An analysis of neurocognitive dysfunction in brain tumors.

BACKGROUND: Neurocognitive dysfunction is an important issue in patients with frontal lobe lesions. These patients who may be in good neurological status may succumb to neurocognitive dysfunction, affecting their daily living and hampering the quality of life. This study aims to correlate pre- and post-operative neurocognitive dysfunction in patients with frontal lobe lesions.
MATERIALS AND METHODS: A prospective analysis of 50 patients of newly-diagnosed frontal lobe tumors of any grade deemed suitable for surgical resection was carried out. All patients underwent neurocognitive testing using frontal assessment battery (FAB), mini mental state examination, and verbal learning and memory test pre- and post-operatively.
RESULTS: In this study, 22 patients had right frontal lobe lesion, whereas in 24 patients, it was located in the left frontal lobe, and 4 patients had bilateral lesions. Only 12 patients were found to be in good FAB score preoperatively, and all of them had symptom duration of less than 3 months. 1-week postsurgery, 26 patients achieved a good score, which increased to 44 at 3rd month. Patients who had psychological dysfunction for more than 3 months had average-to-bad preoperative FAB scores, while at 3rd month postoperatively, only six patients were in average score and none in bad score.
CONCLUSION: Frontal lobe lesion should be kept in mind in patients with neurocognitive dysfunction. FAB is a simple bedside test that should be included in routine neurological examination in daily neurosurgical practice to assess long-term functional outcome in patients with frontal lobe lesions. Copyright:

INTRODUCTION

Frontal lobe controls important cognitive skills in humans, primarily supporting higher level cognitive processes, comprising executive skills and working memory such as emotional expression. It is, in essence, the “control panel” of our personality and our ability to communicate. Not surprisingly, frontal lobe pathologies can have far-ranging effects that can have major impact on educational attainment, employment, judgment, and social functioning.[1]

Neurocognitive dysfunction is a serious problem in patients with frontal lobe tumors. While the theoretical success of surgery of such tumors is traditionally measured by the extent of tumor resection, progression-free survival, and overall survival, neurocognitive dysfunction has now started enjoying considerable attention as an important, yet practical outcome measure.[23] In the initial stages, the decline of neurocognitive function usually remains subtle and thus may remain unrecognized due to lack of suitable and simple tests as well as lack of awareness. However, this hampers the patient's personal, professional, as well as social abilities, leading to a diminution of the quality of life and ability to independently manage things, and this, in turn, also leads to the inability to comply with the therapy. While there are studies regarding neurocognitive dysfunction in brain tumor patients following treatment, only few data are available on strategies for preventing and treating neurocognitive deficits early in the disease course.[4]

The study aims to assess pre- and post-operative neurocognitive dysfunction using frontal assessment battery in patients with newly-diagnosed frontal lobe lesion deemed suitable for surgical resection.

MATERIALS AND METHODS

The present study evaluated 50 prospectively enrolled patients of newly-diagnosed frontal lobe tumors of any grade during the period August 2015 to August 2018 at our institute, which is a tertiary care referral center catering pan-India population, in general, and Northern India, in particular. Patients admitted to our neurosurgery department with a diagnosis of frontal lobe tumor requiring surgical intervention were screened for eligibility to participate in this study. Inclusion criteria included adult patients of age >18 years having either intra- or extra-axial lesions and who are conscious and following basic commands with mini mental state examination (MMSE) score of >24. Exclusion criteria included previous history of psychiatric disorders, any intake of tranquilizers or antipsychotic drugs and obvious psychomotor impairment, lack of attention or comprehension during initial examination, and whose general condition was not appropriate to endure an approximately 10-min interview to perform the frontal assessment battery (FAB) and MMSE. The Institutional Ethics Committee reviewed and approved this study, and all patients provided consent before participation.

All patients fulfilling the inclusion criteria were examined preoperatively. Detailed history including duration between onset of symptoms and diagnosis was recorded. To confirm the lesion, contrast-enhanced magnetic resonance imaging (CEMRI) was performed in every participant, and specific anatomical part of the frontal lobe involved was noted and psychological and neurological deficit correlated with the location of the lesion.

