Vitamin D deficiency promotes intracranial aneurysm rupture.

Intracranial aneurysm rupture causes severe disability and high mortality. Epidemiological studies show a strong association between decreased vitamin D levels and an increase in aneurysm rupture. However, the causality and mechanism remain largely unknown. In this study, we tested whether vitamin D deficiency promotes aneurysm rupture and examined the underlying mechanism for the protective role of vitamin D against the development of aneurysm rupture utilizing a mouse model of intracranial aneurysm. Mice consuming a vitamin D-deficient diet had a higher rupture rate than mice with a regular diet. Vitamin D deficiency increased proinflammatory cytokines in the cerebral arteries. Concurrently, vitamin D receptor knockout mice had a higher rupture rate than the corresponding wild-type littermates. The vitamin D receptors on endothelial and vascular smooth muscle cells, but not on hematopoietic cells, mediated the effect of aneurysm rupture. Our results establish that vitamin D protects against the development of aneurysmal rupture through the vitamin D receptors on vascular endothelial and smooth muscle cells. Vitamin D supplementation may be a viable pharmacologic therapy for preventing aneurysm rupture.

Transcallosal-Transchoroidal Fissure Approach for Midbrain and Thalamic Cavernous Malformations: 2-Dimensional Operative Video.

INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: Cavernous malformations of the third ventricle arise from the medial thalamus and/or periaqueductal midbrain. Microsurgical resection is indicated when the lifetime risk of hemorrhage outweighs the surgical risks. ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: superior sagittal sinus, callosomarginal and pericallosal arteries, corpus callosum, foramen of Monro, choroidal fissure, fornix, thalamostriate veins, internal cerebral veins (ICVs), velum interpositum, and thalamus. ESSENTIAL STEPS OF THE PROCEDURE: The patient consents to the procedure. With the patient supine, the head is turned 90° and laterally flexed 45°. A bifrontal craniotomy positioned two-thirds anterior and one-third posterior to the coronal suture is performed. The interhemispheric fissure is opened, and a 2-cm corpus callosotomy is performed. Choroid plexus cauterization exposes the choroidal fissure. Sharp division of the taenia fornicea opens the velum interpositum, where the thalamostriate vein can be followed around the venous angle to the ICV. The anterior septal vein may be divided to communicate between the foramen of Monro and choroidal fissure. Dissection between the ICVs opens the velum interpositum into the third ventricle. PITFALLS/AVOIDANCE OF COMPLICATIONS: Frontal or deep vein occlusion causes venous infarction, and dissection on the nondominant hemisphere is preferred. Other complications include arterial infarction, fornix injury from choroidal fissure dissection or forniceal retraction, and thalamic or midbrain injury during lesion resection. VARIANTS AND INDICATIONS FOR THEIR USE: The contralateral choroidal fissure is used for low-lying medial thalamic and midbrain lesions. The ipsilateral choroidal fissure is used for high-lying or large lesions extending laterally. Transchoroidal approaches are not needed for superior (transcallosal only) or anterior (contralateral transcallosal-contralateral transforaminal) thalamic lesions. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.

Trauma-specific mindfulness-based cognitive therapy for women with post-traumatic stress disorder and a history of domestic abuse: intervention refinement and a randomised feasibility trial (coMforT study).

