Research - Completed Research

Outcome Studies
Bermans Iskandar, MD

final report

outcome study document

Project title: Quantifying CSF Flow Dynamics Using Real-time MRI
Principal Investigator: Karim Sabra, PhD
Institution: Georgia Tech Research Corporation
Period of Performance: September 2015-August 2016
Award: $50,000.00
Summary of Research: This project aims 1) to quantitatively measure in real-time and non-invasively the cerebrospinal fluid (CSF) flow dynamics using a novel magnetic resonance imaging (MRI) technique in order to investigate the effects of respiration and transient events, such as coughing and sneezing, on SCF flow along the spine, and 2) to determine the applicability of this MRI method to improve the diagnosis of craniospinal disorders and better understand the role CSF flow plays in the pain symptoms experienced by Chiari malformation and syringomyelia patients.

Quantifying CSF Flow Dynamics Using Real-time MRI

Project title: Postoperative Syringomyelia Resolution in Canine Chiari Like Malformation
Principal Investigator: Lauren R Talarico, BS, DVM, CACVIM
Institution: VCA SouthPaws Veterinary Specialty and Emergency Center
Period of Performance: December 2014-November 2015
Award: $57,000.00
Summary of Research: Malformation of the caudal aspect of the skull, similar to Chiari type I disorder of people, has been documented in many breeds of dogs. Even though approximately 95% of all Cavalier King Charles Spaniels are affected by Chiari-like malformation (CLM) other breeds of dogs such as Yorkshire Terriers and Chihuahuas are also commonly affected.
1. To determine objective measurements of syrinx size pre and post-operatively and how changes in the size of the syrinx differs between persistently symptomatic and clinically improved postoperative patients.
2. To correlate the above findings with published human data to determine if cross species differences exist and to look for etiologic clues for this disease in both populations, particularly looking at the variable presentation of Chiari in the human population. This may also help to define which patients are at risk due to the lack of posterior fossa volume versus an obstruction of CSF flow at the outlet.

1 year report

2014 Reports Click on title to watch video presentation.

In Vivo and In Vitro CSF flow Studies in Chiari Malformation An ASAP funded research project, presented by Dr Bryn Martin

Comparative Analysis of Posterior Fossa Volumes in Symptomatic versus Asymptomatic Chiari Malformation
Alan Siu, MD

Multicenter in vitro Assessment of 4D PC MRI for Quantification of Cerebrospinal Fluid Motion in Chiari Malformation and Syringomyelia
Bryn A Martin, PhD

Is CSF Flow the “Holy Grail” to determining Clinic-pathological Significance of Chiari Malformation?
Mark Quigley, PhD

Outcome Studies
Bermans Iskandar, MD

The Genetics of Chiari Type I Malformation (CMI) with or without Syringomyelia
Dr. Allison Ashley-Koch, Center for Human Genetics, Duke University Medical School, Durham, North Carolina

Outcomes in Patients Undergoing Surgical Intervention for Chiari Type I Malformation with Syringomyelia
Bermans J. Iskandar, MD, University of Wisconsin at Madison, Tim M. George, MD, University of Texas at Austin

Importance of the Mechanical Forces in the Pathogenesis of Syringomyelia

Grant Recipient: Francis Loth, PhD, Department of Mechanical and Industrial Engineering, University of Illinois at Chicago

Project Title: Importance of the Mechanical Forces in the Pathogenesis of Syringomyelia

Dates: September 30, 2005 August 31, 2006

Grant Amount: $50,000

A simplified in vitro model of the spinal canal, based on in vivo magnetic resonance imaging (MRI), was used to examine the hydrodynamics of the human spinal cord and subarachnoid space (SAS) with syringomyelia. In vivo MRI measurements of SAS geometry and cerebrospinal fluid (CSF) velocity were acquired in a patient with syringomyelia and used to aid in the in vitro model design and experiment. The in vitro model contained a fluid-filled coaxial elastic tube to represent a syrinx. A computer controlled pulsatile pump was used to subject the in vitro model to a CSF flow waveform representative of that measured in vivo. Transducers measured unsteady pressure both in the SAS and intra-syrinx at four axial locations in the model.

MRI results indicated that the peak-to-peak amplitude of the SAS flow waveform in vivo was approximately ten fold that of the syrinx and in phase. The in vitro flow waveform approximated the in vivo peak-to-peak magnitude. Peak-to-peak in vitro pressure variation in both the SAS and syrinx was approximately 6 mmHg. Syrinx pressure waveform lead the SAS pressure waveform by approximately 40ms. Syrinx pressure was found to be less than the SAS for ~200 ms during the 860 ms flow cycle. Unsteady pulse wave velocity (PWV) in the syrinx was computed to be a maximum of ~25 m/s. Spinal cord wall motion was found to be non-axisymmetric with a maximum displacement of ~140 m, which is below the resolution limit of MRI.

Agreement between in vivo and in vitro MR measurements demonstrated that the hydrodynamics present in the fluid filled coaxial elastic tube system are similar to those present in syringomyelia. Overall, the in vitro study of the unsteady pressure and flow environment within the syrinx and SAS, provides insight into the complex biomechanical forces present in syringomyelia.

