Cognitive functioning and quality of life nine years after bacterial meningitis

Journal of Infection (2010) 61, 330e334

www.elsevierhealth.com/journals/jinf

Cognitive functioning and quality of life nine years after bacterial meningitis Ben Schmand a,b,*, Ed de Bruin b, Jan de Gans a, Diederik van de Beek a a b

Department of Neurology H2, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands Department of Psychology, University of Amsterdam, The Netherlands

Accepted 17 July 2010 Available online 24 July 2010

KEYWORDS Bacterial meningitis; Streptococcus pneumoniae; Neisseria meningitidis; Cognitive disorders; Quality of life

Summary Objective: To examine recovery of psychological functioning nine years after meningitis. Methods: In a follow-up study, cognitive functioning and quality of life were evaluated in 28 adults 8e10 years after recovery from bacterial meningitis (n Z 17 due to Streptococcus pneumoniae; n Z 11 due to Neisseria meningitidis), and 13 controls. Test results were compared with those performed one year after the disease. All patients were well recovered at discharge (defined as a score on the Glasgow Outcome Scale of 5), but some pneumococcal patients still showed cognitive slowness and low quality of life one year after bacterial meningitis. Results: At follow-up, psychological functioning and quality of life of patients and controls were similar. On group level, cognitive functioning had normalized. This was also true for patients after pneumococcal meningitis, although some cognitive slowness persisted on an individual level. Conclusion: Psychological functioning continues to improve slowly during the first decade after bacterial meningitis. ª 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Introduction Adult patients who recovered from bacterial meningitis without neurological signs or physical disabilities still are at risk for neuropsychological impairment.1,2 In particular after pneumococcal meningitis, we found that about one out of four patients suffer from mental slowness, which was related to lower quality of life.1 Others reported a somewhat higher proportion of residual cognitive impairments six years after

the disease.2 In a study that also included pneumococcal patients with slight disability, we found indications of recovery in the first decade after the disease. This was reflected in a rather strong correlation between degree of mental speed and time since disease (R, 0.62).1,3 We could not replicate this finding in a follow-up study of the European Dexamethasone Study,4 nor in a re-analysis of pooled data of our meningitis studies.5 However, these studies were all crosssectional. To examine the possibility of further recovery of

* Corresponding author. Department of Neurology H2, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. Tel.: þ31 20 5663590/þ31 20 5256849; Fax: þ31 20 5669217. E-mail address: [email protected] (B. Schmand). 0163-4453/$36 ª 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.07.006

Cognition and QoL 9 yrs after meningitis cognitive functioning in a longitudinal design, we decided to follow-up our original patient cohort eight years later (nine years after the disease).

Methods All patients and controls who participated in the original study1 were contacted in 2008 and invited for this follow-up evaluation. Patients had suffered meningitis between autumn 1998 and spring 2000 and were recruited from a Dutch observational cohort study.6 Inclusion criteria were age between 16 and 65 years at the time of disease, bacterial meningitis due to Neisseria meningitidis or Streptococcus pneumoniae confirmed by cerebrospinal fluid assessment, and discharged with a Glasgow Outcome Scale score of 5. This implies good physical and mental recovery in the sense that the treating physician expected the patients to be able to function independently and to resume activities of daily life, work included, as before contracting the disease. Control subjects were partners, siblings or friends of the patients without somatic or psychiatric disease. Exclusion criteria for patients and controls included serious illnesses (other than meningitis), preexisting psychiatric disorders (psychosis, mood disorder, anxiety disorder, or mental retardation), and insufficient mastery of the Dutch language. The baseline cognitive evaluation was between November 1999 and January 2001. All patients gave written informed consent for participation in this follow-up study. The study was approved by the ethical review board of the AMC. The same series of tests that was administered at baseline was repeated, whenever possible in parallel form. Four cognitive domains were tested: intelligence, memory, attention and executive functioning, and reaction speed. Current intelligence was tested with the Groningen Intelligence Test (abbreviated version), consisting of subtests for verbal and visuo-spatial reasoning and numerical ability.7 Premorbid intelligence was tested by the Dutch Adult Reading Test.6,8 Verbal memory was tested by the Rey’s Auditory Verbal Learning Test and the subtest Prose Recall from the Rivermead Behavioural Memory Test. Figural memory was tested by the subtest Visual Reproduction from the Wechsler Memory Scale Revised. Attention and executive functioning were tested by Trailmaking Test, Stroop Color-Word Test, category fluency, letter fluency, and Wisconsin Card Sorting Test (WCST). Reaction speed was tested by simple and twochoice reaction tasks. See for further description of the tests and references: Lezak et al.,9 or the Appendix of Van de Beek et al.1 Participants rated their general health and quality of life on the RAND-36 questionnaire.10 Raw scores of the neuropsychological tests were converted into age and education corrected T-scores as provided by the test manuals or in the literature. This was done to enable a more direct comparison of the cognitive performance of the groups, and to correct for the effects of normal aging. For the reaction speed tests age-corrected Tscores were derived from the control subjects of Hoogman et al.5 Group differences in demographic and disease characteristics were tested by chi-square, t-test, or anova. To reduce type I error, differences in neuropsychological scores at baseline and differences in change scores over time were tested by manova with group as between

