Proposal outlining a new approach to spinal cord injury
Saturday, 01 January 2005 00:00
Author: Milan Radojicic MD
Submitted to the Christopher Reeve Paralysis Foundation in 2005
Abstract
By the end of the next decade, 300,000 people will be living with chronic spinal cord injury in the US alone. Improvements in health care delivery have led to an increased survival of acutely spinal cord injured patients and, as a result, a greater percentage of spinal cord injured individuals will experience the chronic stages of the disease. People with chronic spinal cord injuries suffer persisting, and sometimes worsening, neurological deficits, as well as a host of secondary debilitating illnesses. Sadly, some of the most promising therapies for acute spinal cord injury have not been shown to be beneficial in chronic spinal cord injury, for unknown reasons. Indeed, there is a paucity of information in the literature regarding the anatomic and histopathological progression of the disease. One known consequence of chronic spinal cord is post-traumatic syringomyelia, a glial-lined cystic cavitation of the central spinal cord that can progress in size over time and lead to clinical decline. Despite decades of research, the pathogenesis remains a medical mystery, but the initiation and propagation of the disease may be related to altered CSF dynamics in the spinal cord resulting from disturbances in the CSF outflow tracts. Improved understanding of the sequence of anatomic and histopathologic changes involved in chronic spinal cord injury will certainly lead to better therapies.
This study will characterize the evolution of chronic spinal cord injury using anatomic imaging, histopathological analysis and experimental physiological techniques. We will test the hypothesis that ongoing pathogenesis in spinal cord lesions is influenced by altered CSF dynamics. We plan to identify histopathological stages of the disease, along with potential markers of ongoing injury. Finally, we hope to test several therapeutic interventions aimed at restoring favorable CSF dynamics to the injured spinal cord.
Background and significance
Working with a rodent model of chronic spinal cord injury, I have discovered histopathological evidence of altered CSF dynamics in chronic spinal cord injury. These rodents demonstrated progressive dilation of the central canal lumen rostral to the epicenter of injury that was accompanied by loss of ciliated ependymal cells, ependymal region thinning and periependymal changes. This histopathologic sequence is similar to that of chronic hydrocephalus (Kiefer et al., 1998) and points to a potential common pathogenic origin to the two diseases. Indeed, post-traumatic hydrocephalus is a well-known clinical entity and altered CSF dynamics following insults to the brain are well characterized (Czosnyka and Pickard, 2004). Of note, derangements of CSF dynamics following spinal cord injury are increasingly believed to play a role in the initiation and propagation of syringomyelic cysts, a known consequence of chronic spinal cord lesions (Berkouk et al., 2003;Brodbelt et al., 2003b;Carpenter et al., 2003;Chang and Nakagawa, 2003;Chang and Nakagawa, 2004;Cosan et al., 2000;Klekamp et al., 2001;Loth et al., 2001;Milhorat et al., 1993;Stoodley et al., 1999;Brodbelt et al., 2003a;Brodbelt et al., 2003c;Bilston et al., 2003).
The histopathologic features of syringomyelia have been reproduced in experimental models. Syringomyelia was first modeled reliably with intraspinal injections of the irritant kaolin, reproducing in many ways the pathological changes seen in acute hydrocephalus (Milhorat et al., 1993). Subsequent models have utilized intraspinal injections of excitotoxic compounds (Yang et al., 2001;Schwartz et al., 1999;Brodbelt et al., 2003a). However, both experimental models suffer the limitation of being non-traumatic (Schwartz et al., 1999) and require administration of exogenous agents (Lee et al., 2005). I have demonstrated similar cystic pathology in a clinically relevant contusion model of rodent chronic spinal cord injury.
