Autonomic dysreflexia in acute disseminated encephalomyelitis

Autonomic dysreflexia occurs in patients with spinal cord injury, and is characterized by unbalanced sympathetic discharge, precipitated by noxious stimuli from a site below the spinal cord lesion. An 11-year-old boy with acute disseminated encephalomyelitis and spinal cord involvement manifested episodes of intense flushing and sweating, confined to the head and neck region, and associated with hypertension and tachycardia. His signs improved after changing a partly blocked bladder catheter. The clinical features suggested autonomic dysreflexia. Early recognition of autonomic dysreflexia is important because removal of the trigger precipitating the event may be life-saving.     

Organisation of the sympathetic skin response in spinal cord injury

OBJECTIVES: The sympathetic skin response (SSR) is a technique to assess the sympathetic cholinergic pathways, and it can be used to study the central sympathetic pathways in spinal cord injury (SCI). This study investigated the capacity of the isolated spinal cord to generate an SSR, and determined the relation between SSR, levels of spinal cord lesion, and supraspinal connections. METHODS: Palmar and plantar SSR to peripheral nerve electrical stimulation (median or supraorbital nerve above the lesion, and peroneal nerve below the lesion) were recorded in 29 patients with SCI at various neurological levels and in 10 healthy control subjects. RESULTS: In complete SCI at any neurological level, SSR was absent below the lesion. Palmar SSR to median nerve stimuli was absent in complete SCI with level of lesion above T6. Plantar SSR was absent in all patients with complete SCI at the cervical and thoracic level. In incomplete SCI, the occurrence of SSR was dependent on the preservation of supraspinal connections. For all stimulated nerves, there was no difference between recording from ipsilateral and contralateral limbs. CONCLUSIONS: No evidence was found to support the hypothesis that the spinal cord isolated from the brain stem could generate an SSR. The results indicate that supraspinal connections are necessary for the SSR, together with integrity of central sympathetic pathways of the upper thoracic segments for palmar SSR, and possibly all thoracic segments for plantar SSR.     

Autonomic dysreflexia in tetraplegic patients: Evidence for α-adrenoceptor hyper-responsiveness

A controlled study of acute pharmacological intervention was designed to determine whether decreased sympathetic nerve activity in tetraplegic patients results in increased responsiveness of -adrenoceptors which might contribute to vascular hyperreactivity and the clinical scenario of autonomic dysreflexia. The study took place in a university teaching hospital and included six male tetraplegic patients and six age-matched normal male controls. All tetraplegics were 5 months or longer post-traumatic spinal cord injury and all had experienced symptoms of autonomic dysreflexia on at least one occasion. The dorsal foot vein diameter was recorded with a tonometer during local infusions of noradrenaline 0.125–256 ng/min given through a short intravenous needle. In tetraplegic patients, there was a significant shift to the left of the dose—response curve indicating increased venous responsiveness to noradrenaline. The concentration of noradrenaline required to cause a 50% reduction of the resting vein diameter was decreased in tetraplegics (1.6 ng/min, geometric mean) compared to normal controls (10.9 ng/min,p < 0.02). -Adrenoceptor responsiveness in dorsal foot veins is increased in patients with tetraplegia. Hypersensitivity of vascular -adrenoceptors may contribute to autonomic dysreflexia in patients with high spinal cord injury.     

Fatal cerebral hemorrhage due to autonomic dysreflexia in a tetraplegic patient: case report and review.

Autonomic dysreflexia is the most important specific complication of high level spinal cord injury both in tetraplegic and in paraplegic patients above the midthoracic neural segment. It is a life threatening emergency that may lead to apoplexy. We present a case of fatal cerebral hemorrhage due to autonomic dysreflexia in order to demonstrate the gravity of this particular syndrome.     

Clinical manifestations of malfunctioning sympathetic mechanisms in tetraplegia

Patients who are tetraplegic with cervical spinal cord transection do not appear to have cerebral control over the sympathetic nervous system. Soon after transection they are often in a state of spinal shock during which even isolated spinal cord sympathetic activity is absent. This affects, in particular, the cardiovascular system and other homeostatic mechanisms which are dependent on appropriate regulation of the vasculature, such as thermoregulation. After a few weeks isolated spinal cord activity returns but the absence of control absence of control by the brain results in sympathetic malfunction of various systems. Inappropriate inactivity therefore occurs during postural change and causes orthostatic hypotension, while over-activity, which results in the syndrome of autonomic dysreflexia and hypertension, occurs if spinal sympathetic reflexes are activated. Examples are provided of clinical effects of sympathetic malfunction in tetraplegics in relation to circulatory, thermoregulatory, pupillary, genital, gastrointestinal and urinary tract function.     

