Category Archives: Vascular

Update: Cerebral cavernous malformation etiology

Cerebral cavernous malformation (CM) is a sporadic vascular malformation occurring either as an autosomal dominant condition or as a well-known complication of radiation exposure.

see Radiation induced cerebral cavernous malformation.

CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 1).

Although a role for these three genes in the formation of these intracranial vascular lesions has been established since the 1990s, additional works have further elucidated the molecular mechanisms by which mutations in these genes and the resultant aberrant proteins interact, leading to the formation of CCMs.

The three CCM proteins coded by KRIT1, CCM2, and PDCD10 form a trimeric protein complex. Germline loss-of-function mutations in any of these genes may lead to the formation of CCMs. Therefore, it is reasonable to assume that a molecular pathway exists that requires all three proteins to function together correctly for proper cellular function. Moreover, research is demonstrating how each component protein is capable of interacting with numerous other signaling and cytoskeletal molecules allowing for a diverse range of functions in molecular signaling pathways via unique protein–protein interactions.

Significant research findings from 2000 to 2015 have further enhanced our understanding of the pathogenesis of CCM formation. The use of advanced sequencing technologies to characterize genomic mutations and the identification of new signaling pathways and protein–protein interactions have led to great strides in understanding the molecular genetics involved in the development of CCMs. However, many unanswered questions remain, and future studies are clearly needed to improve our understanding of CCM pathogenesis. “Gene to protein to disease” mechanisms involved in the pathogenesis of CCMs should shed further light on potential therapeutic targets. 2).


The Phosphoinositide 3 kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression.

Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment 3).


Studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics 4).

CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified.


Tang et al. identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of cerebral cavernous malformation formation. Activation of TLR4 by Gram negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment 5).

1) , 4)

Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID: 27027284; PubMed Central PMCID: PMC4864035.
2)

Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral Cavernous Malformations: Review of the Genetic and Protein-Protein Interactions Resulting in Disease Pathogenesis. Front Surg. 2016 Nov 14;3:60. Review. PubMed PMID: 27896269.
3)

Kar S, Samii A, Bertalanffy H. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev. 2015 Apr;38(2):229-36; discussion 236-7. doi: 10.1007/s10143-014-0597-8. Epub 2014 Nov 19. PubMed PMID: 25403688.
5)

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 10. doi: 10.1038/nature22075. [Epub ahead of print] PubMed PMID: 28489816.

Weekend effect on subarachnoid hemorrhage

Pandey et al. from, Ann Arbor, Michigan, performed a serial retrospective cross sectional study using the Nationwide Inpatient Sample. All adult discharges with a primary diagnosis of SAH (ICD-9-CM 435) from 2005 to 2010 were included, and records with trauma or arteriovenous malformation were excluded. Unadjusted and adjusted associations between weekend presentation and 3 outcomes (in-hospital mortality, discharge destination, and treatment with clip vs coil) were estimated using chi-square tests and multilevel logistic regression.

A total of 46 093 admissions for spontaneous subarachnoid hemorrhage were included in the sample; 24.6% presented on a weekend, 68.9% on a weekday, and 6.5% had unknown day of presentation. Weekend admission was not a significant predictor of inpatient mortality (25.4% weekend vs 24.9% weekday; P = .44), or a combined poor outcome measure of mortality or discharge to long-term acute care or hospice (30.3% weekend vs 29.4% weekday; P = .23). Among those treated for aneurysm obliteration, the proportion of clipped vs coiled did not change with weekend vs weekday presentation (21.5% clipped with weekend presentation vs 21.6% weekday, P = .95; 21.5% coiled with weekend presentation vs 22.4% weekday, P = .19).

Presentation with nontraumatic SAH on a weekend did not influence mortality, discharge destination, or type of treatment received (clip vs coil) compared with weekday presentation 1).


Deshmukh et al. used data from a prospective audit of aSAH patients admitted between January 2009 and December 2011. The baseline demographic and clinical features of the weekend and weekday groups were compared using the chi-squared test and T-test. Cox proportional hazards models (Proc Phreg in SAS) were used to calculate the adjusted overall hazard of in-hospital death associated with admission on weekend, adjusting for age, sex, baseline WFNS grade, type of treatment received and time from scan to treatment. Sliding dichotomy analysis was used to estimate the difference in outcomes after SAH at 3 months in weekend and weekday admissions.

Those admitted on weekends had a significantly higher scan to treatment time (83.05 ± 83.4 h vs 40.4 ± 53.4 h, P < 0.0001) and admission to treatment (71.59 ± 79.8 h vs 27.5 ± 44.3 h, P < 0.0001) time. After adjustments for adjusted for relevant covariates weekend admission was statistically significantly associated with excess in-hospital mortality (HR = 2.1, CL [1.13-4.0], P = 0.01). After adjustments for all the baseline covariates, the sliding dichotomy analysis did not show effects of weekend admission on long-term outcomes on the good, intermediate and worst prognostic bands.