Of note, in our experimental model of chronic spinal cord injury, progressive dilations of the central canal lumen were accompanied by histologic changes in the surrounding ependymal region and periependymal tissues, as would be predicted by Laplace’s law. Loss of cilia, ependymal region thinning and robust degeneration in periependymal tissues were all observed. It is intriguing to note that neural stem cells have been isolated from periventricular CNS regions (Johansson et al., 1999;Weiss et al., 1996;Yamamoto et al., 2001), including regions near the central canal (Martens et al., 2002). Indeed, ependymal region cells have been shown to proliferate (Bruni and Anderson, 1987;Matthews et al., 1979;Takahashi et al., 2003;Vaquero et al., 1981) and migrate (Johansson et al., 1999;Kojima and Tator, 2002;Mothe and Tator, 2005) after spinal cord injury. Furtherfore, the kinetics of ependymal region cell proliferation and differentiation have been correlated with the recovery of lower limb motor function in rats following contusion injuries (Takahashi et al., 2003). Reports of cell genesis in the ependymal region appear restricted to the glial lineage and have included the generation of ependymal cells (Bruni and Anderson, 1987), reactive astrocytes (Johansson et al., 1999;Mothe and Tator, 2005;Takahashi et al., 2003), oligodendrocyte precursors (Miller and Ono, 1998) and microglia (Carbonell et al., 2005). Glia are supportive cells of the CNS and are a critical for maintaining the structural and functional integrity of the spinal cord after injury. Therefore, I have posited the novel hypothesis that the progressive destruction of the ependymal region, through distensile and cytotoxic means, will result in altered gliogenesis in spinal cord, which may subsequently influence patterns of cystic cavitation. Testing this hypothesis is a key component of this proposal.
By the end of the next decade, 300,000 people will be living with chronic spinal cord injury in the US alone. Improvements in health care delivery have led to an increased survival of acutely spinal cord injured patients and, as a result, a greater percentage of spinal cord injured individuals will experience the chronic stages of the disease. People with chronic spinal cord injuries suffer persisting, and sometimes worsening, neurological deficits, as well as a host of secondary debilitating illnesses. Sadly, some of the most promising therapies for acute spinal cord injury have not been shown to be beneficial in chronic spinal cord injury, for unknown reasons. Indeed, there is a paucity of information in the literature regarding the anatomic and histopathological progression of the disease. One known consequence of chronic spinal cord is post-traumatic syringomyelia, a glial-lined cystic cavitation of the central spinal cord that can progress in size over time and lead to clinical decline. Despite decades of research, the pathogenesis remains a medical mystery, but the initiation and propagation of the disease may be related to altered CSF dynamics in the spinal cord resulting from disturbances in the CSF outflow tracts. Improved understanding of the sequence of anatomic and histopathologic changes involved in chronic spinal cord injury will certainly lead to better therapies.
This study will characterize the evolution of chronic spinal cord injury using anatomic imaging, histopathological analysis and experimental physiological techniques. We will test the hypothesis that ongoing pathogenesis in spinal cord lesions is influenced by altered CSF dynamics. We plan to identify histopathological stages of the disease, along with potential markers of ongoing injury. Finally, we hope to test several therapeutic interventions aimed at restoring favorable CSF dynamics to the injured spinal cord.
Background and significance
Working with a rodent model of chronic spinal cord injury, I have discovered histopathological evidence of altered CSF dynamics in chronic spinal cord injury. These rodents demonstrated progressive dilation of the central canal lumen rostral to the epicenter of injury that was accompanied by loss of ciliated ependymal cells, ependymal region thinning and periependymal changes. This histopathologic sequence is similar to that of chronic hydrocephalus (Kiefer et al., 1998) and points to a potential common pathogenic origin to the two diseases. Indeed, post-traumatic hydrocephalus is a well-known clinical entity and altered CSF dynamics following insults to the brain are well characterized (Czosnyka and Pickard, 2004). Of note, derangements of CSF dynamics following spinal cord injury are increasingly believed to play a role in the initiation and propagation of syringomyelic cysts, a known consequence of chronic spinal cord lesions (Berkouk et al., 2003;Brodbelt et al., 2003b;Carpenter et al., 2003;Chang and Nakagawa, 2003;Chang and Nakagawa, 2004;Cosan et al., 2000;Klekamp et al., 2001;Loth et al., 2001;Milhorat et al., 1993;Stoodley et al., 1999;Brodbelt et al., 2003a;Brodbelt et al., 2003c;Bilston et al., 2003).
