Autonomic impairment is not explained by neurological level of injury or motor-sensory completeness

Introduction:

Beyond the more obvious effects on sensation and movement, chronic spinal cord injury (SCI) impacts multiple organ systems and results in a variety of comorbidities for individuals. People with SCI often present clinically with problems of blood pressure dysregulation,¹ skin pressure injuries,² and bladder and bowel dysfunction.³ When considered together, these secondary medical complications contribute significantly to the mortality and healthcare system cost associated with SCI.⁴ Physiologically, these secondary medical complications from SCI are rooted in disruptions in the autonomic nervous system, which provides normal control over these systems in the uninjured state.⁵ Blood pressure dysregulation is clinically marked by both orthostatic hypotension¹ and autonomic dysreflexia⁶ and centers on interruptions in normal sympathetic vascular control through the injured spinal cord. Skin pressure injuries are often multifactorial, though altered blood pressure and flow and structural changes to the microvasculature likely contribute.^2,7,8 Neurogenic bladder and bowel are both highly rated concerns for individuals with SCI.⁹ Bladder and bowel function are partially regulated by parasympathetic and sympathetic control through the spinal cord.^3,10 Further, with growing evidence of impairments in the autonomic nervous system leading to SCI-immune deficiency syndrome,^11,12 identifying autonomic linkages to common problems such as urinary tract infections becomes feasible.

Despite these established autonomic innervation patterns, there are currently limited clinical tools to quantify autonomic dysfunction after SCI. As such, clinicians rely on readily available information such as Neurological Level of Injury (NLI) or American Spinal Injury Association Impairment Scale (AIS) from the International Standards for Neurological Classification of SCI exam.¹³ For example, classic clinical teaching is that individuals with SCI at or above the T6 level are at risk for autonomic dysreflexia.⁶ However, the difference between a T6 (at risk) and T7 (deemed not at risk) injury is determined only by light touch and sharp-dull discrimination sensation. As such, literature abounds with exceptions to this NLI or AIS teaching^14-16 and unsurprisingly, only about a quarter of physicians utilize the clinical guidance for NLI when considering management of dysreflexia.¹⁷

Survey tools do exist to document autonomic function after SCI. The International Standards for the Assessment of Autonomic Function after Spinal Cord Injury¹³ is a living document which was first released in 2009 and describes the impact of SCI on cardiovascular, pulmonary, sudomotor, bladder, bowel and sexual functions. However, recent studies of this survey’s use in practice indicate that it fails to move beyond surveying individuals’ symptoms and lacks predictive indicators.¹⁸ Another lesser known, but validated tool, the Autonomic Dysfunction Following Spinal Cord Injury (ADFSCI)¹⁹ survey captures the frequency and severity of symptoms of blood pressure instability and importantly, generates a total severity score (0-332) as well as subscores for autonomic dysreflexia and orthostatic hypotension. In past studies, these scores have correlated well to objective measurements of autonomic dysreflexia using ambulatory blood pressure monitoring,¹⁹ and cognitive dysfunction associated with orthostatic hypotension.²⁰ The objective of this study was to identify cross-correlations between typical clinical assessments (NLI and AIS), symptoms of autonomic dysfunction in blood pressure regulation (ADFSCI), and secondary medical complications.

Methods:

Individuals with and without SCI were recruited from outpatient clinics and targeted flyers and were prospectively enrolled in this study, which was approved by the Mass Gen Brigham IRB. Informed consent was obtained from all participants. Individuals with SCI had an International Standards exam completed by a trained physician. We also administered sections III and IV (15 items) of the ADFSCI survey, excluding the health history questions.¹⁹ Finally, to quantify secondary medical complications of SCI, individuals were asked to report:

1. number of urinary tract infections the individual felt they had (treated or untreated with antibiotics) over the past year;

2. the average duration of their bowel program during a typical week;

3. number of unplanned hospitalizations in the past year;

4. number of pressure injuries where the skin was broken (stage II or greater) since their initial SCI.

Health history (targeted to secondary medical complications as above) and demographic information including time since injury were also gathered. As clear normative values for the ADFSCI were not available, we further gathered this as well as demographic data on uninjured controls.

