Cognitive functioning in meningioma patients: a systematic review

Cognitive functioning prior to treatment was examined in 5 studies with a total of 199 meningioma patients eligible for surgery [4, 7, 10, 19, 20] (see Table 1). Overall, in these studies, cognitive functioning has been found impaired. Most commonly affected domains were memory, attention, and executive functions. Cognitive functioning following surgery was investigated in 7 studies including a total of 302 meningioma patients [4, 7‐10, 19, 20] (see Table 1). All studies, except 2 [8, 9], started with a pre-operative assessment. Pre-operative assessments allow to determine possible effects of surgery on cognitive performance. Only 2 [4, 20] of the 5 studies with a repeated (pre-and post-operative) assessment of cognitive function controlled for the influence of practice effects. In general, all studies showed significant improvements following surgery in cognitive functioning, mostly on memory, attention, and executive function. There was no consistency in results across studies with regard to the cognitive domains that did not improve after surgery. However, despite cognitive improvements, all studies (including those without pre-operative assessment) demonstrated that patients (still) had significantly lower scores in various cognitive domains after surgery, compared to healthy controls. For studies including a pre-and post-operative assessment (mean interval between 2 assessments ranging from 3 to 9 months), no clear conclusions can be drawn on the effect of time since surgery on the post-operative cognitive outcome. Severity data (e.g., effect sizes, incidences) were not available for most of them, due to differing populations.

In particular, Tucha and colleagues [4] found significant pre-operative impairments in patients with frontal meningiomas (N = 54) on measures of working memory, attention, and executive functions (lower mean raw scores, longer reaction times, or higher error rates), compared to healthy controls (matched for age, gender, educational level, handedness, and intelligence). After surgery, significant improvements were observed on measures of memory and attention. However, despite these significant improvements, patients’ post-operative status remained significantly impaired in attention and executive functions, compared to healthy controls who were retested over the same intervals. According to the authors, only the better post-operative performance in figural memory (immediate recall) could be partly explained by practice effects by comparing the test results with the healthy control group. Note that the authors classified flexibility and shifting as subdomains of attention. However, these measures can also be considered as components of executive functioning [21].

In addition, Tucha and colleagues [10] conducted a study with elderly meningioma patients (N = 33). These patients showed significant pre-operative impairments on measures of working memory, short-term figural memory, attention, and executive functions (lower mean raw scores, longer reaction times, or higher error rates), compared to healthy controls in the same age-range. After surgery, significant improvements were observed on measures of memory and attention, with the exception of working memory. In this study, patients’ post-operative cognitive status corresponded with the cognitive functioning of the healthy control group (except for working memory). Because the healthy controls were only tested once, it was not possible to rule out practice effects, which may have masked lower performance in the elderly meningioma patients. See the above-mentioned note regarding the classification of cognitive domains by these authors. It was not reported if there was overlap in patients between these 2 studies by Tucha and colleagues; a certain amount of overlap between the patient samples seems possible [4, 10].

In a recent study by Meskal and colleagues [20], meningioma patients (N = 68) had significantly lower mean pre-operative and post-operative standard scores on measures of memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, and executive functioning, compared to (American) normative data as provided by the Central Nervous System Vital Signs battery (i.e. CNS VS), a brief (30 min) computerized battery of neuropsychological tests [22]. Forty-seven out of 68 patients (69 %) scored low or very low on 1 or more cognitive domains. After surgery, significant improvements were observed on all cognitive domains, with the exception of psychomotor speed and reaction time. Twenty-seven out of 62 patients (47 %), scored low or very low on 1 or more cognitive domains after surgery.

The 3MS test used in a study by Yoshii and colleagues [7] showed a subnormal function (mean 3MS score < 85) in 34 meningioma patients pre-operatively. Cognitive function normalized after surgery only in patients with right-sided (n = 17) meningioma (post-surgery mean 3MS score > 85). Note that the authors have chosen for a more stringent cut-off of 85 instead of 77/78, which is generally used as cut-off for cognitive impairment [23]. In addition, patients were tested within 1 month after surgery, which is a very short follow-up time that may identify (more severe) transitory cognitive problems instead of persistent cognitive deficits in left-sided meningioma patients. Furthermore, it was not clearly described by the authors why some patients had only 1 assessment (i.e., prior to, or following surgery), and other patients were assessed twice with the 3MS test (prior to, and following surgery).

Another study, by Koizumi and colleagues [19], evaluated cognitive dysfunction with the MMSE in meningioma patients (N = 10) who also underwent ¹²³I-Iomazenil (IMZ) single-photon emission computed tomography (SPECT) imaging. The mean pre-operative MMSE scores were 19.9 ± 11.4; ranging from 2 to 30. The MMSE cut-off points for normal, mild, moderate, and severe cognitive impairment were not described by the authors. Based on the MSSE cut-off levels application by Folstein and colleagues [24], 3 patients had moderate to mild cognitive impairment (scores on MMSE ranging from 20 to 25), and 3 patients had severe cognitive impairment (scores ranging from 2 to 5); 4 of them had scores of 29–30. Overall, 6 patients scored above the cut-off point of 23. After surgery, a significant improvement in cognitive function (mean post-surgery MMSE: 26.5 ± 3.8) was found. Seven of the 10 patients scored above the cut-off of 23 on the MMSE, which suggests ‘normal’ cognitive functioning in those patients. Note that screening tests such as the MMSE and 3MS are not sensitive enough to discriminate between mild cognitive impairment and normal cognitive functioning [25].

