Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS.

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

Bilateral Upper Cerebellar Hemorrhage Due to Pial Arteriovenous Fistula and Its Pathophysiological Insight.

OBJECTIVES: Bilateral upper cerebellar hemorrhage is extremely rare clinical entity but relatively known as postoperative neurosurgical complication with as-yet unknown etiology. Here, we report a case of bilateral upper cerebellar hemorrhage due to pial arteriovenous fistula (pAVF) and discuss the possible pathophysiology of this bleeding pattern. CASE DESCRIPTION: A 4-year-old boy who was previously healthy presented with a sudden onset of headache, vomiting, and gait instability. Computed tomography revealed atypical bleeding in the sulci of bilateral cerebellar hemispheres facing the tentorium. Despite the symmetric distribution of bleeding, T2-weighted magnetic resonance imaging showed flow void adjacent to the lateral margin of bleeding. Diffusion-weighted magnetic resonance imaging showed increased apparent diffusion coefficient value in the hemorrhagic lesion, suggesting vasogenic edema. Vertebral angiogram revealed a pAVF, which was fed by the hemispheric branch of superior cerebellar artery. It drained via the venous varix, inferiorly into the tortuous and engorged inferior hemispheric vein, indicating venous congestion. On the venous phase of vertebral angiogram, the superior vermian vein, which is one of the main drainers of the superior part of the cerebellum, was not opacified. Transarterial n-butyl-2-cyanoacrylate embolization was performed to prevent rebleeding, and the pAVF was treated successfully. The patient's follow-up has been uneventful for 3 years. CONCLUSIONS: We reported an extremely rare case of cerebellar pAVF presenting as bilateral upper cerebellar hemorrhage. Severe congestion of upper cerebellar veins seemed to be a possible pathophysiology of this specific bleeding pattern.

Collateral pial circulation relates to the degree of brain edema on CT 24 hours after ischemic stroke.

Background Cerebral edema is frequent in patients with acute ischemic stroke (AIS) who undergo reperfusion therapy and is associated with high mortality. The impact of collateral pial circulation (CPC) status on the development of edema has not yet been determined. Methods We studied consecutive patients with AIS and documented M1-middle cerebral artery (MCA) and/or distal internal carotid artery (ICA) occlusion who underwent reperfusion treatment. Edema was graded on the 24-hour non-contrast computed tomography (NCCT) scan. CPC was evaluated at the acute phase (≤6 hours) by transcranial color-coded Doppler, angiography and/or CT angiography. We performed an ordinal regression model for the effect of CPC on cerebral edema, adjusting for age, baseline National Institutes of Health Stroke Scale, Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on admission, NCCT, parenchymal hemorrhagic transformation at 24 hours and complete recanalization at six hours. Results Among the 108 patients included, 49.1% were male and mean age was 74.2 ± 11.6 years. Multivariable analysis showed a significant association between cerebral edema and CPC status (OR 0.22, 95% CI 0.08-0.59, p = 0.003), initial ASPECTS (OR 0.72, 95% CI 0.57-0.92, p = 0.007) and parenchymal hemorrhagic transformation (OR 23.67, 95% CI 4.56-122.8, p < 0.001). Conclusions Poor CPC is independently associated with greater cerebral edema 24 hours after AIS in patients who undergo reperfusion treatment.

Potential role of the Virchow Robin space in the pathogenesis of bacterial meningitis.

