Cognitive deficits are common in patients with brain tumor. Research in the 1930s revealed that brain tumor is associated with changes in patients' personality and mood, while malignant tumor sometimes leads to cognitive deficits.1 In 2000, Tucha et al2 reported that more than 90% of patients with brain tumors displayed impairments in at least one area of cognition. Impairments of executive function were observed in 78% of patients, and impairments of memory and attention were observed in more than 60% of patients.2 Headache, dizziness, and neurological deficits are the most common complaints in patients with brain tumor, while subtle cognitive deficits are often neglected by clinicians.
With the rapid development of modern techniques such as neuro-navigation and intra-operative magnetic resonance imaging (MRI), brain tumor resection has become more precise. These techniques involve no damage to normal brain tissue, and can clearly display both the extent of the tumor and functional brain areas. After combining with adjunctive therapy postoperatively, patients with brain tumor can obtain a prolonged survival life span and a better quality of life than before during their disease-free period.3,4 Thus, evaluation of treatment for these patients should not only focus on progression-free survival, but should also examine functional outcomes and adverse treatment effects in the normal brain.5 Meyers et al6 demonstrated that cognitive performance was even more sensitive than MRI evidence of tumor recurrence. Even mild cognitive impairments may compromise an individual's ability to return to their work or other activities, and neuropsychological rehabilitation is important for patients suffering from this condition.7,8
Cognitive function can thus serve as an early indicator of disease progression, and has prognostic significance that deserves the same amount of attention from clinicians as other neurological outcomes.9,10 Not only is this type of research theoretically important, it also provides useful information for clinical practice.
Many previous studies have examined low-grade glioma (LGG). The characteristically young age of diagnosis and the prolonged survival in LGG means that patients are particularly likely to experience treatment-related cognitive impairments.11
Reijneveld et al12
reported that suspected LGG patients scored better on quality of life, motor function, bladder control and psychomotor functioning than patients with proven LGG. Klein et al13
proposed that tumor itself was the main cause of cognitive deficits. In earlier studies, Busch14
reported that patients with high-grade glioma (HGG) performed worse in cognitive tests than those with LGG. Tumor malignancy thus appears to be an important factor in preoperative cognitive deficits.15
However, Scheibel et al16
reported that tumor lateralization and the type of therapy, but not tumor malignancy, were strongly correlated with cognitive dysfunction. The serious cognitive deficits reported among HGG patients have been proposed to be more likely due to higher incidence of intracranial hypertension. Ek et al17
found that tumors with different localization and lateralization were associated with a variety of neurological patterns of dysfunction. A study by Sweet et al18
supported the notion that localization is closely associated with cognitive effects. Anterior cingulate cortex controls anterior attention and conflict monitoring. Patients' response time for processing conflicts has been found to extend with anterior cingulated damage.19
Tumors involving the pineal region have been found to be associated with memory impairment, visuospatial function, attention, visuomotor function, problem solving and affective disorders.20
Medial temporal lobe epilepsy caused by tumor is reported to cause word-finding deficits, dysfunctional long-term memory storage and recall of novel mnemonic material, and difficulties in learning, attention, naming, visuospatial abilities, executive functions, and intelligence.21
Transient mutism and behavioral change have been associated with surgery affecting the vermis.22
reported that brain tumor-related cognitive deficits were not restricted to any single domain, and that even in cases where deficits were related to tumor localization, patients tended to exhibit global deficits.
With the growing consensus on the effect of lateralization, many studies have demonstrated that left-hemisphere tumors cause verbal deficits, including verbal intelligent quotient (IQ) and memory disorders, while right-hemisphere tumors tend to induce non-verbal memory disorders such as visuospatial and abstract reasoning abilities.23-27 This lateralization effect is also relevant to other treatments, including surgery and adjuvant treatment. Scheibel et al16 reported that after surgery or adjuvant treatment, tumor lateralization had a significant impact on cognition, while malignancy and tumor localization did not. Left-hemisphere lesions were associated with lower scores on verbal tests, while right-hemisphere lesions were related to lower scores on a test of facial recognition. These laterality effects were similar to those found in focal neurological disorders, such as cerebrovascular accident.
It has been proposed that some specific domains of cognition depend on intact function of both the left and right hemispheres. Thus, impairment of either hemisphere would be expected to affect cognitive performance in these domains. If a tumor is located in the left hemisphere, dysfunction would be expected to be more serious. Goldstein reported that either hemisphere damage can exhibit greater word recognition memory impairments. And no significant differences in picture recognition memory were found between right- and left-hemisphere damage patients. However, the left-hemisphere group showed more serious impairment with significantly slower mean picture recognition reaction time than the right-hemisphere group.28 Research in our laboratory is consistent with Goldstein's results.28 We found no significant difference in verbal memory test scores between right and left tumor subgroups preoperatively, meaning that patients with right-hemisphere tumors also suffered verbal memory dysfunction.29 This finding might be explained by the uniqueness and complexity of Chinese characters, which may involve both verbal and non-verbal domains in remembering and processing. Japanese investigators reported that the right hemisphere was more important than the left in distinguishing kanji.30 Therefore, our results are in accord with Klein's view13 that global cognitive deficits are common in brain tumor patients. Rather than reflecting a local effect, these findings indicate that whole brain cooperation is essential for intact cognitive performance.
