Aspirin still unproven as therapy for curbing brain aneurysm growth

Cincinnati — Could an aspirin a day keep an aneurysm at bay?

That was the question asked by stroke researchers in the University of Cincinnati Department of Neurosurgery. The researchers reviewed the cases of 186 patients who had unruptured intracranial (brain) aneurysms that were being monitored for growth at Mayfield Brain & Spine.

They found a tiny difference between patients who took an aspirin daily and those who did not take any aspirin. Aneurysms in the group that took aspirin grew in 11.9% of patients (3 percent per year) while aneurysms in the non-aspirin group grew in 16.5% (4 percent per year). Growth was measured by brain scans.

“Although patients on a daily aspirin regimen demonstrated a lower rate of aneurysm growth, the difference was not statistically significant,” said Andrew Ringer, MD, a neurosurgeon with Mayfield Brain & Spine and the study’s principal investigator. “We need to conduct additional research that involves a larger number of patients from multiple centers.”

The research team is plans to explore additional data collected from thousands of patients treated by the Mayfield Clinic to see if this trend continues, Dr. Ringer said.

The poster is being displayed February 20-21 at the 2017 Annual Meeting of the American Association of Neurological Surgeons / Congress of Neurological Surgeons Joint Cerebrovascular Section in Houston.

A brain aneurysm is bulge on an artery wall that can rupture as it grows thinner and weaker, releasing blood into the space between the brain and the skull, a potentially catastrophic event called a subarachnoid hemorrhage. Of the 30,000 Americans who experience a ruptured brain aneurysm each year, according to the Brain Aneurysm Foundation, 15 percent of patients with a subarachnoid hemorrhage die before reaching the hospital, while 4 out of 7 who recover will have disabilities.

Dr. Ringer, a professor of neurosurgery, said that because the aspirin study was retrospective, the researchers could not be sure that patients were taking aspirin as prescribed. A prospective study in which patients are divided into closely monitored groups – those taking aspirin and those not taking aspirin – would provide greater clarity, Dr. Ringer said.

“It is in the public’s interest to find out whether an inexpensive and accessible drug can help keep small, non-threatening brain aneurysms from becoming larger, more dangerous aneurysms that require endovascular or surgical intervention,” Dr. Ringer said.

Additional co-investigators in the aspirin and aneurysm study are Christopher Carroll, MD, Ryan Tackla, MD, William Jeong, MD, Shawn Vuong, and Joseph Serrone, MD.

The study received no internal or external funding. The investigators stated no conflicts of interest.

 

Originally published from:

https://www.mayfieldclinic.com/MC_PR/PR_17Feb20.htm

 

Questioning the classical flow of CSF

Data has already been adding up which clarifies the classic model of CSF flow that experts rely on, is not correct.  In almost all modern neuroscience literature, since the original work on hydrocephalus by Dr. Dandy, Dr. Blackfin, and Dr. Cushing, CSF is made by the choroid plexus.   Then CSF flows through the lateral ventricles into the foramen of Monroe, into the third ventricle, through the aqueduct of Sylvius, and into the fourth ventricle where it exits the ventricular system through the foramen of Magendie or Lushka into the cerebral subarachnoid space.  Then the CSF bathes the brain or spinal cord but eventually gets absorbed mostly in the arachnoid granulations, which was originally questioned by Dr. Dandy (2-Dandy) or a small amount through the olfactory lymphatic pathway. (1-Oreskovic)

This is the classical pathway which is still used today to formulate theories on how acute hydrocephalus, NPH, low-pressure hydrocephalus (3-Smalley), pseduotumor cerebri, and other CSF flow abnormalities happen.

However, a lab group in Croatia is strongly questioning the classical pathway, and for good reason.(1-Oreskovic). There group has found:

  1. Upright position creates a sub-atmospheric pressure environment intracranially, and a significantly increased pressure region in the lumbar cistern.  Given the physics of fluid dynamics, shouldn’t normal flow go from the lumbar cistern to the head? (4-Klarica)
  2. Acute hydrocephalus created by sudden blockage of the aqueduct of Sylvius or kaolin injection into the cisterna magna does not lead to increased pressure after 21 days.  How does ventriculomegaly form? (5-Mise)
  3. Heavy water in the ventricles never makes it out of the ventricular system, but is found in the blood stream. While marked-insulin does travel from the ventricles to the subarachnoid space, it probably travels from the subarachnoid space to the ventricles.  This suggests that water and thus CSF is not traveling in a unidirectional fashion as Dr. Dandy described, and macromolecules probably travel in both directions due to diffusion. (6-Bulat)

These experimental findings along with the recent discoveries of the brain lymphatic system, the glymphatic system, MRI phase contrast and time-SLIP studies of CSF flow in-vivo, and anecdotal evidence of patients with complete aqueduct blockages (by pineal region tumors) without acute hydrocephalus, brings a person to wonder, do we really have any understanding of CSF flow dynamics?

