Category Archives: Vascular

International Gamma Knife Research Foundation

Upcoming Meetings

ASSFN 2016

IGKRF Biennial Scientific Session
University of Pennsylvania
Philadelphia, Pa.
June 23, 2017
Meeting Brochure

http://www.igkrf.org/

The International Gamma Knife Research Foundation consists of academic and clinical centers of excellence where brain Stereotactic Radiosurgery is performed using the Leksell Gamma Knife. All participating centers have a track record of outcomes research and participation in clinical trials.

The primary goal of the IGKRF is to facilitate retrospective and prospective clinical trials and outcomes analysis that evaluate the role of Gamma Knife radiosurgery in a wide spectrum of clinical indications.

Because individual centers may evaluate only a small number of patients with rare conditions, pooling of information is critical to evaluate and to improve outcomes. Each center has a professional team consisting of one or more neurological surgeons, radiation oncologists, and medical physicists. Participation is by invitation of the Board of Directors. ​ The IGKRF is a non-profit scientific, educational, and research entity incorporated in the state of Pennyslvania.​

Case series

2017

Ding et al. evaluated and pooled AVM radiosurgery data from 8 institutions participating in the International Gamma Knife Research Foundation. Patients with unruptured AVMs and ≥12 mo of follow-up were included in the study cohort. Favorable outcome was defined as AVM obliteration, no postradiosurgical hemorrhage, and no permanently symptomatic radiation-induced changes.

The unruptured AVM cohort comprised 938 patients with a median age of 35 yr. The median nidus volume was 2.4 cm 3 , 71% of AVMs were located in eloquent brain areas, and the Spetzler-Martin grade was III or higher in 57%. The median radiosurgical margin dose was 21 Gy and follow-up was 71 mo. AVM obliteration was achieved in 65%. The annual postradiosurgery hemorrhage rate was 1.4%. Symptomatic and permanent radiation-induced changes occurred in 9% and 3%, respectively. Favorable outcome was achieved in 61%. In the multivariate logistic regression analysis, smaller AVM maximum diameter ( P = .001), the absence of AVM-associated arterial aneurysms ( P = .001), and higher margin dose ( P = .002) were found to be independent predictors of a favorable outcome. A margin dose ≥ 20 Gy yielded a significantly higher rate of favorable outcome (70% vs 36%; P < .001).

Radiosurgery affords an acceptable risk to benefit profile for patients harboring unruptured AVMs. These findings justify further prospective studies comparing radiosurgical intervention to conservative management for unruptured AVMs 1).

2016

Data from a cohort of 2236 patients undergoing GKRS for cerebral AVMs were compiled from the International Gamma Knife Research Foundation. Favorable outcome was defined as AVM obliteration and no posttreatment hemorrhage or permanent symptomatic radiation-induced complications. Patient and AVM characteristics were assessed to determine predictors of outcome, and commonly used grading scales were assessed.

The mean maximum AVM diameter was 2.3 cm, with a mean volume of 4.3 cm3. A mean margin dose of 20.5 Gy was delivered. Mean follow-up was 7 years (range 1-20 years). Overall obliteration was 64.7%. Post-GRKS hemorrhage occurred in 165 patients (annual risk 1.1%). Radiation-induced imaging changes occurred in 29.2%; 9.7% were symptomatic, and 2.7% had permanent deficits. Favorable outcome was achieved in 60.3% of patients. Patients with prior nidal embolization (OR 2.1, p < 0.001), prior AVM hemorrhage (OR 1.3, p = 0.007), eloquent location (OR 1.3, p = 0.029), higher volume (OR 1.01, p < 0.001), lower margin dose (OR 0.9, p < 0.001), and more isocenters (OR 1.1, p = 0.011) were more likely to have unfavorable outcomes in multivariate analysis. The Spetzler-Martin grade and radiosurgery-based AVM score predicted outcome, but the Virginia Radiosurgery AVM Scale provided the best assessment.

GKRS for cerebral AVMs achieves obliteration and avoids permanent complications in the majority of patients. Patient, AVM, and treatment parameters can be used to predict long-term outcomes following radiosurgery 2). ​

1)

Ding D, Starke RM, Kano H, Lee JYK, Mathieu D, Pierce J, Huang P, Missios S, Feliciano C, Rodriguez-Mercado R, Almodovar L, Grills IS, Silva D, Abbassy M, Kondziolka D, Barnett GH, Lunsford LD, Sheehan JP. Radiosurgery for Unruptured Brain Arteriovenous Malformations: An International Multicenter Retrospective Cohort Study. Neurosurgery. 2017 Jun 1;80(6):888-898. doi: 10.1093/neuros/nyx181. PubMed PMID: 28431024.
2)

Starke RM, Kano H, Ding D, Lee JY, Mathieu D, Whitesell J, Pierce JT, Huang PP, Kondziolka D, Yen CP, Feliciano C, Rodgriguez-Mercado R, Almodovar L, Pieper DR, Grills IS, Silva D, Abbassy M, Missios S, Barnett GH, Lunsford LD, Sheehan JP. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. J Neurosurg. 2016 Mar 4:1-9. [Epub ahead of print] PubMed PMID: 26943847.

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

List Price:$94.99

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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