Acute radiation encephalopathy

Acute radiation encephalopathy appears within 2 weeks of the start of brain radiation therapy and occasionally a few hours after the first fraction. The most common symptoms are drowsiness, headache, nausea and vomiting together with a worsening of pre-existing neurological deficits. The main risk factor is the size of the tumour and the dose per fraction (usually >3 Gy/fraction). It rarely occurs nowadays as dose fractionation is restricted and large tumours are routinely debulked before radiation therapy. Patients usually recover quickly although herniation and death have been reported. In an older series, acute radiation encephalopathy occurred in half of patients with brain metastases treated with 15 Gy in two fractions.6 As the conventional dose fractionation for whole brain radiotherapy nowadays is either 20 Gy in five fractions over 1 week or 30 Gy in 10 fractions over 2 weeks,7 this complication almost never occurs.

Sometimes patients report nausea and moderate headache on the evening after the first fraction of radiation therapy. Corticosteroids may help especially in patients with large tumours or with considerable oedema particularly at risk of herniation. Where surgical debulking is not possible, these patients should be prescribed dexamethasone 16 mg per day 2–3 days before the first fraction and the dose per fraction ideally limited to 2 Gy. The pathophysiology of acute radiation encephalopathy probably results from radiation-induced blood-brain barrier disruption, accounting for a rise in intracranial pressure.

Early-delayed radiation encephalopathy

Early-delayed radiation encephalopathy is so called as it starts from 2 weeks to 6 months after completing radiation therapy. The pathophysiology is probably transient demyelination caused by blood-brain barrier disruption and/or oligodendroglial injury. The most common symptoms include fatigue, drowsiness, lethargy, memory and attentional deficits. At its worst, patients may be asleep for most of the day. Somnolence syndrome, characterised by hypersomnolence, nausea and anorexia, was first described in children receiving low-dose radiation therapy for scalp ringworm and after prophylactic cranial radiation therapy for leukaemia; it occurs less commonly in adults. The diagnosis is clinical as neither MR imaging nor EEG shows specific changes. Patients usually improve within a few weeks. There may be a biphasic course with symptoms appearing from days 11 to 21 and then again from days 31 to 35.8 As a result, many oncologists continue corticosteroids during and after radiotherapy.

Pseudoprogression

About 6–12 weeks after the end of radiation therapy, patients may experience worsening of pre-existing neurological deficits, leading to the suspicion of tumour progression. Imaging is usually unhelpful as the MRI may show appearances of tumour progression that resolve over the next few months without any specific antitumour intervention. This phenomenon is known as ‘pseudoprogression’ and occurs in up to 30% of patients with glioblastoma treated with concomitant temozolomide and radiotherapy. Ironically, pseudoprogression may be associated with a better tumour response.9 Patients usually improve within a few weeks or months associated with slow radiological improvement. Advanced imaging techniques such as perfusion-weighted imaging and MR spectroscopy may help to distinguish pseudoprogression from true progression but interpretation is limited by the presence of residual tumour within the irradiated area.

Some patients report poor attention and memory for up to 6 months following brain radiation therapy, which reassuringly does not predict the development of long-term cognitive decline. We, therefore, warn patients who are keen to resume work immediately after radiation therapy that they should inform employers about the possibility of a delayed or phased return.

Brainstem syndrome

An early-delayed subacute brainstem syndrome can occur 1–3 months after radiation therapy for pituitary or head and neck cancer, where the treatment fields overlap the brainstem. Clinical features include ataxia, dysarthria, diplopia and/or nystagmus as well as hearing loss. MR brain scan sometimes shows high signal change within the white matter of the brainstem and the cerebellar peduncles, which may enhance. This condition usually responds to corticosteroids within a few weeks; very rarely it results in coma and death.

Radionecrosis

Radionecrosis is the most common late complication and was first described pathologically in 1948 in a series of patients, one of whom had a recurrent ‘rodent ulcer of the scalp’ and a normal brain.10 It can be difficult to distinguish from tumour recurrence both clinically and radiologically. Nowadays, radionecrosis most commonly follows focal radiation therapy for a brain metastasis but can also occur in patients who have had radiation therapy for extracranial and extra-axial tumours, in whom normal brain was included within the radiation field (eg, head and neck cancer, skull osteosarcoma, pituitary adenoma, clival chordoma). A typical example is bilateral medial temporal lobe necrosis following radiation therapy for pituitary tumours (figure 2) or nasopharyngeal cancer. It is seen less often nowadays due to reduction in dose per fraction and improvements in the delivery of radiation therapy. It is now recognised that the upper limits of a ‘safe dose’ of 55–60 Gy administered to a focal field with fractions of 1.8–2 Gy per day are associated with a less than 5% risk of radionecrosis. Patients with vascular risk factors such as hypertension, diabetes and old age are at higher risk of radionecrosis, as are those who have concomitant chemotherapy. Some patients without any particular risk factors may develop radionecrosis, probably because of increased sensitivity to radiation, such that they develop this complication at conventional dose fractionation.11

