The sequelae of cranial irradiation on human cognition

Neuroscience Letters 382 (2005) 118–123

The sequelae of cranial irradiation on human cognition Vah´e Sarkissian ∗ Department of Neurological Surgery, University of California at San Francisco, 513 Parnassus Ave., San Francisco, CA 94143, USA Received 4 December 2004; received in revised form 19 February 2005; accepted 25 February 2005

Abstract Cranial irradiation (CI) confers remediation of many CNS anomalies. CI, however, carries risks to cognitive performance. A wealth of data describes such deficits specifically in humans. Risk factors that promote increased susceptibility to cognitive decline have also been identified. This paper discusses and grades these risk factors, including age, gender, and the inclusion of chemotherapy, that increase the likelihood of pathologic cognitive development in the human population. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Radiation; Cognition; Neurogenesis; Pediatric; Methotrexate; Female

Despite the plethora of data supporting causality between cranial irradiation (CI) and deterioration of cognitive performance in humans, this process is not fully understood. While we know that age is a critical variable, there continues to be much debate about other factors that effect outcome and remediation. Human data is particularly perplexing, as it trades the experimental control possible when using animals, for a more germane model of human disease. A review of the literature on the effects of CI on cognition, unveils converging findings and important conclusions, especially with regards to the pediatric patient populace. Epidemiologic research shows distinctive patterns in the clinical presentation of CI induced cognitive deficits. For example, the time to clinical presentation of CI propagated cognitive decline, appears to be more chronic rather than acute [38,40,82,101,112,120]. Although one might expect the effects of the irradiation to manifest themselves immediately, negative signs and symptoms often materialize long after the inauguration of radiation therapy [50,59,80,82,101,108]. As well, the specific time-course can be difficult to chart due to methodological problems. Acute data is more readily available than long-term follow-up data in part due to attrition of subjects.

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Evidence suggests that specific characteristics influence the degree of severity of injury. The effects of CI are most pronounced in young patients. The younger the patient, the more likely and the greater the damage to cognitive functioning [5,18,23,28,32,34,39,44,45,51,60,64,77,80,81,86,92,96, 98,100,103,106,109]. Conventionally, children were lumped in the same risk group, however, the impairment is actually greatest in females [18,23,44,60,61,63,77,80,81,92, 94,103,119,120,122]. There is not sufficient data to determine if gender differences appear when CI is inducted in adulthood. The site of intra-axial tumors also plays a role in the degree of damage accrued. Cognitive impairement has been described most thoroughly among children treated for posterior-fossa tumors, particularly, medulloblastomas and ependymomas, which account for about 30% of all newly diagnosed cases of brain tumors in children [16,76,79, 80]. Numerous diagnostic tests, such as the mini-mental status exam and various IQ tests, have been employed [9,29,31,34,75,95,115,117,121,122]. Because no single method of testing is employed, there is a lack of standardization. Thus, results from different studies and time periods are difficult to aggregate, interfering with the analysis of data. A reliable and valid testing paradigm, which assesses various aspects of cognition is needed. Measures with high test–retest reliability under normal conditions would be important for charting the time course of injuries.

