Abstract
Background: Cognitive dysfunction is the most common form of neurologic impairment after subarachnoid hemorrhage (SAH).
Objective: To evaluate the impact of global and domain-specific cognitive impairment on functional recovery and quality of life (QOL) after SAH.
Methods: One hundred thirteen patients (mean age 49 years; 68% women) were evaluated 3 months after SAH. Three simple tests of global mental status and neuropsychological tests to assess seven specific cognitive domains were administered. Four aspects of outcome (global handicap, disability, emotional status, and QOL) were compared between cognitively impaired and unimpaired patients with analysis-of-covariance models controlling for age, race/ethnicity, and education. Multiple linear regression was used to evaluate the relative contribution of global and domain-specific cognitive status for predicting concurrent modified Rankin Scale (mRS) and Sickness Impact Profile (SIP) scores.
Results: Impairment of global mental status on the Telephone Interview of Cognitive Status (TICS) was associated with poor performance in all seven cognitive domains (all p < 0.0005) and was the only cognitive measure associated with poor recovery in all four aspects of outcome (all p ≤ 0.005). Cognitive impairment in four specific domains was also associated with functional disability or reduced QOL. After accounting for global cognitive impairment with the TICS, however, neuropsychological testing did not contribute additional predictive value for concurrent mRS or SIP total scores.
Conclusions: Cognitive impairment impacts broadly on functional status, emotional health, and QOL after SAH. The TICS may be a useful alternative to more detailed neuropsychological testing for detecting clinically relevant global cognitive impairment after SAH.
Much progress has been made in our efforts to understand the pathophysiology of brain injury after subarachnoid hemorrhage (SAH),1-5⇓⇓⇓⇓ and major advances have been made in the acute management of ruptured aneurysms. These advances have forced clinicians and investigators to develop and apply more sensitive instruments to assess treatment outcomes beyond mortality and gross morbidity. It has become increasingly clear that SAH leads primarily to cognitive impairment and that many survivors felt to have made a “good” recovery clinically or on global outcome measures such as the Glasgow Outcome Scale have cognitive deficits and poor health-related quality of life (QOL).6-8⇓⇓ Neuropsychological testing has been used to detect subtle cognitive impairment after SAH,1-6,9-15⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ but the extent to which these deficits actually cause disability (loss of independence in activities of daily living), handicap (limitation of social or societal role function because of impairment or disability), or reduced QOL remains controversial.12 Though memory and psychomotor problems are most prevalent,1,2,4⇓⇓ all domains of cognitive function can be affected by SAH, which reflects the diffuse nature of the hemorrhage.1,2⇓ Whether certain types of domain-specific cognitive dysfunction after SAH are more disabling than others is unknown.
Though detailed neuropsychological testing is invaluable for characterizing the extent and nuances of cognitive impairment in individuals, for several reasons this type of evaluation can be problematic for use as an outcome measure in large clinical studies. First, the testing can be lengthy and arduous, must be performed in person, and cannot be completed by severely impaired patients.1 Second, the specific tests used often vary, and a test battery generates multiple scores that can be difficult to summarize and interpret. Finally, test performance is highly influenced by demographic variables such as age, race/ethnicity, and education.1 An ideal measure of disease-related cognitive impairment after SAH for clinical trials would generate a single global score, be applicable to both severely injured and highly functional patients, be resistant to demographic bias, have good interrater and test–retest reliability, and possess construct validity so that increasing degrees of impairment are associated with increased handicap and disability and reduced QOL.16
There is a long-recognized need to develop and validate outcome measures that are sensitive to the subtle but disabling effects of SAH.6,17,18⇓⇓ In this study, we evaluated the impact of global and domain-specific cognitive impairment on concurrent measures of global handicap, functional disability, emotional status, and QOL after SAH. Specifically, we sought to determine whether one of three simple tests of global cognitive status—all of which can be performed telephonically—might serve as a suitable alternative to more detailed in-person neuropsychological testing for identifying clinically relevant cognitive impairment after SAH.
Patients and methods.
Patient population.
