Identification of direct connections between the dura and the brain.

The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems.

Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain.

The relationships between cerebrospinal fluid (CSF) and brain interstitial fluid are still being elucidated. It has been proposed that CSF within the subarachnoid space will enter paravascular spaces along arteries to flush through the parenchyma of the brain. However, CSF also directly exits the subarachnoid space through the cribriform plate and other perineural routes to reach the lymphatic system. In this study, we aimed to elucidate the functional relationship between CSF efflux through lymphatics and the potential influx into the brain by assessment of the distribution of CSF-infused tracers in awake and anesthetized mice. Using near-infrared fluorescence imaging, we showed that tracers quickly exited the subarachnoid space by transport through the lymphatic system to the systemic circulation in awake mice, significantly limiting their spread to the paravascular spaces of the brain. Magnetic resonance imaging and fluorescence microscopy through the skull under anesthetized conditions indicated that tracers remained confined to paravascular spaces on the surface of the brain. Immediately after death, a substantial influx of tracers occurred along paravascular spaces extending into the brain parenchyma. We conclude that under normal conditions a rapid CSF turnover through lymphatics precludes significant bulk flow into the brain.

Spontaneous Spinal Subarachnoid Hemorrhage: Presentation and Outcome.

BACKGROUND: Spontaneous spinal subarachnoid hemorrhage (SSAH) is a rare but serious condition that can lead to a variety of medical complications. METHODS: Using the Mayo Clinic Rochester database, consecutive patients admitted to the Mayo Clinic Rochester, Minnesota hospital with spontaneous SSAH (not iatrogenic or traumatic) between January 2000 and December 2015 were retrospectively reviewed. Demographic and clinical data and functional outcomes as categorized by the modified Rankin Scale (mRS) score at the time of discharge and at postadmission follow-up were assessed. RESULTS: Eight patients (median age 70 years, range 51-87) were identified. Seven patients presented with acute back pain or headache. Seven patients had poorly controlled chronic hypertension. Two patients had vasculitis and 1 had an arteriovenous malformation. Complications included cord compression (n = 4), hyponatremia (n = 5), sulcal subarachnoid hemorrhage (n = 2), chronic arachnoiditis (n = 1), vasospasm (n = 1), ischemic infarct (n = 1), and late cord ischemia (n = 1). All patients were managed medically including blood pressure control and repeat imaging. One patient had an aneurysm, which was embolized, and 2 received steroids for vasculitis. One patient died during hospitalization and 1 died within a week of discharge. Five patients had improved and 1 had unchanged mRS score at posthospitalization follow-up. CONCLUSIONS: SSAH should be considered in patients with sudden onset of severe back pain and headache, especially if as associated with lower extremity weakness or urinary retention. Our findings suggest that older patients with poorly controlled hypertension are at particular risk for spontaneous SSAH. In our study vascular anomalies were found in 25% of patients, vasculitis in 25%, hyponatremia in 63%, and cord compression in 50%. Cord compression may be managed conservatively. Mortality was 25% in the 3 months following the initial event, primarily due to other medical comorbidities.

Paravascular spaces at the brain surface: Low resistance pathways for cerebrospinal fluid flow.

Clearance of waste products from the brain is of vital importance. Recent publications suggest a potential clearance mechanism via paravascular channels around blood vessels. Arterial pulsations might provide the driving force for paravascular flow, but its flow pattern remains poorly characterized. In addition, the relationship between paravascular flow around leptomeningeal vessels and penetrating vessels is unclear. In this study, we determined blood flow and diameter pulsations through a thinned-skull cranial window. We observed that microspheres moved preferentially in the paravascular space of arteries rather than in the adjacent subarachnoid space or around veins. Paravascular flow was pulsatile, generated by the cardiac cycle, with net antegrade flow. Confocal imaging showed microspheres distributed along leptomeningeal arteries, while their presence along penetrating arteries was limited to few vessels. These data suggest that paravascular spaces around leptomeningeal arteries form low resistance pathways on the surface of the brain that facilitate cerebrospinal fluid flow.

