Clinical manifestations

Presentation and course

Radiation-related nervous system side effects can affect every level of the nervous system and can be classified either anatomically or temporally (Tables 1 and 2).

Table 1. Anatomic Classification of Radiation-Related Nervous System Side Effects

Table 2. Temporal Classification of Radiation-Related Nervous System Side Effects

Accurate diagnosis based on clinical manifestations is critical in order to exclude other potentially treatable disorders, to prevent unnecessary diagnostic procedures and inappropriate antineoplastic therapy, and to allow for meaningful intervention.

Acute complications. Common acute side effects of radiation therapy include fatigue, headache, loss of appetite, nausea, and vomiting, and re-emergence or worsening of preexisting neurologic symptoms.

In the setting of therapeutic radiation therapy, acute radiation encephalopathy is a rare occurrence. It is characterized by lethargy, possibly accompanied by new or progressive focal deficits, headache, nausea, vomiting, fever, and seizures. Onset is within the first two weeks of treatment (may be as early as within 24 hours).

Subacute complications. Lethargy, impaired memory retrieval, and cognitive and behavioral changes may develop within one month from initiation of radiation therapy and extending to within 4 months following radiation therapy completion ("early delayed encephalopathy"). Ataxia, nystagmus, nausea, vomiting, and dysarthria may be present when the brainstem has been irradiated. Patients may experience transient hearing loss from soft tissue swelling and/or inflammatory otitis media.

Subacute myelopathy may occur following radiation therapy to the cervical (less often thoracic or thoracolumbar) spinal cord. Lhermitte sign, transient electric shock sensation with next flexion, may be the sole symptom. The neurologic exam is normal. Symptom onset peaks at 4 to 6 months (range 1 to 30 months) after radiation exposure.

Late (chronic) complications. Late complications of CNS radiation therapy include radiation necrosis, cognitive deficits, endocrinopathies, cranial neuropathies, myelopathy, cerebrovascular disease, and secondary tumors.

Patients with delayed cerebral radiation necrosis may present with headache, personality change, focal deficits, and seizures. These symptoms typically develop insidiously 4 months to 4 years or more (median 14 months) after treatment. Occasionally, gait impairment, incontinence, and dysarthria can occur. Rarely, the presentation is fulminant, and even less commonly, established radiation necrosis may be complicated by acute hemorrhage (10).

A more diffuse late brain injury manifests clinically in progressive cognitive impairment, characterized by deficits in memory, attention, and executive function, fatigue, and even personality change and dementia. Age at irradiation is one primary determinant of this sequelae. The negative impact on neurocognition is more pronounced in children and older adults, particularly over the age of 70. In children, even low doses of cranial irradiation can be associated with declines in IQ and academic achievement. Children may also exhibit memory deficits, fine motor and visual-spatial dysfunction, and psychological disturbances (49; 45).

Radiation to the sellar, parasellar, or hypothalamic regions can result in endocrine dysfunction. Among adults, endocrine dysfunction can occur insidiously, developing over months to years and often undiagnosed. Children who receive brain radiation are even more vulnerable. Patients should undergo regular endocrine evaluation if their treatment was to this region, and they should receive prompt treatment for pituitary deficiencies. The most common radiation-induced endocrinopathies are hypothyroidism and growth hormone deficiency.

Radiation induced optic neuropathy can occur after irradiation of the optic apparatus, including the retina, optic nerve, chiasm and pituitary region, or optic radiation. Painless, progressive, monocular visual loss, or constriction of visual fields is the typical presentation. Altitudinal field cuts are common; "dimming" of vision or "spotty" visual loss are typical patient descriptions. The presence of pain or homonymous field defects weigh strongly against the diagnosis. Onset ranges from three months to several years (median 11 months).

Although the optic nerves are the most sensitive of the cranial nerves to radiation therapy, other cranial neuropathies can develop following exposure to therapeutic radiation (05). Radiation-induced cranial neuropathy occurs 1 to 37 years (mean 5.5 years) following radiation therapy (generally for head and neck or orbital tumors). In order of frequency, cranial nerves XII, XI, X, V, and VI are affected.

Chronic progressive myelopathy is the delayed spinal cord syndrome corresponding to cerebral radiation necrosis (19; 62). It most commonly occurs following radiation therapy of tumors in the chest, mediastinum, cervical region, or head and neck. The syndrome frequently presents with ascending paresthesias, dysesthesias, or sensory loss in one or both lower extremities, followed by weakness and signs of myelopathy. A partial transverse myelitis or Brown-Sequard syndrome is common, as is disturbance of sphincter function. Symptoms begin 3 to 30 months or more (median 20 months) after treatment, and progression is usually gradual over weeks to months.

The cerebral vasculature can be damaged by radiation. Depending on the portion of the vascular tree affected and the type of vascular lesion, transient ischemia, strokes, or hemorrhage can occur and typically in 10 or more years following radiation exposure, necessitating long-term surveillance (60). Children are more vulnerable than adults in their risk of developing radiation-induced vasculopathy. Radiation-induced cerebral microbleeds and large vessel cerebral vasculopathy have been reported in pediatric patients undergoing radiation therapy for brain tumors (50; 29). Radiation-induced cavernous malformations are another manifestation of radiation-related cerebrovascular disease, associated with brain doses in the range of 45 to 60 Gy (52). Moyamoya syndrome is a rare complication of cranial irradiation, particularly in children who received higher doses to the circle of Willis (68). Radiation that is administered to the neck can result in delayed carotid atherosclerosis. Tumor embolization to the brain is a rare cause of stroke.