Meningioma is a common type of benign extracerebral tumor. However, little is known about cognitive function in patients suffering from this condition. Tucha et al31
conducted a 4–9-month postoperative follow-up on patients who underwent frontal meningioma resection. Except in the case of working memory, comparisons between preoperative and postoperative assessments of cognition revealed no differences in memory, visuoconstructive abilities, or executive
function, although a postoperative improvement in attention function was observed. Tucha et al32
also investigated cognition among elderly patients with falx cerebri meningioma and found significant improvements in various domains of cognition after surgery. In addition to tumor lateralization and localization, other factors including lesion size, edema, brain compression, and the occurrence of preoperative seizures may affect cognitive functioning to some extent. A recent study of cognitive abilities among patients with meningioma in our laboratory revealed a slight decline in preoperative performance in patients compared to controls. However, patients' performance IQ declined significantly following surgery, which did not occur in an intra-cerebral subgroup. We proposed that the slow growth of the tumor provided enough time for compensation of normal brain tissue, explaining the preoperative mild cognitive effects. After sudden focal decompression due to surgery, shifting and remodeling of the normal brain tissue may cause a rapid and obvious decline in whole brain function, which could affect cognition more severely than focal damage caused by glioma surgery.
Surgery is widely regarded as an effective invasive treatment for most patients with brain tumor, seeking to balance the minimization of neurological deficits with the maximization of tumor removal.5,33 Many previous studies have examined the impact of surgery for a variety of brain lesions on neurological outcomes, particularly motor and sensory function. However, data on cognitive deficits related to brain surgery are limited.5
Studies have consistently found that surgery has a negative effect on cognitive function among patients with glioma. These effects differ from those of diffuse cognitive disturbance caused by radiotherapy and chemotherapy,12,16
and the extent of tumor removal has not been found to affect cognition.34-36
Some previous studies have reported that surgery-related perioperative complications are the dominant cause of post-operative cognitive deficits, including bacterial meningitis, neurological deficits, shunt infection, and multiple surgeries.37-39
Other researches have indicated that cognitive deficits after surgery are not likely to be caused by surgery or perioperative factors.35,40,41
However, due to the plasticity
of healthy brain tissue, several studies have reported that patients suffering high and low grade glioma exhibit long-term postoperative cognitive improvements, usually after a transient decline of cognitive function.36,40,42-47
Yoshii et al34
reported that this improvement was related to tumor lateralization. However, recovery of preoperative impairment has not been reported for patients with left-hemisphere glioma or meningeoma. Talacchi et al36
reported that, apart from an immediate decline in executive function, the overall cognitive burden remained unchanged and was capable of prospective improvement. However, among children, brain surgery was found to contribute to subsequent cognitive dysfunction affecting multiple domains; this dysfunction may extend to adulthood.48-50
Recent results in our laboratory are partially in accord with Yoshii et al's findings, but do not support the results of Tucha. We found a significant post-operative decline of performance IQ among patients with extra-cerebral tumors, and substantial post-operative improvements of IQ in the right intra-cerebral tumor subgroup in a study of IQ among 103 patients with brain tumor. Tumor lateralization was closely associated with IQ, while tumor size, edema, resection degree were mild contributors. After 6-month follow-up, most patients exhibited improved scores.