Modelling of subarachnoid space width changes in apnoea resulting as a function of blood flow parameters.

During apnoea, the pial artery is subjected to two opposite physiological processes: vasoconstriction due to elevated blood pressure and vasorelaxation driven by rising pH in the brain parenchyma. We hypothesized that the pial artery response to apnoea may vary, depending on which process dominate. Apnoea experiments were performed in a group of 19 healthy, non-smoking volunteers (9 men and 10 women). The following parameters were obtained for further analysis: blood pressure, the cardiac (from 0.5 to 5.0Hz) and slow (<0.5Hz) components of subarachnoid space width, heart rate, mean cerebral blood flow velocity in the internal carotid artery, pulsatility and resistivity index, internal carotid artery diameter, blood oxygen saturation and end-tidal carbon dioxide. The experiment consisted of three apnoeas, sequentially: 30s, 60s and maximal apnoea. The breath-hold was separated for 5minute rest. The control process is sophisticated, involving internal cross-couplings and cross-dependences. The aim of work was to find a mathematical dependence between data. Unexpectedly, the modelling revealed two different reactions, on the same experimental procedure. As a consequence, there are two subsets of cardiac subarachnoid space width responses to breath-hold in humans. A positive cardiac subarachnoid space width change to apnoea depends on changes in heart rate and cerebral blood flow velocity. A negative cardiac subarachnoid space width change to apnoea is driven by heart rate, mean arterial pressure and pulsatility index changes. The described above two different reactions to experimental breath-hold provides new insights into our understanding of the complex mechanisms governing the adaptation to apnoea in humans. We proposed a mathematical methodology that can be used in further clinical research.

Is there a connection between perivascular space and subarachnoid space?

Perivascular spaces (PVSs) surrounding the walls of arteries, arterioles, and venules do not directly communicate with subarachnoid spaces. There are a few reports exhibiting subarachnoid hemorrhage (SAH) and intracerebral hematomas extending to the PVSs by leakage of the leptomeninges that surround arteries. In this report, we present 4 patients of whom 3 had SAH extending into the PVSs in the bilateral basal ganglia and 1 had extension of contrast medium to the PVSs after injection of the contrast medium into the lumbar subarachnoid space. The hemorrhage extending to the PVSs in our 3 patients with SAH could be explained by leakage of the leptomeninges surrounding the arteries. However, how the contrast medium extends to the PVSs is not clear. We think that, although speculative, incomplete or complete defect at the leptomeninges surrounding the arteries resulting in direct continuity between the subarachnoid space and the PVS allows that blood or contrast media to extend to the PVSs.

Tat peptide-decorated gelatin-siloxane nanoparticles for delivery of CGRP transgene in treatment of cerebral vasospasm.

BACKGROUND: Gene transfer using a nanoparticle vector is a promising new approach for the safe delivery of therapeutic genes in human disease. The Tat peptide-decorated gelatin-siloxane (Tat-GS) nanoparticle has been demonstrated to be biocompatible as a vector, and to have enhanced gene transfection efficiency compared with the commercial reagent. This study investigated whether intracisternal administration of Tat-GS nanoparticles carrying the calcitonin gene-related peptide (CGRP) gene can attenuate cerebral vasospasm and improve neurological outcomes in a rat model of subarachnoid hemorrhage. METHOD: A series of gelatin-siloxane nanoparticles with controlled size and surface charge was synthesized by a two-step sol-gel process, and then modified with the Tat peptide. The efficiency of Tat-GS nanoparticle-mediated gene transfer of pLXSN-CGRP was investigated in vitro using brain capillary endothelial cells and in vivo using a double-hemorrhage rat model. For in vivo analysis, we delivered Tat-GS nanoparticles encapsulating pLXSN-CGRP intracisternally using a double-hemorrhage rat model. RESULTS: In vitro, Tat-GS nanoparticles encapsulating pLXSN-CGRP showed 1.71 times higher sustained CGRP expression in endothelial cells than gelatin-siloxane nanoparticles encapsulating pLXSN-CGRP, and 6.92 times higher CGRP expression than naked pLXSN-CGRP. However, there were no significant differences in pLXSN-CGRP entrapment efficiency and cellular uptake between the Tat-GS nanoparticles and gelatin-siloxane nanoparticles. On day 7 of the in vivo experiment, the data indicated better neurological outcomes and reduced vasospasm in the subarachnoid hemorrhage group that received Tat-GS nanoparticles encapsulating pLXSN-CGRP than in the group receiving Tat-GS nanoparticles encapsulating pLXSN alone because of enhanced vasodilatory CGRP expression in cerebrospinal fluid. CONCLUSION: Overexpression of CGRP attenuated vasospasm and improved neurological outcomes in an experimental rat model of subarachnoid hemorrhage. Tat-GS nanoparticle-mediated CGRP gene delivery could be an innovative strategy for treatment of cerebral vasospasm after subarachnoid hemorrhage.

