Autonomic dysreflexia: a cardiovascular disorder following spinal cord injury

Abstract

Autonomic dysreflexia (AD) is a serious cardiovascular disorder in patients with spinal cord injury (SCI). The primary underlying cause of AD is loss of supraspinal control over sympathetic preganglionic neurons (SPNs) caudal to the injury, which renders the SPNs hyper-responsive to stimulation. Central maladaptive plasticity, including C-fiber sprouting and propriospinal fiber proliferation exaggerates noxious afferent transmission to the SPNs, causing them to release massive sympathetic discharges that result in severe hypertensive episodes. In parallel, upregulated peripheral vascular sensitivity following SCI exacerbates the hypertensive response by augmenting gastric and pelvic vasoconstriction. Currently, the majority of clinically employed treatments for AD involve anti-hypertensive medications and Botox injections to the bladder. Although these approaches mitigate the severity of AD, they only yield transient effects and target the effector organs, rather than addressing the primary issue of central sympathetic dysregulation. As such, strategies that aim to restore supraspinal reinnervation of SPNs to improve cardiovascular sympathetic regulation are likely more effective for AD. Recent pre-clinical investigations show that cell transplantation therapy is efficacious in reestablishing spinal sympathetic connections and improving hemodynamic performance, which holds promise as a potential therapeutic approach.

Keywords: C-fibers; autonomic dysreflexia; hyper-reflexia; propriospinal axons; stem cell transplantation; sympathetic dysfunction; α-adrenoceptors.

Figure 1

Illustration of normal cardiovascular autonomic control. For cardiac parasympathetic modulation, long parasympathetic preganglionic neurons within the vagus and glossopharyngeal nerves (Cranial nerves (CN) IX & X) exit from the medulla oblongata, synapsing with short parasympathetic preganglionic neurons which terminate on the sinoatrial (SA) and atrioventricular (AV) nodes to decrease heart rate through the action on acetylcholine. Peripheral blood vessels (v.) are not directly innervated by parasympathetic nerves. Conversely, for cardiac sympathetic regulation, short sympathetic preganglionic neurons from T_1–4 synapse with the autonomic chain, which then connects with long sympathetic postganglionic neurons that terminate on the sinoatrial and atrioventricular nodes, as well as myocardial tissue to increase heart rate and contractility. These nerves also innervate blood vessels of the head, neck and thoracic region in order to regulate blood flow to the upper body. Sympathetic preganglionic neurons below the T₄ segment bypass the sympathetic chain, travel through the collateral ganglia (celiac, superior mesenteric and inferior mesenteric ganglions (g.)) and synapses with sympathetic postganglionic neurons. These neurons terminate on blood vessels of the abdomen, pelvic region and lower limbs and cause vasoconstriction to increase blood pressure.

Figure 2

Graphic examples of spontaneous AD following SCI. The spinal cord was completely transected at T₄ in a Fischer 344 rat. Using a radio-telemetric system connecting with an implantable probe inserted into the descending aorta, resting hemodynamics was recorded every 2 seconds for 24 hours 2 weeks post-injury. The event of spontaneous AD was subsequently detected in data analysis with a program written in Matlab (The Math Works, Inc.), in which MAP peak exceeds the baseline at least 15 mmHg whereas HR must drop by at least 15 beats/min. (A) The blue lines show MAP or HR tracers in a 120-minute period. The vertical green lines indicate the beginning of an AD event, while red dotted lines coincide with the end of the event. The horizontal red lines represent the baseline trace and horizontal green lines are smoothened traces. (B) A representative time-stretched tracer indicates a typical AD response manifested by suddenly increased MAP and simultaneously decreased HR. MAP: Mean arterial pressure; HR: heart rate; AD: autonomic dysreflexia; SCI: spinal cord injury.

Figure 3

Schematic of the pathophysiology of autonomic dysreflexia (AD). (A) Loss of supraspinal control over sympathetic preganglionic neurons is the primary cause of disordered blood pressure regulation and AD after spinal cord injury (SCI). (B) Increased sprouting of C-fibers (CGRP) within the dorsal horn of the sacral region enhances noxious inputs from the pelvic region. Corresponding propriospinal neuron sprouting transmits these noxious signals rostrally to SPNs within the thoracolumbar region. The sympathetic preganglionic neurons (SPNs) within the thoracolumbar region also undergo morphological changes that render them unstable and supersensitive when stimulated, causing them to release massive surges of sympathetic discharge which markedly increases blood pressure. (C) α-Adrenoceptors within the peripheral vasculature become hypersensitive to sympathetic stimulation resulting in a greater degree of vasoconstriction and smooth muscle contraction when activated by catecholamines thus further augmenting the hypertensive responses.

Figure 4

Schematic illustration of the step-by-step protocol for non-pharmacological and acute management of autonomic dysreflexia (AD).