Keywords

Introduction

Aneurysmal subarachnoid hemorrhage (aSAH) accounts for 3 % of strokes. Estimated independence after aSAH varied between 36 and 60 % only [1, 10]. Global and focal neurological deficit in aSAH survivors has been well documented. Recent studies showed that cognitive impairment in aSAH patients might affect their functional outcomes and 27–44 % of patients who returned to the community exhibited cognitive dysfunction [11, 14, 15]. Thus, it is clinically important to better understand the pattern of cognitive dysfunction after aSAH.

The exact cause of cognitive impairment after SAH is not clear. It is postulated that the primary and secondary brain injury, such as delayed cerebral infarction, may contribute to the functional deficit of the patients. Reports in the literature have confirmed that delayed cerebral infarction is related to poor outcome [16, 17, 20]. However, data on the prevalence or pattern of delayed cerebral infarction-related cognitive impairment are lacking. With this in mind, we designed the current study.

Methods

This prospective observational study was performed in four neurosurgical centers in Hong Kong [16–18]. It is registered at ClinicalTrials.gov of the US National Institutes of Health (NCT01038193) and was approved by hospital ethics committees. This study conforms to the Declaration of Helsinki, and written informed consent was obtained from all of the participants or their next of kin.

The patient inclusion criteria were: (1) spontaneous SAH with angiography-confirmed etiology of intracranial aneurysm; (2) hospital admission within 96 h after ictus; (3) age between 21 and 75 years of age; (4) a speaker of Chinese (Cantonese); and (5) informed consent from the patients or their next of kin. The patient exclusion criteria were: (a) a history of previous cerebrovascular or neurological disease other than unruptured intracranial aneurysm or (b) a history of neurosurgical operation before ictus.

Assessments [17, 18]

Assessments were conducted 3 years after ictus by one of the two research assistants (psychology graduates) trained and supervised by a postdoctoral research psychologist. The battery of cognitive assessments had previously been reported in our local Chinese population [17–19]. The choice of the battery of cognitive assessments was based on: (a) previous cognitive studies in local Chinese patients and standard cognitive tests validated in the Cantonese-speaking population; and (b) a balanced battery covering verbal and visuospatial memory, attention and working memory, executive functions, psychomotor speed, and language.

  1. A.

    Verbal memory domain

    1. 1.

      Hong Kong List Learning Test (HKLLT) [3]. The HKLLT was developed based on the California Verbal Learning Test, which has been used in vascular cognitive impairment studies. It is a verbal learning and memory test that consists of two 16-word lists with three learning trials with immediate recall, 10-min delayed recall, and 30-min delayed recall and recognition for each list. The HKLLT has been validated in both healthy and pathological local populations.

  2. B.

    Visuospatial skill and memory domain

    1. 1.

      The Rey Osterrieth Complex Figure is a commonly used test for assessing visuospatial construction skills and visuospatial memory [5, 9].

  3. C.

    Attention and working memory domain

    1. 1.

      Verbal and visual digit span forward and backward from the Chinese Wechsler Memory Scale Third Edition for the examination of simple attention and working memory [6, 13]. Verbal and visual spans have been used as donor scales for composite psychometric measures.

  4. D.

    Executive function and psychomotor speed domain

    1. 1.

      Symbol–Digit Modalities Test. This brief, easy-to-administer, timed coding test is a variant of the Digit–Symbol Coding Task in the Wechsler Adult Intelligence Scale—Third edition. Timed coding tasks have been used in studies that involve subjects with suspected vascular cognitive impairment.

    2. 2.

      Color Trails Test (CTT). This test originated from the Trail Making Test (TMT), which is used for the timed assessment of psychomotor speed and executive functions. Using colored numbers instead of the English alphabet, the CTT is considered to be an acceptable cultural substitute for the original TMT with similar psychometric properties [7].

    3. 3.

      Animal Fluency. This test requires subjects to generate as many animal names as possible in 1 min. It is a simple timed test that sensitively measures speed and activation, as well as such executive processes as clustering, set shifting, and retrieval [4, 8].

