Background

By the end of the next decade, 300,000 people will be living with chronic spinal cord injury in the US alone (Houle and Tessler, 2003). Advances in medical and rehabilitative care have improved survival rates for these individuals, but many experience clinical decline even years after the initial injury. Clinical decline is often accompanied by a slow and progressive cavitation of the central spinal cord, known as post-traumatic syringomyelia, PTS (for a review, see Klekamp, 2002). The pathogenesis of this disease remains poorly understood.

Pathophysiology of post-traumatic syringomyelia

Alterations in cerebrospinal fluid (CSF) dynamics following spinal cord injury are thought to play a role in the initiation and propagation of post-traumatic syringomyelic cysts and cavities (Berkouk et al., 2003;Bilston et al., 2003;Brodbelt et al., 2003b;Brodbelt et al., 2003a;Brodbelt et al., 2003c;Carpenter et al., 2003;Cosan et al., 2000;Chang and Nakagawa, 2003;Chang and Nakagawa, 2004;Klekamp et al., 2001;Loth et al., 2001;Milhorat et al., 1993;Stoodley et al., 1999;Chernoff et al., 2003;Chang and Nakagawa, 2004). Normally, CSF circulates in the subarachnoid space, traverses the spinal cord several times a day and exhibits a craniocaudal flow pattern influenced by the cardiac cycle (Menick, 2001). Some spinal fluid, driven by systolic pulsations, is thought to enter the substance of the cord via the Virchow-Robin perivascular spaces and
flow toward the central canal (Stoodley et al., 1996;Stoodley et al., 1997), an enigmatic structure of the central spinal cord believed to function as a CSF pathway. Indeed, Storer and colleagues have suggested that the flow of fluid through the central canal may comprise a ‘sink’ function whereby harmful metabolites are removed from the cord (Storer et al., 1998). Others believe the spinal cord itself produces extracellular fluid, whose egress toward the subarachnoid space or central canal depends on the pressure differential between the two compartments (Menick, 2001).

Following SCI, normal CSF dynamics may be distorted by a number of possible
mechanisms, including subarachnoid CSF outflow obstructions (Klekamp et al.,
2001;Klekamp, 2002), changes in compliance of the subarachnoid space (Brodbelt et al., 2003c) or elevated intraspinal pressures (Chang and Nakagawa, 2004). Altered CSF dynamics are believed to result in localized spinal cord edema, known as the presyrinx state (Fischbein et al., 1999), that subsequently gives rise to central canal dilation and/or the formation of intraspinal glial-lined parenchymal cysts.

The propagation of intraspinal cavities requires a driving force sufficient to propel fluid via a one-way valve mechanism into the cysts, which oftentime contain fluid at a higher pressure than the subarachnoid space (Lederhaus et al., 1988). Proposed driving forces include cardiac pulsations along vessels (Bilston et al., 2003;Stoodley et al., 1997), postural changes and valsala movements (Gardner and Angel, 1958) and elevated intraspinal pressures (Chang and Nakagawa, 2003). I would additionally suggest consideration of the transient hypertensive episodes of autonomic dysreflexia (for a review, see Bravo et al., 2004;Krassioukov and Weaver, 1995) as a potential driving force.


Prior models of post-traumatic syringomyelia, PTS

The histologic features of PTS have been reproduced in experimental models of
the disease. Experimental syringomyelia was first induced reliably with intraspinal injections of the irritant kaolin, producing histologic results similar to syringomyelia and, in many respects, acute hydrocephalus (Milhorat et al., 1993). Subsequent models utilized intraspinal injections of excitotoxic compounds and produced pathological results with a physiologically relevant mechanism consistent with the neurochemical milieu known to accompany SCI (Brodbelt et al., 2003a;Schwartz et al., 1999;Yang et al., 2001).


Both experimental models suffer the limitation of being non-traumatic (Schwartz et al., 1999) and require administration of exogenous agents (Lee et al., 2005).
Mathematical models of syrinx formation exist and allow the study of pressure
wave propagations in an idealized cerebrospinal fluid system, but suffer the limitation of not taking into account spinal cord parenchymal changes that may influence patterns of dilation (Berkouk et al., 2003;Bhadelia et al., 1997;Bilston et al., 2003;Carpenter et al., 2003;Chang and Nakagawa, 2003;Chang and Nakagawa, 2004;Loth et al., 2001).

Hydromyelosis

A local accumulation of CSF-like fluid near the epicenter of spinal injury and disease that may progress cranially into intact neurological tissue causing neurological decline.  This accumulation of fluid results from impaired CSF dynamics and homeostasis near the site of injury.  The cause of this obstruction is likely related to dural scarring near the epicenter of injury, causing either a mechanical obstruction and/or change in compliance of the dura.  Blood pressure spikes resulting from autonomic dysreflexia may contribute to cavity expansion through a water hammer effect.  Furthermore, oncotic pressure from stagnant cerebrospinal fluid may contribute to cavitary expansion, as well. Subsequent changes in spinal pressure may lead to further vascular compromise of the  cord.

The accumulation of fluid may result from necrosis of tissue, edema and obstructions to CSF flow. Prolonged expsoure to this milieu results in damage to the ciliated ependymal cells that are integrally responsible for CSF homeostasis and cellular signalling in the spinal cord. These ciliated ependymal cells also act as stromal cells for periependymal stem cells capable of gliogenesis and wound repair in the cord. Therefore, disruption of the ependyma will disrupt the balance between injury and repair in the cord toward the further destruction over time, thereby permitting the development of syringomyelic cysts and cavities. In other words, neural stem cells "live" along CSF  pathways and disruptions in CSF flow may alter stem cell behavior and viability.

My approach calls for early intervention in spinal cord injury addressing the following areas:



1.) Maximizing blood flow



-Monitoring blood flow and spinal perfusion pressure, but keeping blood pressure within a certain range



-Pharmacologically and surgically augmenting blood floow



2.) Miniziming edema



-Monitoring structural changes in the cord suggestive of edema and monitoring intraspinal pressure



-Pharmacologically and surgically minimizing intraspinal pressure



3.) Removing obstructions to CSF flow and minimizing accumulation of toxic metabolites and oncotically active fluid



-Pharmacologically inhibiting spinal arachnoiditis and dural scarring



-Surgically relieving obstructions to CSF flow through durotomy and duraplasty



-Drainage of cysts/cavities



-"CSF Dialysis"

The study of spinal cord injury may offer insight into the pathophysiology and treatment of related neurodegenerative disorders including multiple sclerosis, Alzheimer's disease and ALS, as well as stem cell disorders in general.  Therefore, it imperative to push forward with this research effort.

Copyright 2004 - 2009 Milan Radojicic MD.  All rights reserved.

Portions of this article include devices and approaches that are patent pending.



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