Acute Onset of Intracerebral Hemorrhage due to Autonomic Dysreflexia

Autonomic dysreflexia is a clinical emergency syndrome of uncontrolled sympathetic output that can occur in patients who have a history of spinal cord injury. Despite its frequency in spinal cord injury patients, central nervous system complications are very rare. We report a man with traumatic high level incomplete spinal cord injury who suffered hypertensive right thalamic hemorrhage secondary to an episode of autonomic dysreflexia. Prompt recognition and removal of the triggering factor, the suprapubic catheter obstruction which led to hypertensive attack, the patient had a favorable functional outcome after the resorption of the hematoma and effective rehabilitation programme.     

Autonomic dysreflexia: a cardiovascular disorder following spinal cord injury

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.     

A study of the alpha-1 adrenoceptor blocker prazosin in the prophylactic management of autonomic dysreflexia in high spinal cord injury patients

The ability of the alpha-1 adrenoceptor antagonist, prazosin, to reduce the severity and duration of episodes of autonomic dysreflexia was studied in cervical and high thoracic spinal cord injury patients with documented episodes of autonomic dysreflexia. Sixteen patients participated in a double blind parallel group study comparing prazosin 3 mg b.d. with placebo given for 2 weeks. Both groups were matched for age, sex and baseline severity of autonomic dysreflexia episodes. Prazosin was well tolerated and did not produce a significant lowering of resting blood pressure. Compared to baseline measurements, patients allocated to prazosin therapy were found to have fewer severe episodes of autonomic dysreflexia and during these episodes to have significant reductions in average rise in systolic and diastolic blood pressure, symptom duration and requirement for acute antihypertensive medication. The severity of headache during individual autonomic dysreflexia episodes was also diminished with prazosin therapy. No symptom parameter was significantly altered by placebo therapy. It is concluded that prazosin is superior to placebo in the prophylactic management of autonomic dysreflexia and that these findings are consistent with suggestions that alpha-1 adrenoceptors play an important role in the pathogenesis of this syndrome.     

An analysis of circadian rhythmicity of heart rate in tetraplegic human subjects.

Eight tetraplegic human volunteer subjects from the Veterans Administration Hospital in Houston, Texas, had their heart rates monitored at half-hour intervals for 24 hours. Autocovariance analysis demonstrated circadian rhythms of heart rate in four chronic tetraplegic subjects and one acute tetraplegic subject. The remaining three subacute tetraplegic subjects demonstrated no circadian rhythmicity of heart rate. It is postulated that central denervation of the heart from the sympathetic division of the autonomic nervous system in cervical cord injury results in loss of circadian rhythmicity in heart rate until the vagus of the parasympathetic division obtains control, sympathetic spinal cord centres re-establish control, or an orderly interaction of both occurs. Further study appears indicated.     

Cardiovascular dysfunction following spinal cord injury

Both sensorimotor and autonomic dysfunctions often occur after spinal cord injury(SCI). Particularly, a high thoracic or cervical SCI interrupts supraspinal vasomotor pathways and results in disordered hemodynamics due to deregulated sympathetic outflow. As a result of the reduced sympathetic activity, patients with SCI may experience hypotension, cardiac dysrhythmias, and hypothermia post-injury. In the chronic phase, changes within the CNS and blood vessels lead to orthostatic hypotension and life-threatening autonomic dysreflexia(AD). AD is characterized by an episodic, massive sympathetic discharge that causes severe hypertension associated with bradycardia. The syndrome is often triggered by unpleasant visceral or sensory stimuli below the injury level. Currently the only treatments are palliative – once a stimulus elicits AD, pharmacological vasodilators are administered to help reduce the spike in arterial blood pressure. However, a more effective means would be to mitigate AD development by attenuating contributing mechanisms, such as the reorganization of intraspinal circuits below the level of injury. A better understanding of the neuropathophysiology underlying cardiovascular dysfunction after SCI is essential to better develop novel therapeutic approaches to restore hemodynamic performance.     