V. Sarkissian / Neuroscience Letters 382 (2005) 118–123

Measures of IQ are often used to map the course of postirradiative cognitive development [80,86]. Observed declines in overall IQ are most likely a result of failure to continue to learn post-CI at an age-appropriate rate, rather than from a loss of previously acquired knowledge [22,80,86]. Deficits on non-verbal tests, such as visual motor integration, appear early [21,74,90]. Damage to cerebral white matter, as well as failure to develop white matter at a rate appropriate to the developmental stage, could partly account for these measured declines [80]. Attempts at mitigating the effects of CI have had mixed results [42]. Changes in the radiation protocol have been shown to reduce side-effects [33,41]. Dosage titration and fractionation are two strategies that have been consistently reported to attenuate the cognitive decline [33,35,37,38,62,67,68,77,82,89,97,118]. The use of erythropoietin has been demonstrated to be beneficial [104]. The mechanism of action may be secondary to the correction of a hypoxic environment created by the CI [1,31]. Residual microscopic disease in children may be addressed by implantation of low-activity (125)I seeds in the tumor bed at the time of surgery [99]. Conversely, radiation enhancers, such as motexafin gadolinium, have been trialed with inconsistent outcomes [66]. The current drought in treatment options may stem from the lack of an identified pathophysiologic process generating the post-CI cognitive impairments. Some aspects of the progression, however, are known. Vascular injury is one of the major component in the pathogenesis of CI induced CNS toxicity [25,54,64,83,84,114]. Increased microvascular permeability and loss of blood–brain barrier integrity are significant features of this injury [83]. It appears that CI induced cellular hypoxia stimulates the up-regulation of vascular endothelial growth factor (VEGF), which in turn perpetuates endothelial leakage and damage [55,83]. This stimulation of VEGF is mediated by hypoxia-inducible factor-1alpha (HIF1alpha) [83]. The extent of the damage is dose dependent in that increasing the quantity of CI intensifies the vascular damage. It should be noted that the injury is isolated only to the white matter, with no corresponding VEGF increases in the grey matter [54]. Indeed, the potentiation of these microscopic wounds to the vessel walls will precede the leukoencephalopathy (LE), which is characteristic of radiation induced neural injury. It was recently discovered that the instigation of blood–brain barrier disruption by CI induced vascular injury, is paralleled by the amplification of intercellular adhesion molecule-1 (ICAM-1) [84]. When conspicuous morphologic changes are grossly witnessed, the noted LE is a common finding, with older age being catalytic [27,49,81,108,116,121]. The late delayed radiation effects to white matter, investigated by means of (1)H magnetic resonance spectroscopic imaging, have demonstrated a loss of N-acetyl aspartate, and either equivocal or reduced choline and creatine levels in radiation-induced hyper-intensity areas and choline alone in normal appearing white matter. The former indicates arborization and

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membrane damage, while the latter implicates only membrane damage [117]. Despite its presence, white matter lesions may not be the cause of the chronic neurologic dysregulation, because LE has a favorable prognosis, while cognitive impairment is enduring [27]. The favorable prognosis of LE appears to be due to the frequent sparring of axons even when there is collateral unsheathing of myelin [27]. Somnolence syndrome secondary to demyelination, has been posited to be a marker of very late neurologic involvement [11,112]. After CI, deterioration in hippocampal neurogenesis can be quantified. Because it may play an important role in the development of cognitive function, it is being looked into as a potential contributory factor in the development of the cognitive defects after CI [14,52,57,70–72,93,110]. Neurogenesis is a microscopic process that cannot be viewed grossly by current radiologic modalities. Radiologic follow up often reveals no gross anatomic abnormalities, despite the presence of cognitive impairment, which lends credence to microscopic neurogenesis as a prime suspect [9,10,24,57,71,72,83,108]. There are many factors that contribute to the decrease in hippocampal neurogenesis. Radiation-induced reactive oxygen intermediates appear to play a role in mediating this toxicity [57,93,104]. In concert, a chronic inflammatory process may preserve the detrimental milieu [14,57,71,72,104]. On a hormonal level, glucocorticoid is a potent inhibitor of neurogenesis [3,4,12,13,19,58,85,111]. It should be noted, however, that it is not yet proven that an insult to neurogenesis convincingly translates to clinical deficits in cognition. A review by Kempermann et al. [48] offers that newly formed neurons function as part of a chronic adaptation process in the brain, rather than offering any acute benefits. Their theory is supported, by the clinical observation that CI induced cognitive decline is most appreciable at later time points in a patient’s course. Regardless of the nature of the pathophysiologic mechanism, the hippocampus has emerged as one of the main regions of injury [2,6,46,93,110]. This mapping is a result of the specific type of deficits CI induces. Memory loss, in various forms, especially spatial dependent, is a ubiquitous feature of the signs and symptoms reported [2]. There is preliminary evidence for a specific vulnerability of visual attention and memory during the early stages of late radiation damage [8]. In the past, there has been a perception of increased risk for cognitive deficits when chemotherapy has been given jointly with CI. Evaluation of the available literature, however, suggests a contrasting view. The majority of children who endure brain tumors require surgical resection, chased by focal or craniospinal radiotherapy, with or without systemic chemotherapy [80]. Interestingly, the co-inclusion of methotrexate was hypothesized to intensify the cognitive deficits that CI can induce in children. Retrospective studies do not lend much support to this theory. Some studies have found no effects of methotrexate on cognitive decline, while others have shown very small negative effects on cognition from the addition of methotrexate to the treatment regime [6,15,20,26,36,40,47,49,51,64,69,97,102,105]. Furthermore, while the variety and the site of the tumor, whether