331 subjects factor and Hotelling’s trace as test statistic. Significant manova results were followed by post-hoc t-tests to explore which groups differed from each other. Separate manova’s for each cognitive domain were done; the posthoc tests were Bonferroni corrected. Differences in quality of life ratings between groups at follow-up were tested using nonparametric tests (Kruskal-Wallis H tests, respectively) because of skewed score distributions. Change over time in the patient groups was tested with Wilcoxon signed rank tests. The numbers of patients who were cognitively impaired at baseline and at follow-up were determined using a multivariate normative comparison method.11 This method compares the ensemble of scores of each individual patient to those of the entire control group by calculating the sum of the standardized differences and statistically comparing it to the norm. This method was applied for each cognitive domain separately because of the small size of the control group. One overall comparison using all test variables would have led to an unacceptably low ratio of number of variables to sample size (more variables than control subjects). P-values less than 0.05 were considered significant.

Results Forty-one subjects agreed to participate in this follow-up (54% of the original sample; 11 meningococcal patients [44%], 17 pneumococcal patients [65%], and 13 control subjects [52%]). Reasons of loss to follow-up were deceased or too ill to participate (7 patients, 5 controls), not wanting to be reminded of meningitis (3 patients, 2 controls), no reason for refusal given or no response to repeated attempts to contact (7 patients, 2 controls), and migration abroad or moved to an unknown address (6 patients, 3 controls). There were no significant differences between subjects who participated and those who refused with respect to age, gender, educational level, premorbid intelligence, time since disease, or pathogen. Patients were re-examined nine years after the disease (Table 1). Meningococcal patients were younger than pneumococcal patients, with the control group in between. There were no significant group differences in gender distribution, years of education, or premorbid intelligence. The intelligence tests showed significant overall group differences at baseline (P Z 0.001; Table 2). Post-hoc analysis showed that this was due to differences in numerical ability between the patient groups. There was also a significant group difference in change over time (P < 0.001), which was due to the patient groups diverging in different directions on the verbal reasoning task. In the memory domain there were no overall group differences at baseline (P Z 0.54), nor significant group differences in change over time (P Z 0.79). In the domain of attention and executive functioning there were no significant group differences (P Z 0.71), nor significant group differences in change over time (P Z 0.63). At baseline the groups were significantly different with respect to reaction speed (P Z 0.03). Pneumococcal patients were slower than controls on two of the three speed measures. At follow-up there were no significant group differences any more in reaction speed (P Z 0.26), neither were the change scores significantly different (P Z 0.46).

332 Table 1

B. Schmand et al. Patient characteristics.

Age at follow-up, years Female % Education, years Premorbid intelligence IQ Years since meningitis

Pneumococcal patients (n Z 17)

Meningococcal patients (n Z 11)

Control subjects (n Z 13)

P

56.6 53 13.1 97 9.0

41.6 46 14.3 104 9.3

51.4 (15.4) 69 13.2 (1.5) 98 (18) e

0.04 0.48 0.32 0.62 0.11

(12.2) (2.2) (17) (0.6)

(16.7) (2.2) (11) (0.4)

Mean (SD) or percent.

All groups declined over time on the simple reaction speed tests. The patients improved on the binary choice reaction tests, although not significantly, whereas the control group did not change. Compared to controls, a trend towards mental slowness was also visible in the baseline scores of pneumococcal patients on all other speeded tests of attention and executive function. Meningococcal patients showed the same trend, but to a lesser extent. Multivariate normative comparisons of intelligence test scores showed that three meningococcal and three pneumococcal patients were significantly impaired at baseline compared to the control group (P < 0.05 one-tailed). One of the meningococcal patients remained impaired at follow-up; the other five patients returned to normal. One meningococcal patient was memory impaired at baseline and had recovered at follow-up; one pneumococcal patient, who had a normal memory at baseline, was impaired

at follow-up. With respect to the executive domain, none of the patients was significantly different from the control group at baseline, but two patients declined at follow-up (one meningococcal and one pneumococcal). At baseline seven patients (all pneumococcal; 41% of this group) were impaired with respect to reaction speed, of whom four had recovered at follow-up. Two pneumococcal patients, who were not impaired at baseline, had declined at follow-up (they were relatively old: 69 and 73 years). Fig. 1 shows simple reaction times with the dominant hand as a function of age at follow-up in the three groups. There was a subgroup of seven pneumococcal patients who were still slow (visual reaction time of the dominant hand >390 ms). The most conspicuous difference between these patients and the remaining 10 pneumococcal patients was a large difference in premorbid intelligence (DART IQ of 82  13 versus 108  11; P Z 0.001). Also the level of education was