References:
1.Orešković D, Radoš M, Klarica M: New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus. Pediatr Neurosurg:2016
2.Dandy WE: Experimental hydrocephalus. Ann Surg 2:345–351, 1919
3.Smalley ZS, Venable GT, Einhaus S: Low-Pressure Hydrocephalus in Children: a Case Series and Review of the Literature. Neurosurgery, 2017, pp 439–447
4.Klarica M, Radoš M, Erceg G, Petošić A, Jurjević I, Orešković D: The influence of body position on cerebrospinal fluid pressure gradient and movement in cats with normal and impaired craniospinal communication. PLoS ONE 9:e95229, 2014
5.Mise B, Klarica M, Seiwerth S, Bulat M: Experimental hydrocephalus and hydromyelia: a new insight in mechanism of their development. Acta Neurochir (Wien) 138:862–8– discussion 868–9, 1996
6.Bulat M, Lupret V, Orehković D, Klarica M: Transventricular and transpial absorption of cerebrospinal fluid into cerebral microvessels. Coll Antropol 32 Suppl 1:43–50, 2008

Application of emerging technologies to improve access to ischemic stroke care

Neurosurg Focus. 2017 Apr;42(4):E8. doi: 10.3171/2017.1.FOCUS16520.
Application of emerging technologies to improve access to ischemic stroke care.

Vuong SM, Carroll CP, Tackla RD, Jeong WJ, Ringer AJ.

Abstract
During the past 20 years, the traditional supportive treatment for stroke has been radically transformed by advances in catheter technologies and a cohort of prominent randomized controlled trials that unequivocally demonstrated significant improvement in stroke outcomes with timely endovascular intervention. However, substantial limitations to treatment remain, among the most important being timely access to care. Nonetheless, stroke care has continued its evolution by incorporating technological advances from various fields that can further reduce patients’ morbidity and mortality. In this paper the authors discuss the importance of emerging technologies-mobile stroke treatment units, telemedicine, and robotically assisted angiography-as future tools for expanding access to the diagnosis and treatment of acute ischemic stroke.

PMID: 28366070 DOI: 10.3171/2017.1.FOCUS16520

Vascular Diseases of the Spinal Cord: Infarction, Hemorrhage, and Venous Congestive Myelopathy

Abstract

Vascular pathologies of the spinal cord are rare and often overlooked. This article presents clinical and imaging approaches to the diagnosis and management of spinal vascular conditions most commonly encountered in clinical practice. Ischemia, infarction, hemorrhage, aneurysms, and vascular malformations of the spine and spinal cord are discussed. Pathophysiologic mechanisms, clinical classification schemes, clinical presentations, imaging findings, and treatment modalities are considered. Recent advances in genetic and syndromic vascular pathologies of the spinal cord are also discussed. Clinically relevant spinal vascular anatomy is reviewed in detail.

PMID: 27616317

Mouse Model of Congenital Hydrocephalus

Congenital hydrocephalus continues to be a difficult disease to treat.  Unfortunately research which explains the exact mechanisms leading to the development of this disease is lacking, likely as a result of no robust models.

In 2011, Stottmann et al, were looking to find and understand the genes involved with neurodevelopment.  In a mouse model, their lab performed a forward genetic screen using ENU to produce novel mutations with the goal of modeling human genetic defects.  During the screen, they produced a mutation which they called “progressive hydrocephalus” (prh).  At birth, these mice appear normal, but at day 14 they are visibly hydrocephalic and do not survive to the weaning period. The image above shows how the mice look compared to wild type (wt) mice.

Recently our lab discovered a gene that is completely devoid in the prh mice called coiled-coil domain containing protein 39 (Ccdc39).  This gene was found to be richly expressed in cells containing cilia and was ultimately found to be required for the assembly of inner dynein arms for the normal ciliary motility in humans and dogs (Merveille et al.).  This is important because according to Lodish et al.:

the inner-arm dyneins are responsible for producing the sliding forces that are converted to bending; this suggests that inner-arm dyneins are essential for bending

Essentially, if the inner dynein of cilia are not assembled correctly, bending forces within the cilia cannot be generated which then would greatly affect motility of the cilia and thus it’s main function.

Our lab has preliminary data that suggests the prh mutation results in loss of ccdc39 protein within the choroid plexus, and this is what may be causing the hydrocephalus phenotype seen in prh mice.  Thus aims of our research include:

  1. Proving the ccdc39 mutation in prh mice is the cause of the hydrocephalus
  2. Then selectively knocking out the ccdc39 gene in the choroid plexus to prove that cilia disruption within the choroid plexus itself is responsible for the hydrocephalus phenotype seen in prh mice
  3. Show that CSF production is abnormal in choroid plexus cells of the ccdc39 mutants

I hope to gather enough data this year to accomplish each of these goals.  I am excited for this year in the lab and am thankful to Dr. Mangano and Dr. Goto for their mentorship.


