J Neurol DOI 10.1007/s00415-016-8345-3
REVIEW
Cognitive dysfunction in adult patients with neuromyelitis optica: a systematic review and meta-analysis Hao Meng1,2 • Jun Xu2,3 • Chenling Pan4 • Jiaxing Cheng2 • Yue Hu2 Yin Hong5 • Yuehai Shen4 • Hua Dai1
•
Received: 27 September 2016 / Revised: 8 November 2016 / Accepted: 11 November 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Abstract The objective of this study was to investigate cognitive dysfunction in 24–60-year-old neuromyelitis optica (NMO) patients, demographically matched healthy subjects, and MS patients. We conducted a comprehensive literature review of the PubMed, Medline, EMBASE, CNKI, Wan Fang Date, Web of Science, and Cochrane Library databases from inception to May 2016 for case– control studies that reported cognitive test scores in NMO patients, healthy subjects, and MS patients. Outcome measures were cognitive function evaluations, including performance on attention, language, memory, information processing speed, and executive function tests. The metaanalysis included eight studies. NMO patients performed significantly worse on attention (P \ 0.00001), language (P = 0.00008), memory (P = 0.00004), information processing speed (P \ 0.00001), and executive function tests (P = 0.00009) than healthy subjects. There were no significant differences in performance between NMO patients and MS patients on these tests. This meta& Jun Xu
[email protected] 1
Non-Coding RNA Center, Medical College of Yangzhou University, Yangzhou 225001, Jiangsu, China
2
Department of Neurology, Northern Jiangsu People’s Hospital, Yangzhou 225001, Jiangsu, China
3
Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, School of Medicine, Yangzhou University, Yangzhou 225001, Jiangsu, China
4
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan, China
5
Health Management Center, Northern Jiangsu Poeple’s Hospital, Yangzhou 225001, Jiangsu, China
analysis indicates that NMO patients aged 24–60 years have significantly worse cognitive performance than demographically matched healthy subjects. However, this was comparable to the performance of demographically matched MS patients. There is a need for further rigorous randomized controlled trials with focus on elucidating the underlying mechanism of cognitive dysfunction in NMO patients. Keywords Cognitive dysfunction Neuromyelitis optica Multiple sclerosis Meta-analysis
Introduction Neuromyelitis optica (NMO), or Devic’s disease, is an unusual autoimmune demyelinating disease of the central nervous system (CNS). Typical manifestations of the disease include recurrent attacks that can result in severe optic neuritis (ON), transverse myelitis (TM) causing irreversible damage, and permanent disability [1–4]. In fact, untreated, this illness may lead to blindness, tetraplegia, and death. NMO is often misdiagnosed as multiple sclerosis (MS), and has been perceived as a variant of MS. The symptoms of MS and NMO are similar, characterized by abrupt attacks interspersed by periods without attacks and impaired vision and walking, and both conditions involve lesions of the CNS. However, NMO is presently considered to have distinct clinical, pathological, and immunological features [5, 6]. In particular, NMO attacks are more severe than MS attacks. Furthermore, lesions in NMO are usually found on the spinal cord and optic nerves, while lesions in MS affect other areas of the brain.
