Autonomic dysfunctions are a major challenge to individuals following spinal cord injury. Despite this, these consequences receive far less attention compared with motor recovery. This review will highlight the major autonomic dysfunctions following SCI predominantly based on our present understanding of the anatomy and physiology of autonomic control and available clinical data.
Key points
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In addition to motor and sensory deficits individuals with spinal cord injury (SCI) commonly suffer from a myriad of autonomic dysfunctions that vary depending on the level and severity of injury.
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Clinical presentations of autonomic dysfunctions in individuals with SCI could vary from being totally asymptomatic to well-defined symptomatic manifestations that dictate the quality of life.
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Awareness of life-threatening consequences of autonomic dysfunctions in individuals with SCI warrants the necessity of timely diagnosis, close follow-up, and proper management by medical professionals.
Introduction
Spinal cord injury (SCI) predominantly affects young and healthy adults, resulting in devastating paralysis and significant functional alterations of the autonomic nervous system (ANS) that persist throughout the lifespan of the individual. While the injury is localized to a small area of the spinal cord, this local disruption can manifest as widespread dysfunction of both sympathetic and parasympathetic components of the ANS. The impact of autonomic dysfunctions on individuals with SCI is profound, and the clinical presentation of these dysfunctions ranges greatly based on the level of injury to the spinal cord and the extent to which spinal cord autonomic pathways are disrupted. ,
While these alterations in autonomic function have been investigated in various animal models and are well documented in human studies, the recognition and management of autonomic dysfunctions following SCI still represent challenging clinical issues. Until recently, most investigations focused on finding a cure for overt dysfunctions such as motor paralysis, with the majority of clinical trials since 2007 focusing on motor recovery as a primary outcome. Unfortunately, less attention has been paid to the less visible autonomic consequences of SCI. This has remained an issue despite a 2004 landmark study revealing that the restoration of autonomic function, including bladder, bowel, and sexual function, are among top priorities for both individuals with tetraplegic and paraplegic SCI. Despite these values, restoration of autonomic function as a primary outcome of clinical trials has remained consistently underrepresented, such as in the case of autonomic dysreflexia (AD) and impaired thermoregulation, or even decreasing in relative numbers, such as in the case of bladder health and function. Continued research efforts that bring attention to the recognition and management of relatively indiscernible autonomic dysfunctions following SCI are still needed. This review will highlight the major autonomic dysfunctions following SCI predominantly based on our present understanding of the anatomy and physiology of autonomic control and available clinical data.
Disrupted autonomic control following spinal cord injury
Supraspinal autonomic control originating from the brainstem to the spinal autonomic circuits is disrupted following SCI. Autonomic circuits in the spinal cord include sympathetic preganglionic neurons (SPNs), primarily located in the lateral horns of the gray matter of the thoracic and upper lumbar spinal cord segments (T1–L2), and parasympathetic preganglionic neurons (PPNs), located within the sacral spinal cord segments (S2-S4). Both SPNs and PPNs receive tonic supraspinal control via descending autonomic pathways that are commonly disrupted following SCI. In addition to the disruption of supraspinal control over SPNs and spinal PPNs, SCI also instigates (often maladaptive) neuroplasticity predominantly below the level of injury. , The neural plasticity ensuing after SCI can occur at circuitry, neuronal, and synaptic levels. , Rather, vagal parasympathetic pathways that exit supraspinally from the brainstem, are intact in individuals with SCI. Some of the autonomic dysfunctions, such as AD, manifest as a somato-autonomic reflex malfunction. This is because SCI results in maladaptive plasticity of spinal autonomic neurons and the growth factor expression, resulting in progressive structural and electrophysiological changes in nociceptive primary afferents. , , As a result of the anatomy of the ANS, the level of SCI has specific consequences on the types of autonomic dysfunctions observed after injury ( Fig. 1 ). The following sections will summarize our current understanding of the major organ systems implicated in autonomic dysregulation after SCI.
Cardiovascular dysfunctions
Regulation of the cardiovascular system is highly dependent on the balance between sympathetic and parasympathetic nervous systems. The heart receives dual control from SPNs located within T1-T5 spinal cord segments and vagal parasympathetic input (Cranial Nerve X) from the brainstem. The vascular tone and arterial blood pressure (BP) depend on tonic excitatory input to the SPNs from the medullary neurons within the rostroventrolateral medulla. The peripheral vasculature is under tonic sympathetic control, originating from T1-T5 spinal cord segments for the upper body and arms and T6-L2 spinal cord segments for lower body and legs. ,
Depending on the level of SCI, the degree of cardiovascular control may differ dramatically. , In individuals with high cervical SCI (see Fig. 1 ), parasympathetic (vagal) control remains intact, but supraspinal control over the majority of SPNs below the level of injury is disrupted. These individuals typically present with major cardiovascular dysfunctions. In contrast, in individuals with SCI at low-thoracic spinal cord segments, there is a preservation of vagal and sympathetic control of the heart as well as sympathetic control of the vasculature of the upper body and arms. This results in less pronounced cardiovascular dysfunctions.