Meningitis is an infectious disease commonly arising from a bacterial etiology. The rapid progression of morbidity and mortality due to bacterial meningitis requires critical and imminent time-dependent clinical intervention. Although it is unambiguously clear that bacteria must infiltrate the cerebrospinal fluid, the sequence of events in the pathogenesis of bacterial meningitis has not been fully elucidated. Most reviews of the pathogenesis of bacterial meningitis do not specify the anatomical location of bacteria following BBB traversal. We propose an additional hypothesis focusing on the Virchow-Robin space (VRS). The VRS consists of a small, but identifiable perivascular space formed by a sheath of cells derived from the pia mater. The VRS has been described as an immunological space and possibly having a role in several neuropathological diseases. Solute exchange between cerebrospinal fluid and extracellular fluid occurs at the VRS, with subsequent drainage into the subarachnoid space. Because the VRS is continuous with the subpial space, a more direct route to the meninges is facilitated. The involvement of the VRS may have profound implications on the pathogenesis and therapeutic strategies: (1) nasopharyngeal colonization; (2) penetration into the blood stream after crossing the mucosal and epithelial membranes; (3) proliferation in the bloodstream; (4) extravasations through the endothelium of the post-capillary venules to the perivascular VRS; (5) migration from VRS to subpial space; (6) traversal through pia mater, entering the CSF in the subarachnoid space; (7) invasion of the meninges. The implication of the VRS in the pathogenesis of bacterial meningitis would be twofold. First, the VRS could provide an additional route of entry of bacteria into the brain. Second, the VRS could provide an area for bacterial proliferation, and thereby serve as a bacterial reservoir in relatively close proximity to the meninges. The clinical consequences of this hypothesis are: 1) clinical interpretation of laboratory findings, and 2) effective antibiotic delivery into the VRS. If the role of the VRS is established as part of bacterial meningitis pathogenesis, antibiotic pharmacokinetics and pharmacodynamics in the VRS need to be determined. This may result in developing novel antibiotic delivery and clinical strategies to improve morbidity and mortality.

Multiple subpial transections and magnetic resonance imaging.

INTRODUCTION: Multiple subpial transection (MST) has been applied to the treatment of refractory epilepsy when epileptogenic zone involves eloquent areas since 1989. However, there is a lack of data evaluating the effect of this surgical technique on the cortex as measured by Magnetic Resonance Imaging (MRI). PATIENTS AND METHODS: Ten consecutive patients (3F/7M, average age: 18.5 years) were operated on using radiating MST (average: 39; min: 19, max: 61) alone (n=3) or associated with another technique (n=7). Seven patients underwent a post-operative 3.0T MRI while 3 had a 1.5T MRI. Three patients had an early post-operative MRI and 7 a late MRI, among which 3 previously had an intraoperative MRI. RESULTS: The MR sequences that allowed the best assessment of MST-induced changes were T2 and T2*. The traces of MST are more visible on late MRI. These discrete non-complicated stigmas of MST were observed in all 10 studied patients: on the intraoperative MRI they are seen as micro-hemorrhagic spots (hypo-T2), on the early postoperative MRI as a discreet and limited cortical edema whether associated or not with micro-hemorrhagic spots and on the late MRI as liquid micro-cavities (hyper-T2) surrounded with a fine border of hemosiderin. CONCLUSIONS: MST-induced cerebral lesions are best visualized in T2-sequences, mainly on the late postoperatively MRIs. On all the MRI examinations in this study, the MST are only associated with limited modifications of the treated cortical regions.

Impairment of neurovascular coupling in Type 1 Diabetes Mellitus in rats is prevented by pancreatic islet transplantation and reversed by a semi-selective PKC inhibitor.

Streptozotocin (STZ)-induced chronic hyperglycemia has a detrimental effect on neurovascular coupling, linked to increased PKC-mediated phosphorylation and PKC isoform expression changes. Here, we sought to determine whether: 1) selective PKC-α/ß/γ inhibitor, GF109203X, could reverse the effects of chronic hyperglycemia on cerebrovascular reactivity; 2) pancreatic islet transplantation could prevent the development of cerebrovascular impairment seen in a rat model of Type 1 Diabetes. We studied the effect of GF109203X in diabetic (DM), non-diabetic (ND), and transplanted (TR) Lewis rats during either sciatic nerve stimulation (SNS) or the topical applications of the large-conductance Ca2+-operated K+(BKCa) channel opener, NS1619, or the K+ inward rectifier (Kir) channel agonist, KCl. Pial arteriole diameter changes were monitored using a closed cranial window in vivo microscopy technique. The pial arteriole dilatory response associated with SNS was decreased by ~45%, when comparing DM vs either ND or TR rats. Also, pial arteriolar dilations to topical KCl and NS1619 were largely attenuated in DM rats, but not in ND or TR animals. These responses were completely restored by the acute application of GF109203X to the brain surface. The PKC inhibitor had no effect on vascular responses in normoglycemic and TR animals. In conclusion, DM-associated chronic impairment of neurovascular coupling may be readily reversed by a PKC-α/ß/γ inhibitor or prevented via pancreatic islet transplantation. We believe that specific PCK isoforms (α/ß/γ) are mechanistically linked to the neurovascular uncoupling seen with hyperglycemia.