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Importantly, while the etiology of MS remains unclear, a biomarker and possible pathogen [7–9] of NMO, in the form of the aquaporin 4 (AQP4) antibody (NMO-IgG), has recently been identified. NMO-IgG is found in the serum of [70% of NMO patients but B5% of those with [10] MS. AQP4 is a bidirectional water channel protein in the blood– brain barrier. In NMO, NMO-Ig may alter AQP4 and change the permeability and function of the blood–brain barrier. The optic nerve and spinal cord may have higher levels of AQP4 expression than other areas of the CNS, explaining the tendency of NMO for those [11] regions. The discovery of NMO-Ig led to an extension of the diagnostic criteria for NMO and the formulation of the broader concept of NMO spectrum disorders (NMOSD) [12], which includes anti-AQP4-positive and -negative patients. More recently, a subset of NMOSD anti-AQP4negative patients have been identified. These patients have myelin oligodendrocyte glycoprotein (MOG)-IgG, specific clinical characteristics, and less cognitive dysfunction than anti-AQP4-positive patients [13]. Approximately, two-thirds of MS patients have significant cognitive impairment, according to the present recommendations for the evaluation of cognitive impairment in MS [14]. In MS, cognitive dysfunction may result from cortical subpial demyelination concomitant with meningeal infiltration in the gray matter [15], or from secondary pathological changes in the gray matter resulting from progressive damage to the cerebral white matter [16]. In NMO, the neural correlates of cognitive impairment may be attributed to focal reductions in white matter volume and integrity. Some studies have identified reductions in gray matter volume (GMV) and cortical thickness in patients with NMO [17]. However, it remains unknown whether this pathophysiology is associated with cognitive impairment [18, 19]. Reviews on cognitive dysfunction in NMO patients are scarce. The objective of this systematic review and metaanalysis was to investigate cognitive dysfunction in 24–60year-old NMO patients, demographically matched healthy subjects and MS patients. An understanding of the effect of NMO on cognitive dysfunction would provide insight into the pathogenesis of NMO and its manifestations, inform management approaches for NMO patients, and provide a basis for further research.
Methods This study was reported according to the recommendations of the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Group, the PRISMA 2009 guidelines for systematic review and meta-analysis [20, 21] and the Cochrane Collaboration [22].
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Literature search and data sources Two review authors (Hao Meng, Chenling Pan) independently searched the PubMed, Medline, EMBASE, CNKI, Wan Fang Date, Web of Science, and Cochrane Library databases from inception to May 2016 using the keywords: ‘‘cognition’’, ‘‘cognitive ability’’, ‘‘cognitive dysfunction’’, ‘‘cognitive function’’, ‘‘cognitive deficits’’, ‘‘neuromyelitis optica’’, ‘‘NMO’’, ‘‘Devic’s disease’’, ‘‘aging’’, and ‘‘mildaged’’. Further information was obtained from the manual search of the reference lists of relevant articles and reviews. There was no language restriction. Inclusion and exclusion criteria Inclusion criteria: case–control studies that (a) reported the cognitive test scores (or change in test scores) of NMO patients and healthy subjects and/or MS patients aged 24–60 years with C2 time points, who were matched for age, sex and level of education; (b) studies that defined NMO as patients who fulfilled the 1999 [3] or 2007 [4] Wingerchuk diagnostic criteria. Exclusion criteria: (a) studies that did not report neuropsychological tests or diagnostic criteria as outcome measures; (b) studies in which cognitive decline or dementia was not the primary outcome; (c) animal studies; (d) abstracts or unpublished studies. Disagreements on the study selection were resolved by discussion with a third review author (Jun Xu) until a consensus was reached. Data extraction and outcome measures Two review authors (Hao Meng, Chenling Pan) independently extracted information from eligible studies. Relevant data included (a) name of the first author, (b) country, (c) number of NMO patients in the analysis, (d) number of healthy subjects and/or subjects with MS, (e) mean age of patients, and (f) cognitive function evaluations (based on the current recommendations for the evaluation of cognitive impairment in MS [23, 24], Table 1). Disagreements on the data extraction were resolved by discussion with a third review author (Jun Xu). Risk of bias in included studies Two review authors (Hao Meng, Chenling Pan) independently assessed the quality of each study using an assessment tool based on the Newcastle–Ottawa Scale (NOS), which was designed specifically for this study [25]. The scale assessed quality of sample selection, comparability of cohorts, assessment of outcomes, adequacy of follow-up, and drop-out rate [26]. Studies with scores between 0 and 3, 4 and 6, and 7 and 9 were considered low, moderate and
J Neurol Table 1 Cognitive function tests Aspects of cognitive function
Test
Specific functions assessed Evaluates auditory processing speed and working memory
Auditory processing speed and working memory
PASAT 3.0s [33]
Visual spatial processing speed and working memory
SDMT [36]
Assesses visual processing speed and working memory
Verbal learning
CVLT-II [35]
Tests verbal learning and memory function
Verbal fluency
COWAT [34]
Evaluates expressive language
Executive function
WCST [34]
Tests higher executive function
PASAT paced auditory serial addition test, SDMT symbol digit modalities test, CVLT-II California verbal learning test—second edition, COWAT controlled oral word association test, WCST Wisconsin card sorting test
high quality, respectively. Disagreements on risk of bias assessment were resolved by discussion with a third review author (Jun Xu) until consensus was reached. Publication bias was explored using the Egger weighted linear regression test. A P value \0.05 was considered a statistically significant publication bias. Statistical analysis Statistical analyses were performed using Review Manager 5.3 (Cochrane Collaboration, Oxford; http://www.cc-ims. net/RevMan/current.htm). Results were pooled using the inverse variance method. All trials reported outcomes as continuous data; therefore, standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated. Heterogeneity between studies was assessed using the I2 statistic, where I2 \ 25% indicated low heterogeneity, an I2 of 25–50% indicated moderate heterogeneity, and I2 [ 50% indicated high heterogeneity. When heterogeneity could not be explained, a random effects model was employed [27, 28].
