Which pathways must be spared in the injured human spinal cord to retain cardiovascular control?

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Abstract

Cardiovascular abnormalities following spinal cord injury are attributed to autonomic instability caused by a combination of changes occurring within the spinal cord, including loss of descending autonomic control and plastic changes within spinal and peripheral circuits. Previous animal studies have shown that localized disruption of the descending vasomotor pathways results in cardiovascular changes similar to those observed following cord injury. However, the location of these pathways in humans is uncertain. This chapter presents clinical and histopathological findings from individuals with spinal cord injury that associates a common area of white matter destruction with severe cardiovascular symptoms. These data provide evidence that descending vasomotor pathways in the human spinal cord project through the dorsal aspects of the lateral funiculus.

Introduction

People with cervical or high thoracic spinal cord injury face life-long abnormalities in systemic arterial pressure control (Mathias and Frankel, 1992; Karlsson, 1999; Teasell et al., 2000). In general, their basal systemic arterial pressure is lower than normal and is complicated by orthostatic intolerance (Mathias and Frankel, 1992; Cariga et al., 2002). In addition, these cord-injured people experience transient episodes of hypertension, known as “autonomic dysreflexia” that are often associated with disturbances in heart rate and rhythm (Krassioukov et al., 2003; Clydon et al., 2005). The severity of spinal cord injury varies between individuals and impacts greatly upon cardiovascular control. For example, hypotension affects between 20% and 30% of all spinal cord-injured individuals (Piepmeier et al., 1985; Lehmann et al., 1987; Atkinson and Atkinson, 1996). Likewise, the severity of autonomic dysreflexia correlates with completeness of spinal injury as assessed by the American Spinal Injury Association (ASIA) score: only 27% of incomplete quadriplegics present signs of dysreflexia in comparison with 91% of complete quadriplegics (Curt et al., 1997).

Determinations of plasma catecholamine levels in cord-injured individuals, and other evidence, suggest that a decrease in sympathetic neuronal activity is the main cause of the hypotension and postural intolerance (Figoni, 1984; Mathias, 1995; Karlsson et al., 1998; Gao et al., 2002). The decreased sympathetic activity, in turn, presumably results from damage to the spinal pathways that carry facilitatory input from the lower brainstem to the sympathetic preganglionic neurons. The destruction of these descending vasomotor pathways, resulting in the loss of excitatory supraspinal input to the spinal sympathetic preganglionic neurons, is currently considered the major factor for the persistent lack of sympathetic tone after spinal cord injury (Mathias and Frankel, 1992; Atkinson and Atkinson, 1996). Damage to the spinal pathways that carry inhibitory input from the lower brainstem to the sympathetic preganglionic neurons may have a role in autonomic dysreflexia, by allowing exaggerated activity in the spinal reflex circuits, caudal to the lesion, that connect spinal afferent projections to preganglionic neurons.

Damage to the pathways from the lower brainstem to sympathetic preganglionic neurons has a central role in generating the abnormal systemic arterial pressure control, typical of cervical or high thoracic spinal cord injury. Therefore, these pathways are a high priority target for repair, regenerative and neuroprotective treatment. Knowledge of the localization of these pathways in the human spinal cord is therefore essential. This chapter describes an approach to obtaining such knowledge.

Previous work in experimental animals, using electrical stimulation or lesions, led to the conclusion that the pathways for cardiovascular control run in the dorsal aspect of the lateral funiculus of the spinal cord white matter (Kerr and Alexander, 1964; Illert and Gabriel, 1972; Foreman and Wurster, 1973; Lebedev et al., 1986). Henceforth, this area of the white matter will be referred to as Area I (Fig. 1). By contrast, a study in patients undergoing limited cordotomy for the relief of chronic pain resistant to medical treatment, has suggested that these pathways run in the white matter adjacent to the dorsolateral aspect of the intermediolateral cell column (Nathan and Smith, 1987). Henceforth, this area of the white matter will be referred to as Area II (Fig. 1).

This chapter describes a retrospective study of cases of spinal cord injury from which detailed clinical records and spinal cord specimens were available. The cases with the most severe cardiovascular symptoms were identified. It was hypothesized that this case subset would also have the most severe damage to the pathways from lower brainstem to the sympathetic preganglionic neurons. The extent and severity of white matter damage was estimated using stains for myelin and for an axoplasmic marker. This study has shown that the group with the most severe cardiovascular symptoms had the greatest damage in Area I. The remainder of the cases, who had only minor cardiovascular symptoms, or no symptoms at all, had significantly less damage in this area. The degree of damage to Area II did not correlate well with the extent of cardiovascular dysfunction in these individuals.

On the basis of these data it may be concluded that, in humans, the pathways from the lower brainstem to the sympathetic preganglionic neurons run in the dorsal aspect of the lateral funiculus of the white matter. Since this is the general region where previous work on experimental animals (rat, cat, dog, others) had localized similar pathways, this study further confirms the relevance to humans of animal model studies of autonomic dysfunctions after spinal cord injury.

Section snippets

Study groups

We retrospectively reviewed the charts of the spinal cord injury cases included in this study and collected data on age and gender, causes of spinal cord injury, neurological assessment (including severity and level of injury), cardiovascular parameters, and clinical history predating the spinal cord injury, for example, pre-existing cardiovascular disease. Detailed information on cardiovascular parameters was collected during the acute stage of injury in all individuals. We also searched for

Cardiovascular parameters

There were significant differences in the cardiovascular parameters between individuals in Groups 1 and 2. Severe hypotension, bradycardia, and episodes of autonomic dysreflexia, which are signs of disrupted supraspinal cardiovascular control, were prominent among the cases in Group 1. Severe hypotension (neurogenic shock) in the early post-injury period required the administration of vasopressive agents to all individuals in Group 1. Intravenous dopamine was administered, on average, for 7±4.1

Histopathological findings

The spinal cord tissue from the cases included in this study was fixed with 10% buffered formalin for 2 weeks and paraffin embedded. In no case did the postmortem interval exceed 24 h. In each cord injury case, at least one segment caudal to the level of injury (upper thoracic segments) was selected for examination. In Group 3, the third thoracic segment was examined. Two sets of alternate spinal cord sections (5–8 μm) were obtained and stained for: (1) general histology and myelin preservation

Discussion

Previous investigations have demonstrated that hypotension, bradycardia, and autonomic dysreflexia occur more frequently in individuals with severe cervical spinal cord injury (Lehmann et al., 1987; Mathias and Frankel, 1992; Noreau et al., 2000; Silver, 2000). This study has demonstrated a relationship between the location and severity of pathology in the spinal cord and cardiovascular dysfunction in human cases of spinal cord injury. The histological analysis demonstrates that Group 1, with

Acknowledgments

This study was conducted with the support of a Christopher Reeve Paralysis Foundation grant (KB2-0003-1), a Cervical Spine Research Society grant, support from the Canadian Syringomyelia Network, and a grant from the Heart and Stroke Foundation of Ontario (NA4951) awarded to Dr. A. Krassioukov. Dr. J. Furlan (Toronto, ON) was a postdoctoral fellow who conducted a major part of the histopathological analysis. The author also would like to acknowledge Dr. A. Marcillo (Miami, FL), Mrs. Lorraine

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