Systematic reports of the immediate and long-term surgical effects on cognition are rare. Because few standardized scales for measuring neurological status are applied in neurosurgery, and cognitive evaluation is neglected due to the need for specific expertise, multicenter studies tend to be the preferred. It is important for patient compliance to be maximized, particularly after brain surgery.51
Many previous studies have indicated that whole brain radiotherapy is the leading cause of cognitive deficits involving multiple domains, including memory, graphomotor speed, attention, executive function and intelligence. In addition, severe cognitive deterioration caused by radiotherapy has been found to cause permanent dementia.16,17,33,47,52,53
An early study by Sheline et al52 defined acute encephalopathy, early-delayed encephalopathy and late-delayed encephalopathy, to describe neurotoxicity caused by radiation. Cognitive disturbance is a hallmark of diffuse encephalopathy, which can finally lead to dementia or even death.7,53 In addition to direct parenchymal toxic effects, radiotherapy can indirectly affect the central nervous system (CNS), such as via radioactive injury of medium and large vessels.54 The precise pathophysiology of radiation-induced encephalopathy is currently unclear. Both vascular structures and glial cells are affected by late radiation damage, and demyelination and vascular damage have been revealed in histological examination. The glial hypothesis predicts that the primary targets of radiation damage are oligodendrocytes, while the vascular hypothesis predicts that blood-vessel dilatation and wall thickening with hyalinisation, endothelial cell loss and a decrease in vessel density finally lead to white-matter necrosis.55 Endocrine dysfunction can also be caused by radioactive damage to the hypothalamic-pituitary axis, a condition that is commonly overlooked.56 In recent years, neural stem cells were found to play an important role in radiation-induced injury.55 The severity of cognitive dysfunction appears to be proportional to the dose of radiation received by the hippocampus.57
Fraction size, total dose, and target volume extent have been found to significantly impact the incidence and severity of neurotoxicity in patients with glioma.13,58,59 However, most investigations have been retrospective studies, often including a small sample size and lacking proper controls or long-term follow-up. Klein et al13 conducted one large-sample controlled clinical trial, involving mid-term and long-term neuropsychological follow-up of radiation effects. This study included 195 patients with LGG with mean follow-up period of 6 years; they were compared with 100 hematological patients and 195 healthy controls. The results revealed that LGG patients exhibited lower scores in all cognitive domains than the other two groups. Tumor was the main cause of cognitive deficits. However, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy.13 Klein et al60 then conducted a much longer follow-up study of survivors among these patients, at a mean of 12 years after first diagnosis. Attentional dysfunction was found to have deteriorated significantly in patients who received radiotherapy. This deterioration was independent of tumor lateralization, fraction dose size, age, extent of resection and antiepileptic drug use. This progressive decline in attentional function was observed even among patients who received fraction doses that were considered to be safe (≤2 Gy).60 These findings were supported by Corn and colleagues, 61 who reported a strong relation between radiotherapy fraction size and risk of late central nervous system injury, particularly radiation necrosis. Patients who received radiotherapy also performed worse in measures of executive function and information processing speed. White-matter hyperintensities and global cortical atrophy were associated with worse cognitive functioning.62 Surma conducted a study with a mean follow-up period of 10 years, reporting that patients who underwent radiotherapy suffered from more severe cognitive dysfunction than healthy controls. In adults with LGG, postoperative radiotherapy was found to pose a significant risk of long-term leukoencephalopathy and cognitive impairment.58 Apart from a large radiotherapeutic volume (particularly whole-brain radiotherapy), high radiotherapeutic total and fraction dose were identified as potential risk factors that induced cognitive dysfunction in up to 50% of long-term survivors.63 Other important factors linked to increased risk included old age, vascular risk factors such as diabetes, and high blood pressure.
However, a prospective study of the long-term effects of radiotherapy on cognition by Armstrong et al62 reported a selective decline in non-verbal memory 5 years post-radiotherapy, despite long-term improvements in attention, executive function, and verbal memory abilities. Correa indicated that radiotherapy and chemotherapy only exhibited mild effects on non-verbal memory (delayed memory), executive function and quality of life among patients with LGG. Cognitive function was reported to remain stable during 18 months post-radiotherapy.64 Laack et al65 conducted a 3-year cognitive follow-up on patients with supra-tentorial LGG who received radiotherapy, reporting that cognitive function did not significantly change.