The acute abdomen in spinal cord injury patients

After return of the reflex arc below the level of anaesthesia, the spinal cord injury (SCI) patient will manifest an intra-abdominal emergency by the clinical signs of dysreflexia depending upon the level and completeness of the cord lesion. Thirty-six SCI patients are presented to correlate the autonomic response to visceral disease with the level of their cord lesion demonstrating that early recognition and diagnosis is possible in these patients.     

Flexor reflex decreases during sympathetic stimulation in chronic human spinal cord injury

A better understanding of autonomic influence on motor reflex pathways in spinal cord injury is important to the clinical management of autonomic dysreflexia and spasticity in spinal cord injured patients. The purpose of this study was to examine the modulation of flexor reflex windup during episodes of induced sympathetic activity in chronic human spinal cord injury (SCI). We simultaneously measured peripheral vascular conductance and the windup of the flexor reflex in response to conditioning stimuli of electrocutaneous stimulation to the opposite leg and bladder percussion. Flexor reflexes were quantified using torque measurements of the response to a noxious electrical stimulus applied to the skin of the medial arch of the foot. Both bladder percussion and skin conditioning stimuli produced a reduction (43–67%) in the ankle and hip flexor torques (p < 0.05) of the flexor reflex. This reduction was accompanied by a simultaneous reduction in vascular conductance, measured using venous plethysmography, with a time course that matched the flexor reflex depression. While there was an overall attenuation of the flexor reflex, windup of the flexor reflex to repeated stimuli was maintained during periods of increased sympathetic activity. This paradoxical depression of flexor reflexes and minimal effect on windup is consistent with inhibition of afferent feedback within the superficial dorsal horn. The results of this study bring attention to the possible interaction of motor and sympathetic reflexes in SCI above and below the T5 spinal level, and have implications for clinicians in spasticity management and for researchers investigating motor reflexes post SCI.     

The sympathetic skin response in carpal tunnel syndrome

The sympathetic skin response (SSR) is an evoked change in electrical skin potential and is an index of the function of sympathetic pathways. We studied the SSR evoked by electrical stimulation of the median nerve and recording from the contralateral hands in 30 patients with carpal tunnel syndrome (CTS) without clinical autonomic signs and compared the results to the SSR in 30 normal controls. The SSR was absent in the affected hands in seven (23%) patients. In the other carpal tunnel syndrome patients (77%), a significant reduction in the SSR area was seen in the records from the affected hands. Subclinical sympathetic nerve fibre involvement occurs in the affected median nerves in CTS.     

Sympathetic skin response in incomplete spinal cord injury with urinary incontinence

Objectives:

Sympathetic skin response (SSR) is a test for evaluation of the sympathetic sweat gland pathways, and it has been used to study the central sympathetic pathways in spinal cord injury (SCI). This study aimed to assess the autonomic pathways according to normal or abnormal SSR in urinary incontinence patients due to incomplete spinal cord injury.

Materials and Methods:

Suprapubic, palmar, and plantar SSR to the peripheral nerve electrical stimulation were recorded in 16 urinary incontinence patients with incomplete spinal cord injury at various neurological levels and in 30 healthy control subjects.

Results:

All the recordings of SSR from the incomplete SCI patients with urinary incontinence as compared with their counterparts in the control group showed significantly reduced amplitudes with more prominent reduction in the suprapubic area recording site (P value < 0.0004). SSR with significantly prolonged latencies were recorded from palm and plantar areas in response to suprapubic area and tibial N stimuli, respectively (P value < 0.02). In this study, a significantly higher stimulus intensity (P value < 0.01) was needed to elicit SSR in the cases compared with the control group.

Conclusion:

This study showed abnormal SSR in urinary incontinence patients due to incomplete SCI. In addition, for the first time we have described recording of abnormal SSR from the suprapubic area as another way to show bladder sympathetic system involvement.     