Table 2 Neuropsychological test scores at baseline, and change scores at follow-up. Age and education corrected T-scores. Negative change scores indicate decreased performance. Pneumococcal patients (n Z 17)

Meningococcal patients (n Z 11)

Control subjects (n Z 13)

Baseline

Change

Baseline

Change

Baseline

Change

(11.7) (9.5) (10.0)a

6.9(7.1)b 1.5(7.8) 2.3(7.2)

44.2 (10.2) 51.4 (10.1) 58.1 (8.1)a

6.5 (6.8)b 6.4(5.7) 7.8(4.6)

44.2 (4.9) 47.9 (7.2) 51.0 (9.5)

2.5 (10.7) 3.6(8.8) 6.0(7.1)

(6.6) (8.4) (10.6) (13.5) (10.0) (10.0)

0.6(6.7) 3.1(7.0) 3.9(7.4) 5.5(11.3) 5.8 (9.1) 4.2 (7.2)

42.1 43.3 53.0 51.8 57.4 56.6

(10.7) (14.1) (15.2) (18.3) (10.3) (9.3)

4.1 (7.0) 2.6 (10.5) 5.6(13.2) 5.9(18.4) 1.6(11.5) 0.6(12.0)

43.4 46.9 51.3 50.4 59.9 55.1

(11.6) (12.2) (10.3) (8.9) (8.8) (12.2)

0.4 (8.2) 1.5(10.1) 6.7(8.7) 5.9(8.4) 0.2 (10.1) 0.9 (10.5)

(10.5) (9.8) (9.3) (8.0) (8.2)

4.1 (7.7) 3.8 (14.5) 0.9 (10.3) 0.8 (6.0) 0.3(7.9)

52.3 48.7 46.2 47.8 43.1

(10.8) (8.8) (15.7) (8.0) (7.4)

0.7(5.5) 3.4 (6.7) 3.6(12.6) 2.9(6.3) 3.4 (6.6)

53.9 51.7 45.6 50.1 48.5

(10.4) (11.6) (11.8) (9.5) (14.2)

0.1 (6.9) 1.1(7.8) 0.8 (8.7) 2.6(7.4) 0.3(7.2)

(11.5)c (10.0) (16.7)c

7.8(14.8) 3.0(11.1) 7.0 (14.4)

51.5 (5.6) 53.9 (6.5) 43.5 (11.8)

4.2(11.7) 1.6(6.3) 4.8 (9.8)

55.7 (6.3)c 56.2 (5.9) 49.1 (11.1)c

Intelligence Verbal reasoning 50.1 Visuo-spatial reasoning 43.8 Numerical ability 46.2 Memory Rey AVLT total learning 49.3 Rey AVLT delayed recall 49.3 RBMT immediate recall 49.9 RBMT delayed recall 49.6 WMS-R VR immediate 52.1 WMS-R VR delayed 52.1 Attention/executive function Trailmaking B 47.8 Stroop color-words 45.0 WCST total # errors 45.8 Category Fluency 42.7 Letter Fluency 44.0 Visual reaction speed Dominant hand 46.3 Non-dominant hand 50.1 Binary choice 37.6

Mean (SD) of age and education corrected T-scores; intelligence and reaction speed: age-corrected T-scores. T-scores are normally distributed with mean of 50 and SD of 10 points. Superscripts (aec) indicate significant differences between groups (p < 0.01 two-tailed; Bonferroni corrected t-test).

9.3(10.6) 8.5(9.0) 0.7 (14.7)

Cognition and QoL 9 yrs after meningitis

333

Figure 1 Reaction time of the dominant hand (milliseconds) after visual stimuli in the three groups as a function of age.

different (11.7  1.7 versus 14.4  1.9 years; P Z 0.02). Both subgroups did not significantly differ with respect to age, gender, and years since meningitis. Quality of life ratings (Table 3) improved slightly from baseline to follow-up, and none of the patients’ ratings was significantly different from controls at follow-up (P > 0.20 Kruskal-Wallis test). Both patient groups improved with respect to pain ratings, and pneumococcal patients improved with respect to role impairments due to emotional problems (P < 0.05 Wilcoxon signed ranks test).