Results Study identification The search identified a total of 1,560 articles. After screening for eligibility, the full-text version of 174 articles was evaluated. Among these articles, 166 studies that did not report the measurement of cognitive function, included subjects that were not within the specified age range, or had no control group were excluded. Based on the inclusion criteria, eight studies were included for the review (Fig. 1). Study characteristics The characteristics of the included studies are presented in Table 2. Eight studies were eligible for inclusion, involving 273 NMO patients, 233 healthy subjects, and 129 MS patients. Four studies [29–32] included MS patients.
Outcome measures Evaluation of cognitive performance in NMO patients versus healthy subjects The cognitive performance of NMO patients and healthy subjects was evaluated according to current recommendations for the evaluation of cognitive impairment in MS. Auditory processing speed and working memory (Paced Auditory Serial Addition Test [PASAT] 3.0 s) [33], verbal fluency [Controlled Oral Word Association Test (COWAT)] [34], verbal learning [California verbal learning test—Second Edition (CVLT-II)] [35], visual spatial processing speed and working memory [Symbol Digit Modalities Test (SDMT)] [36], and executive function [Wisconsin Card Sorting Test (WCST)] [34]. Six studies, including 227 NMO patients and 185 healthy subjects, evaluated auditory processing speed and working memory using the PASAT 3.0 s. The meta-analysis demonstrated that NMO patients performed significantly worse on the PASAT 3.0 s compared with healthy subjects (SMD: -0.60, 95% CI -0.81 to -0.39; P \ 0.00001; Fig. 2a). Furthermore, there was evidence of moderate heterogeneity between studies (I2 = 7%, P = 0.37). Five studies, which included 203 NMO patients and 188 healthy subjects, evaluated verbal fluency using the COWAT. The meta-analysis demonstrated that NMO patients performed significantly worse on the COWAT than healthy subjects (SMD: -0.54, 95% CI -0.79 to -0.28, P \ 0.00001; Fig. 2b). There was evidence of moderate heterogeneity between studies (I2 = 30%, P = 0.22). Six studies, which included 213 NMO patients and 171 healthy subjects, evaluated verbal learning using the CVLT-II. The meta-analysis demonstrated that NMO patients performed significantly worse on the CVLT-II compared with healthy subjects (SMD: -0.45, 95% CI -0.68 to -0.22, P \ 0.00001; Fig. 2c). There was evidence of moderate heterogeneity between studies (I2 = 15%, P = 0.32).
