Journal of Neuroscience Nursing:
Symptom Clusters in Traumatic Spinal Cord Injury: An Exploratory Literature Review
Hunter Revell, Susan M.
Question or comments about this article may be directed to Susan M. Hunter Revell, PhD RN, at firstname.lastname@example.org. She is an assistant professor, College of Nursing, University of Massachusetts Dartmouth, North Dartmouth, MA.
ABSTRACT: Chronic pain, spasticity, and depression are three common secondary health problems experienced by persons living with traumatic spinal cord injury. Limited research exists related to the interaction of these symptoms and their cumulative effect on patient outcomes and quality of life. This article is a report of an exploratory literature review that uses the conceptual approach of symptom clustering to classify secondary health problems in spinal cord injury. CINAHL, MEDLINE, and PsycINFO databases were searched for studies published in English between 1990 and 2008. Eleven articles met the inclusion criteria for review. Studies were categorized by levels of evidence defined by the American Association of Neuroscience Nurses Clinical Practice Guidelines. Research on the interaction of the symptom pair chronic pain and depression was evident. Several surveys reported the occurrence of multiple symptoms, but none specifically addressed the management of the interactive effects of the symptom cluster chronic pain, spasticity, and depression. Increased disciplinary knowledge of symptom clusters in the spinal cord injury population is needed for research and practice. Furthermore, determining symptom clusters in this population may assist clinicians in providing targeted interventions to simultaneously treat multiple symptoms.
A traumatic spinal cord injury (SCI) begins with a sudden, traumatic blow to the spine and leads to either complete or incomplete disruption of sensory and motor function below the level of injury (National Institute of Neurological Disorders and Stroke, 2010a). Because of advances in medical and pharmacological treatments, persons who sustain traumatic SCIs are not only surviving their initial injuries but are sustaining less severe injuries and living longer. Although data on the number of people living with SCI worldwide are unknown, estimates range from 9,000 people in Australia (Spinal Cord Injuries Australia, 2005) to 40,000 in the United Kingdom (Spinal Injuries Association, 2009) and 250,000 in the United States (National Institute of Neurological Disorders and Stroke, 2010b).
Along with an increased life expectancy, individuals with SCI may experience a wide range of physical and psychosocial health problems (World Health Organization, 2009). The Centers for Disease Control (2006) identified the management of secondary health problems as a major challenge for persons living with SCIs. According to Charlifue, Lammertse, and Adkins (2004), the greatest predictor of health problems in persons with SCIs is a previous incidence of the complication. Chronic health problems impact self-assessed health, life satisfaction (Charlifue et al., 2004), well-being, and the achievement of life goals (Phillips, Vesmarovich, Hauber, Wiggers, & Egner, 2001). Despite an abundance of research, few studies have reported the interactive effects of multiple symptoms, known as symptom clusters, on individuals living with traumatic SCI (Jensen, Kuehn, Amtmann, & Cardenas, 2007; Ulrich, Jensen, Loeser, & Cardenas, 2007). Symptom clusters have been discussed extensively in cancer research and have been identified in other studies with brain injury, cardiac, dialysis, HIV/AIDS, and SCI populations. This article is a report of an exploratory literature review conducted to determine the relationships between secondary health problems experienced by individuals living with traumatic SCI.
When multiple health problems exist in concert with each other, a symptom cluster is formed. Symptom clusters are defined as two to three or more concurrent symptoms that are interrelated. The interaction of symptoms is thought to have an increased, detrimental effect on the individual, with a greater potential for adverse patient outcomes and increased morbidity (Dodd, Miaskowski, & Paul, 2001). Symptom clustering is a conceptual approach used to organize and group multiple symptoms.
The determination of what symptoms to include in a cluster is made in one of several ways. According to Barsevick (2007), symptom clusters are developed "by expert opinion, group comparisons, shared variance among symptoms…, identification of subgroups, influence of symptoms on patient outcomes, or the identification of a common underlying mechanism" (p. 971). In the traumatic SCI population, an example of how to form subgroups is by level of injury. Level and completeness of injury provide a natural way to organize clusters and would include complete quadriplegics, complete paraplegics, incomplete quadriplegics, and incomplete paraplegics. Another method of grouping symptoms is by underlying mechanism; for example, pain may be a common biologic mechanism across symptoms (Barsevick, 2007). To explore the influence of symptoms on patient outcomes in an SCI population, researchers may seek to understand how chronic pain and depression relate to disability. It is essential to clearly define the characteristics of the symptom cluster for additional symptoms to be included or excluded (Barsevick, 2007).