Use of indocyanine green for optical analysis of cortical infarcts in photothrombotic ischemic brains.

BACKGROUND: Currently used techniques for diagnosing ischemic injury, such as magnetic resonance imaging and computed tomography, are not easily accessible for basic research using small animals due to their high cost and low availability. NEW METHOD: We investigated the dynamic recovery of infarct regions in ischemia-injured brains using indocyanine green (ICG), which is inexpensive and readily available. This dye was used to visualize blood vessels and infarct area, and to measure blood flow after a photothrombotic ischemic operation (PIO). Mice were injected with ICG via the tail vein, and a time-series of fluorescence signal images was acquired before and after PIO. We then applied color codes to arteries and veins in the images and analyzed ICG intensity and dynamics. RESULTS: These time-series stacked images showed changes in pial vessel morphology after PIO. Further, a map of maximum fluorescence intensity showed an infarct in the dorsal cortical region. Changes in the blood flow index and mean transit time were also observed in the infarct region after PIO. COMPARISON WITH EXISTING METHOD(S): Our application of ICG imaging provided a range of information on PIO-induced infarcts in mice with relative ease and in a cost-effective manner. CONCLUSION: Our results show that optical imaging using ICG combined with a time-series analysis of molecular dynamics can be a useful tool for the anatomical and physiological monitoring of cortical ischemia.

VAP-1 blockade prevents subarachnoid hemorrhage-associated cerebrovascular dilating dysfunction via repression of a neutrophil recruitment-related mechanism.

Our previous findings indicated that in rats subjected to subarachnoid hemorrhage (SAH), suppression of post-SAH neuroinflammation via vascular adhesion protein-1 (VAP-1) blockade provides significant neuroprotection. We and others have reported that neuroinflammation contributes to cerebral microvascular impairment. Thus, in the present study, we tested the hypotheses that: (1) treatment with LJP-1586, a selective VAP-1 blocker, prevents SAH-associated pial arteriolar dilating dysfunction; and (2) the vasculoprotective effect of LJP-1586 arises from inhibiting SAH-elicited neutrophil recruitment. We utilized an endovascular perforation model of SAH. Rats subjected to SAH were either treated with LJP-1586 or rendered neutropenic via anti-neutrophil-antibody treatment. Findings from these groups were compared to their respective control groups. At 48 h post-SAH, rats were evaluated for neurobehavioral function, pial venular leukocyte trafficking, and pial arteriolar reactivity to topically-applied acetylcholine (ACh) and S-nitroso-N-acetyl penicillamine (SNAP). Pial arteriolar responses decreased at 48 h post-SAH. However, in the presence of LJP-1586, those responses were significantly preserved. Neutrophil-depletion yielded a substantial suppression of SAH-associated leukocyte adhesion and infiltration. This was accompanied by a significant preservation of pial arteriolar dilating function, suggesting a direct link between neutrophil recruitment and the loss of cerebral microvascular reactivity. Moreover, neutrophil depletion also was associated with significant protection of neurobehavioral function. The present findings suggest that attenuating SAH-linked elevation in neutrophil trafficking will protect against the development of microvascular dysfunction and subsequent neurological impairment.

Constriction and dysfunction of pial arterioles after regional hemorrhage in the subarachnoid space.

