Neurotoxic effects of cranial irradiation

Patients can receive cranial irradiation to treat primary or metastatic brain tumours, or as prophylaxis of other cancer. Radiation can be delivered to the lesion(s) using large focused doses (stereotactic radiation), as part of standard fractionated treatments, or to the whole brain (whole brain radiotherapy; WBRT). Potential risk factors for cognitive decline following brain radiation include receiving fractionated radiation doses greater than 2 Gy, total radiation dose, brain volume and location of irradiation, divided‐dose schedules and overall treatment time (Lee 2002). Other risk factors may include combined or subsequent chemotherapy use, age, with those under seven years or greater than 60 years old at higher risk, and comorbid vascular risk factors such as diabetes and hypertension (Crossen 1994; Szerlip 2011). In the identification of treatment‐related neurotoxicity it is important to distinguish symptoms from tumour progression, recurrence or metastases as discontinuation of treatment may lead to irreversible central nervous system (CNS) injury (Dietrich 2008).

The neurotoxic effects of brain radiation can be divided into acute, early‐delayed and late‐delayed radiation encephalopathy (Sheline 1980). Acute radiation encephalopathy, within two weeks of therapy, occurs as a result of disruption to the blood‐brain barrier, and associated vasogenic oedema. Corticosteroids are used at this stage, and may improve symptoms of somnolence and headache, and prevent further neurologic decline. Early‐delayed radiation encephalopathy may occur at one to six months following completion of treatment, and symptoms of short‐term memory and attentional deficits are seen alongside drowsiness and worsening of pre‐existing neurological deficits. A return to baseline is often found within 12 months (Vigliani 1996). This phase is associated with blood‐brain barrier disruption, and reversible demyelination (Taphoorn 2004). In contrast to early complications, late‐delayed radiation encephalopathy is viewed as irreversible. This complication occurs months to years following radiation therapy and manifests as white matter lesions (i.e. leukoencephalopathy) or, in more severe forms, space‐occupying necrosis with mass effect and associated neurological dysfunction (Fink 2012).

The precise relationship between initial acute changes and late/chronic radiation damage to the brain is unknown. Clinically it is characterised by progressive mental slowing and impairment in attention and memory, with less commonly gait ataxia, urinary incontinence, apathy, and pyramidal and extrapyramidal signs (Taphoorn 2003). These cognitive deficits increase in incidence and severity over time (Klein 2002), however the exact incidence is hard to distinguish due to the range of neuropsychological tests, the population and the time at which patients are followed up (Taphoorn 2004). For example, up to 90% of adult brain tumour patients who survive for more than six months following WBRT therapy develop (some form of) cognitive impairment (Crossen 1994), and in up to 5% of long‐term survivors the cognitive impairment progresses to dementia necessitating admission to a nursing home (DeAngelis 1989; Vigliani 1996). The incidence of severe cognitive deficits/late delayed radiation encephalopathy is even higher in patients with primary CNS lymphoma, reaching nearly 100% in patients older than 60 years old (Abrey 1998). Due to these adverse effects of cranial irradiation, the benefit of radiotherapy treatment for patients with a more favourable prognosis, such as with a low‐grade glioma (LGG), or as prophylactic cranial irradiation for small cell lung carcinoma, has been the subject of much debate in the past decade (Gondi 2013).

The mechanism of cranial irradiation‐induced cognitive deficit

The mechanisms by which radiation causes cognitive decline, particularly in learning and memory, have been proposed to relate to metabolic changes, white matter changes and radionecrosis, as well as changes in neuronal function, particularly synaptic plasticity, and long‐lasting damage to hippocampal neurogenesis (Greene‐Schloesser 2013). Of those, impaired white matter radiation changes and neurogenesis are the most thoroughly studied.

The primary mechanism of delayed radiation‐induced white matter changes is associated with secondary endothelial damage and microvascular ischaemic insult (Lyubimova 2004), accompanied by a reduction in the proliferative capacity of glial cells (Van Der Maazen 1993). This leads to a decrease in the volume of cerebral white matter, which is directly associated with cognitive decline (Correa 2004; Mulhern 2004; Reddick 2006). This has been confirmed in a longitudinal study that found medulloblastoma patients receiving a cranial irradiation dose of 36 Gy to show more rapid cerebral white matter volume decrease than those receiving a cranial irradiation dose of 23.4 Gy (Palmer 2002). Rarely, these white matter lesions can increase in size and may progress to frank white matter necrosis characterised by focal cavitations in the white matter within the radiated fields (Anscher 1991). Treatment of radionecrosis involves surgical excision and steroid therapy, and recent studies using bevacizumab, an angiogenesis inhibitor, have also reported high rates of clinical and radiological responses, albeit with small sample sizes (Gonzales 2007; Levin 2011; Torcuator 2009; Wang 2012).

Neurogenesis refers to self renewing cells that may produce neurons, glial cells and lineage‐restricted precursor cells throughout life, associated with normal hippocampal functioning (Zhao 2008). This was explored in a post‐mortem study in patients with medulloblastoma treated with radiotherapy 2 to 23 years prior to analysis, which found significantly lower neurogenesis than controls, matched for age and sex (Monje 2007). Therefore radiotherapy strategies that attempt to spare the crucial areas of neurogenesis may produce better cognitive outcomes, compared to WBRT (Dietrich 2008; Peiffer 2011).