Chronic pain, spasticity, and depression were clustered in this review to explore their interactive effects. The symptoms were selected on the basis of previous research indicating their prevalence in the SCI population, the detrimental impact each symptom has on patient outcomes, and from preliminary research findings of the author (Hunter Revell, 2007). It was anticipated that this conceptual symptom cluster would guide the literature review process, highlighting how the symptoms were similar and/or different between studies.
The hypothesized cluster may also provide the reader with a clearer picture of how symptom clusters can be formed in the SCI population. From a clinical standpoint, each individual will experience the symptoms differently in terms of frequency and severity, whereas from a research perspective, clusters take into account symptom variability and subgroup characteristics. Therefore, despite experiencing a symptom cluster, each individual may not present with all symptoms in the cluster (Barsevick, 2007). Findings from this review will become the basis for future studies with traumatic SCI individuals living with multiple secondary health problems. The hypothesized symptom cluster will require research to test out the relationships between symptoms. It is anticipated that symptoms clusters may inform frameworks of studies and guide the stages of the research process.
The Literature Review
This exploratory literature review was intended to determine the utility of using symptom clustering as a framework to organize symptoms and interpret a synthesis of evidence on the symptom cluster identified. Quantitative and qualitative studies that examined chronic pain, spasticity, and depression in pairs or groups of symptoms were included. All relevant studies were appraised for methodological quality. The level of evidence was categorized according to the clinical practice guidelines established by the American Association of Neuroscience Nurses (2008; Table 1).
The literature search began with a broad exploration of secondary health problems in the SCI population through the use of CINAHL, MEDLINE, and PsycINFO databases. The initial search results revealed system-based health problems that guided the clustering of secondary health problems. A second literature search was conducted with the same databases to identify the use of symptom clusters or multiple symptoms in SCI research. Key search terms included chronic pain, spasticity, depression, secondary health complication*, SCI, traumatic, symptom cluster*, symptom burden, and cluster analysis. The search range included studies published in English from 1990 to 2008. In addition, references cited by the researchers were also reviewed. Studies included in the review consisted of quantitative and qualitative research that focused on adults with traumatic SCI experiencing any combination of the symptoms in the cluster. Because of the limited scope of this exploratory review, research that focused on interventions and scale testing were excluded from the analysis.
Each article was evaluated for its relevance to the symptom cluster identified in the review. Of the initial 103 articles retrieved on secondary health problems, 36 articles met the selection criteria of studies on the specific symptoms. Of those 36 articles, 25 articles were excluded for the following reasons. Sixteen studies were excluded because they had tested treatment interventions, which was not the focus of this review. Additional ineligible articles included two studies on the psychometric testing of scales, two studies that researched individual symptoms, one single case study report, and one study that lacked evidence of approval from an institutional ethics board to conduct research. Eleven articles met both the conceptual and the methodological inclusion criteria for review (Table 2).
Data Extraction and Synthesis
Data were extracted by the author, and articles were grouped by the symptom pair, chronic pain and depression, and the symptom cluster, chronic pain, depression, and spasticity. Because of the heterogeneous nature of the information gathered, synthesis was detailed by narrative summary to provide the reader with an understanding of the evidence available for this symptom cluster.
The following description addresses the individual symptoms of chronic pain, depression, and spasticity. Study results are then grouped by the symptom pair chronic pain and depression and the symptom cluster chronic pain, depression, and spasticity.
Chronic pain in the SCI population is defined as pain that is present for greater than six months (Wilson, Richards, Klapow, DeVivo, & Greene, 2005). Onset often begins within the first year postinjury (Ravenscroft, Ahmed, & Burnside, 2000) but may also arise years later (Barrett, McClelland, Rutkowski, & Siddall, 2003; Henwood & Ellis, 2004). Estimates of study participants experiencing chronic, disabling pain that interfered with daily activity ranged from 39% to 84% (Barrett et al., 2003; Jensen et al., 2007; Noonan, Kopec, Zhang, & Dvorak, 2008; Ravenscroft et al., 2000; Rintala, Loubser, Castro, Hart, & Fuhrer, 1998). The wide range of pain reports may be attributed to the type of pain being studied, for example, musculoskeletal (Barrett et al., 2003) versus neuropathic (Noonan et al., 2008). According to Hitzig et al. (2008), moderate and severe pain was experienced by 49.7% and 31% of study participants, respectively. However, despite the prevalence of chronic pain, 43.5% of the participants also reported no impact on completion of daily activities (Hitzig et al., 2008). Research also examined chronic pain and the variables of intensity and time occurrence. Intensity was reported to increase over time (Henwood & Ellis, 2004); however, Rintala et al. (1998) found no clear correlation between chronic pain and time since injury.