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Figure 2

Radiation necrosis. A 37-year-old patient presenting with severe amnesia 4 years following proton beam therapy for a pituitary adenoma. Axial T2W (A), T1W+gad (B) images show bilateral temporal signal change and oedema with irregular enhancement in medial temporal lobes, typical of radiation necrosis. There was no improvement with corticosteroids and the patient remained severely incapacitated by fatigue and amnesia.

Radionecrosis nowadays most commonly occurs after stereotactic radiosurgery, for example, Gamma Knife treatment for brain metastases (5%–25% of cases) and also for non-neoplastic conditions such as arteriovenous malformations (up to 20% of cases). Symptoms of radionecrosis are indistinguishable from those of tumour recurrence or progression and brain imaging is likewise similar. More recently, an MRI sequence with delayed contrast sequences known as TRAMS (treatment response assessment maps) or contrast clearance analysis has become routinely available in clinical practice as it is both sensitive and specific.12 It requires the acquisition of two standard 3D T1-weighted MR brain scans—one 5 min after injection of gadolinium and another after an hour. The first series is digitally subtracted from the second. The analysis results in high-resolution, volumetric maps that can distinguish regions of contrast clearance (blue) from contrast accumulation (red). Radionecrosis shows up as red due to the poor clearance of contrast in non-viable tissue-containing irradiated vessels, while tumour recurrence shows up as blue due to the rapid clearance through tumour vasculature (figure 3).

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Figure 3

Treatment response assessment maps (TRAMS)/contrast clearance analysis maps contrast-enhanced T1-weighted MRI (T1-Gd, top) and the calculated TRAMS image (bottom) of a patient receiving stereotactic radiosurgery for a malignant melanoma brain metastasis. Before the radiosurgery (left) the enhancing lesion on T1-Gd appears blue in the TRAMS scan. Follow-up MR scan of brain 10 months following stereotactic radiosurgery (right) shows significant shrinkage of the enhancing lesion on T1-Gd, appearing red, suggesting radiation necrosis. (Courtesy of Prof Yael Mardor, Sheba Medical Centre, Israel).

Refractory cases of radionecrosis are treated with dexamethasone and resection of necrotic foci. Corticosteroid dependence can occur. Other treatments such as hyperbaric oxygen or drugs such as pentoxifylline, alpha-tocopherol and pentobarbital have also been tried but without clear evidence of efficacy. A recent systematic review concluded that bevacizumab appeared to be more effective and just as safe as corticosteroids.13

Late-delayed radiation encephalopathy

It has been known for many years that radiotherapy can cause delayed cognitive impairment that varies from mild memory loss to a severe dementia.14 This complication develops more frequently in adult survivors of childhood brain tumours and in patients with low-grade gliomas where the tumour remains in remission for many years.15 MRI shows variable degrees of high T2W signal change in the subcortical white matter and brain atrophy. Some patients deteriorate slowly while most remain stable. Cerebral atrophy may also be strikingly focal where specific lobes of the brain have been irradiated (figure 4). This syndrome has no recognised treatment although some authors have advocated using anticholinesterases for symptomatic benefit.16

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Figure 4

Delayed radiation encephalopathy. A 55-year-old patient treated with bifrontal parallel fields to a right frontal glioma in 1997, presenting with progressive cognitive and behavioural decline 25 years later. Sagittal (A) and coronal T1W (B) shows striking bifrontal and perisylvian atrophy with relative preservation of the parietal and occipital lobes. Note the enhancing residual tumour.