The histopathologic features of syringomyelia have been reproduced in experimental models. Syringomyelia was first modeled reliably with intraspinal injections of the irritant kaolin, reproducing in many ways the pathological changes seen in acute hydrocephalus (Milhorat et al., 1993). Subsequent models have utilized intraspinal injections of excitotoxic compounds (Yang et al., 2001;Schwartz et al., 1999;Brodbelt et al., 2003a). However, both experimental models suffer the limitation of being non-traumatic (Schwartz et al., 1999) and require administration of exogenous agents (Lee et al., 2005). I have demonstrated similar cystic pathology in a clinically relevant contusion model of rodent chronic spinal cord injury.
Of note, in our experimental model of chronic spinal cord injury, progressive dilations of the central canal lumen were accompanied by histologic changes in the surrounding ependymal region and periependymal tissues, as would be predicted by Laplace’s law. Loss of cilia, ependymal region thinning and robust degeneration in periependymal tissues were all observed. It is intriguing to note that neural stem cells have been isolated from periventricular CNS regions (Johansson et al., 1999;Weiss et al., 1996;Yamamoto et al., 2001), including regions near the central canal (Martens et al., 2002). Indeed, ependymal region cells have been shown to proliferate (Bruni and Anderson, 1987;Matthews et al., 1979;Takahashi et al., 2003;Vaquero et al., 1981) and migrate (Johansson et al., 1999;Kojima and Tator, 2002;Mothe and Tator, 2005) after spinal cord injury. Furtherfore, the kinetics of ependymal region cell proliferation and differentiation have been correlated with the recovery of lower limb motor function in rats following contusion injuries (Takahashi et al., 2003). Reports of cell genesis in the ependymal region appear restricted to the glial lineage and have included the generation of ependymal cells (Bruni and Anderson, 1987), reactive astrocytes (Johansson et al., 1999;Mothe and Tator, 2005;Takahashi et al., 2003), oligodendrocyte precursors (Miller and Ono, 1998) and microglia (Carbonell et al., 2005). Glia are supportive cells of the CNS and are a critical for maintaining the structural and functional integrity of the spinal cord after injury. Therefore, I have posited the novel hypothesis that the progressive destruction of the ependymal region, through distensile and cytotoxic means, will result in altered gliogenesis in spinal cord, which may subsequently influence patterns of cystic cavitation. Testing this hypothesis is a key component of this proposal.
Additionally, we have also examined the end-stage pathology of chronic spinal cord injury, which is comprised of large, glial-lined cystic lesions of the central spinal cord. I discovered that some rodents with this end-stage pathology developed tissue bands that spanned the lesion cavities, reminiscent of the septations seen in human syringomyelia. Interestingly, closer inspection of these tissue bands revealed the presence of axons. Moreover, adjacent gliotic areas of spinal cord tissue were found to contain nests of ependymal cells in rosette formations, in which naked axons were engulfed. Further study is needed to characterize the origin and destination of these axons, but these preliminary findings are at least suggestive of a regenerative response in mammals.
Finally, I wish to propose and test a number of therapeutic interventions for spinal cord injury aimed at restoring favorable CSF dynamics to the injured cord, which may provide an environment more hospitable for repair. The treatment of raised intracranial pressures following insults to the brain is very well established (Czosnyka and Pickard, 2004;Licata et al., 2001) and is based on many years of work in experimental neurology establishing a pressure-volume relationship in cranial compartment, first suggested by Alexander Monro in 1783. Using a rodent model of chronic spinal cord injury, I wish to establish a correlation between raised pressures in the intraspinal compartment following spinal cord injuries and known measures of spinal cord injury, including behavioral scales, histopathological analyses and anatomic imaging (MRI). Once established, I wish to test a range of therapeutic interventions, both pharmacologic and surgical, aimed at restoring favorable CSF dynamics and providing an environment more hospitable to repair.
From page 10, "Treatment of elevated intraspinal pressures" Therapies aimed at reducing intraspinal pressure will consist of pharmacologic interventions, such as hyperosmolar infusion therapy, according to standard protocol.
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"
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"
Dialysis of the cerebrospinal fluid (removal of unwanted proteins and metabolites and electrolytes)
such as made possible with the award-winning spinal physiology device revealed on this site
could represent a temporizing treatment.
Ultimate repair of the ependymal lining (see the biological shunt) and reconstitution of local blood
would be the final cure.