Spasticity is defined as increased muscle tone, with hyperexcitabilty of flexor and extensor muscles, exaggerated reflexes, weakness, and joint contractures (Birns & Fitzpatrick, 2008). Spasticity was self-reported by 59% (Noonan et al., 2008) and 71% (Hitzig et al., 2008) of study participants in recent studies, whereas decreased frequency of spasticity was noted in a longitudinal study (25%) at 1, 3, and 5 years postinjury (Johnson, Gerhart, McCray, Menconi, & Whiteneck, 1998). Negative effects of spasticity include increased pain, weakness, and interference with functional abilities such as bathing, dressing, and range of motion activities (Birns & Fitzpatrick, 2008). Spasticity was viewed positively by some individuals because of its ability to tone muscles and to improve joint stability. (Kirshblum et al., 2007).
Along with physiological complications, persons living with SCI are at high risk for depression. Depression rates vary, with one study reporting approximately one third of study participants experiencing depression (Hitzig et al., 2008). Both paraplegics and quadriplegics reported depression to be a prevalent health problem on self-report (Hitzig et al. 2008). However, Johnson et al. (1998) reported that less than 3% of participants experienced depression at 1, 3, and 5 years postinjury. According to Hitzig et al. (2008), increased age and number of years postinjury are related to a decreased incidence of depression.
Chronic Pain and Depression
Research has confirmed a link between chronic pain and depression (Barrett et al., 2003; Jensen et al., 2007; Rintala et al., 1998; Ulrich et al., 2007; Widerstrom-Noga, Felix, Cruz-Almeida, & Turk, 2007; Wilson et al., 2005). Out of the 11 studies in the review, 6 articles address the symptoms of chronic pain and depression. Similarities and differences among the articles are highlighted as follows:
Group comparisons were investigated in three of the studies. Barrett et al. (2003) explored pain in hospitalized SCI patients who were admitted for treatment of other postinjury complications. Patients were placed in either a "pain" or a "no pain" group, and findings indicated that patients with pain had significantly greater levels of psychological distress than did patients without pain (Barrett et al., 2003). Similar pain-depression correlations were found by Wilson et al. (2005) and Widerstrom-Noga et al. (2007).
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Widerstrom-Noga et al. (2007) identified three SCI pain subgroups: dysfunctional, interpersonally supported, and adaptive copers. The subgroups were compared on the variables, level of pain disability, depressed mood, social support, life satisfaction, and demographics, level of injury, and functional independence measures (Table 3). Study results indicated that the greatest level of emotional distress was found in the "dysfunctional cluster" of participants who had severe pain ratings (Widerstrom-Noga et al., 2007), whereas in the study of Wilson et al. (2005), the four subgroups identified included low pain, positive adaptation to pain, minimal distress, and chronic pain syndrome. These subgroups were compared on similar measures with the study of Widerstrom-Noga et al., with the exception of the measures for social support and life satisfaction (Table 3). Wilson et al. also discovered that both the increased pain intensity and the relationship between pain intensity and pain interference were significantly related to higher depressive symptoms.
One study examined the impact of multiple symptoms in an SCI sample. Jensen et al. (2007) explored the reported course, frequency, and severity of seven symptoms (pain, fatigue, numbness, weakness, shortness of breath, vision loss, and memory loss) to determine levels of community reintegration and psychological functioning (Table 3). According to Jensen et al., pain was the most frequently reported symptom (84%), with a severity of pain level of ≥7 on the 0-10 scale. Pain significantly predicted the participants' level of psychological functioning (Jensen et al., 2007). In addition to psychological functioning, researchers studied the relationship between chronic pain and health and chronic pain and functional outcome measures.