We propose to continue experimentation using this in vitro model of syringomyelia in order to determine the influence of various configuration changes on the hydrodynamic environment within the syrinx and SAS. Our previous research demonstrated a phase shift between the syrinx and SAS pressure that could provide a mechanism for syrinx progression. Thus, the proposed work would examine this potential mechanism under various configurations thought to cause syringomyelia. These configuration changes would represent conditions such as coughing, Chiari malformation, flow obstruction due to vertebra misalignment, changes in atmospheric pressure, and spinal cord tension. We will focus on obtaining measurements that provide a more complete understanding of the role of hydrodynamic forces in syringomyelia pathogenesis. Finally, we will continue research to develop novel MRI techniques that will provide detailed information about patient geometry to better assess syringomyelia and Chiari malformation severity.

Investigation on the pathogenesis of post-traumatic syringomyelia (PTS): the roles of central canal occlusion and focal arachnoiditis on the contused and intact rat spinal cord

Grant Recipient: Christopher Shields, M.D., Professor and Chairman, University of Louisville School of Medicine, Louisville, KY

Project Title: Investigation on the pathogenesis of post-traumatic syringomyelia (PTS): the roles of central canal occlusion and focal arachnoiditis on the contused and intact rat spinal cord

Dates: September 30, 2005 August 31, 2006

Grant Amount: $50,000

Syringomyelia is a major complication following spinal cord injury. Its occurrence causes pain and additional neurological impairments. Treatment of syringomyelia following spinal cord injury is limited. The absence of an animal model of post-traumatic syringomyelia (PTS) limits our ability to develop appropriate treatments for this condition. Using a rat, we believe that a model of PTS can be created by surgically induced focal arachnoiditis in the cervical area. We believe that the creation of PTS will be particularly fruitful following an associated spinal cord injury. We plan to surgically create a model that will cause post-traumatic syringomyelia. Animals will be monitored for one year following the surgery by sequential cervical MRI scans, and electrophysiological techniques that monitor descending motor pathways and ascending sensory pathways. Moreover, the rats will be sacrificed to assess the morphological changes on year after surgery. We postulate that if PTS does develop, there will be significant behavioral, electrophysiological, imagine, and morphological changes. If we are successful in creating such a model, this will allow the development of a series of innovative therapies for the management of PTS.

Spatial and Temporal CSF Flow Patterns in Chiari I Malformation and the Development of Syringomyelia

Grant Recipient: Victor Haughton, MD and Bermans Iskandar, MD, University of Wisconsin Medical School

Dates: October 1, 2003 September 30, 2004

Grant Amount: $55,782

This work focuses on examining the role of abnormal CSF dynamics at the foramen magnum in patients with CMI/S. Drs. Haughton and Iskandar believe that it is insufficient to consider only average CSF velocity in trying to understand symptoms and syrinx formation. They propose that a high resolution mapping of CSF flow must be made, including examination of localized “high velocity jets” of CSF that occur during systole and diastole, as well as other inhomogeneities of flow at the diastole, as well as other inhomogeneities of flow at the foramen magnum. Flow in normal subjects and CM/S patients will be characterized in three dimensions at sub-millimeter resolution using newer phase contrast imaging techniques. From this, they hope to understand why symptoms occur, how best to treat them, and to anticipate the occurrence of symptoms in asymptomatic patients.

Pre-clinical Development of GABA Cell Therapy For Chronic Pain After Spinal Cord Injury

Grant Recipient: Mary Eaton, PhD, Assistant Professor of Neurological Surgery, University of Miami

Dates: October 1, 2002 September 30, 2005

Grant Amount: $175,000

Backed by the resources of the Miami Project To Cure Paralysis, Dr. Eaton’s research focused on developing cellular ‘minipumps’ injected near pain-processing areas of the spinal cord to both alleviate and potentially eliminate chronic, neuropathic pain. Dr. Eaton developed cells that secreted (or pumped) GABA, a naturally occurring neurotransmitter in the spinal cord that inhibits pain, and injected the cells into rats with spinal cord injuries. Dr. Eaton’s research suggested that in a severe spinal cord injury, not enough GABA is produced to cope with the injury, and chronic pain ensues. Dr. Eaton hypothesized that inadequate GABA can be compensated for by injecting a ‘minipump’ of cells that secrete GABA near the injury. After developing the GABA-secreting cells, Dr. Eaton studied how well they produced GABA in rats with spinal cord injuries and whether the increased GABA reduced indications of neuropathic pain.

Dr. Eaton’s research showed that the transplanted GABA cells reduced chronic pain behaviors in rats. She intends to move on to human, clinical trials. With no effective treatment currently available for people suffering chronic, neuropathic pain, Dr. Eaton’s work offers hope that one day, relief may be as easy as getting a ‘minipump’ injection.