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Fig. 1 Flowchart of literature search
Seven studies, which included 249 NMO patients and 207 healthy subjects, evaluated visual spatial processing speed and working memory using the SDMT. The metaanalysis demonstrated that NMO patients performed significantly worse on the SDMT compared with healthy subjects (SMD: -0.73, 95% CI -0.93 to -0.53, P \ 0.00001; Fig. 2d). There was evidence of low heterogeneity between studies (I2 = 5%, P = 0.39). Five studies, which included 123 NMO patients and 118 healthy subjects, evaluated executive function using the WCST. The meta-analysis demonstrated that NMO patients performed significantly worse on the WCST compared with healthy subjects (SMD: -0.44, 95% CI -0.39 to -0.18, P = 0.00009; Fig. 2e). There was no evidence of heterogeneity between studies (I2 = 0%, P = 0.65). Evaluation of cognitive performance in NMO vs. MS patients Four studies, which included 153 NMO patients and 129 MS patients, evaluated auditory processing speed and working memory using the PASAT 3.0s. The meta-analysis
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demonstrated no significant difference in performance on the PASAT 3.0 s in NMO patients compared to MS patients (SMD: -0.04, 95% CI -0.27 to 0.20, P = 0.75; Fig. 3a). There was no evidence of heterogeneity between studies (I2 = 0%, P = 0.62). Two studies, which included 96 NMO patients and 72 MS patients, evaluated verbal fluency using the COWAT. The meta-analysis demonstrated no significant difference in performance on the COWAT in NMO patients compared to MS patients (SMD: -0.07, 95% CI -0.38 to 0.23, P = 0.64; Fig. 3b). There was no evidence of heterogeneity between studies (I2 = 0%, P = 0.91). Two studies, which included 112 NMO patients and 88 MS patients, evaluated verbal learning using the CVLT-II. The meta-analysis demonstrated no significant difference in performance on the CVLT-II in NMO patients compared to MS patients (SMD: 0.13, 95% CI -0.32 to 0.59, P = 0.56; Fig. 3c). There was evidence of high heterogeneity between studies (I2 = 56%, P = 0.13). Three studies, which included 126 NMO patients and 102 MS patients, evaluated visual spatial processing speed and working memory using the SDMT. The meta-analysis demonstrated no significant difference in performance on
NA
NA
NA
NA
43.7 ± 13.1
37.1 ± 12.4
35.1 ± 11.3
49.8 ± 8.9
NA
NA
38.8 ± 9.6
38.0 ± 7.0
NA
NA
38.2 ± 9.2
43.5 ± 12.3
Mean age, years
the SDMT in NMO patients compared to patients with MS (SMD: 0.07, 95% CI -0.19 to 0.34, P = 0.58; Fig. 3d). There was no evidence of heterogeneity between studies (I2 = 0%, P = 0.66). One study, which included 82 NMO patients and 58 MS patients, evaluated executive function using the WCST. There was no significant difference in performance on the WCST in NMO patients compared to MS patients (SMD -0.06, 95% CI -0.39 to 0.28, P = 0.74; Fig. 3e).
45 NA
Seven studies [29–32, 34, 37, 38] received a score of C 7 on the risk of bias assessment, and were considered high quality. The remaining studies [39] received a score of 6, and were considered moderate quality. Funnel plots for attention, memory, information processing speed, language and executive function are presented in Figs. 4 and 5. However, these results were difficult to interpret due the small sample size.