BACKGROUND: Women who have experienced domestic violence and abuse (DVA) are at increased risk of developing post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD). In 2014-2015, we developed a prototype trauma-specific mindfulness-based cognitive therapy curriculum (TS-MBCT) for the treatment of PTSD in a DVA population. This study aimed to refine the prototype TS-MBCT and evaluate the feasibility of conducting a randomised controlled trial (RCT) testing its effectiveness and cost-effectiveness. METHODS: Intervention refinement phase was informed by evidence synthesis from a literature review, qualitative interviews with professionals and DVA survivors, and a consensus exercise with experts in trauma and mindfulness. We tested the refined TS-MBCT intervention in an individually randomised parallel group feasibility trial with pre-specified progression criteria, a traffic light system, and embedded process and health economics evaluations. RESULTS: The TS-MBCT intervention consisted of eight group sessions and home practice. We screened 109 women in a DVA agency and recruited 20 (15 TS-MBCT, 5 self-referral to National Health Service (NHS) psychological treatment), with 80% follow-up at 6 months. Our TS-MBCT intervention had 73% uptake, 100% retention, and high acceptability. Participants suggested recruitment via multiple agencies, and additional safety measures. Randomisation into the NHS control arm did not work due to long waiting lists and previous negative experiences. Three self-administered PTSD/CPTSD questionnaires produced differing outcomes thus a clinician administered measure might work better. We met six out of nine feasibility progression criteria at green and three at amber targets demonstrating that it is possible to conduct a full-size RCT of the TS-MBCT intervention after making minor amendments to recruitment and randomisation procedures, the control intervention, primary outcomes measures, and intervention content. At 6 months, none of the PTSD/CPTSD outcomes ruled out a clinically important difference between trial arms indicating that it is reasonable to proceed to a full-size RCT to estimate these outcomes with greater precision. CONCLUSIONS: A future RCT of the coMforT TS-MBCT intervention should have an internal pilot, recruit from multiple DVA agencies, NHS and non-NHS settings, have an active control psychological treatment, use robust randomisation and safety procedures, and clinician-administered measures for PTSD/CPTSD. TRIAL REGISTRATION: ISRCTN64458065 11/01/2019.

Potential Anti-Alzheimer Properties of Mogrosides in Vitamin B12-Deficient Caenorhabditis elegans.

Vitamin B12 deficiency can lead to oxidative stress, which is known to be involved in neurodegenerative diseases such as Alzheimer's disease (AD). Mogrosides are plant-derived triterpene glycosides that exhibit anti-inflammatory and antioxidant activity in animal cell lines and mouse models. Since amyloid-ß toxicity is known to cause oxidative stress and damage to brain cells, we hypothesized that mogrosides may have a protective effect against AD. In this study, we investigated the potential anti-AD effect of mogrosides in vitamin B12-deficient wild-type N2 and in transgenic CL2355 Caenorhabditis elegans expressing amyloid-ß peptide. Our data indicated that mogrosides have a beneficial effect on the lifespan and egg-laying rate of N2 and vitamin B12-deficient N2 worms. Additionally, the results revealed that mogrosides can effectively delay the paralysis of CL2355 worms as determined by serotonin sensitivity assay. Our analysis showed that mogrosides increase the expression of oxidative protective genes in N2 worms fed with vitamin B12-deficient OP50 bacterium. We conclude that mogrosides may exert preventative rather than curative effects that counteract the detrimental vitamin B12-deficient environment in N2 and CL2355 C. elegans by modulating oxidation-related gene expression.

Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm.

Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-ß. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein's protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-ß and subsequent suppression of inflammation. Dietary daidzein's protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

Clip retraction of the tentorium: application of a novel technique for tentorial retraction during supracerebellar transtentorial approaches.

Supracerebellar transtentorial (SCTT) approaches have become a popular option for treatment of a variety of pathologies in the medial and basal temporal and occipital lobes and thalamus. Transtentorial approaches provide numerous advantages over transcortical approaches, including obviating the need to traverse eloquent cortex, not requiring parenchymal retraction, and circumventing critical vascular structures. All of these approaches require a tentorial opening, and numerous techniques for retraction of the incised tentorium have been described, including sutures, fixed retractors, and electrocautery. However, all of these techniques have considerable drawbacks and limitations. The authors describe a novel application of clip retraction of the tentorium to the supracerebellar approaches in which an aneurysm clip is used to suspend the tentorial flap, and an illustrative case is provided. Clip retraction of the tentorium is an efficient, straightforward adaptation of an established technique, typically used for subtemporal approaches, that improves visualization and surgical ergonomics with little risk to nearby venous structures. The authors find this technique particularly useful for the contralateral SCTT approaches.

Effect of elevation of vascular endothelial growth factor level on exacerbation of hemorrhage in mouse brain arteriovenous malformation.

