Jill M. Wecht

Assessment of autonomic dysfunction following spinal cord injury: Rationale for additions to International Standards for Neurological Assessment

We present a preliminary report of the discussion of the joint committee of the American Spinal Injury Association (ASIA) and the International Spinal Cord Society concerning the development of assessment criteria for general autonomic function testing following spinal cord injury (SCI). Elements of this report were presented at the 2005 annual meeting of the ASIA. To improve the evaluation of neurological function in individuals with SCI and therefore better assess the effects of therapeutic interventions in the future, we are proposing a comprehensive set of definitions of general autonomic nervous system dysfunction following SCI that should be assessed by clinicians. Presently the committee recommends the recognition and assessment of the following conditions: neurogenic shock, cardiac dysrhythmias, orthostatic hypotension, autonomic dysreflexia, temperature dysregulation, and hyperhidrosis.

International standards to document remaining autonomic function after spinal cord injury

Abstract This is the first guideline describing the International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI). This guideline should be used as an adjunct to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) including the ASIA Impairment Scale (AIS), which documents the neurological examination of individuals with SCI. The Autonomic Standards Assessment Form is recommended to be completed during the evaluation of individuals with SCI, but is not a part of the ISNCSCI. A web-based training course (Autonomic Standards Training E Program (ASTeP)) is available to assist clinicians with understanding autonomic dysfunctions following SCI and with completion of the Autonomic Standards Assessment Form (www.ASIAlearningcenter.com).

Effect of pamidronate administration on bone in patients with acute spinal cord injury.

Eleven subjects participated in a prospective placebo-controlled trial to address the efficacy of pamidronate in reducing bone loss in persons with acute spinal cord injury (SCI). We administered pamidronate (treatment) or normal saline (placebo) intravenously at baseline (22 to 65 days after injury) and sequentially over 12 months, with follow-up at 18 and 24 months. Regional bone mineral density (BMD) was lost over time, regardless of group. In the treatment group compared with the placebo group, we noted a mild early reduction in loss of total leg BMD. Significant bone loss from baseline occurred earlier in the placebo group at the regional sites than in the treatment group. However, by the end of the treatment and follow-up phases, both groups demonstrated a similar percent bone loss from baseline. Despite an early reduction in bone loss, pamidronate failed to prevent major, long-term bone loss in persons with acute neurologically complete SCI.

Comparison of 24-hour cardiovascular and autonomic function in paraplegia, tetraplegia, and control groups: implications for cardiovascular risk.

Abstract Background Fluctuations in 24-hour cardiovascular hemodynamics, specifically heart rate (HR) and blood pressure (BP), are thought to reflect autonomic nervous system (ANS) activity. Persons with spinal cord injury (SCI) represent a model of ANS dysfunction, which may affect 24-hour hemodynamics and predispose these individuals to increased cardiovascular disease risk. Objective To determine 24-hour cardiovascular and ANS function among individuals with tetraplegia (n = 20; TETRA: C4–C8), high paraplegia (n = 10; HP: T2–T5), low paraplegia (n = 9; LP: T7–T12), and non-SCI controls (n = 10). Twenty-four-hour ANS function was assessed by time domain parameters of heart rate variability (HRV); the standard deviation of the 5-minute average R–R intervals (SDANN; milliseconds/ms), and the root-mean square of the standard deviation of the R–R intervals (rMSSD; ms). Subjects wore 24-hour ambulatory monitors to record HR, HRV, and BP. Mixed analysis of variance (ANOVA) revealed significantly lower 24-hour BP in the tetraplegic group; however, BP did not differ between the HP, LP, and control groups. Mixed ANOVA suggested significantly elevated 24-hour HR in the HP and LP groups compared to the TETRA and control groups (P < 0.05); daytime HR was higher in both paraplegic groups compared to the TETRA and control groups (P < 0.01) and nighttime HR was significantly elevated in the LP group compared to the TETRA and control groups (P < 0.01). Twenty-four-hour SDANN was significantly increased in the HP group compared to the LP and TETRA groups (P < 0.05) and rMSSD was significantly lower in the LP compared to the other three groups (P < 0.05). Elevated 24-hour HR in persons with paraplegia, in concert with altered HRV dynamics, may impart significant adverse cardiovascular consequences, which are currently unappreciated.