Increasing evidence indicates that poor outcomes after brain hemorrhage, especially after subarachnoid hemorrhage (SAH), can be attributed largely to dysfunction of the cerebral microcirculation. However, the cause of this dysfunction remains unclear. Here, we investigated changes in the cerebral microcirculation after regional hemorrhage in the subarachnoid space using the closed cranial window technique in mice. A single pial arteriole on the surface of the brain was punctured to induce a regional hemorrhage in the subarachnoid space. Physiological parameters were monitored during the procedure, and microvessel diameter was measured after hemorrhage. The vasoreactivity of the arterioles in response to hypercapnia as well as to topical application of the vasodilator acetylcholine (ACh) and S-nitroso-N-acetyl-penicillamine (SNAP) were assessed. The constriction of pial arterioles was detected without changes in other physiological parameters. Decreased reactivity of pial arterioles to all of the applied vasodilatory stimuli was observed after hemorrhage. Our results indicate that regional hemorrhage in the subarachnoid space can induce the vasospasm of microvessels and also reduce the vasoreactivity of pial arterioles.

Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets.

BACKGROUND: Cerebral hypoxia/ischemia (HI) is not uncommon during the perinatal period. If occurring, it can result in severe neurologic disabilities that persist throughout life. Salvinorin A, a non-opioid Kappa opioid receptors (KOR) selective agonist, has the potential to address this devastating situation. We have demonstrated that salvinorin A administration before HI, preserves pial artery autoregulative function through both the KOR and extracellular signal-regulated kinases (ERK) pathways. In the present study, we tested the hypothesis that administration of salvinorin A after HI could preserve cerebral autoregulation via KOR and ERK pathway. METHODOLOGY/PRINCIPAL FINDINGS: The response of the pial artery to hypercapnia, hypotension and isoproterenol were monitored before and 1 hour after HI in piglets equipped with a cranial window. Four groups of drug administration were performed after HI. The control group had DMSO (1 µl/kg, i.v.) administrated immediately after HI. Two salvinorin A treated groups had salvinorin A (10 µg/kg, i.v.) administrated 0 and 30 min after HI, respectively. The 4(th) group had salvinorin A and the KOR antagonist norbinaltorphimine (Nor-BIN, 1 µM topical) co-administrated 0 min after HI (n = 5). The dilation responses of the pial artery to hypercapnia and hypotension were impaired after global HI and were preserved with salvinorin A administration immediately or 30 min after HI. The preservation of autoregulation was abolished when nor-BIN was administered. Levels of phosphor-ERK(pERK)/ERK in the cerebrospinal fluid (CSF) were measured before and 1 hour after HI. After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group. The elevated levels of pERK/ERK were not observed with salvinorin A only groups. CONCLUSIONS: Salvinorin A administration 0 and 30 min after HI preserves autoregulation of pial artery to hypercapnia and hypotension via kappa opioid receptor and ERK pathway.

Permeability of dura mater: a possible link between cortical spreading depression and migraine pain? A comment.

In the wake of cortical spreading depression (CSD) it has been suggested that noxious substances diffuse through the dura with resulting firing of epidural nerves. In my view this is unlikely because there are good reasons to suggest that there must be a dura-brain barrier. Alternatively collateral branches from the trigeminal nerve to the pia and the dura may signal what is happening with ions and substances on the brain surface during CSD to the epidural space.

Evaluation by fluid/structure-interaction spinal-cord simulation of the effects of subarachnoid-space stenosis on an adjacent syrinx.