Three hundred twenty-six SAH patients admitted consecutively to the neurologic intensive care unit between July 1, 1996, and March 31, 2000, were prospectively enrolled in the Columbia University SAH Outcomes Project. The diagnosis of SAH was established on the basis of CT or by xanthochromia of the CSF if the CT was negative. Exclusion criteria included SAH from trauma or rupture of an arteriovenous malformation, admission >14 days after onset, and age <18 years; patients with spontaneous nonaneurysmal SAH were included. The study was approved by the hospital’s institutional review board, and in all cases written informed consent was obtained from the patient or a surrogate. The clinical management of the study population has been previously described.1
Clinical assessment.
Basic demographic data (age, gender, race/ethnicity, fluency in English, education level), social and past medical history, and clinical features at onset were obtained by interviewing the patient and family shortly after admission and by reviewing the medical record. Global mental status on day 14 (or discharge if earlier) was evaluated with the Telephone Interview of Cognitive Status (TICS).19 A complete review of the entire hospital course was conducted at the time of discharge by a study neurologist to document important radiologic findings, procedures, and complications, as described previously.1
Three-month follow-up assessment.
Three months after the onset of SAH, each subject was asked to complete a 45-minute telephone or in-person interview (the basic outcomes assessment). In addition, subjects were asked to complete detailed in-person cognitive testing whenever possible (the neuropsychological assessment). All assessment instruments were administered in the participant’s native language (English or Spanish). All evaluations were performed in person for the current analysis. The same assessment was also performed 12 months after SAH; these data are not reported.
The basic outcomes assessment consisted of a structured interview that included items regarding the patient’s interim medical and social history, medications, rehabilitation, and work status. Global handicap was assessed with a 7-point version of the modified Rankin Scale (mRS) rated from death to symptom-free full recovery.20 Neurologic impairment (i.e., focal neurologic deficit) was assessed with the NIH Stroke Scale (NIHSS; scored 0 best, 30 worst).21 Disability in basic activities of daily living (i.e., walking, dressing) was assessed with the Barthel Index22 (scored 20 best, 0 worst), and disability in instrumental activities of daily living (IADL; i.e., using a phone, housekeeping) was assessed with the Lawton IADL Scale (scored 8 best, 30 worst).23 Health-related QOL was assessed with the Sickness Impact Profile (SIP),24 a 136-item behaviorally based questionnaire that we have previously found to be well suited for SAH research.25 To summarize QOL for our primary analysis, we calculated the SIP total score as well as physical and psychosocial dimension scores (scored 0 no dysfunction, 100 maximal dysfunction). We also assessed a single specific aspect of QOL—subjective life satisfaction—with the Life Satisfaction Scale,26 a visual analogue scale that we adapted for use after SAH (scored 15 best, 105 worst). Symptoms of depression and anxiety were assessed with the Center for Epidemiologic Studies–Depression Scale (CES-D27; scored 0 best, 60 worst) and the Spielberger State-Trait Anxiety Inventory (STAI28; scored 20 best, 80 worst).
The neuropsychological assessment consisted of a detailed 3-hour battery of tests designed to assess a variety of cognitive domains (a complete list of the test battery and references is available from the authors by request). To assess global mental status, we administered the TICS,19 the Short Blessed Test of Orientation, Memory, and Concentration,29 and the Verbal Series Attention Test.30 The TICS was developed as a telephone version of the Mini-Mental State Examination and takes approximately 5 to 10 minutes to administer. The TICS evaluates orientation (name, month, date, year, day, season, address, street, city, state, and borough), attention (counting backwards and serial sevens), language (naming, repetition, antonyms), long-term memory (name president and vice-president), motor function (finger tap), and verbal memory (immediate and delayed recall of a 10-item word list) and is scored from 0 (worst) to 51 (best). TICS scores of ≤30 were coded as impaired; this cut-point was found to discriminate between demented and nondemented subjects in a 41-point version of the test that did not include the 10-point delayed recall task.19 The Short Blessed Test evaluates orientation, concentration, and memory, takes only 3 to 5 minutes to administer, and is scored from 28 (worst) to 0 (best); scores of >6 were coded as impaired.31 The Verbal Series Attention Test evaluates attention and concentration only, takes 3 to 5 minutes to administer, and generates separate scores for speed (time to complete the test) and accuracy (number of errors). Age- and education-adjusted Z scores for time and error scores were averaged, and values >2 SD below normal were coded as impaired.