References
  • Stottmann, R. W., Moran, J. L., Turbe-Doan, A., Driver, E., Kelley, M., & Beier, D. R. (2011). Focusing forward genetics: a tripartite ENU screen for neurodevelopmental mutations in the mouse. Genetics, 188(3), 615–624. http://doi.org/10.1534/genetics.111.126862
  • Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000. Section 19.4, Cilia and Flagella: Structure and Movement. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21698/
  • Merveille, A.-C., Davis, E. E., Becker-Heck, A., Legendre, M., Amirav, I., Bataille, G., et al. (2011). CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nature Genetics, 43(1), 72–78. http://doi.org/10.1038/ng.726

When should an ICP monitor be removed in Severe TBI patients?

When should the neurosurgery team take out the ICP monitor after severe TBI?  One paper suggests that we should wait until after 7 days.  Up to 17% of patients have a delayed ICP rise after severe injury.  That is of course assuming that there is no exam or functional status marker to follow, as the authors mention in their discussion.

 

O’Phelan, K. H., Park, D., Efird, J. T., Johnson, K., Albano, M., Beniga, J., et al. (2009). Patterns of increased intracranial pressure after severe traumatic brain injury. Neurocritical Care, 10(3), 280–286. doi:10.1007/s12028-008-9183-7

What is the Chou Procedure?

A procedure used in neurosurgery in an attempt to save a cranioplasty flap after an infection. Paper by Dr. Chou in 1974 describes the procedure.

 

Open debridement. Placement of two channel drains (or 4). Placed superior and inferior in the subgaleal (or subgaleal and epidural).

 

Paper originally used 1 g of Keflin (cefalotin).  Irrigating solution is infused at a rate of 1-2 liters per 24 hours (40-80 mL/hr)  and continued for 5 days.

 

Nursing note: call if output is 10 mL or more different than input.

 

Reference:

Erickson, Seljeskog, and Chou. Suction-irrigation treatment of craniotomy infections. J neurosurgery. 1974 Aug; 41(2):265-7

Guidelines for Pre-operative Antibiotics for Neurosurgery

Antibiotic Doses:

Ancef = 2 grams or 3 grams if >120 kg (30mg/kg in kids) re-dose q4 hr

Clinda = 900mg (10mg/kg in kids) re-dose q6 hr

Vanc = 15mg/kg no re-dosing

*Vanc Dosing –

In a study of 2048 patients undergoing coronary bypass graft or valve replacement surgery receiving vancomycin prophylaxis, the rate of SSI was lowest in those patients in whom an infusion was started 16–60 minutes before surgical incision.

Overall Recommendation on Timing:

Overall, administration of the first dose of antimicrobial beginning within 60 minutes before surgical incision is recommended. Administration of vancomycin and fluoroquinolones should begin within 120 minutes before surgical incision because of the prolonged infusion times required for these drugs. Because these drugs have long half-lives, this early administration should not compromise serum levels of these agents during most surgical procedures.

Population Studies Reveal:

  • S. aureus nasal colonization in the general population decreased from 32.4% in 2001–02 to 28.6% in 2003– 04 (p < 0.01), whereas the prevalence of colonization with MRSA increased from 0.8% to 1.5% (p < 0.05)
  • Between 2007 and 2009, 23.3% of children were colonized with S. aureus, but the proportion of children colonized with MRSA had increased from 8.1% in 2004 to 15.1% in 2009.

Official Recommendation Guideline for Neurosurgery Procedures

A single dose of cefazolin is recommended for patients undergoing clean neurosurgical procedures, CSF-shunting procedures, or intrathecal pump placement (Table 2). Clindamycin or vancomycin should be reserved as an alternative agent for patients with a documented b-lactam allergy (vancomycin for MRSA-colonized patients). (Strength of evidence for prophylaxis = A.)

Official Recommendation Guideline for Spine Procedures

Antimicrobial prophylaxis is recommended for orthopedic spinal procedures with and without instrumentation. The recommended regimen is cefazolin (Table 2). (Strength of evidence for prophylaxis in orthopedic spinal procedures = A.) Clindamycin and vancomycin should be reserved as alternative agents as described in the Common Principles section. If there are surveillance data showing that gram-negative organisms are a cause of SSIs for the procedure, practitioners may consider combining clindamycin or vancomycin with another agent (cefazolin if the patient is not b-lactam allergic; aztreonam, gentamicin, or single-dose fluoroquinolone if the patient is b-lactam allergic). Mupirocin should be given intranasally to all patients known to be colonized with S. aureus.

Clinical practice guidelines for antimicrobial prophylaxis in surgery. American Journal of Health-System Pharmacy, 2013 vol. 70 (3) pp. 195-283