This study provides important data showing excess in-hospital mortality of patients with SAH on weekend admissions served by the United Kingdom’s National Health Service.; However, there were no effects of weekend admission on long-term outcomes 2).


Crowley et al. performed a retrospective cohort study that examined mortality outcomes among patients included in the Nationwide Inpatient Sample (NIS) for 2004. Patients included in the cohort were identified using the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code for SAH. Multivariable logistic regression analyses and Cox proportional hazard regression analyses are used to measure the association of weekend admission on mortality for patients with SAH, adjusted for differences in patient characteristics that also contribute to mortality risk.

Weekend admissions occurred among 27.5% of the 5667 patients with SAH in the NIS database. Weekend admission was not a statistically significant independent predictor of death in the SAH study population at 7 days (OR 1.07, 95% CI 0.91-1.25), 14 days (OR 1.01, 95% CI 0.87-1.17), or 30 days (OR 1.03, 95% CI 0.89-1.19).

Weekend admission is not associated with significantly increased short-term mortality risk among patients hospitalized with SAH 3).

1)

Pandey AS, Wilkinson DA, Gemmete JJ, Chaudhary N, Thompson BG, Burke JF. Impact of Weekend Presentation on Short-Term Outcomes and Choice of Clipping vs Coiling in Subarachnoid Hemorrhage. Neurosurgery. 2017 May 5. doi: 10.1093/neuros/nyx015. [Epub ahead of print] PubMed PMID: 28475807.
2)

Deshmukh H, Hinkley M, Dulhanty L, Patel HC, Galea JP. Effect of weekend admission on in-hospital mortality and functional outcomes for patients with acute subarachnoid haemorrhage (SAH). Acta Neurochir (Wien). 2016 May;158(5):829-35. doi: 10.1007/s00701-016-2746-z. Epub 2016 Mar 1. PubMed PMID: 26928730; PubMed Central PMCID: PMC4826657.
3)

Crowley RW, Yeoh HK, Stukenborg GJ, Ionescu AA, Kassell NF, Dumont AS. Influence of weekend versus weekday hospital admission on mortality following subarachnoid hemorrhage. Clinical article. J Neurosurg. 2009 Jul;111(1):60-6. doi: 10.3171/2008.11.JNS081038. PubMed PMID: 19231928.

Pediatric Vascular Neurosurgery: Principles and Practice of Neurovascular Disorders (Part 1)

Pediatric Vascular Neurosurgery: Principles and Practice of Neurovascular Disorders (Part 1)

Pediatric Vascular Neurosurgery: Principles and Practice of Neurovascular Disorders (Part 1)

List Price: $179.00

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This book answers frequently asked questions about common pediatric neurosurgical conditions related to vascular malformations of the brain and spinal cord, in an attempt to fill in the gap and answer numerous questions that arises after a diagnosis is made.

Pediatric patients with neurosurgical conditions are almost always referred from either primary care physicians, neurologists internists or a specialist in family medicine. Recently, neurosurgeons treating adult population also refer a pediatric patient to their colleague specialized in this field.
There are over 1500 academic and private hospitals in the US who have dedicated tertiary Neurosurgery services and cater thousands of small children every year, in addition to numerous centers that have level 1 and 2 trauma care. However, there are few tertiary level Pediatric centers which can provide quality care for neurosurgical conditions.
This book is specially written and illustrated for residents, fellows and consultants/attendings in all pediatric related specialties, including but not limited to Neurosurgery, Neurology, Pediatrics, Radiology, Anesthesia.

Product Details

  • Published on: 2017-05-08
  • Original language: English
  • Number of items: 1
  • Dimensions: 9.30″ h x .0″ w x 6.10″ l, .0 pounds
  • Binding: Hardcover
  • 325 pages

Editorial Reviews

From the Back Cover
This book focuses on core concepts of vascular neurosurgery in pediatric population,. It is designed to fill the knowledge gaps and to answer the frequently sought questions on various management strategies for commonly encountered pediatric neurosurgical conditions. The chapters, authored by experts in their respective field, provide a standard of care based on current diagnostic and management guidelines for pediatric neurosurgical diseases.

Pediatric Vascular Neurosurgery – Disorders and their Management is specially written and illustrated for residents, fellows and consultants in all pediatric related specialties, including but not limited to Neurosurgery, Neurology, Pediatrics, Neuroradiology and Neuroanesthesia.