Statistics were calculated in RStudio (RStudio Inc., version: 2023.06.1+524). Data were compared between groups with two-sample t tests. Within the group with SCI, correlations of ADFSCI survey scores with NLI and AIS were assessed by Pearson’s correlation coefficients. Secondary medical complications were quantified and summarized with descriptive statistics. Pressure injuries were normalized to time since injury to account for differing risk exposure. The incidence of each secondary complication was then ranked within the SCI cohort and total rankings were summed to generate a marker of global secondary medical complication burden. Simple linear regressions between NLI, AIS, and ADFSCI scores with this global ranked sum were then calculated. Multiple regression models were built utilizing NLI, AIS and ADFSCI as coefficients to predict the ranked sum of secondary medical complications. Statistical significance was considered as p < 0.05. Data were expressed as means ± standard deviations.

Results:

In total, 82 individuals completed the study, including 48 individuals with SCI. Demographics of these individuals are described in Table 1. There were no significant demographic differences between groups by age (p = 0.08), gender, height (p = 0.86), weight (p = 0.94) or body mass index (p = 1.0). For participants with SCI, time since injury ranged from 1.0 to 38.7 years. Most individuals had motor-complete (79% with AIS A or B) spinal cord lesions affecting segment levels C5 through T6 (73%).

Table 1:

Characteristics of study participants. Health history and secondary medical complications also reported for individuals with spinal cord injury. All values reported as mean ± standard deviation unless otherwise stated. NLI, neurological level of injury. AIS, American Spinal Injury Association Impairment Scale.

	Spinal Cord Injury (n=48)	Control (n=34)	P-value
Demographics
Age	34.3 ± 9.7 years	30.7 ± 8.6 years	0.08
Gender, n (%)
Female	9 (19%)	6 (18%)
Male	39 (81%)	28 (82%)
Body mass index	24.1 ± 5.3 kg/m2	24.1 ± 3.4 kg/m2	1.0
Health History
Time since injury	7.2 ± 11.0 years
NLI, n (%)
C1-C4	7 (15%)
C5-C8	19 (40%)
T1-T6	16 (33%)
T7-T12	6 (12%)
AIS, n (%)
A	25 (52%)
B	13 (27%)
C	7 (15%)
D	3 (6%)
Meeting strength guidelines	65 ± 43% of year	37 ± 35% of year	0.002
Meeting aerobic exercise guidelines	63 ± 41% of year	57 ± 37% of year	0.50
Secondary Medical Complications
Urinary tract infections in past year	2.4 ± 3.0
Average duration of bowel program	60.8 ± 41.3 minutes
Hospitalizations in past year	0.94 ± 1.0
Pressure injuries per year of exposure	0.28 ± 0.41

Individuals with SCI scored significantly higher on the ADFSCI survey compared with the control group (46.3 ± 45.7 versus 9.1 ± 10.9, p < 0.0001). Furthermore, there were significant differences in subscores on the autonomic dysreflexia and orthostatic hypotension sub-sections of the ADFSCI between the group with SCI and the control group. For the autonomic dysreflexia sub-section, individuals with SCI scored significantly higher with a mean score of 27.4 ± 28.0 when compared to their uninjured peers (5.7 ± 8.5, p < 0.0001). Of note, since the ADFSCI asks questions such as “how often do you have headaches during the day”, scores for the uninjured control group were rarely zero. Similarly on the orthostatic hypotension questions, individuals with SCI scored significantly higher (18.9 ± 22.5 compared to 3.4 ± 4.2 in the control group, p < 0.0001).

Exploring this relationship further in the group with SCI, total ADFSCI scores (r = 0.34, p = 0.02) and autonomic dysreflexia subscores (r = 0.33, p = 0.02) were weakly positively correlated with more complete spinal cord lesions (AIS A or B). Similarly, a weakly positive relationship between scores on the orthostatic hypotension section of the survey and completeness of injury was observed (r = 0.27, p = 0.06). However, there was not a statistically significant correlation between ADFSCI scores and NLI (p = 0.79-0.87). When considered as a function of ADFSCI scores in simple linear regression models, NLI and AIS account for only 0.1% and 11.4% of variance in total scores (p = 0.81 and p = 0.02, respectively).