Intraoperatively, specific area involved and its extension including edema and compression on the surrounding structures were noted and maximum safe resection was carried out. Tumor tissues of all patients were sent for histopathological evaluation for confirmation of diagnosis. Postoperative CEMRI was performed for assessing the extent of resection. After the patients become neurologically stable, repeat evaluation of FAB was carried out within a week and again at 1 month and 3 months duration.

The FAB[5] is a frontal lobe function testing method developed in 2000 by Dubois et al. which is composed of six subtests, namely similarities, lexical fluency, motor series, conflicting instructions, go/no-go, and prehension behavior. The possible total FAB scores range from 0 to 18. The major advantage of FAB includes capability of performing at bedside within about 5 min and without the need of any specialized equipment and is said to cover a relatively broad range of frontal lobe functions. For pre- and post-operative FAB score comparison, we divided the FAB score into good (13–18), average (10–12), and bad (<10) scores.

The patients were also subjected to MMSE test as described by Folstein et al.[6] that is composed of orientation, registration, attention and calculation, and recall and language with a maximum score of 30. No cognitive impairment has a score of 24–30, mild cognitive impairment has a score of 18–23, and a score of 0–17 signifies severe cognitive impairment.

For assessing the short- and long-term memory, verbal learning and memory test was employed. The examiner read a list of 15 words to the patient and asked him to repeat the words afterward. After five rounds, the sum of remembered words of each round is recorded that measured the short-term memory. After about 30 min, the examiner read out a list of words that contain the original 15 words from the list but also with 35 distracting words. The patient was asked to decide for each word whether it was in the original list or not. The number of correctly recognized minus false-positive words measured the adjusted recognition which quantified both short-term and long-term memory.[7]

Statistical analysis

All statistical analysis was done using Statistical Package for the Social Sciences version 19.0, IBM, Armonk, NY, United States. Categorical variables were presented as frequency values, and nonparametric Mann–Whitney test was used for continuous variables with a nonnormal distribution and presented as mean ± standard deviation and compared using Chi-square test. P value was calculated using paired t-test comparing means and P < 0.05 was considered as statistically significant. Mean FAB scores of the individual patients were calculated, and preoperative values were compared with the postoperative values at 1 week, 1 month, and 3rd month.

RESULTS

The mean age of the participants in this study was 54 years (range 21–78 years); of them, 32 were men and 18 were women. Forty-nine (98%) were right-handed and the median Karnofsky score of the patients was 90 (range 60–100). The average time taken for assessment of FAB was 8 min (range 6–12 min). Detailed history and clinical examination revealed that 20 (40%) patients presented with psychological dysfunction preceding motor deficit while 6 (12%) patients presented with psychological dysfunction alone without any motor deficit.

Twenty-two patients had lesion in the right frontal lobe, whereas in 24 patients, it was located in the left frontal lobe and 4 patients had bilateral lesions. Of them, right and left dorsolateral prefrontal cortex (DLPFC) lesions were seen in 12 and 14 patients, respectively; right and left medial prefrontal cortex (MPFC) lesions were present in 8 patients each, and right and left basifrontal lesions were present in 4 patients each.

Mean duration between onset of psychological symptoms and radiological diagnosis was 5.8 months (range 1–12 months). The FAB scores of the patients were divided into good, average, and bad preoperatively and compared with postoperatively at 1 month and at 3 months [Table 1]. The results indicated that only 24% of the patients were in good FAB score preoperatively, and all of them had symptom duration of less than 3 months. 1-week postsurgery, patients improved symptomatically and 52% of the patients could achieve a good score, which increased to 88% at 3rd month. Patients who had psychological dysfunction for more than 3 months had average to bad FAB preoperative scores (N = 38), while at 3rd month, only 12% of the patients were in average score and none in bad score.

