Evaluate the safety and efficacy of dura sealant patch in reducing cerebrospinal fluid leakage following elective cranial surgery (ENCASE II): study protocol for a randomized, two-arm, multicenter trial.

BACKGROUND: Cerebrospinal fluid (CSF) leakage is a frequent and challenging complication in neurosurgery, especially in the posterior fossa, with a prevalence of 8%. It is associated with substantial morbidity and increased healthcare costs. A novel dural sealant patch (LIQOSEAL) was developed for watertight dural closure. The objective of this study is to clinically assess the safety and effectiveness of LIQOSEAL as a means of reducing intra- as well as postoperative CSF leakage in patients undergoing elective posterior fossa intradural surgery with a dural closure procedure compared to the best currently available dural sealants. METHODS: We will conduct a two-arm, randomized controlled, multicenter study with a 90-day follow-up. A total of 228 patients will be enrolled in 19 sites, of which 114 will receive LIQOSEAL and 114 an FDA-approved PEG sealant. The composite primary endpoint is defined as intraoperative CSF leakage at PEEP 20 cm H2O, percutaneous CSF leakage within 90 days of, wound infection within 90 days of or pseudomeningocele of more than 20cc on MRI or requiring intervention. We hypothesize that the primary endpoint will not be reached by more than 10 patients (9%) in the investigational arm, which will demonstrate non-inferiority of LIQOSEAL compared to control. DISCUSSION: This trial will evaluate whether LIQOSEAL is non-inferior to control as a means of reducing CSF leakage and safety TRIAL REGISTRATION: ClinicalTrials.gov NCT04086550 . Registered on 11 September 2019.

Performance of Standardized Relative CBV for Quantifying Regional Histologic Tumor Burden in Recurrent High-Grade Glioma: Comparison against Normalized Relative CBV Using Image-Localized Stereotactic Biopsies.

BACKGROUND AND PURPOSE: Perfusion MR imaging measures of relative CBV can distinguish recurrent tumor from posttreatment radiation effects in high-grade gliomas. Currently, relative CBV measurement requires normalization based on user-defined reference tissues. A recently proposed method of relative CBV standardization eliminates the need for user input. This study compares the predictive performance of relative CBV standardization against relative CBV normalization for quantifying recurrent tumor burden in high-grade gliomas relative to posttreatment radiation effects. MATERIALS AND METHODS: We recruited 38 previously treated patients with high-grade gliomas (World Health Organization grades III or IV) undergoing surgical re-resection for new contrast-enhancing lesions concerning for recurrent tumor versus posttreatment radiation effects. We recovered 112 image-localized biopsies and quantified the percentage of histologic tumor content versus posttreatment radiation effects for each sample. We measured spatially matched normalized and standardized relative CBV metrics (mean, median) and fractional tumor burden for each biopsy. We compared relative CBV performance to predict tumor content, including the Pearson correlation (r), against histologic tumor content (0%-100%) and the receiver operating characteristic area under the curve for predicting high-versus-low tumor content using binary histologic cutoffs (≥50%; ≥80% tumor). RESULTS: Across relative CBV metrics, fractional tumor burden showed the highest correlations with tumor content (0%-100%) for normalized (r = 0.63, P < .001) and standardized (r = 0.66, P < .001) values. With binary cutoffs (ie, ≥50%; ≥80% tumor), predictive accuracies were similar for both standardized and normalized metrics and across relative CBV metrics. Median relative CBV achieved the highest area under the curve (normalized = 0.87, standardized = 0.86) for predicting ≥50% tumor, while fractional tumor burden achieved the highest area under the curve (normalized = 0.77, standardized = 0.80) for predicting ≥80% tumor. CONCLUSIONS: Standardization of relative CBV achieves similar performance compared with normalized relative CBV and offers an important step toward workflow optimization and consensus methodology.

A Multicenter Pilot Study on the Clinical Utility of Computational Modeling for Flow-Diverter Treatment Planning.