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.Copyright 2004 - 2009 Milan Radojicic MD. All rights reserved.
Reference List
1. Barbiro-Michaely, E., Mayevsky, A., Knoller, N., Hadani, M. 2005. In vivo multiparametric monitoring of brain functions under intracranial hypertension following mannitol administration. Neurol.Res. 27, 88-93.
2. Berkouk, K., Carpenter, P. W., Lucey, A. D. 2003. Pressure wave propagation in fluid-filled co-axial elastic tubes. Part 1: Basic theory. J.Biomech.Eng 125, 852-856.
3. Bilston, L. E., Fletcher, D. F., Brodbelt, A. R., Stoodley, M. A. 2003. Arterial pulsation-driven cerebrospinal fluid flow in the perivascular space: a computational model. Comput.Methods Biomech.Biomed.Engin. 6, 235-241.
4. Brodbelt, A. R., Stoodley, M. A., Watling, A., Rogan, C., Tu, J., Brown, C. J., Burke, S., Jones, N. R. 2003a. The role of excitotoxic injury in post-traumatic syringomyelia. J.Neurotrauma 20, 883-893.
5. Brodbelt, A. R., Stoodley, M. A., Watling, A. M., Tu, J., Burke, S., Jones, N. R. 2003b. Altered subarachnoid space compliance and fluid flow in an animal model of posttraumatic syringomyelia. Spine 28, E413-E419.
6. Brodbelt, A. R., Stoodley, M. A., Watling, A. M., Tu, J., Jones, N. R. 2003c. Fluid flow in an animal model of post-traumatic syringomyelia. Eur.Spine J. 12, 300-306.
7. Bruni, J. E., Anderson, W. A. 1987. Ependyma of the rat fourth ventricle and central canal: response to injury. Acta Anat.(Basel) 128, 265-273.
8. Carbonell, W. S., Murase, S. I., Horwitz, A. F., Mandell, J. W. 2005. Infiltrative microgliosis: activation and long-distance migration of subependymal microglia following periventricular insults. J.Neuroinflammation. 2, 5.
9. Carpenter, P. W., Berkouk, K., Lucey, A. D. 2003. Pressure wave propagation in fluid-filled co-axial elastic tubes. Part 2: Mechanisms for the pathogenesis of syringomyelia. J.Biomech.Eng 125, 857-863.
10. Chang, H. S., Nakagawa, H. 2003. Hypothesis on the pathophysiology of syringomyelia based on simulation of cerebrospinal fluid dynamics. J.Neurol.Neurosurg.Psychiatry 74, 344-347.
11. Chang, H. S., Nakagawa, H. 2004. Theoretical analysis of the pathophysiology of syringomyelia associated with adhesive arachnoiditis. J.Neurol.Neurosurg.Psychiatry 75, 754-757.
12. Cosan, T. E., Tel, E., Durmaz, R., Gulec, S., Baycu, C. 2000. Non-hindbrain-related syringomyelia. Obstruction of the subarachnoid space and the central canal in rats. An experimental study. J.Neurosurg.Sci. 44, 123-127.
13. Czosnyka, M., Pickard, J. D. 2004. Monitoring and interpretation of intracranial pressure. J.Neurol.Neurosurg.Psychiatry 75, 813-821.
14. Czosnyka, M., Whitehouse, H., Smielewski, P., Simac, S., Pickard, J. D. 1996. Testing of cerebrospinal compensatory reserve in shunted and non-shunted patients: a guide to interpretation based on an observational study. J.Neurol.Neurosurg.Psychiatry 60, 549-558.
15. Johansson, C. B., Momma, S., Clarke, D. L., Risling, M., Lendahl, U., Frisen, J. 1999. Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96, 25-34.
16. Kiefer, M., Eymann, R., von, T. S., Muller, A., Steudel, W. I., Booz, K. H. 1998. The ependyma in chronic hydrocephalus. Childs Nerv.Syst. 14, 263-270.
17. Klekamp, J., Volkel, K., Bartels, C. J., Samii, M. 2001. Disturbances of cerebrospinal fluid flow attributable to arachnoid scarring cause interstitial edema of the cat spinal cord. Neurosurgery 48, 174-185.