Non-pharmacological experimental treatments for spinal cord injury: a review.

INTRODUCTION: Spinal cord injury is a complex result of primary mechanical damage and the secondary vascular compromise and inflammatory reactions. Depending on timing, different treatment modalities may have various effects. CONCLUSIONS: We review the latest advances in terms of non-pharmacological experimental treatments.

Absence of abnormal vessels in the subarachnoid space on conventional magnetic resonance imaging in patients with spinal dural arteriovenous fistulas.

Spinal dural arteriovenous fistula (DAVF) is an uncommon condition that can be difficult to diagnose. This often results in misdiagnosis and treatment delay. Although conventional MRI plays an important role in the initial screening for the disease, the typical MRI findings may be absent. In this article, the authors present a series of 4 cases involving patients with angiographically proven spinal DAVFs who demonstrated cord T2 prolongation on conventional MRI but without abnormal subarachnoid flow voids or enhancement. These cases suggest that spinal DAVF cannot be excluded in symptomatic patients with cord edema based on conventional MRI findings alone. Dynamic Gd-enhanced MR angiography (MRA) was successful in demonstrating abnormal spinal vasculature in all 4 cases. This limited experience provides support for the role of spinal MRA in patients with abnormal cord signal and symptoms suggestive of DAVF even when typical MRI findings of a DAVF are absent.

CP or not CP? A review of diagnoses in a cerebral palsy register.

The purpose of this study was to document the inaccuracy rate of diagnosis of cerebral palsy recorded on the South Australian Cerebral Palsy Register. A total of 402 children born in South Australia from 1993 to 2002 and notified to the Register as having cerebral palsy were identified through the Register database, and 21 children (5.2%) were later identified to have a noncerebral palsy diagnosis. Of these, 5 had either a metabolic or a neurodegenerative disorder and 2 had a syndromic disorder (1 Joubert syndrome and 1 Sotos syndrome); the remaining 14 children had one of the following final diagnoses: developmental delay, gross motor delay, perinatal myositis, spinal subdural and subarachnoid arteriovenous malformation, and Erb's palsy. In 16 of 21 children (76%), the diagnosis was changed at 5 years of age or older. Studies based on population registers may need to take into account the possibility of misclassification, estimated to be at least 5.2% in this study. A complete clinical assessment at the time of diagnosis followed by regular reassessment would enable the clinician to exclude children with alternative diagnoses, which has important implications for clinical management and research based on cerebral palsy registers.

The influence of the relative timing of arterial and subarachnoid space pulse waves on spinal perivascular cerebrospinal fluid flow as a possible factor in syrinx development.