OBJECTIVE: A high level of vascular endothelial growth factor (VEGF) has been implicated in brain arteriovenous malformation (bAVM) bleeding and rupture. However, direct evidence is missing. In this study the authors used a mouse bAVM model to test the hypothesis that elevation of focal VEGF levels in bAVMs exacerbates the severity of bAVM hemorrhage. METHODS: Brain AVMs were induced in adult mice in which activin receptor-like kinase 1 (Alk1, a gene that causes AVM) gene exons 4-6 were floxed by intrabasal ganglia injection of an adenoviral vector expressing Cre recombinase to induce Alk1 mutation and an adeno-associated viral vector expressing human VEGF (AAV-VEGF) to induce angiogenesis. Two doses of AAV-VEGF (5 × 109 [high] or 2 × 109 [low]) viral genomes were used. In addition, the common carotid artery and external jugular vein were anastomosed in a group of mice treated with low-dose AAV-VEGF 6 weeks after the model induction to induce cerebral venous hypertension (VH), because VH increases the VEGF level in the brain. Brain samples were collected 8 weeks after the model induction. Hemorrhages in the bAVM lesions were quantified on brain sections stained with Prussian blue, which detects iron deposition. VEGF levels were quantified in bAVM tissue by enzyme-linked immunosorbent assay. RESULTS: Compared to mice injected with a low dose of AAV-VEGF, the mice injected with a high dose had higher levels of VEGF (p = 0.003) and larger Prussian blue-positive areas in the bAVM lesion at 8 or 9 weeks after model induction (p = 0.002). VH increased bAVM hemorrhage in the low-dose AAV-VEGF group. The overall mortality in the high-dose AAV-VEGF group was 26.7%, whereas no mouse died in the low-dose AAV-VEGF group without VH. In contrast, VH caused a mortality of 50% in the low-dose AAV-VEGF group. CONCLUSIONS: Using mouse bAVM models, the authors provided direct evidence that elevation of the VEGF level increases bAVM hemorrhage and mouse mortality.

Contralateral Supracerebellar-Infratentorial Approach for Resection of Thalamic Cavernous Malformations.

BACKGROUND: Surgical resection of cavernous malformations (CM) in the posterior thalamus, pineal region, and midbrain tectum is technically challenging owing to the presence of adjacent eloquent cortex and critical neurovascular structures. Various supracerebellar infratentorial (SCIT) approaches have been used in the surgical armamentarium targeting lesions in this region, including the median, paramedian, and extreme lateral variants. Surgical view of a posterior thalamic CM from the traditional ipsilateral vantage point may be obscured by occipital lobe and tentorium. OBJECTIVE: To describe a novel surgical approach via a contralateral SCIT (cSCIT) trajectory for resecting posterior thalamic CMs. METHODS: From 1997 to 2017, 75 patients underwent the SCIT approach for cerebrovascular/oncologic pathology by the senior author. Of these, 30 patients underwent the SCIT approach for CM resection, and 3 patients underwent the cSCIT approach. Historical patient data, radiographic features, surgical technique, and postoperative neurological outcomes were evaluated in each patient. RESULTS: All 3 patients presented with symptomatic CMs within the right posterior thalamus with radiographic evidence of hemorrhage. All surgeries were performed in the sitting position. There were no intraoperative complications. Neuroimaging demonstrated complete CM resection in all cases. There were no new or worsening neurological deficits or evidence of rebleeding/recurrence noted postoperatively. CONCLUSION: This study establishes the surgical feasibility of a contralateral SCIT approach in resection of symptomatic thalamic CMs It demonstrates the application for this procedure in extending the surgical trajectory superiorly and laterally and maximizing safe resectability of these deep CMs with gravity-assisted brain retraction.

Reduction of shunt dependency rates following aneurysmal subarachnoid hemorrhage by tandem fenestration of the lamina terminalis and membrane of Liliequist during microsurgical aneurysm repair.