Autonomic dysreflexia after spinal cord transection or compression in 129Sv,C57BL,and Wallerian degeneration slow mutant mice

To study plasticity of central autonomic circuits that develops after spinal cord injury (SCI), we have characterized a mouse model of autonomic dysreflexia. Autonomic dysreflexia is a condition in which episodic hypertension occurs after injuries above the midthoracic segments of the spinal cord. As synaptic plasticity may be triggered by axonal degeneration, we investigated whether autonomic dysreflexia is reduced in mice when axonal degeneration is delayed after SCI. We subjected three strains of mice, Wld(S), C57BL, and 129Sv, to either spinal cord transection (SCT) or severe clip-compression injury (CCI). The Wld(S) mouse is a well-characterized mutant that exhibits delayed Wallerian degeneration. The CCI model is an injury paradigm in which significant the axonal degeneration is due to secondary events and therefore delayed relative to the time of the initial injury. We herein demonstrate that the incidence of autonomic dysreflexia is reduced in Wld(S) mice after SCT and in all mice after CCI. To determine if differences in afferent arbor sprouting could explain our observations, we assessed changes in the afferent arbor in each mouse strain after both SCT and CCI. We show that independent of the type of injury, 129Sv mice but not C57BL or Wld(S) mice demonstrated an increased small-diameter CGRP-immunoreactive afferent arbor after SCI. Our work thus suggests a role for Wallerian degeneration in the development of autonomic dysreflexia and demonstrates that the choice of mouse strain and injury model has important consequences to the generalizations that may be drawn from studies of SCI in mice.     

Input–output relationships of a somatosympathetic reflex in human spinal injury

Objectives  Spinal cord injury results in loss of supraspinal control of sympathetic outflow, yet preservation of spinal reflexes. Given the importance of reflex activation of sympathetic vasoconstrictor neurones to the generation of autonomic dysreflexia, we assessed the input–output relationship of the spinal somatosympathetic reflex induced by electrical activation of cutaneous afferents over the lower abdominal wall. Methods  In 13 spinal cord-injured subjects (C4-T10) we tested the hypothesis that the magnitude and duration of the vasoconstriction is directly related to the magnitude and duration of the stimulus train. Cutaneous vasoconstriction was measured with photoelectric plethysmography over a finger and toe; continuous blood pressure was recorded by radial artery tonometry, heart rate by ECG chest electrodes and sweat release by skin conductance. Four sets of trains of cutaneous electrical stimuli (20 Hz 1 s, 20 Hz 20 s, 20 Hz 1 s alternating on-and-off for 20 s and 1 Hz 20 s) were applied to the abdominal wall (10 mA) at 2-min intervals. Results  Nine subjects showed vasoconstrictor responses to the stimulus trains. On average, both the magnitude and duration of the responses were similar irrespective of the type of stimulus train. Interpretation  We conclude that there is a non-linear relationship between somatic inputs and sympathetic vasoconstrictor outputs, and argue that a sustained vasoconstriction need not imply continuous sensory input to the spinal cord.     

Plasticity of lumbosacral propriospinal neurons is associated with the development of autonomic dysreflexia after thoracic spinal cord transection

Complete thoracic (T) spinal cord injury (SCI) above the T6 level typically results in autonomic dysreflexia, an abnormal hypertensive condition commonly triggered by nociceptive stimuli below the level of SCI. Overexpression of nerve growth factor in the lumbosacral spinal cord induces profuse sprouting of nociceptive pelvic visceral afferent fibers that correlates with increased hypertension in response to noxious colorectal distension. After complete T4 SCI, we evaluated the plasticity of propriospinal neurons conveying visceral input rostrally to thoracic sympathetic preganglionic neurons. The anterograde tracer biotinylated dextran amine (BDA) was injected into the lumbosacral dorsal gray commissure (DGC) of injured/nontransected rats immediately after injury (acute) or 2 weeks later (delayed). At 1 or 2 weeks after delayed or acute injections, respectively, a higher density (P < 0.05) of BDA(+) fibers was found in thoracic dorsal gray matter of injured vs. nontransected spinal cords. For corroboration, fast blue (FB) or cholera toxin subunit beta (CTb) was injected into the T9 dorsal horns 2 weeks postinjury/nontransection. After 1 week transport, more retrogradely labeled (P < 0.05) DGC propriospinal neurons (T13-S1) were quantified in injured vs. nontransected cords. We also monitored immediate early gene c-fos expression following colorectal distension and found increased (P < 0.01) c-Fos(+) cell numbers throughout the DGC after injury. Collectively, these results imply that, in conjunction with local primary afferent fiber plasticity, injury-induced sprouting of DGC neurons may be a key constituent in relaying visceral sensory input to sympathetic preganglionic neurons that elicit autonomic dysreflexia after high thoracic SCI.     