Cytokines and Neuropathic Pain in Syringomyelia

Grant Recipient: Joshua Adler, MD, Associate Professor of Neurology, Wayne State University

Dates: October 1, 2002 September 30, 2003

Grant Amount: $50,000

Dr. Adler proposed using an animal model to investigate the role of cytokines in neuropathic pain associated with syringomyelia. According to Online Medical Dictionary, a cytokine is a protein released by cells of the immune system that acts as a mediator in the generation of an immune response. Dr. Adler hypothesized that neuropathic pain in syringomyelia is mediated by cytokines, which either increase, or cause abnormal distribution of, pain-associated peptides. In fact, Dr. Adler’s preliminary data suggested that one cytokine, interleukin-1, leads to an increase in substance P. Substance P has been associated with central pain, and abnormal distribution of substance P has been found post-mortem in people with syringomyelia.

Specifically, Dr. Adlers study involved creating syringomyelia in rats through chemical injection. Once he verified that the rats were showing signs of neuropathic pain, he examined them for increased levels of interleukin-1, substance P and several other substances.

Dr. Adler advanced his work on the use of cytokines (a naturally occurring protein) to regulate neuropathic pain in rats with induced syringomyelia, an alternate approach to cell transplant. Dr. Adler will use these results in applying for a larger grant from the NIH. This is in keeping with ASAPs strategy to seed promising research with the hope that it transitions after one to two years to larger funding sources.

Importance of the Mechanical Forces in the Development of Syringomyelia for Patients With Chiari Malformation

Grant Recipient: Francis Loth, PhD, Assistant Professor, Department of Mechanical and Industrial Engineering, University of Illinois-Chicago

Dates: October 1, 2002 September 30, 2003

Grant Amount: $50,000

A mechanical engineer, Dr. Frank Loth proposed a research study that built upon his previous work in this area. His team at UIC has developed software that uses MRI data to build a patient-specific, mathematical model of CSF in the region around a Chiari malformation. Dr. Loth proposed investigating the role pressure plays in syrinx formation, progression and regression. To do this, he built physical models that closely matched the human body’s spinal canal and recreated the conditions present in syringomyelia. The models allowed him to experiment in a way not possible inside the human body. Using MRI data obtained from a Chiari/syringomyelia patient, Dr. Loth built two models of the spinal canal and cord, one before and one after a decompression surgery. With the models, Dr. Loth studied how the fluid in and around a syrinx behaved with a focus on analyzing the pressure around the syrinx.

Dr. Loth built upon his work in developing 3-D models of the CSF/spinal cord system to allow examination of CSF pressure changes in the vicinity of the syrinx and associated geometry changes (compliance) during the cardiac cycle. Unique to his work, Dr. Loth constructed the first functional mechanical model of the CSF/spinal cord system for a CMI/S patient, allowing him to analyze conditions that are conducive to syrinx formation. Quite often, research leads to difficult questions that ultimately advance our understanding of how things work. Interestingly, Dr. Loth found that the CSF pressure was higher in the syrinx than outside (in the subarachnoid space). The paradox that he noted is that fluid flow always goes from high to low pressure and that one would expect that conditions would be unfavorable for syrinx formation.

Dr. Loth believes that studying the pressure environment in the spinal canal may be the key to understanding the development of syringomyelia. Armed with this knowledge, physicians may be able to refine their surgical techniques, predict when a syrinx will form or regress and develop entirely new treatment options.

Chiari I Malformation and Syringomyelia in Identical Twins Discordant for Chronic Fatigue Syndrome

Grant Recipient: Dedra Buchwald, MD, Director, Chronic Fatigue Syndrome Cooperative Research Center, University of Washington

Dates: August 1, 2000 July 31, 2001

Grant Amount: $10,900

Dr. Buchwald has performed extensive evaluations on the central nervous system function of 22 sets of identical twins. The grant contributed to funding for CINE MRIs during the period August 1, 2000 to July 31, 2001 (paid December 2003). The ongoing study will help determine if there is evidence of Chiari malformation, syringomyelia or any signs of abnormal cerebral spinal fluid flow that could be related to chronic fatigue syndrome and/or fibromyalgia. (The Chronic Fatigue Syndrome Cooperative Research Center is currently funded by NIH.)

Chiari Malformation I/Syringomyelia Genetic Research Study

Grant Recipient: Marcy C. Speer, PhD, Associate Research Professor, Department of Medicine, Center for Human Genetics, Duke University

Dates: 1998

Grant Amount: $100,000

The Center for Human Genetics at Duke University, in collaboration with Dr. Thomas Milhorat and colleagues of North Shore University Hospital/Manhasset NY and the American Syringomyelia Alliance Project, is investigating the hereditary basis of Chiari type I malformations with or without syringomyelia. Research is aimed at learning if CM1/S is indeed caused by factors inherited through the family and, if so, which genes are involved.

More than 150 families joined the initial phase of the CM1/S research study and provided detailed family histories and blood samples. We reported familial aggregation in a large study of 364 CM1/S patients. Of these study participants, 21 of the patients’ families had two or more cases of CM1/S within the family. Thanks to all of the families who generously participated in the study, we were able to successfully accomplish the first step of the genetic research, which showed familial aggregation of CM1/S.