Table 1

Analysis of individual variables of frontal assessment battery and frontal assessment battery scores of the patients pre- and post-operatively

FAB	Score	Preoperative	1 week	1 month	3 months
Conceptualization	3	0	10	14	18
	2	20	24	32	28
	1	14	14	4	4
	0	16	2	0	0
Mental flexibility	3	0	14	18	20
	2	24	22	30	28
	1	22	14	2	2
	0	4	0	0	0
Programming	3	14	22	30	30
	2	24	20	20	20
	1	10	8	0	0
	0	2	0	0	0
Conflicting instructions	3	18	26	24	28
	2	20	20	24	20
	1	12	4	2	2
	0	0	0	0	0
Inhibitory control	3	10	14	22	24
	2	20	28	26	24
	1	18	8	2	2
	0	2	0	0	0
Prehension behavior	3	24	26	36	34
	2	22	24	12	14
	1	4	0	2	2
	0	0	0	0	0
FAB score (%)	Good (13-18)	12 (24)	26 (52)	34 (68)	44 (88)
	Average (10-12)	20 (40)	18 (36)	16 (32)	6 (12)
	Bad (<9)	18 (36)	6 (12)	0	0

FAB – Frontal assessment battery

Analysis of individual variables of frontal assessment battery [Table 1]

Conceptualization

No patients scored the maximum score of 3 preoperatively but postoperatively at 1 week, 10 patients scored 3 which increased to 14 at 1 month and 18 at 3rd month. There were 16 patients with score 0 preoperatively; however, at the end of 3 months, the conceptualization improved and none of the patients were in score 0.

Mental flexibility

In this task again, none of the patients were able to achieve the maximum score of 3 preoperatively; however, at 3 months postoperatively, 20 patients were able to achieve the score 3.

Programming

Significant improvement in motor programming was seen postoperatively. While 14 patients scored 3 preoperatively, the number increased to 30 at 1st and 3rd month postoperatively.

Conflicting instructions

18 patients scored 3 preoperatively which rose to 28 at 3rd postoperative month.

Inhibitory control

Only 10 patients had a score of 3 preoperatively while 24 patients improved to this score at 3rd postoperative month.

Prehension behavior

No patients in this study scored 0 either pre- or post-operatively. Maximum improvement was seen at the 1st postoperative month with 36 patients scoring 3.

The results showed that there was improvement in each task of FAB, but maximum improvement was seen in motor programming, conflicting instructions, and environmental autonomy, and maximum improvement was seen at the 1st and 3rd postoperative month.

Loss of memory

In our study, 30 (60%) patients had some degree of memory loss. Of them, 14 (47%) had recent memory loss, while 16 (53%) had remote memory loss. After 1 month of surgery, 16 (53%) patients recovered and 8 (27%) were left with recent memory loss and 6 (20%) with remote memory loss. However, at 3rd month of follow-up, major improvement was seen in recovery of remote memory loss with only 2 (6.7%) patients showing persistent remote memory loss.

Tumor location and frontal assessment battery findings

FAB scores were compared according to the location of the lesion and data analyzed [Table 2]. It was found that significant improvement (P = 0.002) of neurocognition was seen in tumors located in the medial frontal areas than dorsolateral areas postoperatively. Improvement of FAB scores was also seen in tumors located in the orbitofrontal area; however, this was not statistically significant (P = 0.23). No correlation on FAB performance was established on lesions located in the dominant/left hemisphere with that of the nondominant/right side.

Table 2

Pre- and post-operative comparison of frontal assessment battery scores according to location of lesion

Location of lesion	Number of patients	FAB analysis	Preoperative value	1 week	1 month	3 months
Right DLPFC	12	Mean	11.33	11.83	14.17	15.17
		SD	1.21	3.31	2.32	1.72
		P	0.7	0.05	0.002
Left DLPFC	14	Mean	9.86	12.43	14.14	15.29
		SD	3.72	3.26	2.12	2.21
		P	0.04	0.02	0.01
Right MPFC	8	Mean	11.75	13.25	13.85	14.24
		SD	2.50	2.23	2.40	1.40
		P	0.01	0.03	0.02
Left MPFC	8	Mean	9.54	13.50	16.25	16.60
		SD	2.52	1.73	0.50	0.58
		P		0.02	0.01	0.01

