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Address correspondence to Yangkun Chen Department of Neurology, Dongguan People's Hospital (Affiliated Dongguan Hospital, South Medical University), Dongguan, Guangdong Province, China.
Department of Neurology, Dongguan People's Hospital (Affiliated Dongguan Hospital, South Medical University), Dongguan, Guangdong Province, ChinaFaculty of Neurology, Guangdong Medical University, Dongguan, Guangdong Province, China
The aim of this prospective cohort study was to assess the incidence and risk factors of delirium following acute ischemic stroke, as well as its effects on functional outcome.
Methods
Two hundred and sixty-one patients with acute ischemic stroke were screened for delirium during the first week after admission. Delirium was diagnosed according to the Confusion Assessment Method. If delirium was present, delirium rating scale-revised-98 was used to assess its severity. Neurologic deficits were assessed with the National Institutes of Health Stroke Scale (NIHSS). Brain magnetic resonance imaging assessment quantified the infarction, white matter lesions, and medial temporal lobe atrophy. Functional outcome assessment included the modified Rankin Scale and Lawton Instrumental Activities of Daily Living scale at 3 and 6 months after the index stroke.
Results
Thirty-eight (14.6%) patients with acute ischemic stroke developed delirium during the first week of admission. Patients with poststroke delirium (PSD) were older, had higher NIHSS scores on admission, and were more likely to have a previous stroke, an infection, and a left cortical infarct. Furthermore, left cortical infarction, older age, severer neurological deficit and having a previous stroke increased the risk of PSD. PSD was associated with a worse functional outcome.
Conclusion
The incidence of delirium was 14.8% in the first week after admission with acute ischemic stroke. Age, having a previous stroke, stroke severity, and left-cortical infarction were independently predictors of PSD. PSD may result in a significantly worse functional outcome.
Delirium is the result of the interplay between patient characteristics (eg, frailty, low cognitive reserve, and cerebral damage) and exogenous factors (eg, medication, infections, and stress).
Poststroke delirium (PSD) is a common complication in the acute phase of stroke. There are only a small number of studies that have investigated the incidence of PSD, which varies from 11.8% to 66%.
However, these studies recruited both hemorrhagic and ischemic stroke patients and had conflicting findings. It appears critical to study a homogeneous group of subjects.
Thus, we conducted this study to investigate the incidence, risk factors, and effects on functional outcome of PSD in Chinese patients with ischemic stroke.
Materials and Methods
Participants and Setting
The study was conducted at Division I, Department of Neurology, Dongguan People's Hospital between June 1st, 2016 and June 30th, 2017. The inclusion criteria for the study were as follows: (1) aged over 18 years; (2) first or recurrent acute ischemic stroke occurring within 7 days before admission; and (3) had brain magnetic resonance imaging (MRI) examination. The exclusion criteria were as follows: (1) transient ischemic attack, cerebral hemorrhage, subdural hematoma, or subarachnoid hemorrhage; (2) central nervous system diseases other than stroke (eg, dementia, Parkinson's disease, or multiple sclerosis); and (3) severe mental disorders before the index stroke (eg, schizophrenia). The study protocol was approved by the Ethics Committee of Dongguan People's Hospital. The consent of all subjects was obtained in accordance with the Declaration of Helsinki.
Collection of Demographic and Clinical Data
Socio-demographic and clinical variables including age, sex, history of stroke, vascular risk factors, and treatment were recorded on a standard data collection form. The subtype of ischemic stroke was judged by neurologists during hospitalization based on the Trial of Org 10172 in Acute Stroke Treatment subtype system.
Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial TOAST. Trial of Org 10172 in acute stroke treatment.
PSD was assessed by a trained neurologist Jianfeng Qu (JFQ). Each patient was screened for delirium for the first time between day 1 and 3 after admission, and for a second time between day 5 and 7. If the patient was discharged before day 5, only the first screening was performed. We aimed to screen the patients for PSD twice, as PSD can occur at any time during the hospitalization period.
DRS-R-98 includes a 13-item severity scale and a 3-item diagnostic scale. The severity scale quantifies multiple parameters such as language, thought process, two motoric presentations, and the components of cognition. Items 1 to 14 were scored on a 4-point scale and items 15 and 16 were scored on a 3-point scale, resulting in a range for the total score from 0 to 46. The Chinese version of the DRS-R-98 has been validated.