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on the left or right side of the brain, may account for some of the acute losses identified, these variables do not seem to contribute to the late-developing effects of CI on cognitive functioning [30,56,78]. Thus, by extension, the primary role of CI alone causing the cognitive damage is strengthened. Pediatric endocrinologic malfunction is also wellrecognized as sequelae of CI. Hypopituatarism, via hypothalamic-hypophyseal failure, often supersedes even memory incompetence as the most common side-effect of CI in children [63,65,88,99,107,113]. Stratification places somatotrophin as the pre-eminent deficiency [63,113]. This is logical, as it is the most sensitive of the anterior pituitary hormones to irradiation, followed by gonadotrophins, adrenocorticotrophic hormone (ACTH) and thyroid-stimulating hormone (TSH) [113]. Eighteen gray has been cited to be potent enough to result in growth hormone deficiency, while a dosage of 40 Gy is capable of educing the various other neuroendocrinologic anomalies [63]. In 1992, one study confirmed that children treated for primary CNS tumors with irradiation suffer greater growth hormone deficiencies than those managed with surgery alone [73]. In adults, as in children, the differentiation between the negative neuropsychological effects of a pre-existing CNS tumor and those caused by CI has been challenging to make. This is partly due to the cognitive deficits that primary CNS tumors themselves can cause in humans [87,98]. Looking at CI in cases of non-intra-axial CNS tumors or those that have not relapsed, may provide a clearer indication of what effect CI itself is having on human thinking [17,87,88,98]. In cases where the primary tumor is not suspected to invade deep into the cerebral quadrants, such as nasopharyngeal carcinoma and rhabdomyosarcoma, radiotherapy is the treatment of choice [17,53,88]. Yet, significant mental decline still emerges [7,17,88]. The mechanism of injury would, therefore, be attributable to the radiotherapy and not the malignancy. In fact, some papers have postulated that cognitive decline in adults may be underreported partly due to these factors [7,24]. Based on the success that CI has had in eradicating dysplasia, it is a treatment modality that cannot be abandoned any time soon. Rather, the pathophysiologic mechanism by which its sequelae are encouraged should be more clearly delineated. Towards this goal, the region of the hippocampus may deserve further scrutiny as a molecular nexus is pursued. Furthermore, heightened susceptibility in young females offers a specific patient group from whose internal physiology, pathologic mediators may be identified and targeted. For example, recently it was discovered that the distribution of GABAergic neurons of the stria terminalis is not equal between males and females [91]. This is of interest as these neurons are an integral part of cortisol’s negative feedback loop on the CNS [43]. Therefore, because we know that glucocorticoid imparts a deleterious effect on hippocampal neurogenesis and that females appear to be more susceptible to the cognitive decline secondary to CI, this neuronal pathway may prove to be of particular

importance in the development of this pathologic condition. In the interim, the scientific community has reported a robust relationship between CI and cognitive decline in humans. Further investigation into its consequences is warranted in an effort to establish a commensal, rather than destructive, relationship between CI and the patients who require it.

Acknowledgement I would like to thank Carolyn Phinney for her invaluable help in editing this manuscript.

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