A finite-element numerical model was constructed of the spinal cord, pia mater, filum terminale, cerebrospinal fluid in the spinal subarachnoid space (SSS), and dura mater. The cord was hollowed out by a thoracic syrinx of length 140 mm, and the SSS included a stenosis of length 30 mm opposite this syrinx. The stenosis severity was varied from 0% to 90% by area. Pressure pulse excitation was applied to the model either at the cranial end of the SSS, simulating the effect of cranial arterial pulsation, or externally to the abdominal dura mater, simulating the effect of cough. A very short pulse was used to examine wave propagation; a pulse emulating cardiac systole was used to examine the effects of fluid displacement. Additionally, repetitive sinusoidal excitation was applied cranially. Bulk fluid flow past the stenosis gave rise to prominent longitudinal pressure dissociation ("suck") in the SSS adjacent to the syrinx. However, this did not proportionally increase the longitudinal motion of fluid in the syrinx. The inertia of the fluid in the SSS, together with the compliance of this space, gave a resonance capable of being excited constructively or destructively by cardiac or coughing impulses. The main effect of mild stenosis was to lower the frequency of this resonance; severe stenosis damped out to-and-fro motions after the end of the applied excitation. Syrinx fluid motion indicated the fluid momentum and thus the pressure developed when the fluid was stopped by the end of the syrinx; however, the tearing stress in the local cord material depended also on the instantaneous local SSS pressure and was therefore not well predicted by syrinx fluid motion. Stenosis was also shown to give rise to a one-way valve effect causing raised SSS pressure caudally and slight average cord displacement cranially. The investigation showed that previous qualitative predictions of the effects of suck neglected factors that reduced the extent of the resulting syrinx fluid motion and of the cord tearing stress, which ultimately determines whether the syrinx lengthens.

SNP improves cerebral hemodynamics during normotension but fails to prevent sex dependent impaired cerebral autoregulation during hypotension after brain injury.

Traumatic brain injury (TBI) is a leading cause of morbidity in children and boys are disproportionately represented. Hypotension is common and worsens outcome after TBI. Previous studies show that adrenomedullin, a cerebrovasodilator, prevented sex dependent impairment of autoregulation during hypotension after piglet fluid percussion brain injury (FPI). We hypothesized that this concept was generalizable and that administration of another vasodilator, sodium nitroprusside (SNP), may equally improve CBF and cerebral autoregulation in a sex dependent manner after FPI. SNP produced equivalent percent cerebrovasodilation in male and female piglets. Reductions in pial artery diameter, cortical CBF, and cerebral perfusion pressure (CPP) concomitant with elevated intracranial pressure (ICP) after FPI were greater in male compared to female piglets during normotension which was blunted by SNP. During hypotension, pial artery dilation (PAD) was impaired more in the male than the female after FPI. However, SNP did not improve hypotensive PAD after FPI in females and paradoxically caused vasoconstriction in males. SNP did not prevent reductions in CBF, CPP or autoregulatory index during combined hypotension and FPI in either sex. SNP aggravated ERK MAPK upregulation after FPI. These data indicate that despite prevention of reductions in CBF after FPI, SNP does not prevent impairment of autoregulation during hypotension after FPI. These data suggest that therapies directed at a purely hemodynamic increase in CPP will fail to improve outcome during combined TBI and hypotension.

Reduced blood brain barrier breakdown in P-selectin deficient mice following transient ischemic stroke: a future therapeutic target for treatment of stroke.

BACKGROUND: The link between early blood- brain barrier (BBB) breakdown and endothelial cell activation in acute stroke remain poorly defined. We hypothesized that P-selectin, a mediator of the early phase of leukocyte recruitment in acute ischemia is also a major contributor to early BBB dysfunction following stroke. This was investigated by examining the relationship between BBB alterations following transient ischemic stroke and expression of cellular adhesion molecule P-selectin using a combination of magnetic resonance molecular imaging (MRMI), intravital microscopy and immunohistochemistry. MRMI was performed using the contrast, gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) conjugated to Sialyl Lewis X (Slex) where the latter is known to bind to activated endothelium via E- or P selectins. Middle cerebral artery occlusion was induced in male C57/BL 6 wild-type (WT) mice and P-selectin-knockout (KO) mice. At 24 hours following middle cerebral artery occlusion, T1 maps were acquired prior to and following contrast injection. In addition to measuring P- and E-selectin expression in brain homogenates, alterations in BBB function were determined immunohistochemically by assessing the extravasation of immunoglobulin G (IgG) or staining for polymorphonuclear (PMN) leukocytes. In vivo assessment of BBB dysfunction was also investigated optically using intravital microscopy of the pial circulation following the injection of Fluorescein Isothiocyanate (FITC)-dextran (MW 2000 kDa). RESULTS: MRI confirmed similar infarct sizes and T1 values at 24 hours following stroke for both WT and KO animals. However, the blood to brain transfer constant for Gd DTPA (Kgd) demonstrated greater tissue extravasation of Gd DTPA in WT animals than KO mice (P < 0.03). In the P selectin KO mice, Delta T1 stroke -Delta T1 contralateral control cortex, decreased significantly in the Gd-DTPA(sLeX) group compared to Gd-DTPA, indicative of sLeX mediated accumulation of the targeted contrast agent. Regarding BBB function, in the P-selectin KO mice compared to WT control mice, there was an attenuation in the extravasation of IgG (P < 0.001), a trend for decreased FITC extravasation and less infiltration of PMN leukocytes (P < 0.001) thereby supporting the observed increase in Kgd permeability in stroke brain of WT compared to KO mice. CONCLUSION: P-selectin expression contributes to enhanced BBB dysfunction at 24 hours after transient focal cerebral ischemia.