For each PSD patient, follow-up of delirium was performed until it was cured, which was defined as having a negative CAM. The PSD patients were treated by their neurologists according to national clinical practice guidelines.
All participants were followed up for 6 months via telephone. We assessed the clinical outcomes at 3 and 6 months according to the modified Rankin Scale (mRS) and functional status. Functional status was evaluated by the Lawton Instrumental Activities of Daily Living (IADL) scale.
The IADL examines a person's present functional level and identifies improvement or deterioration over time. The eight domains of function measured by the IADL are using a telephone, shopping, food preparation, housekeeping, laundry, mode of transportation, responsibility for own medications, and handling finances. The total IADL score is calculated by summing the points obtained for each item. The maximum IADL score is 32. A higher IADL score reflects poorer IADL performance. We defined a poor outcome as an mRS score greater than or equal to 3 or an IADL total score greater than 75th percentile of the IADL total score.
MRI Assessment
Brain MRI scans, including T1-weighted imaging, T2-weighted imaging and diffusion-weighted imaging (DWI) were performed on each participant with a 3.0-T system (Sonata, Siemens Medical, Erlangen, Germany) within 7 days of admission. DWI spin-echo echo-planar imaging (EPI; time of repeatation/time of echo/excitation = 2162/76/1, matrix = 128 × 128, field of view [FOV] = 230 mm, slice thickness/gap = 6 mm/1 mm, EPI factor = 47, acquisition time = 25.9 seconds) with three orthogonally applied gradients was used with a b value of 0 and 1000. Axial SE T1 (TR/TE/excitation = 488/15/1, FOV = 230 mm, slice thickness/gap = 6 mm/1 mm, matrix = 256 × 256, time of acquisition = 1 minute 24.8 seconds) and TSE T2 (TR/TE/excitation = 3992/110/2, turbo factor = 15, FOV = 230 mm, slice thickness/gap = 6 mm/1 mm, matrix = 512 × 512, time of acquisition = 1 minute 55.8 seconds) images were also acquired.
A neurologist (YKC) who was blinded to each patient's clinical information and assessment results measured the MRI variables as follows:
(1)
Brain infarcts: The sites and volume of acute lesions in DWI were examined. The sites of the acute infarcts were divided into cortical regions (frontal, temporal, parietal and occipital lobes), subcortical regions (subcortical white matter, basal ganglia, and thalamus), brain stem, and cerebellum. The total area of acute infarcts on DWI was measured with manual outlines. Acute infarcts were defined as areas of restricted water diffusion identified on DWI with b values of 1000 combined with hypointensity on the corresponding apparent diffusion coefficient map. The total volume was calculated by multiplying the total area by the sum of the slice thickness and the gap.
(2)
White matter lesions (WMLs): The severity of WMLs was graded using a 4-point scale developed by Fazekas et al.
The rater judged the severity of MTLA on the coronary section based on standard MRI scans, ranging from 0 to 4 with 0 representing no atrophy and 4 representing severe atrophy.
Intrarater reliability tests were carried out by the same MRI rater (YKC) on 10 stroke patients. The intrarater agreement of the MRI measurements was good to excellent: infarction volume intraclass coefficient, .82; WML intrarater kappa, .86; MTLA intrarater kappa, .83.
Statistical Analysis
The statistical analyses were carried out using SPSS for Windows (version 24.0, SPSS Inc., Chicago, IL). Descriptive data are presented as proportions, means or medians, as appropriate. A univariate analysis comparing putative risk factors between patients with and without PSD was performed. As the sample size of PSD patients was limited, risk factors with P < .005 were then analyzed using multivariate logistic regression with a forward stepwise selection strategy. If the correlations between any of the putative risk factors were greater than or equal to .50, additional correlation analyses were carried out to rule out collinearity. Subsequently, the noncollinear variables with small P values (in the univariate analysis) were entered into the logistic regression model. In the multivariate logistic regression, the odds ratio (OR) of any independent risk factor was interpreted as the risk of nonremission of PSD when all other risk factors were held constant. For the analysis of outcome data (categorical data), adjusted ORs were calculated using logistic regression with a backward elimination procedure. The significance level was set at P < .05 (2-sided).