Cardiac autonomic responses to progressive head-up tilt in individuals with paraplegia

Beat-to-beat fluctuations in heart rate are partially controlled by the autonomic nervous system and may be altered by a spinal cord injury. The purpose of the present investigation was to examine the role of the autonomic nervous system in modulating the heart rate response to head-up tilt (HUT) in subjects with low lesion paraplegia. Nineteen subjects with paraplegia and nine age-, height-, and weight-matched control subjects consented to participate. A three lead ECG was used to acquire heart rate (HR), cardiac sympathetic [low frequency component of R-R interval variability (LFRRI)], vagal [high frequency component of R-R interval variability (HFRRI)] and sympatho-vagal balance (LF/HF). A finger photoplethysmograph was used to assess beat-to-beat blood pressure for the estimation of sympathetic vasomotor tone [low frequency component of peak systolic blood pressure variability (LFSBP)]. The results showed a significant main effect for tilt angle for the HR response to HUT, which was comparable between the groups. LFRRI was significantly increased (P < 0.001) and HFRRI was significantly reduced (P < 0.001) across tilt angle in the control group, whereas subjects with paraplegia demonstrated no significant change in LFRRI, but significantly reduced HFRRI (P < 0.001) across tilt angle. There was a significant interaction effect for LF/HF (P < 0.05). LFSBP was significantly reduced in the group with paraplegia compared to controls (P < 0.05). These findings suggest that although cardiac autonomic control is intact, there is a blunted sympathetic response to HUT in subjects with low lesion paraplegia, which may implicate an altered baroreceptor response to acute orthostatic provocation.

A Small-Scale Clinical Trial to Determine the Safety and Efficacy of Testosterone Replacement Therapy in Hypogonadal Men with Spinal Cord Injury

Men with spinal cord injury are at an increased risk for secondary medical conditions, including metabolic disorders, accelerated musculoskeletal atrophy, and, for some, hypogonadism, a deficiency, which may further adversely affect metabolism and body composition. A prospective, open label, controlled drug intervention trial was performed to determine whether 12 months of testosterone replacement therapy increases lean tissue mass and resting energy expenditure in hypogonadal males with spinal cord injury. Healthy eugonadal (n = 11) and hypogonadal (n = 11) outpatients with chronic spinal cord injury were enrolled. Hypogonadal subjects received transdermal testosterone (5 or 10 mg) daily for 12 months. Measurements of body composition and resting energy expenditure were obtained at baseline and 12 months. The testosterone replacement therapy group increased lean tissue mass for total body (49.6 ± 7.6 vs. 53.1 ± 6.9 kg; p < 0.0005), trunk (24.1 ± 4.1 vs. 25.8 ± 3.8 kg; p < 0.005), leg (14.5 ± 2.7 vs. 15.8 ±2.6  kg; p = 0.005), and arm (7.6 ± 2.3 vs. 8.0 ± 2.2 kg; p < 0.005) from baseline to month 12. After testosterone replacement therapy, resting energy expenditure (1328 ± 262 vs. 1440 ± 262 kcal/d; p < 0.01) and percent predicted basal energy expenditure (73 ± 9 vs. 79 ± 10%; p < 0.05) were significantly increased. In conclusion, testosterone replacement therapy significantly improved lean tissue mass and energy expenditure in hypogonadal men with spinal cord injury, findings that would be expected to influence the practice of clinical care, if confirmed. Larger, randomized, controlled clinical trials should be performed to confirm and extend our preliminary findings.

Infusion of Neostigmine–Glycopyrrolate for Bowel Evacuation in Persons with Spinal Cord Injury

Defecatory complications are common after spinal cord injury (SCI) and have been attributed, in part, to an imbalance of the autonomic nervous system between parasympathetic and sympathetic effects on the colon. Because parasympathetic (i.e., cholinergic) input to the bowel may be downregulated after SCI, it was hypothesized that neostigmine, a medication that increases cholinergic tone by blocking the metabolism of acetylcholine, might promote bowel evacuation in these persons. Since neostigmine is known to cause bradycardia and bronchoconstriction, we also assessed whether these side-effects could be prevented by coadministration of neostigmine with glycopyrrolate, an anticholinergic agent that has limited activity on the muscarinic receptors of the colon. The hypothesis was tested in 13 persons with SCI in whom videofluoroscopy was carried out after instillation of a barium oatmeal paste into the rectum and descending colon. On separate days, subjects received, in a randomized, blinded design, one of three intravenous infusates (normal saline, 2 mg neostigmine, or 2 mg neostigmine + 0.4 mg glycopyrrolate). The effect of these infusates on bowel evacuation of the barium paste, heart rate, and airway resistance was determined. Both neostigmine and neostigmine + glycopyrrolate resulted in prompt bowel evacuation. The nadir heart rate was lower after neostigmine alone than with the combination. Neostigmine administration increased both total and central airway resistance, an effect that was not observed with the coadministration of glycopyrrolate. Other side-effects of neostigmine and the combination of drugs included muscle fasciculations and dry mouth, both of which were mild and short-lived. Abdominal cramping was noted in subjects with spinal cord lesions below thoracic level 10. These results indicated that neostigmine/glycopyrrolate administration is safe and well tolerated in persons with chronic SCI.