Discussion NA not applicable, NMO neuromyelitis optica, MS multiple sclerosis, NOS Newcastle–Ottawa Scale
China Wang et al. [34]
8
44
47.4 ± 13.4
6.6 ± 6.7
NA
NA
26 51.9 ± 54.7 China Yao Liu et al. [32]
8
23
35.4 ± 10.7
42.5 ± 29.4
27
33.15 ± 9.40
30
14
NA
6.6 ± 6.5
NA
14 8.6 ± 4.4
6.2 ± 6.8 44.8 ± 12.1
36.8 ± 12.4 14
36 6 China
Argentina
Zhang et al. [39]
Vanotti et al. [30]
7
NA
37.93 ± 10.57
21
45
NA
6.0 ± 4.0
NA NA
34.0 ± 8.0 8.0 ± 4.0
3.2 ± 1.5 39.5 ± 10.8
36.0 ± 7.0 82
8
8
China
Korea
He et al. [38]
Su HK, et al. 2016 [31]
21
58
22
30
NA
9.7 ± 4.9
NA
43.4 ± 12.1
NA 3.4 ± 1.5
7.3 ± 5.4 43.5 ± 12.3
39.4 ± 10.6 22 8
7
China
NA
He et al. [37]
Blanc et al. [29]
30
NOS Score
Mean age, years
30
Sample size, n Sample size, n Sample size, n
Disease duration, years
Patients with MS Patients with NMO
Mean age, years
Disease duration, years
Risk of bias in included studies
Country Reference
Table 2 Characteristics of the eight prospective studies included in the meta-analysis
Healthy Subjects
Disease duration, years
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This meta-analysis considered studies that used neuropsychological tests to evaluate overall cognitive capacities in NMO patients and demographically matched healthy subjects and/or MS patients. To the authors’ knowledge, this is the first meta-analysis that evaluated the association between NMO and cognitive capacity in terms of memory, learning, information processing speed, and executive function. The findings suggest that NMO patients aged 24–60 years had significantly worse cognitive performance than demographically matched healthy subjects, but this performance was comparable to demographically matched MS patients. Results of the meta-analysis demonstrated that NMO patients performed significantly worse than healthy subjects across all cognitive capacities. The effect sizes were largest for CVLT-II, PASAT 3.0s, and SDMT. When comparing NMO with MS patients, the meta-analysis did not reveal a significant difference in cognitive capability. These results were surprising based on the different pathophysiology of NMO and MS. Abnormalities in MS affect the brain, while NMO damage is traditionally perceived to be limited to the optic nerves and spinal cord. MS patients had a greater degree of brain atrophy, which was evidenced by cortical thinning, when compared with NMO patients; this may be differentiated from NMO patients through the cortical thinning of the insula and parahippocampus [32]. However, similarities in cognitive performance in NMO and MS patients may be explained by recent findings in NMO spectrum disorder. This indicates
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Fig. 2 Cognitive performance in NMO patients vs. healthy subjects
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Fig. 3 Cognitive performance in NMO patients vs. MS patients
that brain involvement [40] is more common in NMO than previously thought. Although this observation was based on a broader population of patients compared with those included in the current meta-analysis, further investigations are needed. It is difficult to accurately compare cognitive dysfunction between NMO and MS patients. Studies have used different neurophysiological tests to assess cognitive performance. There may be variations in intervals, from an acute attack to cognitive performance evaluation or in
therapies, comorbidities, or stage of the disease. Interestingly, the size of many brain lesions in NMO spectrum disorder may decrease over time. The influence of such pathological changes on cognitive performance in patients with definitive NMO warrants consideration. This meta-analysis has three strengths. First, the NOS was used to asses risk of bias, which revealed that all included studies were of moderate to high quality. Second, the included studies only involved patients with definitive NMO, and patients with NMO spectrum disorder were not
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J Neurol Fig. 4 Funnel plot of cognitive performance in NMO patients vs. healthy subjects
Fig. 5 Funnel plot of cognitive performance in NMO patients vs. MS patients
considered in the analyses. Third, multiple areas of cognition were used as outcomes from this study in an attempt to assess overall cognitive performance, which is the result of the different and independent aspects of functioning. However, this meta-analysis was associated with some limitations. First, the sample size was small and there was considerable heterogeneity between studies. This negated the opportunity to perform meaningful subgroup analyses,
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which may have provided insight into variables associated with cognitive dysfunction in NMO and MS patients. Furthermore, this would have allowed the identification of important differences and demonstration of the efficacy of any of the interventions. Second, the samples were drawn mainly from Asian populations across a variety of settings (hospitals and community). Therefore, the generalizability of these findings remains questionable.
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In conclusion, this meta-analysis indicates that 24–60year-old NMO patients have significantly worse cognitive performance compared with demographically matched healthy subjects, but this performance was comparable to demographically matched MS patients. Further rigorous randomized controlled trials with focus on elucidating the underlying mechanism of cognitive dysfunction in NMO patients should be conducted.
16.
17.
18. 19.
Acknowledgements This study was supported by the National Natural Science Foundation of China (No. 81471215 and No. 81271211 to Jun Xu). 20. Compliance with ethical standards Conflicts of interest All authors have declared that there are no conflicts of interest in relation to the subject of this article. 21.
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