The long-term cognitive effects of radiotherapy in patients with low-grade gliomas have been reported in a study comparing 195 patients with low-grade glioma (of whom 104 had been treated with radiotherapy) with a matched series of patients with low-grade haematological malignancies and healthy controls, followed up for at least 6 years. Patients with low-grade glioma experienced significant problems across a range of Health-Related Quality of Life domains, including neurocognitive deficits, but these were associated with tumour changes. Only high dose per fraction (>2 Gy) resulted in significant added cognitive decline.17 Interestingly, the same group published their findings after a follow-up of 12 years and found that the patients who had received radiotherapy even at doses less than 2 Gy/fraction showed a progressive decline in attentional and executive functioning and speed of information processing. Fifty-three per cent patients who had radiotherapy developed cognitive deficits in at least five of 18 neuropsychological test areas compared with 27% patients who had not received radiation therapy.18

Whole brain radiotherapy was the standard treatment for brain metastases until the last decade but causes cognitive decline in over 60% of patients within 2–6 months of treatment. It has now been replaced by stereotactic radiosurgery for fit patients with stable or controlled extracranial disease and a reasonable prognosis from their underlying cancer (at least 6 months).19 Hippocampal sparing techniques are gaining in popularity for patients with brain metastases who are not suitable for treatment with stereotactic radiosurgery, but these techniques have not yet been shown to provide a consistent cognitive advantage

In patients with primary CNS lymphoma who have been traditionally treated with combined high-dose intravenous methotrexate chemotherapy followed by whole brain radiotherapy, the incidence of severe cognitive impairment increases with age, reaching 83% in patients over 60 years.20 Based on the results of a randomised phase 2 study by a European consortium (the IELSG-32 study), the standard of care across Europe for fit patients with primary CNS lymphoma aged under 70 years is now a chemotherapy regimen known as Methotrexate, Ara-C, Thiotepa and Rituximab (MATRIX) followed by autologous stem cell transplantation, a strategy that avoids using whole brain radiotherapy altogether, thus reducing potentially fatal neurotoxicity.21

Radiation-induced secondary normal pressure hydrocephalus

Radiation-induced dementia is characterised by a ‘subcortical dementia’ pattern associated with diffuse white matter injury, usually starting within 2 years of treatment. Patients may present with a picture similar to normal pressure hydrocephalus and develop progressive memory loss, reduced attention, gait difficulties, urinary incontinence and fatigue. There may be emotional lability and apathy that is difficult to distinguish from depression. Antidepressants are frequently tried but do not improve cognitive function. Eventually, patients may develop akinetic mutism. MR scan of brain shows ventricular enlargement, diffuse confluent subcortical white matter change, with cortical and subcortical atrophy.

There is no specific treatment for radiation-induced dementia. However, ventriculoperitoneal shunting is sometimes tried with incomplete and short-lived improvement (figure 5).22 Deterioration occurs in about 80% of cases and death generally occurs within 4 years after the onset of the disorder.

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Figure 5

Secondary normal pressure hydrocephalus. A 66-year-old with left occipital glioblastoma treated with concomitant chemoradiation. Within a year of radiotherapy (54 Gy in 30 fractions) she became increasingly unsteady due to an apraxic gait with urinary incontinence and mild memory loss. Her condition improved with ventriculoperitoneal shunting but the improvement was short-lived and she died of progressive disease 9 months later. Coronal T1W post-Gd immediately after radiotherapy (A) showing normal ventricular dimensions and 1 year later (B) showing dilatation of posterior horns and fourth ventricle and sulcal effacement. Note tumour recurrence around the left lateral ventricle with surrounding oedema.

Radiation-Induced brain tumours

Irradiated patients are more prone than the general population to developing second brain and spine tumours. Meningiomas (70%) (figure 6), gliomas (20%) and sarcomas (10%) are the most common tumours and develop many years (mean onset 12 years) or decades after treatment. In a study of over 10 000 patients treated for tinea capitis with low-dose (1.5 Gy) radiation, the relative risk for all tumours was 6.9 and the risk for glioma was 2.6.23 This has been confirmed in several other studies. In patients treated for childhood acute lymphoblastic leukaemia, the relative risk is so high22 as to justify screening MR brain imaging for adult survivors.24

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Figure 6

Radiation induced meningiomas. A 48-year-old patient presenting with new onset generalised seizures; she had received whole brain radiotherapy 30 years previously for a pineal germinoma. Coronal contrast-enhanced T1W image shows two meningiomas both within the midline, one arising from the falx and one from the tentorium, with no evidence of tumour recurrence in the pineal gland.