OBJECTIVEShunt-dependent hydrocephalus is an important cause of morbidity following aneurysmal subarachnoid hemorrhage (aSAH) in excess of 20% of cases. Hydrocephalus leads to prolonged hospital and ICU stays, well as to repeated surgical interventions, readmissions, and complications associated with ventriculoperitoneal (VP) shunts, including shunt failure and infection. Whether variations in surgical technique at the time of aneurysm treatment may modify rates of shunt dependency remains a matter of debate. Here, the authors report on their experience with tandem fenestration of the lamina terminalis (LT) and membrane of Liliequist (MoL) at the time of open microsurgical repair of the ruptured aneurysm.METHODSThe authors conducted a retrospective review of 663 consecutive patients with aSAH treated from 2005 to 2015 by open microsurgery via a pterional or orbitozygomatic craniotomy by the senior author (M.T.L.). Data collected from review of the electronic medical record included age, Hunt and Hess grade, Fisher grade, need for an external ventricular drain, and opening pressure. Patients were stratified into those undergoing no fenestration and those undergoing tandem fenestration of the LT and MoL at the time of surgical repair. Outcome variables, including VP shunt placement and timing of shunt placement, were recorded and statistically analyzed.RESULTSIn total, shunt-dependent hydrocephalus was observed in 15.8% of patients undergoing open surgical repair following aSAH. Tandem microsurgical fenestration of the LT and MoL was associated with a statistically significant reduction in shunt dependency (17.9% vs 3.2%, p < 0.01). This effect was confirmed with multivariate analysis of collected variables (multivariate OR 0.09, 95% CI 0.03-0.30). Number-needed-to-treat analysis demonstrated that tandem fenestration was required in approximately 6.8 patients to prevent a single VP shunt placement. A statistically significant prolongation in days to VP shunt surgery was also observed in patients treated with tandem fenestration (26.6 ± 19.4 days vs 54.0 ± 36.5 days, p < 0.05).CONCLUSIONSTandem fenestration of the LT and MoL at the time of open microsurgical clipping and/or bypass to secure ruptured anterior and posterior circulation aneurysms is associated with reductions in shunt-dependent hydrocephalus following aSAH. Future prospective randomized multicenter studies are needed to confirm this result.

Nonclinical safety biomarkers of drug-induced vascular injury: current status and blueprint for the future.

Better biomarkers are needed to identify, characterize, and/or monitor drug-induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI.

Translation strategy for the qualification of drug-induced vascular injury biomarkers.

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commission's Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes.

Deep arteriovenous malformations in the basal ganglia, thalamus, and insula: multimodality management, patient selection, and results.

OBJECTIVE: This study sought to describe a single institution's experience treating arteriovenous malformations (AVMs) of the basal ganglia, thalamus, and insula in a multimodal fashion. METHODS: We conducted a retrospective review of all deep AVMs treated at our institution between 1997 and 2011 with attention to patient selection, treatment strategies, and radiographic and functional outcomes. RESULTS: A total of 97 patients underwent initial treatment at our institution. 64% presented with hemorrhage with 29% located in the basal ganglia, 41% in the thalamus, and 30% in the insula. 80% were Spetzler-Martin grade III-IV. Initial treatment was microsurgical resection in 42%, stereotactic radiosurgery (SRS) in 45%, and observation in 12%. Radiographic cure was achieved in 54% after initial surgical or SRS treatment (71% and 23%, respectively) and in 63% after subsequent treatments, with good functional outcomes in 78% (median follow-up 2.2 years). Multivariate logistic regression analysis revealed treatment group and age as factors associated with radiographic cure, whereas Spetzler-Martin score and time to follow-up were significantly associated with improved/unchanged functional status at time of last follow-up. Posttreatment hemorrhage occurred in 11% (7% of surgical and 18% of SRS patients). CONCLUSIONS: Modern treatment of deep AVMs includes a multidisciplinary approach utilizing microsurgery, SRS, embolization, and observation. Supplementary grading adds meaningfully to traditional Spetzler-Martin grading to guide patient selection. Surgical resection is more likely to result in obliteration compared with SRS, and is associated with satisfactory results in carefully selected patients.

Deep arteriovenous malformations in the Basal Ganglia, thalamus, and insula: microsurgical management, techniques, and results.