Individuals with cervical and high thoracic SCI (above T6) face a wide spectrum of cardiovascular dysfunctions, including low resting blood pressure (BP), orthostatic hypotension (OH), and AD, in addition to abnormalities in heart rate and rhythm ( Fig. 2 ). Low resting arterial pressure results from the loss of descending tonic activation of SPNs from sympathoexcitatory neurons in the rostroventrolateral medulla. OH, affects the majority of those living with SCI and is defined as a reduction in systolic arterial BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg in response to an orthostatic challenge (such as transfer of individuals from supine to seating or standing position). During an episode of OH, the brain and heart receive less blood than usual, resulting in symptoms including dizziness, light-headedness, loss of consciousness, and cognitive impairment. , , The severity of OH is associated with an increased risk of stroke and reduced cerebrovascular health, as well as all-cause mortality.
In addition to low blood pressure, individuals with cervical and high thoracic also experience episodes of life-threatening elevation in blood pressure, known as AD. AD is defined as a sudden elevation in systolic blood pressure greater than 20 mm Hg from baseline as a response to noxious or innocuous stimuli originating below the level of lesion. , Observed in more than half of the SCI population with injury above T6 and rarely in SCI as low as T10, AD can be life-threatening as the sudden elevations in systolic blood pressure can rise beyond 300 mm Hg. , If poorly managed, AD can result in devastating consequences, including myocardial ischemia, brain hemorrhage, seizures, and even death. , , Following SCI, AD typically emerges during the subacute and chronic stages of human SCI, presenting within the first few months after SCI above T6, however, providers must be aware it can arise in the acute phase within days after SCI. The presentation of AD is associated with a plethora of autonomic signs, including sudden headache, blurred vision, palpitations, flushing, piloerection, diaphoresis, and anxiety. Furthermore, episodes of AD are commonly accompanied by profound bradycardia. , However, it has been shown that 35% to 50% of episodes of AD can be asymptomatic, making the diagnosis of this potentially invisible condition challenging.
Cardiac dysfunctions are also common following SCI above T6, including altered cardiac output and stroke volume and development of arrhythmias. Cardiac output, a product of heart rate and stroke volume, is under multifactorial control involving central and peripheral autonomic, humoral, and other mechanisms. Notably, the disruption of sympathetic circuits inhibits the direct stimulation of the sinoatrial node by sympathetic fibers leaving T1-T5 levels. Furthermore, there is an impaired release of catecholamines that typically stimulate beta-1 adrenergic receptors on ventricular muscle both during rest and exercise. In well-trained healthy individuals, cardiac output can increase up to 7-fold during maximal exercise. SCI that disrupts the sympathetic autonomic control of the heart can alter maximal cardiac output by affecting heart rate and stroke volume. , , This can impact maximal oxygen uptake and can be detrimental during activities requiring increased exertion, including exercise. It is important to note that these findings have been demonstrated to be worse depending on the level of injury. Individuals with tetraplegic SCI (ie, a high cervical SCI) will typically present with profound cardiac dysfunction relative to individuals with paraplegic SCI. , Presence of unstable arterial blood pressure control and inability to exercise, place individuals with SCI at significantly elevated risk of cardiovascular morbidity (three times increased odds for heart disease and four times for stroke) and mortality.
In summary, cardiovascular dysfunction in individuals with SCI stems from disrupted autonomic control, presenting with unstable BP control ranging from low arterial BP due to OH and episodes of extreme hypertension due to AD. The severity of cardiovascular dysfunctions varies with the level and the severity of injury, with higher cervical injuries leading to more pronounced cardiovascular issues. Recognizing and understanding these cardiovascular autonomic dysfunctions is a crucial step in preventing and managing cardiovascular morbidity and mortality in individuals with SCI (Cragg JJ, 2012).