Effects of white, grey, and pia mater properties on tissue level stresses and strains in the compressed spinal cord.

Recent demographics demonstrate an increase in the number of elderly spinal cord injury patients, motivating the desire for a better understanding of age effects on injury susceptibility. Knowing that age and disease affect neurological tissue, there is a need to better understand the sensitivity of spinal cord injury mechanics to variations in tissue behavior. To address this issue, a plane-strain, geometrically nonlinear, finite element model of a section of a generic human thoracic spinal cord was constructed to model the response to dorsal compression. The material models and stiffness responses for the grey and white matter and pia mater were varied across a range of reported values to observe the sensitivity of model outcomes to the assigned properties. Outcome measures were evaluated for percent change in magnitude and alterations in spatial distribution. In general, principal stresses (114-244% change) and pressure (75-119% change) were the outcomes most sensitive to material variation. Strain outcome measures were less sensitive (7-27% change) than stresses (74-244% change) to variations in material tangent modulus. The pia mater characteristics had limited (<4% change) effects on outcomes. Using linear elastic models to represent non-linear behavior had variable effects on outcome measures, and resulted in highly concentrated areas of elevated stresses and strains. Pressure measurements in both the grey and white matter were particularly sensitive to white matter properties, suggesting that degenerative changes in white matter may influence perfusion in a compressed spinal cord. Our results suggest that the mechanics of spinal cord compression are likely to be affected by changes in tissue resulting from aging and disease, indicating a need to study the biomechanical aspects of spinal cord injury in these specific populations.

The long-term microvascular and behavioral consequences of experimental traumatic brain injury after hypothermic intervention.

Traumatic brain injury (TBI) has been demonstrated to induce cerebral vascular dysfunction that is reflected in altered responses to various vasodilators. While previous reports have focused primarily on the short-term vascular alterations, few have examined these vascular changes for more than 7 days, or have attempted to correlate these alterations with any persisting behavioral changes or potential therapeutic modulation. Accordingly, we evaluated the long-term microvascular and behavioral consequences of experimental TBI and their therapeutic modulation via hypothermia. In this study, one group was injured with no treatment, another group was injured and 1 h later was treated with 120 min of hypothermia followed by slow rewarming, and a third group was non-injured. Animals equipped with cranial windows for visualization of the pial microvasculature were challenged with various vasodilators, including acetylcholine, hypercapnia, adenosine, pinacidil, and sodium nitroprusside, at either 1 or 3 weeks post-TBI. In addition, all animals were tested for vestibulomotor tasks at 1 week post-TBI, and animals surviving for 3 weeks post-TBI were tested in a Morris water maze (MWM). The results of this investigation demonstrated that TBI resulted in long-term vascular dysfunction in terms of altered vascular reactivity to various vasodilators, which was significantly improved with the use of a delayed 120-min hypothermic treatment. In contrast, data from the MWM task indicated that injured animals revealed persistent deficits in the spatial memory test performance, with hypothermia exerting no protective effects. Collectively, these data illustrate that TBI can evoke long-standing brain vascular and spatial memory dysfunction that manifest different responses to hypothermic intervention. These findings further illustrate the complexity of TBI and highlight the fact that the chosen hypothermic intervention may not necessarily exert a global protective response.