BACKGROUND AND PURPOSE: Selection of the correct flow-diverter size is critical for cerebral aneurysm treatment success, but it remains challenging due to the interplay of device size, anatomy, and deployment. Current convention does not address these challenges well. The goals of this pilot study were to determine whether computational modeling improves flow-diverter sizing over current convention and to validate simulated deployments. MATERIALS AND METHODS: Seven experienced neurosurgeons and interventional neuroradiologists used computational modeling to prospectively plan 19 clinical interventions. In each patient case, physicians simulated 2-4 flow-diverter sizes that were under consideration based on preprocedural imaging. In addition, physicians identified a preferred device size using the current convention. A questionnaire on the impact of computational modeling on the procedure was completed immediately after treatment. Rotational angiography image data were acquired after treatment and compared with flow-diverter simulations to validate the output of the software platform. RESULTS: According to questionnaire responses, physicians found the simulations useful for treatment planning, and they increased their confidence in device selection in 94.7% of cases. After viewing the simulations results, physicians selected a device size that was different from the original conventionally planned device size in 63.2% of cases. The average absolute difference between clinical and simulated flow-diverter lengths was 2.1 mm. In 57% of cases, average simulated flow-diverter diameters were within the measurement uncertainty of clinical flow-diverter diameters. CONCLUSIONS: Physicians found computational modeling to be an impactful and useful tool for flow-diverter treatment planning. Validation results showed good agreement between simulated and clinical flow-diverter diameters and lengths.

Accurate Patient-Specific Machine Learning Models of Glioblastoma Invasion Using Transfer Learning.

BACKGROUND AND PURPOSE: MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data. MATERIALS AND METHODS: We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models. RESULTS: Tumor cell density significantly correlated with relative CBV (r = 0.33, P < .001), and T1-weighted postcontrast (r = 0.36, P < .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (r = 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (r = 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (r = 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (r = 0.39, mean absolute error = 16.55%). CONCLUSIONS: Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.

Functional and physical outcomes following use of a flexible CO2 laser fiber and bipolar electrocautery in close proximity to the rat sciatic nerve with correlation to an in vitro thermal profile model.

This study compared functional and physical collateral damage to a nerve when operating a Codman MALIS Bipolar Electrosurgical System CMC-III or a CO2 laser coupled to a laser, with correlation to an in vitro model of heating profiles created by the devices in thermochromic ink agarose. Functional damage of the rat sciatic nerve after operating the MALIS or CO2 laser at various power settings and proximities to the nerve was measured by electrically evoked nerve action potentials, and histology of the nerve was used to assess physical damage. Thermochromic ink dissolved in agarose was used to model the spatial and temporal profile of the collateral heating zone of the electrosurgical system and the laser ablation cone. We found that this laser can be operated at 2 W directly above the nerve with minimal damage, while power settings of 5 W and 10 W resulted in acute functional and physical nerve damage, correlating with the maximal heating cone in the thermochromic ink model. MALIS settings up to 40 (11 W) did not result in major functional or physical nerve damage until the nerve was between the forceps tips, correlating with the hottest zone, localized discretely between the tips.

Evaluation of 4D vascular flow and tissue perfusion in cerebral arteriovenous malformations: influence of Spetzler-Martin grade, clinical presentation, and AVM risk factors.

BACKGROUND AND PURPOSE: The role of intracranial hemodynamics in the pathophysiology and risk stratification of brain AVMs remains poorly understood. The purpose of this study was to assess the influence of Spetzler-Martin grade, clinical history, and risk factors on vascular flow and tissue perfusion in cerebral AVMs. MATERIALS AND METHODS: 4D flow and perfusion MR imaging was performed in 17 patients with AVMs. Peak velocity and blood flow were quantified in AVM feeding and contralateral arteries, draining veins, and the straight sinus. Regional perfusion ratios (CBF, CBV, and MTT) were calculated between affected and nonaffected hemispheres. RESULTS: Regarding flow parameters, high-grade AVMs (Spetzler-Martin grade of >2) demonstrated significantly increased peak velocity and blood flow in the major feeding arteries (P < .001 and P = .004) and straight sinus (P = .003 and P = .012) and increased venous draining flow (P = .001). The Spetzler-Martin grade significantly correlated with cumulative feeding artery flow (r = 0.85, P < .001) and draining vein flow (r = 0.80, P < .001). Regarding perfusion parameters, perinidal CBF and CBV ratios were significantly lower (P < .001) compared with the remote ratios and correlated negatively with cumulative feeding artery flow (r = -0.60, P = .014 and r = -0.55, P = .026) and draining vein flow (r = -0.60, P = .013 and r = -0.56, P = .025). Multiple regression analysis revealed no significant association of AVM flow or perfusion parameters with clinical presentation (rupture and seizure history) and AVM risk factors. CONCLUSIONS: Macrovascular flow was significantly associated with increasing Spetzler-Martin grade and correlated with perinidal microvascular perfusion in cerebral AVMs. Future longitudinal studies are needed to evaluate the potential of comprehensive cerebral flow and perfusion MR imaging for AVM risk stratification.

Quantifying Intracranial Aneurysm Wall Permeability for Risk Assessment Using Dynamic Contrast-Enhanced MRI: A Pilot Study.