Measuring cognitive deficits

Cognitive functioning has been measured objectively using a battery of validated neuropsychological tests that assess different cognitive abilities (Gehring 2009; Meyers 1998); these can include tests such as digit span (Wechsler 1981), the Hopkins Verbal Learning Test (Brandt 1991) and the Controlled Oral Word Association test (Benton 1989), to assess working memory, short‐ and long‐term memory, and verbal fluency. Cognitive function has also been determined through the use of brief mental status evaluations, such as the Mini‐Mental State Examination (MMSE). Whilst the MMSE is often shorter than neuropsychological testing, it has been associated with poor sensitivity in detecting cognitive deficits (Meyers 2003). Other studies have used subjective patient reports of cognitive concerns, such as in memory and concentration (Lidstone 2003; Mukand 2001). These are suggested to be confounded by a patient's lack of appreciation regarding their cognitive impairments, and correlations with fatigue and depression, rather than cognitive test performance (Cull 1996). An additional consistent finding from the research literature is that correlations between subjectively assessed cognitive symptoms and objectively determined cognitive functioning are quite modest, with correlation coefficients generally ranging from 0.20 to 0.30 (Klein 2002).

Differences in the time points at which cognitive functioning is measured are also present, both in pharmacological and non‐pharmacological intervention studies. One study carried out assessments at baseline, and at four weeks of modafinil or methylphenidate use (Gehring 2012), whereas another continued to follow patients at 8, 16, 24 and 52 weeks following initiation of the drug memantine (Brown 2013). In cognitive rehabilitation studies patients were assessed at baseline, at the end of a seven‐week intervention and at six months (Gehring 2009), compared to baseline, at the end of a two‐week intervention and at three months (Locke 2008). These studies also demonstrate the variations in duration of the intervention.

The variations in tools available, use of both objective and subjective measures, differences in time points at which cognitive functioning is measured and the differences in intervention duration highlight the caution that must be taken when combining and generalising results and conclusions.

Pharmacological

We define pharmacological interventions as a drug given by any route at any therapeutic dose with the intention of preventing or treating cognitive deficits in persons who have received cranial irradiation.

Studies investigating the pharmacological prevention of cognitive impairment frequently occur in patients undergoing cranial irradiation during participation. For example, memantine (Brown 2013), used in the treatment of Alzheimer's Disease, and lithium (Khasraw 2012), used in the treatment of psychiatric disorders, have both been investigated for their neuroprotective role during irradiation.

Studies of pharmacological treatment for cognitive impairment after cranial irradiation have largely focused on psychostimulants (methylphenidate and modafinil, and donepezil). Improvements in both subjective and objective cognitive functioning were seen in one study investigating the effects of methylphenidate and modafinil in brain tumour patients, 83% of which had received cranial irradiation (Gehring 2012). Donepezil, used in the treatment of Alzheimer's Disease, has also been found to show improvements in cognitive symptoms in brain‐irradiated adults (Shaw 2006).

Non‐pharmacological

We define non‐pharmacological interventions as any non‐drug intervention given with the intention of treating or preventing cognitive deficits during or following cranial irradiation. These can include, but are not limited to, medical, psychological and behavioural interventions, as well as alternative interventions such as the use of dietary supplements.

Medical interventions include any biomedical intervention given to a person in which the intervention is not primarily investigating cancer treatment or control. For example, a study exploring the use of hyperbaric oxygen therapy in cranially irradiated brain tumour patients found improvements in nine of 31 neuropsychological tests in six of seven patients, although this did not reach significance (Hulshof 2002).

Psychological interventions may include (but are not limited to) retraining, education and compensation strategies. A randomised clinical trial investigating the use of cognitive rehabilitation in glioma patients, 61% of which had received cranial irradiation, investigated computer‐based retraining and compensatory strategies. A significant improvement in objective and subjective cognitive functioning, as well as perceived burden and mental fatigue, was found (Gehring 2009).

Behavioural interventions can include exercise, as well as behavioural modification interventions.

Dietary supplements such as Ginkgo biloba have also been investigated in irradiated brain tumour patients, with some findings of cognitive improvement, although results are confounded by a high drop‐out rate (Attia 2012).

Pharmacological

Pharmacological interventions may prevent cognitive deficits via their neuroprotective role during WBRT such as memantine, an N‐Methyl‐D‐aspartate receptor antagonist (Brown 2013), and lithium, found to reduce oxidative distress via the glutathione system (Machado‐Vieira 2007).

Pharmacological interventions may ameliorate cognitive deficits via their involvement in critical neurotransmitter pathways. Methylphenidate is a CNS stimulant found to have a positive effect on attention due to its action on the brain centre for attention control, the fronto‐striatal network, by increasing dopamine and noradrenaline concentrations (Volkow 2002). Another centrally acting drug is donepezil, a reversible cholinesterase inhibitor involved in inhibiting the breakdown of the neurotransmitter acetylcholine. This may have a cognitive enhancing effect in cancer patients by prolonging and improving cholinergic function, associated with learning and memory (Steinberg 2011).

Non‐pharmacological

Medical interventions have also been considered to help prevent or treat cognitive deficits. Hyperbaric oxygen therapy has been used to improve damage to the nervous system by stimulating angiogenesis, the process through which new blood vessels are formed from pre‐existing blood vessels (Gill 2004).

Psychological interventions may help prevent and improve cognitive deficits by retraining cognitive capacities such as attention and memory, or via compensation strategies such as memory aids (Gehring 2009). These interventions target the plasticity of the brain, via restoration or reorganisation of function.

Behavioural interventions, such as exercise, may also help ameliorate or prevent cognitive deficits. Exercise has been associated with increases in cerebral blood flow, increased hippocampal neurogenesis, changes in neurotransmitter release and arousal levels and brain structure, and particularly through the involvement of a Brain Derived Neurotrophic Factor (Gligoroska 2012).

Other non‐pharmacological interventions, such as those involving diet modification, may also play a role in improving cognitive functioning. The dietary supplement Ginkgo biloba has been associated with regulating signalling pathways, cellular metabolism and gene transcription (Smith 2003).