Simple regression models using NLI and AIS also failed to sufficiently predict the rank total secondary medical complications experienced by individuals with SCI (Figure 1A and 1B). NLI explained 7.2% of the variance in individuals’ rank total complications (p = 0.07). Similarly, AIS explained only 3.3% of variation in rank total complications (p = 0.23). In contrast to NLI and AIS, ADFSCI total score was a significant predictor, explaining nearly three times (31.2%) as much variation in rank total secondary medical complications that individuals reported after SCI (Figure 1C, p < 0.0001). A multiple regression model that factored ADFSCI score and NLI was marginally better at predicting rank total medical complications (R² = 0.37, p < 0.0001).

Figure 1: Scatter plots fitted with linear regression models that tested.

NLI (A), AIS (B), and total ADFSCI scores (C) as predictors of ranked total secondary medical complications in individuals with SCI. NLI, neurological level of injury. AIS, American Spinal Injury Association Impairment Scale. ADFSCI, Autonomic Dysfunction Following Spinal Cord Injury.

Discussion:

In a demographically similar sample, individuals with SCI demonstrated higher reports of symptomatic autonomic blood pressure instability on the ADFSCI questionnaire than controls. While this is generally expected, our data indicated that within the group of individuals with SCI, these higher scores on ADFSCI are only partially explained by NLI or completeness of injury graded on the AIS. Typically in clinic, more rostral and complete injuries are thought to be associated with more symptoms of autonomic dysfunction. Herein, we quantify this, demonstrating that NLI and AIS account for less than 12% of variance in ADFSCI total scores, respectively. These findings reinforce that subjective symptoms of autonomic nervous system disturbance vary widely after SCI and motor/sensory assessment using the International Standards cannot be relied upon to evaluate autonomic function.

Mirroring these findings, secondary medical complications were found to have only limited positive correlations to more rostral NLI and complete AIS. This also is not entirely unexpected, as NLI and AIS are based off of motor and sensory impairments. As previous literature has suggested, these clinical assessments provide an incomplete picture of autonomic integrity after SCI.^21-23

Contrasting this, symptoms of autonomic dysfunction on ADFSCI had over three times higher correlation for identifying secondary medical complications over the bedside motor/sensory exam. This is an important linkage, suggesting that symptoms of autonomic blood pressure dysregulation may better relate to history of secondary medical complications such as number of urinary tract infections, lifetime skin pressure injuries, and time for bowel program. The connection between these systems may initially seem disparate, though there is strong evidence that the autonomic nervous system plays a key regulatory role in all. Similar objective correlations between different components of the autonomic nervous system have previously been demonstrated, with absence of sweat responses (a sudomotor function) predicting autonomic dysreflexia (a cardiovascular response) during urodynamics tests after SCI.²⁴ This likely speaks to improved specificity of using autonomic tests, as opposed to motor/sensory assessments, to predict other outcomes influenced by autonomic dysfunction. Future work to characterize autonomic dysfunction and correlate this to such outcomes could provide important clinical insights.

Limitations

In the present study, we created a measure that specifically captured frequency of several medical complications after SCI. This approach allowed us to rank and relate secondary complications to scores on the ADFSCI survey when existing validated instruments (e.g., Spinal Cord Injury Secondary Conditions Scale²⁵) categorize frequency broadly to relate health conditions to independence and, therefore, lack the specificity needed for this study. Additionally, the self-report in ADFSCI’s and history of secondary complications administration is subject to recall bias based on which symptoms are most salient to the respondent.^19,26 This introduces potential variability, especially when compared to objective testing on the International Standards exam. To improve future predictive ability, objective testing of autonomic dysfunction could be beneficial. Finally, our sample of those with SCI included adults with primarily cervical and thoracic, motor/sensory complete (AIS A or B) injuries, and future studies exploring these relationships in those with lumbar and motor/sensory incomplete SCI would improve the generalizability of these findings.

Conclusion:

Fitting with clinical observations, neurological level of injury and motor/sensory completeness provide only limited insights into which individuals with SCI have symptoms of blood pressure instability or secondary medical complications. Interestingly, symptoms of blood pressure instability outperformed the clinical motor/sensory bedside exam, with improved correlations to histories of secondary medical complications after SCI.

Data Availability:

The authors agree to make data available upon reasonable request to corresponding author.