In Klein's investigation,13,60
patients received various types of radiotherapy, which were not restricted to whole brain radiotherapy or focal radiotherapy. An increasing number of recent studies include a comparison between these two types of radiotherapy. However, there is a dearth of randomized controlled clinical trials comparing the effects of whole brain radiotherapy (WBRT) and focal radiosurgery (RS) on patients with primary brain tumor. As such, this question remains contentious. Surma-aho et al58
reported that both focal and whole brain radiotherapy can cause cognitive deficits. Jalali et al66
reported that 28 patients with a median age of 13 years presented with unchanged overall mean full-scale IQ at 2-year follow-up after stereotactic conformal radiotherapy, while one third of patients showed a >10% decline in full-scale IQ as compared to baseline. The results of Aoyama
et al's trial indicated that for patients with brain metastasis, WBRT plus stereotactic radiosurgery was able to protect from early cognitive decline, in accord with Roos
' findings. However, another two clinical trials reported that RS combined with WBRT led to worse cognitive outcomes.67-70
Many pharmaceutical treatments are associated with cognitive function. Antiepileptics are commonly used for patients with brain tumor to avoid temporary or permanent epilepsy. However, it has been reported that antiepileptics have cognitive side effects.71-74
Nearly 71% of patients with LGG are prescribed one or more antiepileptic drugs to prevent seizures.75
Older antiepileptic drugs such as phenytoin, carbamazepine, and valproic acid may result in impairments of attention, cognitive slowing, and reduced efficiency of encoding and retrieval.74,76
New generation drugs such as lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate and zonisamide are preferred to control brain tumor-related epilepsy, because they are associated with fewer drug interactions and side effects.72,76-78
Levetiracetam has been reported to lead to worse performance in mini-mental state examination (MMSE
), but is safe and efficacious, with positive impacts on quality of life.75
Long-term use of lamotrigine was reported to be well-tolerated, with little sedation or cognitive impairment.79
Topiramate was found to be associated with cognitive impairment after 24 weeks of treatment in a randomized double-blind study.80
Oxcarbazepine was found to cause no clinically relevant cognitive impairments.81
Correa reported that antiepileptic polytherapy, treatment history, and disease duration all contributed to psychomotor slowing. If patients took more than two antiepileptics, they tended to have lower scores on tests of executive function. Surprisingly, antiepileptic treatment rather than seizure frequency was associated with more pronounced cognitive dysfunction in a large sample of LGG patients, regardless of cancer treatment status.72
For patients with malignant brain tumors, chemotherapeutics with short- and long-term impacts on the CNS are needed to delay tumor progression. However, investigating the neurotoxic side-effects of chemotherapy alone can be difficult, because most patients have already been treated with radiotherapy.82 Attention, concentration and memory are reported to be the primary areas of impairment related to radiotherapy.83 In contrast to late radiation encephalopathy, the CNS side-effects of chemotherapy tend to arise during, or shortly after, drug administration.33 Due to the leakage of the blood-brain barrier caused by radiotherapy, chemotherapy given after, or even during radiotherapy will increase the neurotoxicity of higher doses.71,84-86 Thus, intrathecal chemotherapy, compared with systemically applied chemotherapy, has a much higher likelihood of causing CNS toxicity.78,84,85 For patients with primary CNS lymphoma, chemotherapy-related cognitive impairment was observed in one or more of the following domains: attention, executive function, memory, psychomotor speed and language (particularly naming or fluency). Other clinical trials have shown that patients either remained stable or had exhibited cognitive improvement during the course of initial chemotherapy, provided their tumor was responsive to treatment.87-90 Carmustine, methotrexate and cytarabine have all been found to induce central neurotoxicity.84,91-94 In animal models, these three treatment types were found to exhibit neurotoxicity in neural stem cell populations located in the subventricular zone and dentate gyrus. Primary pathological lesions including demyelination, inflammation and microvascular injury have been postulated as the mechanisms underlying this effect.95 Investigations of the cognitive side-effects of temozolomide, a new chemotherapeutic treatment for patients with glioma, have recently begun.96 It was reported that progression-free glioblastoma patients undergoing radiotherapy with concomitant and adjuvant temozolomide treatment do not exhibit cognitive deterioration.97
Corticosteroids are frequently used for patients to relieve brain edema, but have been reported to have several side-effects, including emotional dysfunction and dementia-like cognitive changes. Corticosteroid-related dementia is characterized by deficits in memory retention, attention, concentration, mental speed and efficiency, and occupational performance. Reduction of steroid medications was found to be helpful for recovering normal cognitive function.98 However, Domes et al99 demonstrated that an appropriate dosage of cortisol can improve memory performance. In addition, functional impairment of the hypothalamus-hypophysis-adrenal axis has been found to cause memory disorder. Cognitive deficits in patients with brain tumors are likely to be alleviated by steroids, because of the treatment of brain edema.33 Therefore, to avoid further cognitive dysfunction, when brain edema is controlled, the use of steroids should be limited as much as possible.
As the survival of patients with brain tumors is increasingly prolonged by new developments in medical research, the effects of tumors and treatment on cognitive function have become more important. Recent studies have reported that patients' cognitive function is associated with multiple factors including tumor type, lateralization, and the use of antiepileptics, surgery, radiotherapy and chemotherapy. Radiotherapy has been examined over several years, and is reported to be closely correlated with cognitive deficits and survival. The mechanisms underlying the neurotoxicity of radiotherapy continue to be investigated. However, it can be difficult to determine the cognitive effects of other treatments, such as chemotherapy, antibiotics, antiepileptics, and steroids. Future research is needed to clarify these potential treatment effects. For clinical physicians, cognitive function should be regarded as an important prognostic index, and neuropsychological tests should be used in regular examinations. When making clinical decisions, neurosurgeons should take cognitive function into consideration. These assessment strategies have the potential to improve patients' quality of life and extend the period of survival.
Acknowledgements: We would like to thank Dr. GUO Qi-hao for his assistance with the scale usage and neuropsychological knowledge.
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