Cognitive performance in seven different domains (verbal memory, visual memory, motor functioning, reaction time, executive function, visuospatial functioning, and language functioning) was evaluated by selecting two neuropsychological tests for each domain (table 1); tests were selected on the basis of face validity and the availability of published normative data. Performance was deemed impaired in a particular domain if the average norm-adjusted Z score of the two tests was >2 SD below reference values.
Table 1 Neuropsychological test performance
Statistical analysis.
All analyses were performed using commercially available statistical software (SPSS 9.01; SPSS, Chicago, IL). Two-tailed t-tests were used to compare continuous variables, and the χ2 test was used to compare categorical variables. We evaluated follow-up bias by comparing selected demographic, clinical, and radiographic variables between patients who underwent neuropsychological testing and those who did not. The relationship between global and domain-specific cognitive impairment was evaluated by comparing domain Z scores in patients with and without global impairment according to each of the three tests we administered. Student’s one-sample t-test was used to test individual test Z scores for significant differences from zero. Spearman’s ρ was calculated to evaluate the degree of correlation between demographic, emotional health, and outcome variables.
We evaluated relationships between various aspects of 3-month cognitive status and outcome ratings with a series of analysis-of-covariance (ANCOVA) models32 controlling for age, years of education, and ethnicity (white versus nonwhite). Cognitive status was coded as the independent variable (impaired versus unimpaired), and global handicap (mRS), disability (Barthel Index and Lawton IADL Scale), QOL (SIP total, physical, and psychosocial scores), depression (CES-D), and anxiety (STAI) scores were coded as dependent variables.
For subsequent analyses, we identified a single “best test” of global mental status based on the strength and extent of its association with domain-specific cognitive testing and different aspects of outcome. To identify specific QOL categories that are affected by global cognitive impairment, we used ANCOVA models to compare SIP category scores between impaired and unimpaired patients while controlling for age, education, and race/ethnicity. To evaluate the clinical relevance of neuropsychological testing after accounting for global cognitive impairment, we used a series of four-block multiple linear regression models to compare the explanatory power (R2) of global and domain-specific cognitive status for predicting concurrent mRS and summary SIP scores. In blocks 1 and 2, we controlled for demographic (age, education, race/ethnicity) and emotional health (CES-D) variables that exhibited significant Spearman correlations with cognitive status or functional outcome (we excluded English fluency owing to collinearity with race/ethnicity, and STAI scores because of collinearity with CES-D scores). In block 3, we forced in the “best test” of global mental status, and in block 4, we used a forward stepwise selection procedure to identify domain scores that contributed additional predictive value for mRS or SIP summary scores.33
Statistical significance was set at p ≤ 0.05 for the analysis of follow-up bias and the multiple linear regression models. Because of the large number of comparisons, we used partial Bonferroni correction for the analysis of 3-month cognitive and outcome measures (p ≤ 0.005, based on three global mental status scores and seven domain scores), the comparison of domain-specific cognitive function in globally impaired versus unimpaired patients (p ≤ 0.007, based on seven domain scores), and the comparison of SIP category scores in globally impaired versus unimpaired patients (p ≤ 0.004 based on 12 categories).
Results.
Follow-up bias.
Figure 1 shows the follow-up status of the 326 patients enrolled in the study. Of 250 patients (77%) known to be alive at 3 months, 214 (86%) were evaluated with the basic outcomes assessment and 113 (46%) underwent neuropsychological testing. The most common reasons for failure to undergo neuropsychological testing were patient refusal (n = 46) and cognitive impairment severe enough to preclude assessment (n = 30). Patients who underwent neuropsychological testing were significantly younger, less often white, and had better 3-month mRS scores than those who did not (table 2). The two groups were similar with regard to clinical disease severity, complications, and 14-day TICS scores. The mean follow-up interval was 107 ± 21 days.
Figure 1. Flow diagram of patient follow-up.
Table 2 SAH subjects alive at 3 months who did or did not undergo neuropsychological testing
Study population.
The 113 patients who underwent neuropsychological testing ranged in age from 19 to 86 years (see table 2). Forty-nine (43%) were Hispanic, 48 (43%) were white non-Hispanic, 14 (12%) were black non-Hispanic, and 2 (2%) were Asian. Sixty-seven (59%) of the participants were native English speakers, 14 (12%) spoke English fluently as a second language, and 32 (28%) were not fluent in English. A ruptured aneurysm was identified in 103 cases (91%); 89 were treated with surgical clipping, 13 with coil embolization, and in 1 patient, the aneurysm was not repaired.