Chronic pain was associated with decreased perceived health. Barrett et al. (2003) measured global health rating between two groups (Pain-No Pain) and discovered that fewer patients with pain perceived their global health as being high. Patients were asked to rate the perceived difficulty of problems encountered after SCI, and pain was found to be ranked fifth on a 0 (not hard at all) to 10 (extremely hard) scale (Table 3). According to Barrett et al., pain is not the reason patients are readmitted to hospitals; however, pain does have a major impact on perceived health and ability to take part in activities. Self-assessed health was also measured in the study of Rintala et al. (1998) by using a 4-point Likert scale. Similar to Barrett et al., there was a correlation between chronic pain and health, with participants reporting lower self-assessed health with the presence of pain (Rintala et al., 1998).
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Chronic pain and its interaction with other confounding variables resulted in lower social functioning. Ulrich et al. (2007) explored the associations between pain severity, psychological distress, functional disability, and mediator catastrophizing (Table 3). Results revealed that the combination of psychological distress and pain severity may be especially harmful to psychosocial functioning. Psychological distress and the interaction between pain severity and psychological distress significantly contributed to the prediction of the outcome variable, community integration (Ulrich et al., 2007). Jensen et al. (2007) also investigated social functioning through community integration. Findings supported the results of the study of Ulrich et al., with the social integration domain being significantly associated with pain. Conversely, Rintala et al. (1998) found no relationship between pain and social integration.
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Several studies investigated the relationship between chronic pain and disability-related outcome variables. Rintala et al. (1998) surveyed community-based men living with SCI to assess chronic pain and its relationship to impairment, disability, handicap, and subjective well-being (Table 3). Disability was significantly related to location of pain, with upper extremity pain correlating with greater disability. Whereas in the study of Barrett et al. (2003), 45% of the patients who experienced high levels of pain had low reported disability, with only 17% of patients reporting high levels of disability. Mixed results were noted in the study of Widerstrom-Noga et al. (2007), which also investigated the impact of pain on disability. According to Widerstrom-Noga et al., disability did not differ significantly between SCI pain subgroups, suggesting that activities such as mobility and self-care were independent of pain severity. However, participants with the highest levels of pain did report greater pain-induced disability on a separate measure related to social activity and occupation (Widerstrom-Noga et al., 2007).
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Chronic Pain, Depression, and Spasticity
The remaining studies in the review address the symptoms of chronic pain, spasticity, and depression. Three studies (Hitzig et al., 2008; Johnson et al., 1998; Noonan et al., 2008) investigated the occurrence of multiple secondary health conditions in SCI samples. The discussion of the results is limited to the conditions of pain, spasticity, and depression. Through a secondary data analysis, Noonan et al. (2008) studied 70 participants with traumatic central cord syndrome to determine the impact of associated conditions, including neuropathic pain, spasticity, bowel, bladder, and/or sexual dysfunction and decreased motor function on health status, symptom satisfaction, and quality of life (QOL; Table 3; Noonan et al., 2008). Study results indicated that participants reported spasticity to be the most prevalent condition (59%), followed by chronic neuropathic pain (39%). Spasticity was significantly associated with the physical component score, but not the mental component score of a generic health status measure (Medical Outcomes Survey Short Form-36 [SF-36]). Interestingly, spasticity had no effect on the SF-36 or a measure of satisfaction with symptoms after adjusting for confounders. This finding suggests that subjects were able to adapt to their spasticity and effectively manage the symptom with little impact on their perceived health or QOL. However, chronic pain was significantly associated with the physical and mental health components of the health status measure and with poor satisfaction with symptoms ratings (Noonan et al., 2008).
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Hitzig et al. (2008) conducted a study with 781 Canadian adults and determined self-report incidence of the health problems and how they related to age, years postinjury, and impairment (Table 3). Chronic pain (moderate to severe) and depression were reported by 45% and 30% of the sample, respectively. However, the odds ratio of reporting depression decreased with years postinjury, and no statistically significant associations were found between age, years postinjury, and impairment with chronic pain or spasticity (Hitzig et al., 2008).