Results
Three hundred and ninety-four patients with first-ever or recurrent acute ischemic stroke were consecutively admitted. Of these patients, 62 were excluded because they did not have MRI data, four were excluded because they died before the first screening, and 18 were excluded because death appeared imminent. One patient was aged <18 years, 11 had severe mental retardation, 6 had a severe language barrier, 23 were transferred to another department because of capacity problems, and 8 refused to provide informed consent. Hence, 261 patients were included in the analysis (Fig. 1).
The baseline characteristics of the patients are summarized in Table 1. The study sample consisted of 184 men (70.5%) and 77 women (29.5%), with a mean age of 61.3 years (range, 19-91). The median NIHSS score at the time of first screening was 4 (range, 0-28).
Table 1Demographic and clinical characteristics of the study sample
Characteristics
Mean (SD)/Median inter quartile range/n (%) n = 261
Age (years)
61.3 (14.8)
Men
184 (70.5%)
Hypertension
175 (67.0%)
Diabetes mellitus
58 (22.2%)
Previous stroke
46 (17.6%)
NIHSS on admission
4 (2-9)
Infectious
35 (13.4%)
Stroke subtype
Large artery
117 (44.8%)
Small artery
66 (25.3%)
Cardioembolism
29 (11.1%)
Other etiologies
11 (4.2%)
Unknown etiologies
38 (14.6%)
Location of infarcts
L-cortical region
72 (27.6%)
R-cortical region
52 (19.9%)
L-subcortical region
95 (36.4%)
R-subcortical region
74 (28.4%)
Brainstem
54 (20.7%)
Cerebellum
27 (10.3%)
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation.
Thirty-eight out of 261 (14.6%) patients developed PSD. In the PSD assessment process, three patients had delirium screening only once, as one patient died and another two were discharged within 5 days of admission. We recorded the time from the delirium onset to each patient's discharge or death as the duration of PSD. Between day 1 and 3 after admission, 35 (13.4%) patients were diagnosed with PSD and in the second screening stage (between day 5 and 7 after admission), an additional three patients (1.1%) developed PSD. The mean duration of the PSD was 4 days (range, 1-11 days).
Univariate Analysis
In the univariate analysis, patients with PSD were older, had higher NIHSS scores at admission and had more frequent previous strokes and infections, in comparison with their counterparts without PSD. They also had significantly more frequent left cortical infarcts, a larger infarct volume, and severer MTLA scores (Table 2).
Table 2Comparisons of clinical and MRI variables between patients with and without PSD
Abbreviations: DWMH, deep white matter hyperintensities; MRI, magnetic resonance imaging; MTLA, medial temporal lobe atrophy; NIHSS, National Institutes of Health Stroke Scale; PSD, poststroke delirium; PVH, periventricular hyperintensities.
Mean (SD), t test.
† n(%), chi-square test.
‡ M(Qu−QL), Mann-Whitney U test; L, left; R, right.
MTLA and infarct volume were not included in the multivariate logistic regression model as they were highly correlated with age (r = .605) and NIHSS score(r = .539), respectively. Thus, age, NIHSS score at admission, previous strokes, infections, and presence of left cortical infarcts were entered into the model. Except for infections, all of the other variables were significant predictors of PSD. The presence of left cortical infarcts had an OR of 3.802 (95%CI = 1.683-8.587, P < .001) (Table 3).
Table 3Multivariate logistic regression of risk factors for PSD
Variable
β
OR (95% CI)
P value
Age
.035
1.036(1.008-1.065)
.011
NIHSS on admission
.095
1.099(1.030-1.174)
.005
Previous stroke
1.285
3.615(1.458-8.967)
.006
Infections
.927
2.527 (.905-7.057)
.077
L-cortical infarction
1.335
3.802(1.683-8.587)
.001
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; OR, odds ration; PSD, poststroke delirium.
Effects of PSD on Clinical and Functional Outcomes
The PSD patients had poor outcomes at 3 and 6 months, which were measured using the IADL scale. Even after adjusting for age, NIHSS score at admission and presence of a previous stroke, PSD was still associated with the 3-month IADL score, but not with the 6-month IADL score. PSD patients had significantly higher mRS scores at 3 and 6 months after stroke. However, this association became nonsignificant after adjusting for age, NIHSS score at admission, and presence of a previous stroke (Table 4). The duration and severity of PSD were not associated with mRS or IADL scores (Table 5).