SD – Standard deviation; FAB – Frontal assessment battery; MPFC – Medial prefrontal cortex; DLPFC – Dorsolateral prefrontal cortex

Histopathological findings

High-grade gliomas constituted 60% of the patients in this study, and of them, glioblastoma multiforme (GBM) was the most common histopathological finding seen in 20 (40%) patients. Other lesions included pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNET), oligodendroglioma (ODG), transitional meningioma, and tuberculoma. Irrespective of the tumor type, however, patients achieved comparable FAB scores. Benign tumor patients did not achieve higher scores than the malignant counterpart. Therefore, histopathological diagnosis was not associated with a difference in preoperative FAB scores.

Postoperative improvement of presenting symptoms (other than psychological dysfunction)

This is depicted in Table 3. Most common associated complaint was seizures (54%) followed by headache in 52% of the patients. 80%–90% improvement was seen in headache after surgery at 3-month follow-up period, while 70% improvement was seen in reduction of seizure episodes. 60%–80% improvement was seen in weakness, while in 20%, it persisted. 32% of the patients had speech disturbances preoperatively, and 87% of them had improvement postoperatively after speech therapy.

Table 3

Postoperative improvement of associated complaints

Associated complaints	Number of patients (%)	Postoperative improvement (1st week) (%)	Postoperative improvement (1st month) (%)	Postoperative improvement (3rd month) (%)
Headache	26 (52)	16 (61)	22 (84)	24 (92)
Seizures (GTCS; CPS)	28 (56); 4 (8)	16 (57); 2 (50)	18 (64); 2 (50)	20 (71); 2 (50)
Loss of vision	6 (12)	4 (66)	4 (66)	4 (66)
Speech disturbances	16 (32)	10 (62)	14 (87)	14 (87)
Bladder and bowel involvement	10 (20)	6 (60)	8 (80)	8 (80)
Vertigo	2 (4)	2 (100)	2 (100)	2 (100)
Involuntary movements	2 (4)	2 (100)	2 (100)	2 (100)
Paresis/plegia	10 (20)	4 (40)	6 (60)	8 (80)

CPS – Complex partial seizures; GTCS – Generalized tonic-clonic seizures

Table 4 shows the results of pre- and post-operative FAB score comparison. Statistically significant improvement of all the six tasks of FAB was seen at 3rd month, and significant improvement of all the tasks except conflicting instructions was noted at the 1st postoperative month. However, at 1st postoperative week, statistically significant improvement of only conceptualization and mental flexibility was found.

Table 4

Statistical significance of each task of frontal assessment battery score

FAB tasks	Preoperative and 1-week postoperative score comparison	Preoperative and 1-month postoperative score comparison	Preoperative and 3-month postoperative score comparison
Conceptualization	0.0023	0.0001	0.0001
Mental flexibility	0.0001	0.0001	0.0001
Programming	0.053	0.002	0.006
Conflicting instructions	0.284	0.08	0.02
Inhibitory control	0.73	0.04	0.01
Environmental autonomy	0.134	0.03	0.007

FAB – Frontal assessment battery

DISCUSSION

The current study demonstrates that neurocognitive decline is an important issue in patients with frontal lobe tumors even in good neurological condition and before any treatment options are initiated. This is significant because in view of favorable neurological and general health condition, neurocognitive dysfunction might be unrecognized or underestimated. The results of this study suggest the importance in neurosurgical practice to preoperatively assess not only language functions but also additional different cognitive domains such as executive functions and memory skills, as well as to develop a standardized cognitive task protocol for cortical language areas, memory, and executive functions. These functions are critical in postoperative functional outcome, interpersonal and social relationships, and health-related quality of life in brain tumor patients. The gravity of psychological manifestations is indicated by the stigma that patients face in surviving in the society and workplace.[8] These symptoms should not be ignored and should be identified preoperatively to be followed up after surgery, and psychiatric consultation should be a part of management to provide the patient a quality social and productive life. Satisfaction rates of patients and their informal caregivers improve when an intervention is offered, and more research is needed to determine the most effective intervention components and the most appropriate timing for the delivery of the intervention.[9]

It is common neurosurgical misconception that cognitive functions may rarely be surgically damaged, are diffusely localized, and are less vulnerable as motor and language functions. However, conversely, neuropsychological assessment shows that these cognitive deficits are far more common than previously assumed on the basis of clinical impression and observation, both before and after surgery.