In order to diagnose a radiation-induced tumour, there must be a long interval between the treatment and the occurrence of the second tumour (there have been cases developing over 60 years later), the tumour has to grow within the radiation field or at its margins, and be of a different histological subtype to the primary tumour. These tumours have a poor prognosis as such patients have limited reserve for further radiotherapy. However, the longer the gap between the original treatment and the secondary tumour, the more scope there may be due to normal tissue recovery.

Radiation-Induced vasculopathy

Radiation can damage the intracranial vasculature leading to ischaemic stroke or haemorrhage. The carotid artery can become stenotic after cervical radiotherapy for lymphomas or head and neck cancers and occasionally can rupture a few weeks after radiation therapy causing death. However, late-delayed complications are more frequent and generally occur many years after treatment (median time about 20 years for extracranial arteries, 7 years for intracranial arteries). Radiation-induced vasculopathy is an accelerated form of atherosclerosis and often occurs in unusual locations, for example, the distal internal carotid artery. It has been described within 2 years of proton beam therapy for childhood brain tumours.25 The lesions consist of one or more arterial stenoses or occlusions of the carotid or cerebral arteries within the radiation portal. Pathological findings include destruction of the internal elastic lamina and replacement of the normal intima and media with fibrous tissue. Treatment includes managing vascular risk factors and, where appropriate, carotid endarterectomy. However, surgery may be more difficult because of vascular fibrosis and poor wound healing. If a patient with previous radiation therapy develops a stroke, it should not be assumed to be due to radiation vasculopathy unless it is within the radiation portal, and other risk factors should be sought.

Moyamoya disease

Moyamoya disease is a progressive occlusive cranial vasculopathy characterised by abnormal anastomoses and netlike blood vessels at the apices of the intracranial internal carotid arteries, the proximal anterior cerebral arteries and middle cerebral arteries.26 It results in decreased cerebral blood flow with an increased risk of stroke, transient ischaemic attacks and focal seizures. It often develops in patients who had cranial radiation therapy as young children, particularly those treated for optic chiasm glioma, a condition often associated with neurofibromatosis type 1, which is a risk factor for vasculopathy in itself. The strong association between neurofibromatosis type 1 and moyamoya is one of the reasons why radiation has been replaced with chemotherapy in younger children with optic pathway gliomas. Treatment is aimed at preventing further strokes through surgical revascularisation procedures.

Radiation-induced cavernomas, angiomatous malformations and aneurysms

Vascular malformations such as telangiectasias and cavernomas are increasingly being recognised as a long-term complication of brain radiotherapy, due to the routine inclusion of gradient-echo and susceptibility weighted sequences in modern MRI protocols. When present, their main risk is intracranial haemorrhage, but this is rare.27 There have been occasional cases of radiation-induced intracranial aneurysms reported with fatal outcomes.

SMART syndrome

Stroke-like migraine attacks after radiation therapy (SMART syndrome) is a poorly understood late complication of brain radiation therapy for both primary and secondary brain tumours. It presents with a combination of migraine-like headaches and cortical dysfunction including seizures and focal neurological deficits, for example, aphasia, neglect and hemiparesis. Seizures may be prolonged and respond poorly to antiseizure medication. Corticosteroids do not seem to help. It has a distinctive radiological appearance with pial enhancement and cortical high signal change within the radiotherapy field. It is now recognised that neurological deficits can persist even after radiological improvement.28 There is imaging evidence (from CT perfusion studies) that SMART syndrome is caused by reversible hemispheric hypoperfusion,29 but there is often elevated relative cerebral blood volume in the acute phase on dynamic susceptibility contrast perfusion MR imaging (figure 7). There is no known treatment for SMART syndrome although anecdotally, L-arginine has been used to good effect in two reported acute cases. One of our patients who had four previous severe attacks of SMART every 15 months has not had an attack for 3 years since taking L-arginine, which is available without prescription and non-toxic.

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Figure 7

SMART syndrome. A 68-year-old patient who had received radiation therapy 8 years previously for a left frontal astrocytoma. He subsequently developed a rapid onset of continuous focal motor aware seizures, loss of speech and right hemiparesis that gradually improved over the next 3 months, leaving him with moderate dysphasia and mild hemiparesis. There was no response to high-dose intravenous corticosteroids. Imaging at the onset shows swollen left hemisphere with diffuse high signal and sulcal effacement on axial T2W (A) and pial enhancement (B) with high relative cerebral blood volume on perfusion-weighted imaging (C). The appearances had resolved and returned to baseline 3 months later (D and E).