About the Author
Dr Abhishek Agrawal, M.D.: House Staff, Department of Neurosurgery/ Radiology, Brigham and Women’s’ Hospital, Harvard Medical School, Boston.

Dr Gavin Britz, MBCCh, MPH, MBA, FAANS: Chairman, Department of Neurosurgery, Methodist Neurological Institute, Houston, Texas

Book: Neurosurgical Intensive Care

Neurosurgical Intensive Care

Neurosurgical Intensive Care

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Decompression is still the mainstay of surgical intervention for neurosurgeons treating neurocritical care patients. However, during the last 20 years, an evolution away from a mechanistic approach has transformed neurocritical care into an increasingly multidisciplinary field. Neurosurgical Intensive Care, 2nd Edition reflects this new paradigm, authored by a neurosurgeon with contributions from experts in the fields of neurology, vascular neurology, interventional neuroradiology, anesthesiology, critical care, traumatology, nutrition, and advanced practice nursing.

Neuromonitoring advances have enabled customized interventions tailored to each patient’s unique circumstances. The critical care of neurosurgical patients has evolved from an emphasis on pulmonary care (ventilation and oxygenation) to a more nuanced understanding of cerebral protection measures required to manage a disrupted blood-brain-barrier. This edition encompasses advances in the use of ICP monitors, external ventricular devices, brain tissue oxygen monitoring devices, cerebral microdialysis, fluid and electrolyte correction, as well as the increasing use of continuous EEG in the ICU.

Key Features

  • Straightforward summaries for each stage of patient care including bedside exams, neuroimaging, lab work, triage procedures, sedation and pain management, neuropharmacology, nutritional needs, administration of fluids, and more.
  • 159 tables and figures facilitate rapid evaluation and decision making.
  • Clinical pearls on a wide range of ICU scenarios – from pathophysiology and management of coma – to interventions for spinal cord injury, multisystem injuries, acute ischemic stroke, and pediatric cases.
  • Insights on how to handle family communication and spiritual needs, medical-legal issues, and discharge planning

This compact, highly practical handbook provides a stellar reference for managing critically ill neurosurgical patients in the ICU. It is a must-have resource for nurses, medical students, residents, fellows, and attending physicians who treat these patients.


Product Details

  • Published on: 2017-05-01
  • Original language: English
  • Dimensions: 5.00″ h x .0″ w x 8.00″ l,
  • Binding: Paperback
  • 576 pages

Update: PulseRider Aneurysm Neck Reconstruction Device

PulseRider

http://www.pulsarvascular.com/

see Video

The PulseRider Aneurysm Neck Reconstruction Device is intended for use with embolic coils in the treatment of intracranial aneurysms originating on or near a vessel bifurcation.

In the early 1990’s, endovascular treatment using embolic coils for the treatment of intracranial aneurysms was established. Since then, there has been a significant body of peer-reviewed literature written by medical experts regarding the use, safety, and efficacy of these detachable embolic coils. With the publishing of the ISAT (Intracranial Subarachnoid Aneurysm Trial) trial data in 2005, which compared clinical outcomes of neurosurgical clipping and endovascular coiling, embolic coiling became the preferred method for treatment of the majority of unruptured intracranial aneurysms [ISAT 2003, Molyneux et al. 2005].

Since then, there has been a revolution in interventional neuroradiology which includes a shift toward catheter based procedures. Unfortunately, for a variety of reasons there are not always endovascular treatment options available to some patients with intracranial aneurysms, especially if the neck of the aneurysm is wide. Additionally there is a range of concerns relating to patient comorbidities, aneurysm geometry or the location of the lesion. Consequently there are many challenges, even today, when treating patients with such lesions. Hence there has been significant research in this arena to develop adjunctive devices to be used with embolic coils as well as sole therapy devices.


The PulseRider has an open cell frame. The unique frame configuration opens to conform to the vessel walls. The PulseRider is specifically designed to resolve the shortcomings of current endovascular devices by preserving luminal patency and hemodynamic flow through the parent vessel bifurcation, while minimizing exposed metal in order to encourage early endothelialization while securely retaining embolic agents within the aneurysm sac. The PulseRider is delivered through commercially available microcatheters using standard endovascular techniques. The implant is retrievable and may be repositioned by retracting it into the microcatheter at any time during or after deployment (prior to detachment). The implant is designed with an open frame to maintain luminal patency. It is deployed at the parent vessel bifurcation and across the aneurysm neck to provide a support framework, bridging the aneurysm neck while retaining embolic agents within the aneurysm. The PulseRider is electrolytically detached from the delivery wire.


In the early experience with the Pulse Rider device its use was safe and effective as an adjunct in the treatment of bifurcation aneurysms arising at the basilar apex or carotid terminus 1).