BACKGROUND: Arteriovenous malformations (AVMs) in the basal ganglia, thalamus, and insula are considered inoperable given their depth, eloquence, and limited surgical exposure. Although many neurosurgeons opt for radiosurgery or observation, others have challenged the belief that deep AVMs are inoperable. Further discussion of patient selection, technique, and multimodality management is needed. OBJECTIVE: To describe and discuss the technical considerations of microsurgical resection for deep-seated AVMs. METHODS: Patients with deep AVMs who underwent surgery during a 14-year period were reviewed through the use of a prospective AVM registry. RESULTS: Microsurgery was performed in 48 patients with AVMs in the basal ganglia (n=10), thalamus (n=13), or insula (n=25). The most common Spetzler-Martin grade was III- (68%). Surgical approaches included transsylvian (67%), transcallosal (19%), and transcortical (15%). Complete resection was achieved in 34 patients (71%), and patients with incomplete resection were treated with radiosurgery. Forty-five patients (94%) were improved or unchanged (mean follow-up, 1.6 years). CONCLUSION: This experience advances the notion that select deep AVMs may be operable lesions. Patients were highly selected for small size, hemorrhagic presentation, young age, and compactness-factors embodied in the Spetzler-Martin and Supplementary grading systems. Overall, 10 different approaches were used, exploiting direct, transcortical corridors created by hemorrhage or maximizing anatomic corridors through subarachnoid spaces and ventricles that minimize brain transgression. The same cautious attitude exercised in selecting patients for surgery was also exercised in deciding extent of resection, opting for incomplete resection and radiosurgery more than with other AVMs to prioritize neurological outcomes.

Pregabalin induces hepatic hypoxia and increases endothelial cell proliferation in mice, a process inhibited by dietary vitamin E supplementation.

The preceding article identified key components of pregabalin's mode of action on nongenotoxic hemangiosarcoma formation in mice, including increased serum bicarbonate leading to decreased respiratory rate, increased blood pH, increased venous oxygen saturation, increased vascular endothelial growth factor and basic fibroblast growth factor expression, increased hepatic vascular endothelial growth factor receptor 2 expression, and increased iron-laden macrophages. Increased platelet count and platelet activation were early, species-specific biomarkers in mice. Dysregulated erythropoiesis, macrophage activation, and elevations of tissue growth factors were consistent with the unified mode of action for nongenotoxic hemangiosarcoma recently proposed at an international hemangiosarcoma workshop (Cohen, S. M., Storer, R. D., Criswell, K. A., Doerrer, N. G., Dellarco, V. L., Pegg, D. G., Wojcinski, Z. W., Malarkey, D. E., Jacobs, A. C., Klaunig, J. E., et al. (2009). Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance. Toxicol. Sci. 111, 4-18). In this article, we present evidence that pregabalin induces hypoxia and increases endothelial cell (EC) proliferation in a species-specific manner. Dietary administration of pregabalin produced a significant 35% increase in an immunohistochemical stain for hypoxia (Hypoxyprobe) in livers from pregabalin-treated mice. Increased Hypoxyprobe staining was not observed in the liver, bone marrow, or spleen of rats, supporting the hypothesis that pregabalin produces local tissue hypoxia in a species-specific manner. Transcriptional analysis supports that rats, unlike mice, adapt to pregabalin-induced hypoxia. Using a dual-label method, increased EC proliferation was observed as early as 2 weeks in mouse liver and 12 weeks in bone marrow following pregabalin administration. These same assays showed decreased EC proliferation in hepatic ECs of rats, further supporting species specificity. Dietary supplementation with vitamin E, which is known to have antioxidant and antiangiogenic activity, inhibited pregabalin-induced increases in mouse hepatic EC proliferation, providing confirmatory evidence for the proposed mode of action and its species-specific response.

Preclinical studies of PF-04849285, an interferon-α8 fusion protein for the treatment of HCV.