OBJECT: The mechanisms of syringomyelia have long puzzled neurosurgeons and researchers alike due to difficulties in identifying the driving forces behind fluid flow into a syrinx, apparently against a pressure gradient between the spinal cord and the subarachnoid space (SAS). Recently, the synchronization between CSF flow and the cardiac cycle has been postulated to affect fluid flow in the spinal cord. This study aims to determine the effect of changes in the timing of SAS pressure on perivascular flow into the spinal cord. METHODS: This study uses a computational fluid dynamics model to investigate whether the relative timing of a spinal artery cardiovascular pulse wave and fluid pressure in the spinal SAS can influence CSF flow in the perivascular spaces. RESULTS: The results show that the mass flow rate of CSF through a model periarterial space is strongly influenced by the relative timing of the arterial pulse wave and the SAS pressure. CONCLUSIONS: These findings suggest that factors that might alter the timing of the pulse wave or the fluid flow in the SAS could potentially affect fluid flow into a syrinx.

Multiple spinal dural arteriovenous fistulae and deterioration post lumbar puncture.

We report a 73-year-old man presenting with bilateral leg numbness and weakness. Three spinal dural arteriovenous fistulae (SDAVF) were found after clinical deterioration post lumbar puncture (LP). This patient highlights the difficulties in the diagnosis and management of SDAVF, and the risks of LP.

Spinal accessory nerve cavernous malformation.

We present the first reported case of a spinal accessory nerve cavernous malformation. A 54-year-old Caucasian male presented with a several-year history of progressive, vague bilateral upper and lower extremity paresthesias and pain. MRI of the spine revealed a heterogenously enhancing mass in the dorsal aspect of the spinal canal at the level of the atlas with mild spinal cord compression. The lesion was resected and upon gross and histologic examination it was a cavernous malformation embedded within a branch of the spinal accessory nerve. Post-operatively, the patient had no complications and some improvement in his symptoms. To our knowledge, this is the first report of a patient with a spinal accessory nerve cavernous malformation, and this should be considered in the differential of lesions in the craniocervical region.

Impact of early surgery after aneurysmal subarachnoid haemorrhage.

OBJECTIVES: To investigate the effect of early aneurysm surgery (<72 h) on outcome in patients with subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: We studied two consecutive series of patients with aneurysmal SAH [postponed surgery (PS) cohort, n = 118, 1989-1992: surgery was planned on day 12 and early surgery (ES) cohort, n = 85, 1996-1998: ES was performed only in patients with Glasgow Coma Scale (GCS) >13]. We used multivariable logistic regression analysis to assess outcome at 3 months. RESULTS: Favourable outcome (Glasgow Outcome Scale 4 or 5) was similar in both cohorts. Cerebral ischemia occurred significantly more often in the ES cohort. The occurrence of rebleeds was similar in both cohorts. External cerebrospinal fluid (CSF) drainage was performed more often in the ES cohort (51% vs 19%). Patients with cisternal sum score (CSS) of subarachnoid blood <15 on admission [adjusted odds ratio (OR) for favourable outcome: 6.4, 95% confidence interval (CI) 1.0-39.8] and patients with both CSS <15 and GCS > 12 on admission benefited from the strategy including ES (OR 10.5, 95% CI 1.1-99.4). CONCLUSIONS: Our results support the widely adopted practice of ES in good-grade SAH patients.

[Brain injuries in relation to morphological structure of dura mater spinalis in pregnant women].

Morphological and histochemical investigations on dura mater spinalis of the lumbar site in 5 women of reproductive age dead from accidents and 5 women dead during deliveries due to hemorrhage were carried out. It was found that one of the etiological factors of head-aches after subarachnoid anesthesia was functional reduction of mechanic and supporting function of dura mater spinalis along with elasticity loss of fibrous tissue, edema and friability. The stable non-healing postpuncture defect of dura mater spinalis resulted in liquorrhea with subsequent development of the "liquorrhea hypotension" syndrome.

Theoretical analysis of the pathophysiology of syringomyelia associated with adhesive arachnoiditis.