The safety and probable benefit of the PulseRider (Pulsar Vascular, Los Gatos, California) for the treatment of broad-necked, bifurcation aneurysms was studied in the context of the prospective, nonrandomized, single arm clinical trial-the Adjunctive Neurovascular Support of Wide-neck aneurysm Embolization and Reconstruction (ANSWER) Trial.

Aneurysms treated with the PulseRider device among sites enrolling in the ANSWER trial were prospectively studied and the results are summarized. Aneurysms arising at either the carotid terminus or basilar apex that were relatively broad necked were considered candidates for inclusion into the ANSWER study.

Thirty-four patients were enrolled (29 female and 5 male) with a mean age of 60.9 years (27 basilar apex and 7 carotid terminus). Mean aneurysm height ranged from 2.4 to 15.9 mm with a mean neck size of 5.2 mm (range 2.3-11.6 mm). In all patients, the device was delivered and deployed. Immediate Raymond I or II occlusion was achieved in 82.4% and progressed to 87.9% at 6-month follow-up. A modified Rankin Score of 2 or less was seen in 94% of patients at 6 months.

The results from the ANSWER trial demonstrate that the PulseRider device is safe and offers probable benefit as for the treatment of bifurcation aneurysms arising at the basilar apex or carotid terminus. As such, it represents a useful addition to the armamentarium of the neuroendovascular specialist 2).

1)

Spiotta AM, Chaudry MI, Turk AS, Turner RD. Initial experience with the PulseRider for the treatment of bifurcation aneurysms: report of first three cases in the USA. J Neurointerv Surg. 2016 Feb;8(2):186-9. doi: 10.1136/neurintsurg-2014-011531. Epub 2015 Jan 5. PubMed PMID: 25561583.
2)

Spiotta AM, Derdeyn CP, Tateshima S, Mocco J, Crowley RW, Liu KC, Jensen L, Ebersole K, Reeves A, Lopes DK, Hanel RA, Sauvageau E, Duckwiler G, Siddiqui A, Levy E, Puri A, Pride L, Novakovic R, Chaudry MI, Turner RD, Turk AS. Results of the ANSWER Trial Using the PulseRider for the Treatment of Broad-Necked, Bifurcation Aneurysms. Neurosurgery. 2017 Apr 25. doi: 10.1093/neuros/nyx085. [Epub ahead of print] PubMed PMID: 28449126.

Book: Color Atlas of Brainstem Surgery

Color Atlas of Brainstem Surgery

Color Atlas of Brainstem Surgery

List Price:$249.99

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The highly complex specialty of brainstem surgery requires many years of study, a focus on precision, and a passionate dedication to excellence to prepare the neurosurgeon for navigating significant anatomic challenges. Although the brainstem is technically surgically accessible, its highly eloquent structure demands rigorous surgical decision-making. An in-depth understanding of brainstem and thalamic anatomy and the safe entry zones used to access critical areas of the brainstem is essential to traversing the brainstem safely and successfully.

This remarkable, one-of-a-kind atlas draws on the senior author’s decades of experience performing more than 1,000 surgeries on the brainstem, thalamus, basal ganglia, and surrounding areas. Its content is organized by anatomic region, enabling readers to study separate subdivisions of the brainstem, each of which has its own unique anatomic and surgical considerations. From cover to cover, the atlas provides readers with technical guidance on approach selection, the timing of surgery, and optimization of outcomes-elucidated by more than 1700 remarkable color illustrations, dissections, clinical images, and line drawings.

Key Highlights

  • Beautifully detailed, highly sophisticated brain slices and dissections by Kaan Yagmurlu, who trained under the internationally renowned neuroanatomist and neurosurgeon Albert Rhoton Jr.
  • Color illustrations clearly labeled with callouts and other indicators of foci of interest delineate multiple safe entry zones to the brainstem
  • More than 50 detailed patient cases highlight each patient’s history of previous neurological disorders, presenting symptoms, preoperative imaging, diagnosis, the planned surgical approach, patient positioning, intraoperative and postoperative imaging, and outcome
  • Seven animations and more than 50 surgical videos elucidate approach selection, anatomy, and surgical outcomes of thalamic region and brainstem lesions

This illuminating atlas provides insights into the complexities of the hallowed halls of the brainstem. Neurosurgeons and neurosurgical residents alike who glean knowledge from the clinical pearls throughout each section will no doubt become more adept surgeons, to the ultimate benefit of their patients.


Product Details

  • Published on: 2017-04-15
  • Original language: English
  • Dimensions: 12.30″ h x 1.30″ w x 9.40″ l,
  • Binding: Hardcover
  • 416 pages