BACKGROUND AND PURPOSE: Pathological changes in the intracranial aneurysm wall may lead to increases in its permeability; however the clinical significance of such changes has not been explored. The purpose of this pilot study was to quantify intracranial aneurysm wall permeability (K(trans), VL) to contrast agent as a measure of aneurysm rupture risk and compare these parameters against other established measures of rupture risk. We hypothesized K(trans) would be associated with intracranial aneurysm rupture risk as defined by various anatomic, imaging, and clinical risk factors. MATERIALS AND METHODS: Twenty-seven unruptured intracranial aneurysms in 23 patients were imaged with dynamic contrast-enhanced MR imaging, and wall permeability parameters (K(trans), VL) were measured in regions adjacent to the aneurysm wall and along the paired control MCA by 2 blinded observers. K(trans) and VL were evaluated as markers of rupture risk by comparing them against established clinical (symptomatic lesions) and anatomic (size, location, morphology, multiplicity) risk metrics. RESULTS: Interobserver agreement was strong as shown in regression analysis (R(2) > 0.84) and intraclass correlation (intraclass correlation coefficient >0.92), indicating that the K(trans) can be reliably assessed clinically. All intracranial aneurysms had a pronounced increase in wall permeability compared with the paired healthy MCA (P < .001). Regression analysis demonstrated a significant trend toward an increased K(trans) with increasing aneurysm size (P < .001). Logistic regression showed that K(trans) also predicted risk in anatomic (P = .02) and combined anatomic/clinical (P = .03) groups independent of size. CONCLUSIONS: We report the first evidence of dynamic contrast-enhanced MR imaging-modeled contrast permeability in intracranial aneurysms. We found that contrast agent permeability across the aneurysm wall correlated significantly with both aneurysm size and size-independent anatomic risk factors. In addition, K(trans) was a significant and size-independent predictor of morphologically and clinically defined high-risk aneurysms.

Intracranial 4D flow MRI: toward individualized assessment of arteriovenous malformation hemodynamics and treatment-induced changes.

BACKGROUND AND PURPOSE: Arteriovenous malformations are an important etiology of hemorrhagic stroke. However, current imaging modalities and risk do not provide insights into individual AVM hemodynamics and its role in pathophysiology. The aims of this study are to determine whether intracranial 4D flow MR imaging can provide insights into arteriovenous malformation hemodynamics independent of the Spetzler-Martin grade and to report the changes in flow observed during staged embolization. MATERIALS AND METHODS: Intracranial 3D blood flow was assessed in 20 patients with AVM (age = 39 ± 15 years, Spetzler-Martin grade ranging from 1-4) with the use of 4D flow MR imaging (temporal resolution = 45 ms, spatial resolution = [1.2-1.6mm](3)). AVM hemodynamics were visualized by means of time-integrated 3D pathlines depicting the AVM arterial feeding and venous draining patterns over the cardiac cycle. Analysis included the grading of feeding and draining velocities on a 3-point scale (0 = low <25 cm/s, 1 = medium <50 cm/s, 2 = high >50 cm/s). For 4 of 20 patients undergoing 4D flow MR imaging follow-up after staged embolization, peak velocities were quantified in arterial feeders, draining veins, the sagittal sinus, and contralateral arteries. RESULTS: In 50% of the cases with Spetzler-Martin grade >2, heterogeneous flow (velocity grade differences >1) was found across arteries and veins. Velocities in draining veins increased from Spetzler-Martin grade = 1 (grading = 0.5 ± 0.6) to Spetzler-Martin grade ≥3 (1.1 ± 0.6), whereas arterial velocities were similar (1.7 ± 0.6 versus 1.5 ± 0.6). In the postembolization subgroup of 4 patients, 4D flow MR imaging demonstrated successively more compact AVM and redistribution of velocities. Changes in arterial and venous velocities during treatment were highly different among individuals. CONCLUSIONS: Spetzler-Martin grade does not reflect differences in 3D AVM arterial and venous hemodynamics, and an individual assessment of AVM hemodynamics may be needed for improved lesion characterization. Four-dimensional flow MR imaging may have the potential to monitor and guide embolization treatment planning.

Predictors of hemorrhage volume and disability after perimesencephalic subarachnoid hemorrhage.

