Discovering the Origin of Syrinx Fluid

1. Discovering the Origin of Syrinx Fluid

2. Syringomyelia • Fluid collection within the center of the spinal cord that expands the diameter of the spinal cord • Causes spinal cord injury and dysfunction Weakness and loss of muscle Loss of pain and temperature sensation Stiffness and lack of control of the legs (lower extremity spasticity

3. Possible Origins of Syrinx Fluid in Chiari I malformation • Increased fluid production in the spinal cord • From filtered blood (serum) entering the spinal cord through abnormal, leaky small blood vessels (capillaries) • Syrinx related to spinal cord tumors • From filtered blood (serum) entering the spinal cord through capillaries that are under higher than normal pressure • Mechanism in syrinx related to spinal cord arteriovenous malformations • Decreased drainage of fluid from the spinal cord • Obstructed outflow of CSF from the central canal of the spinal cord • Decreased movement of CSF out of the spinal cord and into the subarachnoid space • Obstructed outflow or decreased absorption of CSF from the brain results in hydrocephalus so why couldn’t decreased removal of fluid from the inside of the spinal cord result in syringomyelia? • From CSF entering the spinal cord from the subarachnoid space outside the spinal cord due to increased CSF pressure (hydrostatic pressure)

4. Why Is This Research Important? • Research addresses an unanswered medical or scientific question: • What is the Origin of Syrinx Fluid? • Research provides new knowledge, in this case knowledge of the process by which a syrinx develops. • Knowledge could lead to new ways of thinking about the condition of syringomyelia and its treatment. • Knowledge might lead to better treatments for dealing with syrinx formation and resolution. • Knowledge might indicate ways to prevent a syrinx from developing in a patient with asymptomatic Chiari I malformation or in a patient who has experienced spinal trauma.

5. Does Chiari I Syrinx Fluid Originate from CSF (cerebrospinal fluid)? Historical Evidence: • Chiari I patients with increased fluid diffusely (edema) within the spinal cord can later develop a syrinx • Syrinx fluid in Chiari I-related syringomyelia is chemically identical to CSF, whereas syrinx fluid in syringomyelia associated with tumors and AVM’s have a higher protein concentration than CSF, reflecting its origin as a blood filtrate • Myelogram dye enters the syrinx from the CSF in the spinal subarachnoid space on a delayed basis

6. 3 Months Before Surgery 1 Week Before Surgery Syrinx Development

7. Stages of Fluid Accumulation and Syrinx Formation in Chiari I-Related Syringomyelia • Chiari I without a syrinx Normal spinal cord • Pre-syringomyelia Diffuse increase in s.c. fluid • (Infrequently documented) • Syringomyelia Expanded fluid collection in the spinal cord • Post-syringomyelia Narrow fluid collection

8. CT-Myelogram Study • Eligibility: Patients with Chiari 1-syringomyelia, primarily spinal syringomyelia, or tumor-related syringomyelia • Rationale: Because myelogram dye is in solution in the CSF, dye will acts as a marker of the movement of CSF (cerebrospinal fluid) • Hypothesis: More dye (CSF) will enter the syrinx before compared to after surgery • Procedure: CT-myelogram before and 1 week after surgery • Baseline CT image through the syrinx • Inject local anesthetic into the skin of the low back • Insert a 22 gauge (a small diameter) spinal needle • Measure CSF pressure • Remove 10 mL (2 teaspoons) of CSF • Inject 10 mL of myelogram dye (300 mg/mL of organically-bound iodine) into the CSF in the subarachnoid space • CT cut through the syrinx every 2 hours for 10 hours and then at 24 hours after the injection; make a graph of the result

9. CT-Myelogram Study Subjects Chiari I-related syringomyelia 18 Primarily spinal syringomyelia 10 • Post-traumatic • Focal arachnoiditis Spinal cord tumor 7 • Hemangioblastoma

10. Entry of dye (CSF) into the Syrinx SAS Syrinx K(1,2) 1 2 K(2,1) Spinal Cord Wall

11. Hounsfield Units vs. Dye Concentration

12. Patients with Syrinx Shunts were Excluded from Analysis 20 Concentration in SAS, mg/ml Concentration in Syrinx, mg/ml 15 Concentration, mg/ml 10 5 0 0 5 10 15 20 25 30 Time post-injection, hr