Biomechanical study of cervical flexion myelopathy using a three-dimensional finite element method.

OBJECT: The goal of this study was to perform a biomechanical study of cervical flexion myelopathy (CFM) using a finite element method. METHODS: A 3D finite element model of the spinal cord was established consisting of gray matter, white matter, and pia mater. After the application of semi-static compression, the model underwent anterior flexion to simulate CFM. The flexion angles used were 5 degrees and 10 degrees , and stress distributions inside the spinal cord were then evaluated. RESULTS: Stresses on the spinal cord were very low under semi-static compression but increased after 5 degrees of flexion was applied. Stresses were concentrated in the gray matter, especially the anterior and posterior horns. The stresses became much higher after application of 10 degrees of flexion and were observed in the gray matter, posterior funiculus, and a portion of the lateral funiculus. CONCLUSIONS: The 5 degrees model was considered to represent the mild type of CFM. This type corresponds to the cases described in the original report by Hirayama and colleagues. The main symptom of this type of CFM is muscle atrophy and weakness caused by the lesion of the anterior horn. The 10 degrees model was considered to represent a severe type of CFM and was associated with lesions in the posterior fand lateral funiculi. This type of CFM corresponds to the more recently reported clinical cases with combined long tract signs and sensory disturbance.

Differences in adrenoreception in the microcirculatory bed of the pia mater in normotensive and spontaneously hypertensive rats.

Adrenoceptors in pial vascular bed of normotensive Wistar-Kyoto rats are distributed unevenly during stimulation of the superior cervical ganglion, their density was maximum in the 5th-generation arteries. In spontaneously hypertensive rats (SHR) the density of adrenoceptor is lower than in normotensive rats and their number is maximum in the 1st-generation arteries.

Atypical growth pattern of a meningioma in an adult.

A 49-year-old woman presented with a rare atypical growth pattern of meningioma without evidence of dural attachment manifesting as chronic headache associated with transient paresthesia and left motor disorders. On admission, neurological examination showed no abnormalities. Magnetic resonance (MR) imaging revealed a right temporo-parieto-occipital lesion, which appeared to involve the subdural space and filling the cortical sulci. The lesion caused peritumoral white matter edema. The tumor appeared hypointense on T(1)-weighted and hyperintense on T(2)-weighted MR images, with homogeneous enhancement after contrast administration. A biopsy of the lesion was performed. Histological examination indicated that the lesion was a meningioma. Intraparenchymal meningiomas should be considered in the differential diagnosis of intraaxial lesions in patients of any age.

Meningioma without dural attachment: case report, classification, and review of the literature.

BACKGROUND: The primary occurrences of meningiomas without attachment to the dura are rare. Clinical considerations and pathophysiologic mechanisms about these tumors have not been sufficiently explored, and a complete classification has not been accomplished. CASE DESCRIPTION: A 16-year-old adolescent boy presented with epileptic seizure for 9 years. Neurologic deficits were not found on admission. Magnetic resonance imaging revealed a 25 x 23-mm mass lesion without dural attachment located in the parietooccipital region. The tumor was iso-intense on T1-weighted and hyperintense on T2-weighted images, and became clearly and heterogenously enhanced with gadolinium. During surgery, a right parietooccipital craniotomy revealed the tumor was completely buried in the sulcus occipitalis anterior. Total removal of the tumor was accomplished. Histologic examination indicated that the lesion was an atypical meningioma. CONCLUSION: According to sites of the tumor, supratentorial meningiomas without dural attachment are classified into 5 varieties, and posterior fossa meningiomas without dural attachment into 4 categories. Except for intraventricular ones, meningiomas without dural attachment predominantly occur in males. The average age is about 20 years younger than that of meningiomas in general. Fibroblastic meningiomas constitute the major subtype. Intraparenchymal or subcortical meningiomas should be considered as one type, which may arise from arachnoid cells of the pia mater within brain sulcus.