OBJECTIVE: The determinants of subarachnoid hemorrhage (SAH) volume and an atypical pattern of blood are not clear. Our objective was to determine if reduced platelet activity on admission and abnormal venous drainage are associated with greater SAH volume. METHODS: We prospectively identified noncomatose patients with SAH without an identifiable aneurysm. We routinely measured platelet activity on admission and recorded aspirin use. SAH volumes were calculated with a validated technique. CT angiograms were reviewed by a certified neuroradiologist for venous drainage. Patients were followed for clinical outcomes through 3 months with the modified Rankin Scale (mRS). Data are Q1-Q3. RESULTS: There were 31 patients in the cohort. Thirty (97%) underwent an angiogram on admission, and 25 (81%) an additional delayed angiogram. SAH volume was lowest with normal venous drainage bilaterally (4.4 [3.7-16.4] mL) and higher with 1 (12.9 [3.7-20.4]) or 2 (20.9 [12.5-34.6] mL, p = 0.03) discontinuous venous drainages. Patients with reduced platelet activity had more SAH on the diagnostic CT (17.5 [10.6-20.9] vs 6.1 [2.3-15.3] mL) (p = 0.046). SAH volume was greater for patients requiring drainage for hydrocephalus (16.4 [11.5-20.5] vs 5.4 [2.7-16.4] mL) (p = 0.009). Outcomes at 3 months were generally excellent (median mRS = 0, no symptoms). CONCLUSIONS: Discontinuous venous drainage and reduced platelet activity were associated with increased SAH volume and hydrocephalus. These factors may explain thick SAH and reduce the need for repeated invasive imaging in such patients.

Preoperative Onyx embolization of aggressive vertebral hemangiomas.

We report the first use of Onyx in the embolization of spinal tumors in 2 cases of aggressive vertebral hemangioma. In both cases, Onyx embolization provided effective preoperative tumor devascularization after the initial prolonged particulate embolization with Embospheres made little overall impact. Onyx enables a more rapid and visible embolization than particles and is less technically demanding than traditional liquid embolic agents, such as n-butyl cyanoacrylate.

Third nerve paresis caused by vascular compression by the posterior communicating artery.

OBJECTIVE AND IMPORTANCE: Third nerve paresis frequently occurs because of external compression by an internal carotid-posterior communicating artery aneurysm. We report 1 case of third nerve palsy because of direct vascular compression by the posterior communicating artery. CLINICAL PRESENTATION: A 69-year-old man presented to the hospital with the sudden onset of left third nerve palsy and a history of chronic headaches. A cerebral angiogram showed a cavernous aneurysm of the left internal carotid artery as well as a large dilatation of the left posterior communicating artery. INTERVENTION: A left transylvian approach exposed an infundibulum of the left posterior communicating artery in contact with and creating an indentation on the third cranial nerve. The artery was dissected free of the nerve, and vascular decompression was achieved with complete resolution of the oculomotor nerve paresis. CONCLUSION: Third nerve palsy may in some cases result from direct vascular compression by the posterior communicating artery, particularly if associated with a broad infundibulum.

Failure of a saphenous vein extracranial-intracranial bypass graft to protect against bilateral middle cerebral artery ischemia after carotid artery occlusion: case report.

OBJECTIVE AND IMPORTANCE: We present the case of a patient who experienced bilateral middle cerebral artery infarctions after Hunterian ligation and trapping of a ruptured right cavernous aneurysm, despite a high-flow extracranial-intracranial bypass. This is a rare complication, and it highlights the need for further refinements in our understanding of the hemodynamic insufficiency created by major vessel sacrifice. CLINICAL PRESENTATION: The patient was a 59-year-old woman who experienced multiple episodes of massive epistaxis before undergoing angiography, which revealed left internal carotid artery occlusion and an irregular right cavernous aneurysm. The patient was then transferred to our center for treatment. The patient was neurologically intact at presentation, and her epistaxis was controlled by nasal packing. INTERVENTION: The patient underwent an extracranial-intracranial bypass from the external carotid artery to the M2 segment of the right middle cerebral artery, followed by trapping of the aneurysm. Despite evidence of graft patency, the patient experienced bilateral middle cerebral artery distribution infarctions after surgery. CONCLUSION: Although extracranial-intracranial bypasses protect the majority of patients who undergo carotid artery ligation from ischemic complications, this case demonstrates that hemodynamic insufficiency can occur even with a high-flow saphenous vein graft. Better ways to quantitate the hemodynamic needs of the brain after major vessel sacrifice may facilitate matching of the revascularization strategy to the specific needs of each patient, thus further reducing the likelihood of ischemic complications.

Resection of a large arteriovenous fistula of the brain using low-flow deep hypothermic cardiopulmonary bypass: technical case report.