Estrogen reduces the severity of autonomic dysfunction in spinal cord-injured male mice

Autonomic dysreflexia is an autonomic behavioural condition that manifests after spinal cord injury (SCI) and is characterized by acute, episodic hypertension following afferent stimulation below the level of the injury. Common triggers of autonomic dysreflexia include colorectal distension (CRD), and various somatic stimuli. The development of autonomic dysreflexia is dependent, in part, upon the degree of intraspinal inflammation and the resultant spinal neuroplastic changes that occur following SCI. 17beta-estradiol (E) has neuroprotective, anti-inflammatory and smooth muscle relaxant properties, and is therefore a candidate drug for the treatment and/or prevention of autonomic dysreflexia. Autonomic dysreflexia was assessed in adult male mice treated with E. We investigated whether E could be acting centrally by altering: (1) the size of the small diameter primary afferent arbor, (2) the degree of microglia/macrophage infiltration at the site of the injury, or (3) the amount of fibrous scarring present at the injury site. To determine whether E could be working through uncoupling protein-2 (UCP-2), a protein involved with inflammation and regulated by estrogen in some tissues, autonomic dysreflexia was assessed in E-treated adult male mice lacking UCP-2 (UCP-2 KO). 17beta-estradiol was equipotent at reducing autonomic dysreflexia in both UCP-2 KO and WT mice following CRD but not tail pinch. We have shown that E reduces autonomic dysreflexic responses to visceral but not somatic stimulation in male mice independent of the size of the primary afferent arbour, the degree of chronic inflammation, and the presence of UCP-2.     

Heart rate variability is altered following spinal cord injury

Spinal cord injury (SCI) patients are know to suffer from autonomic failure as a result of their injury. The magnitude of the dysautonomia resulting from such an injury is difficult to predict or characterize and, in varying degree, it impedes the recovery of physiological homeostasis. This study is intended to investigate the effectiveness of heart rate variability (HRV) analysis as a method of quantifying and characterizing autonomic function in patients with traumatic spinal myelopathy. HRV analysis was carried out in 13 male SCI patients (six tetraplegic, seven paraplegic) and 13 age-matched, able-bodied controls. Twenty-four hour ambulatory and sleep ECG tracings were obtained. Time domain, amplitude, and power spectral analyses were used to study HRV and autonomic function. Both tetraplegic (20±12 ms, mean ±SD) and paraplegic (22±8 ms) subjects demonstrated significant loss of low frequency 24-hour HRV compared to able-bodied controls (36±14 ms, p<0.05) and during sleep. This was interpreted as being consistent with predominantly sympathetic denervation uninfluenced by degree of physical activity. There were no significant differences between groups in parasympathetically mediated high frequency HRV. We conclude that HRV analysis is capable of distinguishing between SCI or able-bodied humans and among tetraplegic and paraplegic patients. Patterns of altered HRV may be useful in more completely characterizing or stratifying changes in physiology associated with injury level and may have diagnostic, prognostic, or therapeutic significance.     

Latest Approaches for the Treatment of Spasticity and Autonomic Dysreflexia in Chronic Spinal Cord Injury

Two of the most prevalent secondary complications following spinal cord injury (SCI), besides loss of function and/or sensation below the level of injury, are uncontrolled muscle spasticity and hypertensive autonomic dysreflexia. Despite the desires of the SCI community, there have been few advances in the treatment and/or management of these fundamental impediments to the quality of life associated with chronic SCI. Therefore, the purpose of this review is to focus on current drug treatment strategies that alleviate symptoms of spasticity and autonomic dysfunction. Subsequently, looking ahead, we discuss whether individuals suffering from autonomic dysreflexia and/or muscle spasms can take certain compounds that specifically and rapidly block the neurotransmission of pain into the injured spinal cord to get rapid relief for both aberrant reflexes for which painful stimuli below the level of SCI are common precipitants.