Discussion Nine years after bacterial meningitis cognitive function and quality of life of our patients had largely returned to normal. The residual mental slowness and mild memory impairments one year after the disease, that we reported earlier,1,5 were no longer detectable at group level. A minority of pneumococcal patients remained slow; they were characterized by a relatively low premorbid intelligence. Quality of life ratings of the patients were no longer

Table 3

different from those of the controls. These findings suggest that bacterial meningitis patients continue to improve after the first few years since they contracted the disease. This corroborates the suggestion that we made earlier on the basis of cross-sectional data.3 In our earlier baseline study we found cognitive slowing in 27% of the pneumococcal patients and in one of the meningococcal patients (16% in the total sample).1 A trend in this direction was still visible at follow-up nine years after the disease. Schmidt et al.2 reported more cognitive impairments (37%) in their patients after a mean of six years since disease (range 1e12 years). Both studies are very comparable with respect to patient characteristics (not considering viral meningitis patients of the Schmidt study), and with respect to the methods of cognitive assessment used. Schmidt et al. note that the divergence in percentages is probably due to the criteria for impairment. Had they applied our criteria, then the rate of impairment in their study would have been 10% (versus 16% in ours). Given our current finding of further recovery after the first few years, the difference in percentages in both studies may be explained as a consequence of time since disease. Some comments are in order on several of our findings. First, the loss to follow-up was considerable. Only just over half of the original subjects participated. However, it is unlikely that the loss to follow-up was selective in the sense that only well functioning patients participated. The largest loss was unrelated to the meningitis (migration, unrelated illness, death). Five subjects refused because they did not want to be reminded of the disease (14% of the loss to follow-up). We take this as a sign that they did not experience any long term sequelae. Although there were no clear indications for selectivity of the loss, it nonetheless caused a decrease of statistical power. Consequently, we may have overlooked subtle cognitive impairment at follow-up. However, the normalization of the quality of life ratings suggests that we did not miss important deficits. Otherwise the patients probably would have had more subjective complaints. Second, the multivariate normative comparisons within each cognitive domain showed that some individuals had improved while a few others had declined over the years. With the

Quality of life. RAND-36 subscale scores at baseline and follow-up.

Subscale

Physical functioning Role impairment due to physical problems Role impairment due to emotional problems Vitality Mental health Social functioning Pain Experienced general health

Pneumococcal patients (n Z 17)

Meningococcal patients (n Z 11)

Controls (n Z 12)

Baseline

Follow-up

Baseline

Follow-up

Follow-up

80.0 (16.9) 55.9 (42.0)

84.8 (13.9) 73.5 (40.0)

83.1 (16.5) 78.1 (41.1)

89.5 (20.3) 90.9 (30.2)

85.8 (16.1) 85.4 (31.0)

74.5 (38.2)

100 (0.0) *

87.5 (35.4)

84.8 (34.5)

94.4 (19.2)

61.3 75.5 90.6 51.4 71.9

68.2 74.5 87.5 87.0 77.3

66.3 79.3 85.4 76.7 74.2

62.1 80.0 77.9 51.2 71.5

(19.5) (13.6) (27.4) (10.1) (10.0)

70.0 82.6 87.5 81.4 77.6

(19.7) (8.9) (16.5) (18.4) * (24.2)

(13.8) (11.1) (17.4) (9.7) (12.8)

(22.1) (17.1) (17.7) (24.1) * (17.5)

Mean (SD). * Z significant change compared to baseline (p < 0.05 two-tailed; Wilcoxon signed rank test).

(14.0) (8.0) (15.8) (20.8) (9.3)

334 exception of the reaction speed domain, these changes concerned small numbers of patients, and we consider this random fluctuation unrelated to meningitis. Third, the decline in the verbal reasoning score of pneumococcal patients and the increase of this score in meningococcal patient probably also reflect random variation due to small sample size, and consequently these changes are without meaning. We conclude that adult patients with bacterial meningitis, who recover well according to neurological standards, may still have some cognitive impairment during the first years after the disease. This is especially true for pneumococcal meningitis. However, these impairments continue to improve slowly during the first decade after the disease.

Conflicts of interest None declared.

Funding This study was supported in part by a grant from the Meningitis Research Foundation, UK (DvdB grant No 03/03). DvdB is also supported by personal grants from the Netherlands Organisation for Health Research and Development (ZonMw) (NWO-Veni grant no. 916.76.023) and the AcademicMedical Center (AMC Fellowship).

Acknowledgement We thank Martine Hoogman, Heleen Vaessen, Claudia van der Lugt, and Danielle Keizer for their help in data collection, and Cox Schouten for her help in data management.

B. Schmand et al.

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