Respiratory dysfunction
The diaphragm is the crucial skeletal respiratory muscle that receives somatic input from the phrenic nerve (C3-C5) to contract and facilitate the expansion of the chest wall, thoracic volume, and passive inspiration. Forced respiration requires the further involvement of the skeletal intercostal and abdominal muscles. SCI can result in skeletal muscle paralysis and respiratory impairment. The ANS is responsible for governing bronchial airway diameter and regulating airway secretions. , The major autonomic control of bronchi smooth muscles is parasympathetic and originates from the nucleus ambiguous via the vagus nerves (Cranial Nerve X) to control bronchoconstriction. Airway mucus secretion is also predominately under parasympathetic vagus control. Smooth muscle cells within the bronchi walls receive sympathetic innervation from SPNs originating from the thoracic spinal cord segments to promote bronchodilation. In cervical SCI, sympathetic control is lost; thus, predominant parasympathetic vagal input will lead to bronchial hyperreactivity, acute bronchospasm, and bronchoconstriction. , The acute period following SCI is crucial for the management of increased airway secretions due to predominant parasympathetic input and the absence of effective mechanisms to clear them due to respiratory muscle paralysis. , Given that respiratory complications, notably pneumonia, result in the highest mortality among individuals with SCI within the first year following injury, recognition, and management of respiratory dysfunction is of utmost importance.
Thermoregulation and sweating dysfunctions
Thermoregulation is the ability to precisely control core body temperature and relies on appropriate central nervous system integration of peripheral vasculature control, sweating (sudomotor control), and involuntary shivering to maintain core temperature. Temperature dysregulation is defined as the inability to maintain the normal core body temperature. Due to abnormal cardio-vasomotor control of peripheral and splanchnic vasculature, individuals with SCI have an impaired ability to redistribute blood from peripheral to central compartments (and vice versa). Furthermore, individuals with SCI also present with abnormal control of sweating, contributing to the abnormal thermoregulation in this population. Individuals with high cervical SCI typically present with minimal to no sweating (hypo or anhidrosis) below the level of injury, as their injury is above the most cephalad spinal cord segment (T1), contacting SPNs involved in sudomotor control. However, excessive sweating (hyperhidrosis) on the face and upper body may also occur secondary to a massive sympathetic reflex activation commonly observed during AD. Thermoregulatory dysfunction, including abnormal sweating after SCI, predisposes these individuals to heat-related illnesses (ie, heat cramps, heat exhaustion, heat syncope, heat stroke). Furthermore, athletes with SCI are particularly affected by the lack of sweating and thermoregulation during exercise in temperate and hot conditions and are predisposed to heat-related illnesses. ,
Neurogenic bowel dysfunction
The function of the lower gastrointestinal (GI) tract relies on the somatic, autonomic, and enteric nervous systems. , The enteric nervous system (composed of a submucosal and myenteric plexus) provides intrinsic motility to the entire tract and is modulated by autonomic input originating from the brainstem and spinal cord. Midgut organs (distal duodenum, jejunum, ileum, proximal colon up to the splenic flexure) receive parasympathetic innervation from the vagus nerve and sympathetic innervation from T5-T12. In contrast, hindgut organs (distal colon, rectum, internal anal sphincter) receive parasympathetic innervation from S2-S4 via pelvic nerve and sympathetic innervation from L1-L2.
Autonomic control of the bowel is compromised following SCI, giving rise to a consequence known as neurogenic bowel. Neurogenic bowel can manifest as constipation, abdominal pain, and incontinence, which can interfere with the quality of life, independence, dignity, and participation. Neurogenic bowel dysfunctions following SCI can be presented as upper motor neuron (UMN) bowel syndrome, referring to injury above the sacral spinal cord, and lower motor neuron (LMN) bowel syndrome results from damage to the sacral spinal cord. Due to the lack of descending supraspinal input, UMN bowel syndrome is characterized by a hyperreflexic bowel and anal sphincter. In addition, suprasacral injury was demonstrated to lead to increased gastrointestinal transit time of the proximal and descending colon. In contrast, LMN bowel syndrome is characterized by an areflexic bowel, leading to constipation and increased transit times within the distal colon and rectum, in addition to incontinence due to an atonic external anal sphincter. , Depending on the severity of the injury, individuals may also experience a lack of anorectal sensation and a lack of awareness of bowel fullness, contributing to fecal incontinence. This is of crucial importance since bowel distension due to fecal impaction is the second most common cause of AD, , thus proper evaluation of bowel dysautonomia following SCI is paramount to not only managing gastrointestinal health but also cardiovascular health in those with cervical and upper-thoracic SCI.
Neurogenic lower urinary tract dysfunction
Major functions of the urinary bladder include urine storage and micturition, which depend on the coordination between the autonomic and somatic nervous systems. , , Urine storage is facilitated by the relaxation of the detrusor and contraction of the internal urethral sphincter from sympathetic input originating at T12-L1 and contraction of the external urethral sphincter under the voluntary somatic control from Onuf’s nucleus at S2-S4. The sensation of bladder fullness initiates a sacral reflex from somatic bladder afferents to parasympathetic neurons originating from S2-S4, resulting in the contraction of the detrusor. Postganglionic parasympathetic fibers travel as the pelvic nerve to promote detrusor contractility. Postganglionic sympathetic fibers travel as the hypogastric nerve to suppress detrusor contraction in addition to promoting the contraction of the prostatic urethra. In addition, supraspinal descending input promotes parasympathetically mediated detrusor contraction, inhibition of sympathetic output to the internal urethral sphincter, and somatic relaxation of the external urethral sphincter via the pudendal nerve.