Neurologic impairment.
Ninety-five (84%) patients had a normal NIHSS score of 0 at 3-month follow-up. The median score of the 18 patients with an abnormal score was 3.5 (range 1 to 19).
Cognitive impairment.
Performance of the study population at 3-month follow-up was significantly lower than published normative values on all of the cognitive tests administered (see table 1) with the exception of the Token Test, which evaluates verbal comprehension. The proportion of subjects coded as impaired (>2 SD below the normative mean) in each domain was highest for verbal memory (42%) and motor functioning (39%) and lowest for executive functioning (18%), visuospatial functioning (21%), and visual memory (23%). Among the global mental status tests we administered, the rate of impairment was highest for the Verbal Series Attention Test (43%), intermediate for the TICS (36%), and lowest for the Short Blessed Test (26%). Neuropsychological test Z scores for all seven of the specific domains we evaluated were worse in patients with global cognitive impairment, regardless of whether the Verbal Series Attention Test (mean Z-score difference 1.27, all p ≤ 0.003), Short Blessed Test (mean Z-score difference 1.20, all p ≤ 0.001), or TICS (mean Z-score difference 1.45, all p < 0.0005) was used to make this determination (data not shown).
Relationship between cognitive status and outcome.
Three-month measures of cognitive function that showed a significant relationship with at least one concurrent measure of outcome after correcting for age, education, and race/ethnicity are shown in table 3. The TICS was the only measure of cognitive function that showed a significant relationship with all aspects of outcome, including global handicap (mRS), disability (Lawton IADL Scale), QOL (SIP psychosocial and total scores), and emotional health (CES-D and STAI). The Short Blessed Test showed relationships with global handicap (mRS), disability (Barthel Index and Lawton IADL Scale), and the SIP physical dimension but not with emotional status or the SIP psychosocial dimension or total score. Verbal Series Attention Test performance was related only to the SIP physical dimension. Four specific cognitive domains—visual memory, reaction time, motor function, and visuospatial function—were related to at least one measure of disability or QOL. By contrast, verbal memory, language, and executive function had no relationship with any measure of outcome.
Table 3 Relationship between cognitive impairment and outcome measures 3 months after SAH, adjusted for age, education, and race/ethnicity
The three measures of outcome that were most consistently associated with cognitive impairment were basic and instrumental activities-of-daily-living performance (Barthel Index and Lawton IADL Scale) and physical QOL assessed with the SIP: All three were significantly related to at least one measure of global mental status and two or more cognitive domains. The Life Satisfaction Scale had no relationship with cognitive status.
Impact of global cognitive impairment on QOL.
We identified the TICS as the “best” simple test of clinically relevant cognitive dysfunction because it had a slightly stronger association with neuropsychological test performance than the Verbal Series Attention Test and Short Blessed Test and because of its broad association with recovery in all of the aspects of outcome that we evaluated (see table 3). Figure 2 shows the relationship between impairment on the TICS and different categories of QOL assessed with the SIP. Though impaired patients had worse scores in nearly all subscales except work and eating, after controlling for age, education, and race/ethnicity, these differences were significant only for emotional behavior, communication, and alertness behavior (p ≤ 0.004, ANCOVA).
Figure 2. Sickness Impact Profile category scores in patients with (diamonds) or without (squares) cognitive impairment on the Telephone Interview of Cognitive Status 3 months after subarachnoid hemorrhage. Higher scores (scaled 0 to 100) denote worse quality of life. Asterisk denotes a significant difference between impaired and unimpaired patients after adjustment for age, race/ethnicity, and years of education (p < 0.004, analysis of covariance).