  5. E.

    Language domain

    1. 1.

      Modified Boston Naming Test (mBNT). The Boston Naming Test is the most frequently used confrontation naming test for assessing language. Here, we have used a validated modified version that contains 15 stimuli appropriate for use in Chinese cultures.

Cognitive domain scores were computed by averaging the z scores of the respective test measures derived from the established age-matched and education-matched norms. A cognitive domain deficit was defined through a cognitive domain z score less than −1.65 (below the fifth percentile). We used the presence of two or more cognitive domain deficits rather than any cognitive domain deficits as the definition of cognitive impairment as in neuropsychological outcome study of the International Subarachnoid Aneurysm Trial (ISAT) [12].

Statistical Analysis

The statistical analyses were generated using IBM SPSS Statistics for Windows 21 (SPSS, Chicago, Illinois, USA). Categorical data are presented as number (percentages) and numerical data are presented as means ± standard deviations (SD), unless otherwise stated. Categorical data were analyzed using the chi-square test or Fisher’s exact test, and continuous data were analyzed using the unpaired Student’s t-test or Mann–Whitney U-test, as appropriate. Statistical significance was indicated by a two-tailed probability value of less than 0.05

Results

One hundred and twenty patients completed the neurocognitive assessment at 1 year. The patient cohort was previously reported [17]. In brief, the patient characteristics are shown in Table 1. One hundred and five (88 %) patients had favorable outcome as defined by the modified Rankin Scale (mRS) 0–2.

Table 1 Patient profiles
Full size table

One or more cognitive domain deficits were found in 6 (32 %) patients with delayed cerebral infarction and 23 (23 %) patients without delayed cerebral infarction (odds ratio: 1.57, 0.54–4.58, p = 0.290). Cognitive impairment (two or more domain deficits) was found in 4(21 %) patients with delayed cerebral infarction and 11(11 %) patients without delayed cerebral infarction (odds ratio: 2.18, 0.61–7.76, p = 0.192). Cognitive domain deficits commonly affected in aSAH patients with delayed cerebral infarction were verbal memory (21 % vs 4 %; odds ratio: 6.47, 1.45–28.66, p = 0.021), language (16 % vs 6 %; odds ratio: 2.97, 0.67–13.09, p = 0.152), and visuospatial memory and skill (13 % vs 5 %; odds ratio: 2.42, 0.75–7.83, p = 0.126) domains (Table 2).

Table 2 Cognitive domain deficit in patients with and without delayed cerebral infarction (DCI)
Full size table

Discussion

Functional outcome of patients with aSAH is usually assessed by mRS. Cognitive domain function can interact with the patient’s physical ability in determining his or her real functional independence. This interaction also affects the potential and capability of patients in returning to their usual work and usual quality of life.

We showed that DCI worsened cognitive domain functions in aSAH patients and that verbal memory domain deficit was significantly associated with DCI. Verbal memory is predominantly mediated by the medial temporal lobes, including the hippocampus and parahippocampus network. A previous study showed significant reduction in bilateral hippocampal volumes among patients with aSAH [2]. A similar finding was observed in visuospatial memory and function domain and language domain.

The proportions of patients with executive and psychomotor speed domain deficit are similar in those with and without DCI. The executive function is predominantly mediated by the frontal lobes and it encompasses higher cortical function such as planning, inhibition, problem solving, attention, and decision making [1]. One possibility that two groups of patients have a similar prevalence of executive function domain deficit is that the executive and psychomotor speed domain function may be mainly affected by the primary hemorrhage.

There were limitations in the current study. First, although the domain-based neuropsychological battery we used has been validated in a Chinese population with established norm, it is possible that it was not sensitive enough to measure subtle cognitive changes. Second, the cognitive domain outcomes are dichotomized for analyses and the patient number did not allow matched analyses. Finally, fatigue can adversely affected performance because the battery of cognitive assessments is tiring.

Conclusion

In conclusion, our study showed a distinct pattern of cognitive domain deficits in a prospective observational SAH cohort. These findings should be further investigated in future multicenter prospective studies.