OBJECTIVE: To apply a theoretical model to analyse the derangement of cerebrospinal fluid (CSF) dynamics in syringomyelia associated with adhesive arachnoiditis. METHODS: An electrical circuit model of CSF dynamics in the spine was used. With this model, the derangement of CSF dynamics in adhesive arachnoiditis was simulated. The effects of various surgical procedures were then analysed, such as syringo-subarachnoid shunting, subarachnoid bypass, and foramen magnum decompression. RESULTS: When CSF flow in the subarachnoid space was obstructed at a certain point, the pressure inside the spinal cord increased in the segment immediately distal to the blockage. This location of increased pressure corresponded to the preferred site of syrinx formation in adhesive arachnoiditis. Syringo-subarachnoid shunting, subarachnoid bypass, and foramen magnum decompression were all effective at reducing this pressure gradient. CONCLUSIONS: Blockage of the spinal subarachnoid CSF pathway produces a relative increase in the pressure inside the spinal cord distal to the blockage point. Repetitive formation of this pressure gradient then induces CSF leakage into the spinal parenchyma, leading to the formation of syringomyelia. Using this model, alternative surgical procedures could be suggested that might be effective in treating this disease.

[Vascular complications after acoustic neurinoma surgery]. / Complications vasculaires apres chirurgie du neurinome de l'acoustique.

OBJECTIVE: To report six cases of vascular complications occurring after acoustic neuroma surgery and to discuss the postoperative signs and symptoms that should alert the surgeon, in order to undertake the appropriate treatment as soon as possible. METHODS: Four hundred thirty-two cases of acoustic tumors operated by the same surgeons between January 1991 and December 2000 were reviewed. RESULTS: Six cases of vascular complications were identified: one case of cerebral vasospasm secondary to persistence of subarachnoid blood after injury to Dandy's vein; three cases of arterial infarction giving rise to a partial anterior inferior cerebellar artery (AICA) syndrome with an unusual nystagmus in two cases (ipsilateral in one patient and strong controlateral in one patient presenting preoperative vestibular areflexia); one case of hematoma of the cerebello-pontine angle (CPA) causing strong ipsilateral nystagmus; and one case of venous infarction of the cerebellar vermis secondary to accidental sinus thrombosis. CONCLUSIONS: Vascular complications after acoustic neuroma surgery are potentially devastating and should be identified as early as possible. Rapid extubation is recommended for systematic neurologic assessment. Among abnormal signs and symptoms that should alert the surgeon, marked nystagmus ipsilateral to the operated side or contralateral in patient presenting preoperative vestibular areflexia appears to be of great value.

Evaluation of hyperintense vessels on FLAIR MRI for the diagnosis of multiple intracerebral arterial stenoses.

BACKGROUND AND PURPOSE: Hyperintense vessel sign (HVS) on fluid-attenuated inversion recovery (FLAIR) has been described in hyperacute stroke patients with arterial occlusion. We sought to determine whether HVS was more frequent in patients with intracerebral arterial stenoses than in those without stenosis regardless of the presence of a brain infarct. METHODS: In this case-control study (19 symptomatic patients with multiple intracerebral arterial stenoses compared with 19 age-matched asymptomatic patients without stenosis), we looked for HVS (ie, focal or tubular hyperintensities in the subarachnoid space) on FLAIR images. We compared the proportion of HVS-positive patients in the 2 groups and evaluated the concordance between the arterial distribution of stenoses on angiogram and that of HVS on FLAIR. RESULTS: HVS was found in 13 of 19 patients (68%) in the study group and 1 of 19 control patients (5.2%) (P<0.0001). The concordance between the territorial distribution of stenoses on angiogram and HVS on FLAIR was higher for the right and left middle cerebral artery (kappa=0.6 and 0.63, respectively) compared with the right and left anterior cerebral artery (kappa=0.35 and 0.2, respectively). HVSs were observed in 1 of 7 patients with posterior cerebral artery stenoses on angiogram. HVSs were seen equally in patients with acute focal (7 of 10) or diffuse (6 of 9) cerebral involvement. In the 6 HVS-positive patients with acute stroke confirmed by MRI, additional HVSs were observed in a different arterial territory than that of the stroke lesion. CONCLUSIONS: Although their significance remains unclear, multiple HVSs are more frequently observed in symptomatic patients with multiple intracerebral stenoses than in asymptomatic patients without stenosis.