In our study, 40% of frontal lobe lesion patients were presented with psychological symptoms earlier than neurological deficit. A literature review suggested the rate in the range of 51%–78%,[1011] while another study[12] reported the rate as 21%. A few quantitative studies do indicate that behavioral problems are more evident in patients with frontal tumors than in controls without neurological compromise.[13] Previous studies have shown that pretreatment neurocognitive impairments have been associated with GBM[1415] and meningiomas,[16] and this study adds to this knowledge by assessing FAB of patients with wide range of frontal lobe tumors.

In this study, we had gone through detailed history and clinical examination of the patients including neurological and psychological assessment. As the aim of the study was pre- and post-operative comparison of psychological dysfunction, our need was to choose from a number of tests that measure the neurological and psychological functions of brain, and we found many of these tests are highly cumbersome, difficult, and time-consuming for neurosurgeons. The FAB is mainly used in neurological patients in Alzheimer's disease, schizophrenia, stroke, and various other neuropsychiatric disorders to find out frontal lobe dysfunctions[1718] and is a simple, yet highly powerful bedside test that demands only some 10 min to perform.[5] However, for FAB to perform, patients need to be conscious and oriented, so we screened patients by performing MMSE and considered patients who scored >24 points.

Functionally, the frontal lobe is divided into DLPFC and MPFC both located in front of premotor area and the basifrontal areas of both the frontal lobes. Processing of visuospatial memory occupies a complex array of neural systems, and distinct prefrontal cortex areas play an important role for this task and are recruited to process information of visual recognition and location.[1920] In this study, we tried to relate the location of lesion and difference in performance of FAB score, and we found early improvement of FAB scoring in MPFC lesions compared to DLPFC which was statistically significant at 3-month follow-up, while no statistically significant improvement was seen in patients where lesion was located in bilateral frontal and basifrontal areas. The DLPFC has afferent connections from specific sensory cortices and dense interconnections with premotor areas, frontal eye fields, and lateral parietal cortex and is primarily associated with cognitive and executive functions.[2122] A previous study[22] has shown that DLPFC lesions confer vulnerability to cognitive decline. The current study shows that improvements in FAB scores in DLPFC lesions are significantly less which is likely due to damage of complex interconnections of this area.

Specific psychological dysfunction occurs either due to frontal lobe space-occupying lesion, mass effect of area, or disruption of cortical and subcortical connections, which controls psychological functions.[232425] The psychological manifestations that occurred because of mass effect or edema gets resolved early due loss of mass effect after surgery; however, due to infiltrative nature of lesions, psychological and neurological symptoms remain for long time.

The major limitation of this study is the limited number of patients recruited. Further research is needed to substantiate and extend the current findings. No significant improvement in basifrontal location in our cohort of patients may be explainable by only fewer number of patients with lesions in this location, so large sample is required to conclude a definite correlation. The present study demonstrates how patients with newly-diagnosed frontal lobe tumors in good neurological condition can be evaluated for surgical therapy in a routine clinical setting by using a simple bedside test. Even patients who do not display overt neurological deficits may suffer from neurocognitive dysfunction that can be uncovered by the FAB.

CONCLUSION

The FAB is a simple, bedside, and less time-consuming psychological test that should be included in routine neurological examination in daily neurosurgical practice to assess the long-term functional outcome and quality of life in patients with frontal lobe lesions. This study shows that almost 40% of the patients presents with some sort of neurocognitive dysfunction before the onset of neurological symptoms, so frontal lobe lesion should be kept in mind in such patients. Brain imaging should be advised for early diagnosis and neurosurgical management in such patients in addition to psychiatric counseling.

Financial support and sponsorship

Financial support was received from department research funds.

Conflicts of interest

There are no conflicts of interest.