Table 4 shows the explanatory value of the TICS and the additional value of domain-specific cognitive impairment for predicting mRS and SIP summary scores after adjustment for demographics (age, education, and race/ethnicity) and emotional health (CES-D scores). In these models, the total explained variance (R2) was low for the mRS (0.341), moderate for the SIP physical dimension (0.448), and high for the SIP psychosocial dimension (0.697) and total score (0.631). The proportion of explained variance related to TICS performance (R2 associated with addition of the TICS divided by total R2) was 27% for the mRS, 18% for the SIP physical dimension, 5% for the SIP psychosocial dimension, and 8% for the SIP total score. Neuropsychological testing of motor function added additional predictive value for the SIP physical dimension (6% of the explained variance), and visuospatial function added additional predictive value for the SIP psychosocial dimension (4% of the explained variance). However, after accounting for demographics, depression, and TICS scores, neuropsychological testing did not add further predictive value for mRS or SIP total scores.
Table 4 Explanatory value of demographics, depression, TICS performance, and domain-specific cognitive dysfunction for predicting global handicap and quality-of-life scores 3 months after SAH
Discussion.
In this study, we analyzed the relative impact of global and domain-specific cognitive impairment on four aspects of outcome after SAH: global handicap, disability, emotional status, and QOL. Certain types of domain-specific impairment were associated with functional disability and, to a lesser extent, reduced QOL but not with global handicap or emotional health. By contrast, impairment on the TICS, a brief test of global mental status that can be administered by phone, was associated with reduced scores in all four aspects of outcome that we evaluated. After accounting for global cognitive impairment with the TICS, more detailed neuropsychological testing did not contribute additional predictive value for concurrent ratings of global handicap (mRS) or overall QOL (SIP total score). Our findings confirm the debilitating nature of SAH-related cognitive dysfunction and indicate that the TICS is a reasonable alternative to more detailed neuropsychological testing for evaluating cognitive status in this patient population.
The vast majority of our patients (84%) had a normal NIHSS score 3 months after SAH. Cognitive dysfunction was much more common, with 18 to 42% of patients scoring in the impaired range in each of the specific neuropsychological domains we tested. As confirmed by others,1,2,4⇓⇓ the highest rates of impairment were related to verbal memory and motor functioning (about 40%) and the lowest in visual memory, visuospatial function, and executive function (about 20%). Impairment of global mental status also occurred with high frequency, ranging from 48% for the Verbal Series Attention Test to 26% for the Short Blessed Test. Not all of the cognitive impairment in our patients can be assumed to be disease related, however, because demographic variables such as age, race/ethnicity, and education have a profound impact on test performance.1 By contrast, demographics have no effect on stroke scales such as the NIHSS that assess focal neurologic deficit. To determine if a risk factor or study intervention modulates the extent of brain damage, it would be preferable to measure only disease-related cognitive impairment after SAH. Clinical trials and outcome studies need to control for demographic bias on cognitive test performance after SAH by referencing scores to normative data or through statistical corrections, particularly if culturally diverse populations are studied; few have done so to date.1
After correcting for demographics, four of the seven specific cognitive domains that we evaluated—visual memory, visuospatial function, reaction time, and motor functioning—were associated with poor recovery in at least one measure of disability or QOL (see table 3). Impairment in all of these domains was related to reduced basic activities-of-daily-living performance (e.g., walking, toileting, dressing, eating), and three were related to reduced IADL performance (e.g., shopping, keeping house, using a telephone). Impaired motor functioning and reaction time were also associated with the physical dimension of the SIP. These findings indicate that when neuropsychological testing is used to assess outcome after SAH, particular attention should be paid to psychomotor speed and visuospatial memory and function. In a previous study of this patient cohort, we found that CT evidence of global cerebral edema was predictive of impairment in these domains.1 Verbal memory, executive function, and language function had no relationship with any measure of outcome, which suggests that impairment in these areas may not be as debilitating. This lack of association may also be explained by selection bias with underrepresentation of more severely-affected patients, our small sample size, and the relatively early timing of follow-up.
In addition to neuropsychological testing, we evaluated three simple tests of global mental status—TICS, Short Blessed Test, and Verbal Series Attention Test—with the goal of identifying a “best” simple test for assessing cognitive status after SAH. Each of these tests can be completed by subjects that are too impaired to complete more extensive testing and can be administered by telephone, if necessary. All seven domains of neuropsychological test performance were significantly reduced in patients classified as impaired by these tests. Impairment on the TICS and Short Blessed Test was associated not only with functional disability and reduced QOL but also with increased global handicap on the mRS (see table 3). Though the TICS had slightly weaker associations with global handicap and disability than the Short Blessed Test, it had unique associations with psychosocial aspects of QOL (SIP psychosocial dimension), depression (CES-D), and anxiety (STAI). These findings indicate that the Short Blessed Test, which is briefer than the TICS and was less often abnormal, identifies only severe impairment and is less sensitive to more subtle cognitive disturbances that affect QOL. The Verbal Series Attention Test, which tests concentration and psychomotor speed, was abnormal in a larger proportion of patients than the TICS but was associated only with the SIP physical dimension, as seen with reaction time and motor function impairment.