BACKGROUND: This study presents preclinical data of a novel interferon (IFN)-α8 fusion protein, PF-04849285, and compares it with IFN-α2 and pegylated IFN-α2; the latter being the current standard of care for HCV. METHODS: The antiviral properties were evaluated in vitro using the HCV replication assay (replicon) and the general encephalomyocarditis virus assay. The binding affinity to both IFNR-subunits was assessed using surface plasmon resonance. Ex vivo experiments using cynomolgus monkey and human blood were used for the evaluation of induction of IFN-inducible biomarkers (interferon inducible protein 10 [IP-10], 2'-5'-oligoadenylate synthetase [OAS2] and interleukin-6 [IL-6]). The molecule was tested intravenously and subcutaneously in cynomolgus monkey in a single dose study for two weeks at 0.01, 1, 5 and 20 mg/kg. Each route and dose combination was given to a single male animal, blood samples were collected for evaluation of biomarkers and pharmacokinetics. The compound was also tested in cynomolgus monkey in a multiple dose study for four weeks, with a twice-a-week dosing prior to a three-week wash-out period for toxicokinetics, pharmacokinetics, and biomarker evaluation at 20, 50 or 100 mg/kg subcutaneously and 20 mg/kg intravenously. RESULTS: The molecule is 10× more potent than the pegylated IFN-α2a, with potency similar to the unmodified IFN-α2a. No unanticipated findings were observed in cynomolgus monkey when dosed up to 20 mg/kg, >10,000-fold margin over the anticipated efficacious human dose. CONCLUSIONS: The biomarker and toxicological findings were consistent with a potent IFN molecule. The potency and pharmacokinetic properties of the molecule are consistent with dosing at least every two weeks with the potential for monthly dosing' and not 'at least twice daily' as presented in the original [corrected].

Supratentorial cavernous malformations in eloquent and deep locations: surgical approaches and outcomes. Clinical article.

OBJECT: Resection of cavernous malformations (CMs) located in functionally eloquent areas of the supratentorial compartment is controversial. Hemorrhage from untreated lesions can result in devastating neurological injury, but surgery has potentially serious risks. We hypothesized that an organized system of approaches can guide operative planning and lead to acceptable neurological outcomes in surgical patients. METHODS: The authors reviewed the presentation, surgery, and outcomes of 79 consecutive patients who underwent microresection of supratentorial CMs in eloquent and deep brain regions (basal ganglia [in 27 patients], sensorimotor cortex [in 23], language cortex [in 3], thalamus [in 6], visual cortex [in 10], and corpus callosum [in 10]). A total of 13 different microsurgical approaches were organized into 4 groups: superficial, lateral transsylvian, medial interhemispheric, and posterior approaches. RESULTS: The majority of patients (93.7%) were symptomatic. Hemorrhage with resulting focal neurological deficit was the most common presentation in 53 patients (67%). Complete resection, as determined by postoperative MR imaging, was achieved in 76 patients (96.2%). Overall, the functional neurological status of patients improved after microsurgical dissection at the time of discharge from the hospital and at follow-up. At 6 months, 64 patients (81.0%) were improved relative to their preoperative condition and 14 patients (17.7%) were unchanged. Good outcomes (modified Rankin Scale score ≤ 2, living independently) were achieved in 77 patients (97.4%). Multivariate analysis of demographic and surgical factors revealed that preoperative functional status was the only predictor of postoperative modified Rankin Scale score (OR 4.6, p = 0.001). Six patients (7.6%) had transient worsening of neurological examination after surgery, and 1 patient (1.3%) was permanently worse. There was no surgical mortality. CONCLUSIONS: The authors present a system of 13 microsurgical approaches to 6 location targets with 4 general trajectories to facilitate safe access to supratentorial CMs in eloquent brain regions. Favorable neurological outcomes following microsurgical resection justify an aggressive surgical attitude toward these lesions.

Supracerebellar-supratrochlear and infratentorial-infratrochlear approaches: gravity-dependent variations of the lateral approach over the cerebellum.

OBJECTIVE: Lateral supracerebellar-infratentorial approaches are established for lesions in ambient cistern and posterolateral midbrain, but published surgical experiences do not describe results with this approach in the sitting position. Gravity retraction of the cerebellum opens this surgical corridor and dramatically alters exposure, creating 2 variations of the lateral supracerebellar-infratentorial approach: the supracerebellar-supratrochlear approach and the infratentorial-infratrochlear approach. METHODS: We reviewed our experience treating cavernous malformations and arteriovenous malformations (AVMs) of the posteroinferior thalamus and posterolateral midbrain by use of supracerebellar-supratrochlear and infratentorial-infratrochlear approaches. Microsurgical technique, clinical data, radiographic features, and neurological outcomes were evaluated. RESULTS: During an 11-year surgical experience with 341 cavernous malformation patients and 402 AVM patients, 8 patients were identified, 6 with cavernous malformations and 2 with AVMs. Infratentorial-infratrochlear approaches were used in 4 patients (50%), including 3 with inferolateral midbrain cavernous malformations. Supracerebellar-supratrochlear approaches were used in 4 patients (50%), including 2 with posterior thalamic lesions surfacing on pulvinar. Resections were radiographically complete in all cases. There were no new, permanent neurological deficits, nor were there any medical or surgical complications. There has been no evidence of rebleeding or recurrence. CONCLUSIONS: Gravity retraction of the cerebellum transforms the lateral supracerebellar-infratentorial approach, enhancing exposure and approach trajectories that can be achieved with patients in prone or lateral positions. The increased upward viewing angle of the supracerebellar-supratrochlear approach accesses the posteroinferior thalamus. The increased downward-viewing angle of the infratentorial-infratrochlear approach accesses cerebellomesencephalic fissure and posterolateral midbrain. These approaches open wide corridors for safe surgical resection of symptomatic cavernous malformations and AVMs.