Neurogenic lower urinary tract dysfunction (NLUTD) is a common consequence of SCI and can lead to complications such as detrusor-sphincter-dyssynergia (DSD), incontinence, vesicoureteral reflux and are commonly associated with urinary tract infections, low urinary tract (LUT) stones, and AD. Depending on the level of injury, the NLUTD can be classified as either UMN bladder when above the sacral cord, mixed neurogenic bladder at the sacral cord, or LMN bladder when below the sacral cord. After the initial period of spinal shock has subsided, signs of UMN injury will manifest as detrusor hyperreflexia and DSD due to the disruption of descending pathways that coordinate detrusor and sphincter contractility. , Due to detrusor overactivity and elevations in detrusor pressures, the individuals may have a lower cystometric capacity and risk of vesicoureteral reflux. Additionally, individuals with SCI can have an impaired sensation of bladder fullness and may experience AD triggered by bladder distension. , Injury to the conus medullaris or the cauda equina could produce a mixed pattern or LMN-bladder, characterized by an areflexic bladder with a flaccid EUS, resulting in incontinence.
Recognizing the signs and symptoms of NLUTD is critical to inform appropriate management, including scheduling fluid intake, developing a bladder routine, and choosing a catheter, to reduce LUT complications.
Sexual dysfunction
Genital arousal, orgasm, and ejaculation are three major sexual processes coordinated by the sensory, autonomic, and somatic functions. , Autonomic control of the reproductive organs is principally governed by sympathetic neurons from T10-L2, traveling as the hypogastric nerve, and parasympathetic neurons from S2-S4, traveling as the pelvic nerve. , Sexual dysfunction following SCI can impact self-esteem, intimacy, fertility, sexual satisfaction, and overall quality of life. Regaining sexual function and intimacy remains a significant priority in this population.
Genital arousal is classified as psychogenic (genital vasocongestion from mental or visual sexual stimuli) or reflexogenic. , Both branches of the ANS are thought to contribute to psychogenic arousal in women (vaginal lubrication and accommodation) and men (penile erection). On the other hand, autonomic control of reflexogenic arousal is solely determined by the parasympathetic nervous system. Therefore, individuals with SCI above the lumbosacral cord may be capable of full or partial reflexogenic vaginal lubrication or erection in response to local stimulation. Sacral SCI can impair the reflexogenic component of arousal; however, psychogenic arousal may still be possible.
Orgasm, not to be confused with ejaculation, is the subjective sensation of a climax during sexual activity. , , The autonomic control of orgasm is poorly understood. It has been shown that the ability of persons with SCI to orgasm is decreased in SCI compared with able-bodied men and often not possible in those with sacral SCI. Furthermore, men with incomplete SCI were described as more likely to experience orgasmic sensations using vibrostimulation compared with those with complete SCI.
Ejaculation commonly coincides with orgasm in men and is a process controlled by sympathetic, parasympathetic, and somatic nervous systems. , The first stage of ejaculation is seminal emission and relies on hypogastric nerve outflow to promote the peristalsis and contraction of the vas deferens and seminal vesicles, respectively. , Sperm is transported upward from the testes to the seminal vesicles and mixed with prostatic secretions. Bladder neck smooth muscles around the prostatic urethra are contracted, in addition to the EUS (via pudendal nerve), to prevent retrograde ejaculation into the bladder. , This is followed by propulsatile ejaculation, which expels the seminal fluid through the urethral meatus and depends on input from the pelvic nerve. SCI can cause anejaculation, with or without orgasm. , Ejaculatory volume has shown to be reduced following SCI, and retrograde ejaculation can also occur. , Ejaculation achieved by sexual activity or sperm retrieval methods (penile vibrostimulation and electroejaculation) can also provoke AD and electrophysiological abnormalities in cervical and midthoracic SCI above T6 , ( Fig. 3 ), so precautions can be taken. Furthermore, while sperm numbers often remain high, the semen quality of men living with SCI is typically poor, characterized by reduced sperm motility and viability. , Poor semen quality is thought not to be from altered scrotal temperature or hormonal alterations but from a high number of cytokines in the seminal plasma. Whether these characteristics can improve with repeated electroejaculation has been a subject of debate. ,