OBJECTIVE AND IMPORTANCE: We present the second report in the literature on the use of low-flow hypothermic cardiopulmonary bypass to aide in the surgical resection of a large intraparenchymal arteriovenous fistula. CLINICAL PRESENTATION: The patient was a 46-year-old man who was found to have a left sylvian arteriovenous fistula with a giant varix during a workup for chronic left frontal headaches and was referred to our center for management. A cardiac workup revealed a cardiac output of 9 L per minute. INTERVENTION: Endovascular embolization of the lesion was initially attempted without success because of the high flow within the lesion and the large diameter of the feeding arteries. We then planned combined and staged endovascular and surgical approaches to gradually eliminate the fistula. Endovascular embolization, both transarterial and transvenous, could not be performed because of the high flow in the fistula. Despite the stepwise reduction of flow during the course of several weeks via surgical exposures and arterial ligations, the fistula remained difficult to remove because of its size and the turgor of the varix. Once hypothermic low-flow circulatory bypass was used, however, decompression of the sac allowed access to the afferent vasculature. CONCLUSION: The use of low-flow hypothermic circulatory bypass can facilitate the surgical extirpation of certain large intraparenchymal arteriovenous fistulas.

Treatment of aneurysmal subarachnoid hemorrhage.

Subarachnoid hemorrhage is a formidable and common health care problem. Early diagnosis and management are crucial to reduce the morbidity form this complex and multifaceted disease. Open surgery and endovascular techniques both aim at eliminating the source of hemorrhage. The choice of therapy can be made rationally based on an understanding of the merits, risks, and limitations of each therapy. The care of pregnant patients with subarachnoid hemorrhage and patients who harbor both aneurysms and AVMs can be approached rationally with an understanding of the complex pathophysiology behind these clinical scenarios. Familiarity with the signs of mild SAH, and advances in familial screening, noninvasive imaging, and therapies for vasospasm will continue to lessen the toll of this dramatic illness on the public well-being.

[Changes in the 24-hour rhythm of plasma melatonin in patients with liver cirrhosis--relation to sleep architecture]. / Veränderung des 24-Stunden-Rhythmus von Plasma-Melatonin bei Patienten mit Leberzirrhose--Beziehung zur Schlafarchitektur.

OBJECTIVE: To assess the 24 hr plasma melatonin profile as a marker of the output rhythm from the circadian clock and to study sleep diaries as reflection of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. PATIENTS: A total of 14 subjects, 7 non-alcoholic cirrhotics and 7 age-, sex-, and educationally-matched controls. Exclusion criteria were factors that could affect melatonin levels (intercontinental travel, shift work, therapy with betablockers or corticosteroids). MEASUREMENTS: Plasma melatonin was measured every 30 min for 24 hr by radioimmuno assay and sleep recordings by polysomnography. Neuropsychological testing included visual reaction time. Trailmaking test A and B and the Digit Symbol Test. Sleep diaries were kept for the week prior to admission. RESULTS: Time of onset of melatonin rise was displaced from 19:50 +/- 26 min in the controls to 21:30 +/- 13 min (p = 0.013) in patients with liver cirrhosis. The time of peak melatonin levels was consistently and significantly delayed from 00:36 +/- 33 min in controls to 5:36 +/- 29 min (p < 0.001) in patients. Cirrhotic subjects showed markedly elevated melatonin levels during daytime, when melatonin is normally absent. Polysomnographic tracings showed no differences in patients and controls, but sleep diaries indicated more frequent nocturnal awakenings (p = 0.05) and daytime naps. CONCLUSIONS: A marked alteration of plasma melatonin rhythm is found in cirrhotic patients with subclinical hepatic encephalopathy. This disruption may reflect changes in the output of the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is possible that some of the metabolic disturbances that lead to hepatic encephalopathy may also alter the function of the biological "clock".

Disruption of the diurnal rhythm of plasma melatonin in cirrhosis.

OBJECTIVES: To assess 24-hour plasma melatonin profile as a marker of output rhythm from the circadian clock and to study sleep diaries as reflections of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. SETTING: Clinical research center in a university hospital. PATIENTS: Seven patients with cirrhosis but not alcoholism and seven age-, sex-, and education-matched controls. MEASUREMENTS: Neuropsychological testing to confirm subclinical hepatic encephalopathy. Plasma melatonin levels measured every 30 minutes for 24 hours by radioimmunoassay. Sleep diaries kept for 1 week before admission. RESULTS: Patients with cirrhosis had markedly elevated melatonin levels during daytime hours; in addition, the time of onset of melatonin increase and the time at which melatonin levels peaked were consistently and significantly delayed in these patients. Sleep diaries indicated more nocturnal awakenings and more frequent daytime naps in patients with cirrhosis. CONCLUSION: Disruption of the diurnal rhythm of melatonin may reflect alterations of circadian function that could contribute to the disturbances of the sleep-wake cycle frequently seen in patients with cirrhosis.