Because impairment on the TICS is representative of more detailed cognitive test performance and is associated with poor outcome in nearly all aspects of recovery, it serves as a useful alternative to neuropsychological testing in clinical trials. In fact, detailed testing might be overly sensitive to subtle problems that are not truly debilitating. To directly address this issue, we evaluated the explanatory value of TICS scores and domain-specific cognitive scores for predicting concurrent mRS and SIP summary scores in a series of multiple linear regression models while controlling for demographic variables (age, race/ethnicity, and years of education) and emotional status (CES-D scores). After forcing demographics, depression scores, and TICS performance into these models, neuropsychological testing added no further predictive value for SIP total and mRS scores, both of which are commonly used as endpoints in SAH clinical trials and outcomes research (see table 4). In addition to the TICS, motor function accounted for 25% of the variance explained by cognitive status in the SIP physical dimension and visuospatial function accounted for 46% of this variance in the SIP psychosocial dimension (see table 4).
These results indicate that whereas the TICS alone does not give a complete picture of disabling cognitive problems after SAH, it can identify clinically meaningful impairment nearly as effectively as detailed neuropsychological testing. The TICS has excellent interrater reliability19,34⇓ and has also been shown to be a valid screening instrument for dementia in stroke patients.34 Other advantages of the TICS include its brevity (administration time 5 to 10 minutes), broad applicability (less than half of those who completed the TICS at 3 months underwent neuropsychological testing; see table 2), and lack of a ceiling effect (no patient in our study sample scored a top score of 51; see table 1). Its main disadvantage is susceptibility to demographic bias, but this problem hampers all cognitive tests.1
Though impairment on the TICS in our study was associated with worse scores in nearly all subscales of the SIP except work and eating, these differences were significant only for emotional behavior, communication, and alertness behavior after controlling for demographics (see figure 2). Interestingly, patients’ subjective complaints and the QOL domains that most consistently differ from those of reference populations relate to physical problems,8,35⇓ which is counterintuitive, because SAH causes primarily cognitive deficits. Our findings confirm this observation: Cognitive impairment in general was most consistently associated with functional disability and reduced physical QOL (see table 3). This can be understood by the consistent complaints of SAH patients with regard to mental and physical fatigue, decreased energy, and reduced stamina, which in general make it harder to “do things.”
Four limitations of this study deserve mention. Perhaps the most important is that our follow-up period was only 3 months, and many participants were probably still in the active phase of recovery. Because our goal was to explore relationships between cognitive impairment and outcome, we performed our analysis at an early time point when these problems are most evident.2,4,36⇓⇓ Though cognitive and adjustment problems can persist for many years after SAH,37 it is unclear whether impairment on the TICS is associated with reduced QOL in the long term; this will be the subject of a future report. Second, our results may not be applicable to older or more severely disabled SAH patients who cannot undergo neuropsychological evaluation; our study population was younger, less often white, and had better mRS scores than those who did not undergo cognitive testing (see table 2). Third, the varied ethnic and socioeconomic background of our study population may have magnified the impact of demographic bias on our results; statistical correction of the type we performed may not be necessary in studies of more homogeneous populations. Finally, though the cutoff values we used to classify impairment were selected according to published criteria and generally accepted methodology, it is possible that our results may have been different had different cutoff values or a continuum of graded impairment (i.e., mild, moderate, and severe) been used.
Acknowledgments
Supported by a grant-in-aid (no. 9750432N) from the American Heart Association (S.A.M.).
Acknowledgment
The authors thank Lydia Artiola i Fortuny, PhD, for granting permission to use a Spanish version of the California Verbal Learning Test (Aprendizaje Verbal: Palabras).
- Received April 1, 2002.
- Accepted August 9, 2002.
References
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