant insights into underlying mechanisms of injury and the effectiveness of various treatments. We developed a novel method to track the movement of mice in two dimensions using computer vision and neural network algorithms. By using this system we demonstrated that mice exposed to chlorine (Cl(2)) gas developed impaired locomotion and increased immobility for up to 9 h postexposure. Postexposure administration of buprenorphine, a common analgesic agent, increased locomotion and decreased immobility times in Cl(2)- but not air-exposed mice, most likely by decreasing Cl(2)-induced pain. This method can be adapted to assess the effectiveness of various therapies following exposure to a variety of chemical and behavioral noxious stimuli.