18. Kojima, A., Tator, C. H. 2002. Intrathecal administration of epidermal growth factor and fibroblast growth factor 2 promotes ependymal proliferation and functional recovery after spinal cord injury in adult rats. J.Neurotrauma 19, 223-238.
19. Kusaka, G. 2004. New lumbar method for monitoring cerebrospinal fluid pressure in rats.
20. Lee, G. Y., Jones, N. R., Mayrhofer, G., Brown, C., Cleland, L. 2005. Origin of macrophages in a kaolin-induced model of rat syringomyelia: a study using radiation bone marrow chimeras. Spine 30, 194-200.
21. Licata, C., Cristofori, L., Gambin, R., Vivenza, C., Turazzi, S. 2001. Post-traumatic hydrocephalus. J.Neurosurg.Sci. 45, 141-149.
22. Loth, F., Yardimci, M. A., Alperin, N. 2001. Hydrodynamic modeling of cerebrospinal fluid motion within the spinal cavity. J.Biomech.Eng 123, 71-79.
23. Martens, D. J., Seaberg, R. M., van der, K. D. 2002. In vivo infusions of exogenous growth factors into the fourth ventricle of the adult mouse brain increase the proliferation of neural progenitors around the fourth ventricle and the central canal of the spinal cord. Eur.J.Neurosci. 16, 1045-1057.
24. Matthews, M. A., St Onge, M. F., Faciane, C. L. 1979. An electron microscopic analysis of abnormal ependymal cell proliferation and envelopment of sprouting axons following spinal cord transection in the rat. Acta Neuropathol.(Berl) 45, 27-36.
25. Milhorat, T. H., Nobandegani, F., Miller, J. I., Rao, C. 1993. Noncommunicating syringomyelia following occlusion of central canal in rats. Experimental model and histological findings. J.Neurosurg. 78, 274-279.
26. Miller, R. H., Ono, K. 1998. Morphological analysis of the early stages of oligodendrocyte development in the vertebrate central nervous system. Microsc.Res.Tech. 41, 441-453.
27. Mothe, A. J., Tator, C. H. 2005. Proliferation, migration, and differentiation of endogenous ependymal region stem/progenitor cells following minimal spinal cord injury in the adult rat. Neuroscience 131, 177-187.
28. Noble, L. J., Maxwell, D. S. 1983. Blood-spinal cord barrier response to transection. Exp.Neurol. 79, 188-199.
29. Schwartz, E. D., Yezierski, R. P., Pattany, P. M., Quencer, R. M., Weaver, R. G. 1999. Diffusion-weighted MR imaging in a rat model of syringomyelia after excitotoxic spinal cord injury. AJNR Am.J.Neuroradiol. 20, 1422-1428.
30. Stoodley, M. A., Gutschmidt, B., Jones, N. R. 1999. Cerebrospinal fluid flow in an animal model of noncommunicating syringomyelia. Neurosurgery 44, 1065-1075.
31. Takahashi, M., Arai, Y., Kurosawa, H., Sueyoshi, N., Shirai, S. 2003. Ependymal cell reactions in spinal cord segments after compression injury in adult rat. J.Neuropathol.Exp.Neurol. 62, 185-194.
32. Vaquero, J., Ramiro, M. J., Oya, S., Cabezudo, J. M. 1981. Ependymal reaction after experimental spinal cord injury. Acta Neurochir.(Wien.) 55, 295-302.
33. Weiss, S., Dunne, C., Hewson, J., Wohl, C., Wheatley, M., Peterson, A. C., Reynolds, B. A. 1996. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J.Neurosci. 16, 7599-7609.
34. Yamamoto, S., Yamamoto, N., Kitamura, T., Nakamura, K., Nakafuku, M. 2001. Proliferation of parenchymal neural progenitors in response to injury in the adult rat spinal cord. Exp.Neurol. 172, 115-127.
35. Yang, L., Jones, N. R., Stoodley, M. A., Blumbergs, P. C., Brown, C. J. 2001. Excitotoxic model of post-traumatic syringomyelia in the rat. Spine 26, 1842-1849.
Copyright Milan Radojicic MD 2004 - 2009.
Last Updated ( Friday, 18 September 2009 07:52 )