13. After Surgery Before Surgery 20 Subarachnoid CSF Spinal cord tissue Syrinx fluid 15 10 Concentration, mg/ml 5 0 0 10 20 30 40 50 Time after injection, hr 20 Subarachnoid CSF Spinal cord tissue Syrinx fluid 15 10 Concentration, mg/ml 5 0 0 10 20 30 40 50 Time after injection, hr Syringomyelia from Chiari I

14. Two compartment fit to background subtracted measurement in syrinx from PreOp CT-myelogram Two compartment fit to background subtracted measurement in syrinx from PostOp CT-Myelogram 100 100 -1 -1 -1 -1 k = 0.093 hr k = 0.076 hr k = 0.084 hr k = 0.040 hr efflux influx influx efflux 80 80 60 60 H. U. H. U. 40 40 Measurement Measurement 20 20 Simulation Simulation 0 0 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 Time, hours Time, hours Dye Movement, Chiari I Before and After Surgery JW

15. Slow Decrease in Syrinx Size after Chiari I Surgery Mirrors Change in CSF Movement Into the Syrinx and Syrinx Fluid Movement Out of the Syrinx Figure 1. On T1-weighted sagittal MR images, a syrinx that is present before surgery (A) is little changed by 1 week after surgery (B), but then progressively becomes smaller by 3 months (C) and 1 year after surgery (D).

16. Chiari I Syrinx Resolution—A Slow Process Figure 3. On T1-weighted sagittal MR images, a syrinx (A) that is present before surgery becomes smaller by 1 week (B), and has nearly disappeared by 3 months after surgery that opens CSF pathways at the foramen magnum.

17. Primary Spinal Syringomyelia Before Surgery After Surgery

18. Primary Spinal Syringomyelia—More dye in the syrinx before, compared to after surgery

19. Before Surgery After Surgery 5 0 5 0 H . U . S A S H . U . S A S 4 0 4 0 H . U . S C H . U . S C H . U . S y r i n x H . U . S y r i n x Iopamidol mg/ml 3 0 3 0 2 0 2 0 1 0 1 0 0 0 0 1 0 2 0 3 0 4 0 5 0 6 0 0 1 0 2 0 3 0 4 0 5 0 6 0 t i m e ( h r s ) t i m e ( h r s ) Primary Spinal Syringomyelia-- Less Dye Enters the Syrinx after Surgery

20. Primary Spinal Syringomyelia Before Surgery After Surgery Before Surgery 3 Mos. After Surgery

21. More Myelogram Dye Enters the Syrinx in Syringomyelia Not Associated With Spinal Cord Tumors than in Patients with Spinal Cord Tumors

22. More Myelogram Dye Enters the Syrinx in Syringomyelia Not Associated With Spinal Cord Tumors than in Patients with Spinal Cord Tumors

23. Std Dev Number Mean 100 57 Chiari With Syrinx 18 122 Primarily Spinal Syrinx 10 70 55 54 Spinal Cord Tumor 7 More Myelogram Dye Enters the Syrinx in Syringomyelia Not Associated With Spinal Cord Tumors than in Patients with Spinal Cord Tumors

24. Maximal Syrinx Intensity 300 Pre-Op 250 Post-Op 200 150 Hounsfield Units 100 50 0 Maximal syrinx intensity measurements for subjects with Primarily Spinal Syringomyelia before surgery (blue) and after surgery (red).

25. Average Change in Maximal Syrinx Intensity 1.4 Pre-Op 1.2 Post-Op * 1 0.8 Hounsfield Units, normalized 0.6 * 0.4 0.2 0 Primary Spinal Syrinx Chiari I Malformation Combined Non-Tumor Syrinx (n=8), *p<0.05 with Syrinx (n=11) (n=19), *<0.05 Both Primary Spinal Syrinx group and Combined Non-Tumor Syrinx group had significant decrease in maximal syrinx dye concentration after surgery (p<0.05).

26. Unifying Theory of Syringomyelia Pathophysiology Chiari I Primary Spinal