Although in a longitudinal study Johnson et al. (1998) investigated secondary health conditions in a sample of SCI survivors at 1 year (n = 357), 3 years (n = 269), and 5 years (n = 170) postinjury. Participants completed questionnaires to assess health complications (Table 3). The secondary health conditions, problematic spasticity and pain, were reported to occur in greater than 25% of all study participants at all time points. Although spasticity reportedly decreased over time, pain increased over the three periods. Less than 3% of participants reported feeling depressed over all periods, with pain interfering with reports of QOL at years one and three (Johnson et al., 1998).
In an additional study, Ravenscroft et al. (2000) investigated the prevalence, the severity, and the impact of chronic pain in a sample of 216 SCI patients (Table 3). Results revealed that chronic pain had a significant impact on daily activities, and muscle spasms were reported by 25% of the participants to be an exacerbating factor of their pain. The pain-depression link was confirmed with 39% of study participants identifying pain as a contributing cause of depression (Ravenscroft et al., 2000).
Henwood and Ellis (2004) collected data that further support the proposed symptom cluster. Researchers studied 24 SCI individuals living in the community to explore their experiences with chronic neuropathic pain. Participants in Henwood and Ellis' study identified physical factors such as bladder infections, constipation, and spasticity and emotional factors such as stress, anxiety, and depression as augmenters to the intensity of their pain. As stated by one of the participants, "the spasm tends to gear where the pain is and it will make the pain worse" (p. 42). Spasms were problematic when they interacted with pain and then disturbed sleep. This interaction then in turn increased fatigue and pain intensity (Henwood & Ellis, 2004).
This exploratory literature review highlighted studies on the symptom pair of chronic pain and depression and the symptom cluster of chronic pain, depression, and spasticity in the traumatic SCI population. The symptom cluster presented broadens our understanding of the impact of these health problems on persons living with traumatic SCI, including the interaction between symptoms and their confounding effects on QOL, disability, and achievement of life goals. It is anticipated that additional symptoms may be added to the cluster upon further investigation.
There are several reports regarding the occurrence of chronic pain and the impact of chronic pain on functional ability and QOL. In five studies (Barrett et al., 2003; Jensen et al., 2007; Ravenscroft et al., 2000; Ulrich et al., 2007; Wilson et al., 2005), pain ratings were determined by using a numeric rating scale. As a multidimensional symptom, a magnitude determination of pain may not be inclusive enough to fully describe pain. Thus, the limited measurement of pain in these studies may begin to explain the variability in frequency and the impact of pain on outcome measures. The addition of pain measures, similar to measures used by Rintala et al. (1998), may be beneficial in future investigations.
In the six studies on the symptom pair chronic pain and depression, increased pain was significantly related to increased depression. However, the measures used to evaluate depression (Table 3) and the impact of depression on functional ability and QOL varied across studies. The chronic pain-depression studies also investigated variables such as level of pain disability, social support (Widerstrom-Noga et al., 2007), pain interference (Wilson et al., 2005), catastrophizing (coping; Ulrich et al., 2007), impairment, disability, and handicap (Rintala et al., 1998), which further limit the ability to generalize their findings.
Mixed results were reported regarding the secondary health problem, spasticity, in terms of its frequency and severity. Study participants experienced spasticity as either problematic or not problematic, suggesting that spasticity could occur but may not interfere with perceived health or impair functioning, as noted by Noonan et al. (2008). Data collected by participant self-report, in the qualitative study by Henwood and Ellis (2004), showed that participants were able to elaborate on the role spasticity played in their experiences with chronic pain (Henwood & Ellis, 2004). Spasticity was also measured with a variety of instruments (Table 3), which limits cross-study comparisons.
Identification of secondary health problems was part of the study design in three studies. Both Hitzig et al. (2008) and Noonan et al. (2008) assessed secondary health problems through participant self-report. The findings on frequency of symptoms experienced were helpful; however, there was no detail provided regarding the characteristics of the symptoms, such as duration or severity. Additional symptom detail would have provided a more complete picture of the impairments. Future studies regarding secondary health problems and symptom clusters should include standardized tools to measure secondary health problems.
Most studies in the review used cross-sectional designs (Barrett et al., 2003; Hitzig et al., 2008; Jensen et al., 2007; Noonan et al., 2008; Ravenscroft et al., 2000; Rintala et al., 1998; Ulrich et al., 2007; Widerstrom-Noga et al., 2007). This type of design allows for larger sample sizes but limits the ability to address longitudinal changes in secondary health conditions. There were only two prospective studies in the review (Johnson et al., 1998; Wilson et al., 2005). Future research might employ longitudinal designs to account for changes in symptoms over time, to determine the influence of factors such as age and years postinjury on symptom clusters, and to determine the impact of symptoms clusters on health status and QOL. Johnson et al. (1998) recommend for researchers to follow participants for decades to truly understand the secondary health problems of individuals living with SCI.