Van Nieuwenhuizen and colleagues [6] found significantly lower mean Z-scores in patients with a wait-and-scan policy (N = 21) on measures of psychomotor speed and working memory, compared to normative matched healthy controls from the Maastricht Aging Study (i.e., MAAS [26]). Note that this study was conducted in a specific group of meningioma patients, in which the tumor was small, growing slowly, and was not causing symptoms or if surgery carried too many risks, particular for older patients who are more vulnerable to develop complications after surgery due to their medical condition.

Steinvorth and colleagues [27] included 10 patients admitted only for fractioned stereotactic radiotherapy (FSRT) instead of surgery. However, the authors did not report cognitive results. Note that the patients who were included in the studies by Van Nieuwenhuizen and colleagues [6] and Steinvorth and colleagues [27] were substantially different (e.g., smaller tumor volumes, inoperable meningiomas after subtotal resection or recurrence) from those patients who were admitted for surgical treatment. Therefore, the results of the aforementioned 2 studies cannot be generalized to the general population of meningioma patients admitted for surgery.

In another study by Van Nieuwenhuizen and colleagues [8] in which some (n = 18) meningioma patients were tested only after surgery and not before, significantly lower mean standard scores were found on a number of verbal memory subtests, compared to normative healthy controls. The authors concluded that these patients had significantly lower cognitive functioning than healthy controls. Attention and executive function were not impaired in these patients. The patients of this study were compared with patients (n = 18) who received adjuvant radiotherapy after surgery (RTx+). The results of the latter patient group are discussed in the section on effects of adjuvant radiotherapy. It should be noted that although overlap in patients between this study and the above-mentioned study of Van Nieuwenhuizen cannot be ruled out, this is not likely since the study in patients who had already undergone surgery [8] preceded the study in patients in whom surgery was not performed [6].

Similar to the aforementioned study, Krupp and colleagues [9] investigated cognitive functioning after surgery without a pre-operative assessment in 91 patients. Compared with published normative population values, major deficits in attention appeared in patients of approximately 55 years of age, worsening in patients with increasing age. Significant negative correlations were found between age and attention performance in patients older than 55, as well as with the intelligence factors verbal knowledge, technical ability, and word fluency. No such correlation was found for reasoning and age. Since no pre-treatment assessment was available in the aforementioned 2 studies, the specific effects of the brain tumor or surgery on cognitive performance cannot be determined.

Three studies investigated cognitive functioning in meningioma patients who had undergone radiotherapy after surgery [2, 5, 8]. These studies described the same [2, 5] or an overlapping ([8]) patient sample, but investigated different types of research questions. In these studies, patients in whom the tumor could only be partially resected and patients with a recurrence after surgery received adjuvant radiotherapy.

The study by Van Nieuwenhuizen and colleagues [8] investigated the exclusive effects of adjuvant radiotherapy after surgery by comparing patients who had surgery only (RTx−) with patients who had surgery and adjuvant radiotherapy (RTx+). The authors found no significant differences in mean standard scores on all cognitive measures (memory, attention, executive function, and perception) between RTx− (n = 18) and RTx+ (n = 18) patients (which may be patients with different tumor characteristics). No comparisons were made for cognitive functioning between the RTx+ group and healthy controls. In this study, additional radiotherapy did not have deleterious effects on cognitive functioning. The studies by Dijkstra and colleagues [5] and Waagemans and colleagues [2] did not differentiate between the effects of surgery and/or radiotherapy. In the study by Dijkstra and colleagues [5], patients (N = 89) showed significantly lower mean Z-scores on measures of verbal memory, visual memory, working memory, information processing, psychomotor speed, and executive function (most impaired), compared to normative matched healthy controls (from MAAS [26]). No significant differences were found for attention. Note that the proportions of patients with cognitive deficits (defined as 1.5 SD below the mean of a matched control group) was not reported by these authors. The study by Waagemans and colleagues [2] focused on HRQoL and reported similar findings on cognitive functioning in meningioma patients (N = 89) as in the study by Dijkstra and colleagues [5]. A common limitation of the aforementioned studies was an absence of a pre-treatment assessment of cognitive functioning. Also noteworthy is the large standard deviation (SD) of tumor volumes in these studies.

Only 1 study [27] investigated the effects of FSRT following surgery in meningioma patients (n = 30). In this study, cognitive function was evaluated before and after FSRT. Patients had normal mean percentile scores, except for a slow information processing speed prior to radiotherapy. After the first fraction, a transient decline in memory and, at the same time, improvements in attentional functions were observed. No deteriorations were seen during the further follow-up, but further increases in memory and attention were observed. Note that the improvement in attention was considered as a practice effect, since a comparable improvement was also observed in a control group, included in an earlier report by these authors [27].