In this prospective observational study, we found that the incidence of PSD was 14.8%, indicating that delirium was common in the acute stage of ischemic stroke. PSD was associated with age, previous stroke history, stroke severity, infection, and left cortical infarction. Furthermore, most of the delirium occurred early after stroke. Patients with PSD had a relatively poor functional outcome, suggesting that more attention should be paid to PSD by healthcare professionals. As studies attempting to investigate PSD were very limited, our study added to the knowledge of the psychiatric complications of stroke.
The PSD incidence of 14.8% in our study is similar to the findings of previous studies (11.8%–66%).
The various reported incidences of PSD may be due to case-mix, different definitions of delirium, different age groups included, sample size, and where and how the stroke patients were treated. As PSD may increase the length of hospitalization, mortality and poor outcomes,
screening for delirium should be carried out as soon as possible for hospitalized ischemic stroke patients.
In our study cohort, delirium was more frequent in patients with infarction in the left cortex. This finding is novel and opposes the findings of earlier studies. Some previous studies showed that PSD may correlate with issues with the right hemisphere,
However, they recruited a patient cohort with both hemorrhagic and ischemic strokes, resulting to a heterogeneous study sample. Moreover, they used brain computed tomography scans rather than MRI scans to evaluate stroke.
Our study showed that functional outcome (measured using the IADL scale at 3 months after the index stroke) was worse in subjects with PSD, even after adjusting for possible confounders. This finding concurred with the findings of previous studies.
However, when we used the mRS score as the outcome, PSD did not appear to affect it. The IADL is a comprehensive measure comprising assessments of both physical and mental function, while the mRS assesses physical deficits rather than mental disability.
Thus, it is understandable that PSD, which is mainly a cognitive dysfunction, would correlate with the IADL score rather than the mRS score. In addition to the above functional outcome, mortality, hospital stay duration, and Barthel Index have also been found to be worse after delirium, according to the literature.
The advantage of our study was that we recruited a more homogenous study sample and used the brain MRI scans rather than computed tomography scans to evaluate the infarcts as well as the pre-existing brain abnormalities. As we know, MRI is more precise at locating the sites of infarction and more sensitive for detecting WMLs.
There were also some limitations in our study. First, the sample size was relatively small. Second, we did not evaluate the cognitive status or the effects of medication in our patients, which have been found to be correlated with PSD in some studies.
PRospective Observational POLIsh Study on post-stroke delirium (PROPOLIS): methodology of hospital-based cohort study on delirium prevalence, predictors and diagnostic tools.
However, assessment of cognitive function may not be very reliable in the acute phase of stroke. Third, we did not assess the NIHSS score at follow-up after stroke, which led to an inadequate evaluation of poststroke residual neurological deficits.
In conclusion, we found an incidence of delirium of 14.8% in the first week after admission with acute ischemic stroke. Age, having a previous stroke, stroke severity, and left-cortical infarction were independently predictors of PSD. If delirium complicates ischemic stroke, it may result in a significantly worse functional outcome. Healthcare professionals should pay more attention to the early recognition of and intervention for delirium in stroke management.
Author contributions
JF and YK conceived and designed the research. JF, GP, HH and HP collected the data. JF, YK and WM analyzed the data and prepared the tables. WM revised the manuscript critically for important intellectual content.
References
American Psychiatric Association
DSM-5 task force. Diagnostic and statistical manual of mental disorders: DSM-5.
American Psychiatric Publishing,
Arlington2013: 596-601
Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial TOAST. Trial of Org 10172 in acute stroke treatment.
PRospective Observational POLIsh Study on post-stroke delirium (PROPOLIS): methodology of hospital-based cohort study on delirium prevalence, predictors and diagnostic tools.
☆Grant support: Medical Scientific Research Foundation of Guangdong Province, China (grant no: B2017054 ) and Dongguan Medical Science and Technology Fund (General Project, grant no: 201510515000391 ).
☆Disclosure of Conflict of Interest: All authors declare that there is no conflict of interest.
Mean (SD), t test.
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