One study investigated the mediating role of social support on the experience of chronic pain in the SCI population. Widerstrom-Noga et al. (2007) found that a combination of social support types was associated with less disability and depressed mood and with higher life satisfaction in chronic pain participants. It can be hypothesized that social support may be a modifying factor in a symptom cluster model and therefore would be beneficial to measure its influence on symptom clusters, perceived health status, and QOL.
Two studies (Noonan et al., 2008; Ulrich et al., 2007) included a conceptual model to guide study design and methodology. Noonan et al. (2008) used a model to explain the proposed relationships among SCI, associated conditions (e.g., neuropathic pain, spasticity), and secondary conditions (e.g., pressure ulcers). The model also included personal factors hypothesized to influence health and QOL outcomes. The model of Noonan et al. provided a visual explanation for why variables were included in the study, whereas Ulrich et al. (2007) used a conceptual model to highlight the associations between pain severity, distress, catastrophizing, and functioning. There are numerous benefits to using a conceptual model to guide research, and frameworks such as symptom clustering should be considered when planning studies with individuals with SCI.
Implications for Practice
Individuals living with traumatic SCIs require routine and comprehensive healthcare throughout their lifetimes. Health professionals must focus on the unique aspects of aging with an SCI (Chiodo et al., 2007), and strong community-based follow-up is needed because of an increased risk for developing secondary health problems (Hitzig et al., 2008). With a clearer understanding of how secondary health problems present (frequency, severity, duration) over time and impact health and QOL, then more effective tailored health-promotion programs can be instituted (Hitzig et al., 2008).
Having an understanding of the interaction between multiple symptoms and how symptoms influence patient outcomes is essential for all health professionals. However, nurses in particular play a pivotal role in the assessment and management of these individuals. Through a holistic approach, nurses are afforded a comprehensive understanding of the person living with SCI (Delp & Ruth-Sahd, 2005). During patient assessment, nurses may discern the characteristics of a symptom cluster. Once the nurse identifies the presence of a cluster, additional related symptoms might be easier to detect (Barsevick, 2007). In the future, the education of healthcare professionals can focus on the assessment of symptom clusters and strategies for management. According to Jensen et al. (2007), "patient care and functioning are likely maximized when clinicians assess then treat as appropriate each of the biologic, psychologic, and social problems or issues that may be contributing to dysfunction in any one patient" (p. 642). Nurses also need to educate SCI individuals regarding the influence of multiple symptoms on their health outcomes, with the hope of increasing disclosure of information and improving QOL.
Implications for Research
To date, research related to symptom clusters in the SCI population has been limited. Studying symptom clusters would allow researchers to determine the influence of individual symptoms on each other. For example, the occurrence of one symptom may cause another symptom to occur, or the interaction of multiple symptoms may lead to poor patient outcomes with greater functional limitation. Moreover, the impact of symptom clusters on physical and psychosocial functioning and social and community integration should be investigated (Jensen et al., 2007).
Focusing on symptom clusters may assist researchers in understanding how the treatment of one symptom may adversely affect other symptoms and ultimately provide a scientific basis for assessing and treating symptom clusters (Barsevick, Whitmer, Nail, Beck, & Dudley, 2006). Future intervention studies may focus on the efficacy of a single intervention, known as a crossover intervention, on multiple symptoms in a cluster (Barsevick, 2007).
Exploratory literature reviews have the potential to uncover relationships among secondary health problems in individuals living with traumatic SCIs. Symptom clusters may inform theoretical frameworks of studies and be used to guide hypothesis generation, study design, and data collection and analysis. Determining clusters in the traumatic SCI population may assist clinicians in providing targeted treatments that focus on an entire cluster rather than a single symptom. Targeted, crossover interventions can provide cost-effective, optimum care. Future review articles are recommended to highlight alternative symptom clusters and to address the substantive impact symptom clusters have on patient outcomes and QOL.
The author is grateful to Drs. Eileen O'Neill and Kimberly Christopher for their thoughtful revision of the manuscript.
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