Autonomic dysreflexia after spinal cord injury: Systemic pathophysiology and methods of management

Abstract

Traumatic spinal cord injury (SCI) has widespread physiological effects beyond the disruption of sensory and motor function, notably the loss of normal autonomic and cardiovascular control. Injury at or above the sixth thoracic spinal cord segment segregates critical spinal sympathetic neurons from supraspinal modulation which can result in a syndrome known as autonomic dysreflexia (AD). AD is defined as episodic hypertension and concomitant baroreflex-mediated bradycardia initiated by unmodulated sympathetic reflexes in the decentralized cord. This condition is often triggered by noxious yet unperceived visceral or somatic stimuli below the injury level and if severe enough can require immediate medical attention. Herein, we review the pathophysiological mechanisms germane to the development of AD, including maladaptive plasticity of neural circuits mediating abnormal sympathetic reflexes and hypersensitization of peripheral vasculature that collectively contribute to abnormal hemodynamics after SCI. Further, we discuss the systemic effects of recurrent AD and pharmacological treatments used to manage such episodes. Contemporary research avenues are then presented to better understand the relative contributions of underlying mechanisms and to elucidate the effects of recurring AD on cardiovascular and immune functions for developing more targeted and effective treatments to attenuate the development of this insidious syndrome following high-level SCI.

Keywords: Hypertension; Maladaptive plasticity; Primary afferent; Propriospinal; Sprouting; Sympathetic.

Figure 1

Diagrammatic representation of the neuroanatomical circuitry thought to be involved in autonomic dysreflexia triggered by pelvic visceral stimulation, as well as potential neuronal pathway silencing paradigms. Descending vasomotor fibers (blue) originating in the brainstem and hypothalamus modulate the tonic activity of sympathetic preganglionic neurons (SPN; red) throughout the intermediolateral cell column (IML) in the thoracolumbar spinal cord. After complete spinal cord injury at or above the T6 segment, SPN which innervate the adrenal medulla and blood vessels below the injury are segregated from descending control pathways, allowing for unrestrained sympathetic reflex activity that leads to hypertension. Injury further leads to maladaptive sprouting of both primary afferent c-fibers (purple) and ascending propriospinal tracts (green) originating in the lumbosacral dorsal gray commissure (DGC). These ascending “relay” neurons are thought to convey sensory information from the bladder and colon (i.e., distension) rostrally towards SPN. Emerging neuronal silencing techniques may allow for investigations into the role of specific neuroanatomical pathways involved in AD. One example might be to employ double infection of ascending lumbosacral propriospinal neurons with the HiRET-eTeNT vector (red syringe), which is retrogradely transported (dotted black lines) from nerve terminals in the IML to lumbosacral DGC also infected with AAV-rtTAV vector (blue syringe). Doxycycline-induced silencing of these neurons could then allow for direct investigation into their roles in facilitating AD during pelvic visceral stimulation.