Neuropyschological profile of reversible cognitive impairment in a patient with a dural arteriovenous fistula.

OBJECTIVE AND IMPORTANCE: Patients with dural arteriovenous fistulas (dAVFs) may present with cognitive impairment secondary to venous hypertension or ischemia. CLINICAL PRESENTATION: We present a patient with a dAVF supplied by the posterior meningeal artery who presented with severe encephalopathy and imaging consistent with bilateral thalamic ischemia. RESULTS: Detailed pre-operative neuropsychological testing documented severe cognitive deficits across multiple domains, localizing diffusely in the cerebral cortex, beyond that which would be expected from purely thalamic involvement. Approximately 2 months following a combined endovascular and surgical repair, repeat neuropsychological testing documented a dramatic improvement in cognitive symptoms while MRI abnormalities in the thalami resolved. CONCLUSION: Detailed neuropsychological testing may be useful in patients presenting with dAVFs in order to identify cognitive impairment, which may be out of proportion to imaging findings. Recognition of dAVF-associated cognitive impairment may lead to more aggressive, timely treatment in patients with otherwise lower-risk lesions. This detailed testing can also provide a baseline in order to document cognitive recovery after fistula repair.

Transcranial motor evoked potentials during basilar artery aneurysm surgery: technique application for 30 consecutive patients.

OBJECTIVE: Microsurgical clipping of basilar artery aneurysms carries a risk of neurological compromise resulting from midbrain or thalamic ischemia. Somatosensory evoked potential (SSEP) monitoring and electroencephalography are the standard techniques for assessing the level of cerebroprotective anesthesia and monitoring ischemia during temporary occlusion or after permanent clipping. Transcranial motor evoked potential (TcMEP) monitoring was added to determine whether this modality improved intraoperative monitoring. METHODS: Combined SSEP/electroencephalographic/TcMEP monitoring was used for 30 consecutive patients with basilar artery apex aneurysms in the past 1.5 years. Voltage thresholds were recorded before, during, and after aneurysm treatment for the last 10 patients. RESULTS: All 30 patients underwent an orbitozygomatic craniotomy for clipping (28 patients), wrapping (1 patient), or superficial temporal artery-superior cerebellar artery bypass (1 patient). Electrophysiological changes occurred for 10 patients (33%), elicited by temporary clipping (6 patients), permanent clipping (3 patients), or retraction (1 patient). Isolated SSEP changes were observed for one patient, isolated TcMEP changes for five patients, and changes in both TcMEPs and SSEPs for four patients. Among patients with simultaneous changes, TcMEP abnormalities were more robust and occurred earlier than SSEP abnormalities. Impaired motor conduction was detected first with an increase in the voltage threshold (from 206 +/- 22 to 410 +/- 49 V, P < 0.05, n = 3) and then with loss of TcMEP responses. SSEP and TcMEP signals returned to baseline values for all patients after corrective measures were taken. CONCLUSION: TcMEP monitoring can be safely and easily added to traditional neurophysiological monitoring during basilar artery aneurysm surgery. These results suggest that TcMEPs may be more sensitive than SSEPs to basilar artery and perforating artery ischemia. This additional intraoperative information might minimize the incidence of ischemic complications attributable to prolonged temporary occlusion or inadvertent perforator occlusion.