Arterial Stiffness in Persons With Paraplegia

Abstract Background: Arterial stiffness recently has been identified as an independent risk factor for cardiovascular disease. An accurate andnoninvasive estimate of arterial stiffness can be made through close examination of the pulse wave contour, and is expressed as theaugmentation index (Al). lncreased stiffness is associated with increased systolic blood pressure (SBP) , pulse pressure, and reducedbaroreceptor sensitivity. The purpose of this study was to compare the common carotid Al in participants with paraplegia vsable-bodied controls as weil as compare group differences for blood pressure while supine and in response to gravitational stress. Participants: Study participants were 19 healthy individuals with paraplegia (below T6) and 9 able-bodied controls matched forage, height, and weight. Methods: An electronic tilt table was used for testing responses to gravitational stress at 4 angles (− 10°, 10°, 35°, and 75°). Alwas assessed at each angle of tilt using an externally applied high-fidelity strain-gauge transducer placed over the right commoncarotid artery. Results: Al was augmented in the group with paraplegia compared with the able-bodied group (8.0 ± 3.9 vs 6.7 ± 2.8 ,respectively; P < 0.05). Supine blood pressure and the SBP response to tilt did not differ between the groups, and there were notilt-angle effects on SBP. Conclusion: In normotensive persons with paraplegia, Al was increased significantly compared with matched able-bodied controls,which may suggest the premature development of arterial disease in this population.

Decentralized cardiovascular autonomic control and cognitive deficits in persons with spinal cord injury.

Abstract Spinal cord injury (SCI) results in motor and sensory impairments that can be identified with the American Spinal Injury Association (ASIA) Impairment Scale (AIS). Although, SCI may disrupt autonomic neural transmission, less is understood regarding the clinical impact of decentralized autonomic control. Cardiovascular regulation may be altered following SCI and the degree of impairment may or may not relate to the level of AIS injury classification. In general, persons with lesions above T1 present with bradycardia, hypotension, and orthostatic hypotension; functional changes which may interfere with rehabilitation efforts. Although many individuals with SCI above T1 remain overtly asymptomatic to hypotension, we have documented deficits in memory and attention processing speed in hypotensive individuals with SCI compared to a normotensive SCI cohort. Reduced resting cerebral blood flow (CBF) and diminished CBF responses to cognitive testing relate to test performance in hypotensive non-SCI, and preliminary evidence suggests a similar association in individuals with SCI. Persons with paraplegia below T7 generally present with a normal cardiovascular profile; however, our group and others have documented persistently elevated heart rate and increased arterial stiffness. In the non-SCI literature there is evidence supporting a link between increased arterial stiffness and cognitive deficits. Preliminary evidence suggests increased incidence of cognitive impairment in individuals with paraplegia, which we believe may relate to adverse cardiovascular changes. This report reviews relevant literature and discusses findings related to the possible association between decentralized cardiovascular autonomic control and cognitive dysfunction in persons with SCI.

Effects of Midodrine Hydrochloride on Blood Pressure and Cerebral Blood Flow During Orthostasis in Persons With Chronic Tetraplegia

OBJECTIVE To determine the mean arterial pressure (MAP) and middle cerebral artery mean blood flow velocity (MFV) responses to 5 and 10mg midodrine during head-up tilt (HUT) in persons with tetraplegia. DESIGN Prospective dose-response trial. SETTING James J. Peters Veterans Administration Medical Center. PARTICIPANTS Persons (N=10) with chronic tetraplegia (duration of injury=23+/-11 y). INTERVENTION A dose titration study was performed over 3 testing days: control (no drug), 5mg midodrine (5mg), or 10mg midodrine (10mg) during 30 minutes of baseline (predrug/no drug), 30 minutes of supine rest postdrug/no drug, 15 minutes of progressive HUT (5 minutes at 15 degrees , 25 degrees , 35 degrees ), and 45 minutes of 45 degrees HUT. MAIN OUTCOME MEASURES MAP and MFV response to midodrine supine and during HUT. RESULTS Ten milligrams of midodrine significantly increased MAP while supine and during the HUT maneuver. Of note, the mean increase in MAP during HUT with 10mg was a result of a robust effect in 2 persons, with minimal change in the remaining 8 study subjects. The reduction in cerebral MFV during HUT was attenuated with 10mg. CONCLUSIONS These findings suggest that midodrine 10mg may be efficacious for treatment of hypotension and orthostatic hypotension in select persons with tetraplegia. Although midodrine is routinely prescribed to treat orthostatic hypotension, the results of our work suggests limited efficacy of this agent, but additional studies in a larger sample of subjects with spinal cord injury should be performed.