Radiation-induced CNS tumors constitute a small but serious risk for patients undergoing radiotherapy for the management of cerebral neoplasms. Studies of pediatric survivors who developed second brain tumors have found that meningiomas are the most common. The average latency period for the appearance of the second tumor was eight years, but meningiomas had a longer latency period, ranging from 16 to 30 years in one study. Other common second cancer histologies include peripheral nerve sheath tumors and gliomas. The symptoms of radiation-induced intracranial tumors are indistinguishable from those of their nonradiation-induced counterparts, but radiation-induced intracranial tumors are typically more aggressive pathologically and clinically. Radiation-induced meningiomas, for example, are higher grade with high labeling indices, may appear with multiple synchronous tumors, and tend to recur more frequently and earlier after gross total resection (54; 66). NF2 gene rearrangements, which appear to be specific to radiation-induced meningiomas, have been described in approximately half of patients with such tumors (02).

In addition to CNS-specific side effects, a constellation of acute or late nonneurologic symptoms are common after cranial irradiation (Table 3).

Table 3. Nonneurologic Side Effects of Cranial Irradiation

The most common and often most debilitating effect of cranial radiation therapy is progressive fatigue (usually between weeks 3 and 5 in fractionated radiotherapy), which may often persist for several weeks after the completion of therapy.

Prognosis and complications

Except in some patients with acute encephalopathy, the acute and subacute complications of radiation are generally mild, transient, or treatable with corticosteroids. The symptoms of early delayed encephalopathy begin to resolve within 2 to 4.5 months of onset (04), whereas those of subacute myelopathy disappear within four months of onset. Recognition of these acute and subacute syndromes permits early intervention or reassurance and may obviate the need for invasive or expensive diagnostic interventions and therapy directed at presumed tumor recurrence.

In contrast, the late complications of radiation are generally progressive and severe. They typically result in significant disability and are of particular concern in patients with potentially curable disease (eg, childhood acute leukemias, intracranial germ cell tumors, pituitary tumors, and meningiomas), or tumors compatible with long survival (eg, oligodendrogliomas and limited brain metastases with well-controlled systemic disease).

Biological basis

Etiology and pathogenesis

Although the histopathology of some forms of radiation-induced nervous system injury has been described, the etiologies of many of the conditions described above are still not well understood.

Acute toxicity (occurring within hours to weeks of treatment) is related to edema and inflammation. This theory is supported by neuroimaging data and the clinical observation of steroid responsiveness. Newer data suggest that inflammation may be associated with early injury to neuronal lineages, accessory cells and their progenitors in the brain, and supporting structures. Late injuries (occurring months to decades after treatment) has multifactorial causes, including vascular injury, stem cell depletion, and changes in the neural microenvironment (37; 32).

Cerebral radiation necrosis and radiation myelopathy are the best characterized radiation-related syndromes from a histopathologic standpoint. Fibrinoid necrosis, endothelial proliferation, hyalinization and thickening of vessel walls, adventitial fibroblast proliferation, thrombosis, telangiectasias, and multinucleated astrocytes all contribute to coagulative white matter necrosis.

Reversible radiation myelopathy is characterized by prominent demyelination with axonal loss but only minimal vascular injury (33).

The histologic alterations in diffuse late brain injury with cognitive decline are less dramatic and less specific. Gliosis, neuronal loss, and white matter spongiform changes predominate (15). Vasculopathy in the form of endothelial damage, microvascular abnormalities, and disruption in cerebral blood flow are seen. Alterations in dendritic spines, which may disrupt synaptic neurotransmission, have also been observed. There is neural stem cell loss in the hippocampi in particular (37; 32). Imaging studies have found certain brain regions to demonstrate greater postradiation changes, resembling accelerated aging in some cases. Particularly radiosensitive brain substructures may include the hippocampi, fornix, and corpus callosum (25; 56).

Radiation-induced optic neuropathy is similarly thought to be due to damage to endothelium and neuroglial cell progenitors leading to vaso-occlusion, demyelination, and neuronal degeneration (34).

Epidemiology

The incidence of radiation-induced nervous system complications varies with the radiation dose, volume of tissue irradiated, fractionation scheme, and radiation technique; degree of edema; patient age; underlying diseases (malignant and nonmalignant); concomitant treatments; and length of survival after completion of radiation treatment. Risk of deficits after cranial irradiation increases with higher radiation therapy dose, larger fraction size, larger field size, and extremes of age at time of treatment. As these same factors are also associated with higher burden of disease, the causative relationship is confounded. Analyses of neurocognitive function are also confounded by factors such as surgery, chemotherapy (particularly concurrent and sometimes even temporally offset radiosensitizing agents), immunotherapy, targeted agents, and tumor characteristics. Finally, patients’ underlying conditions such as hypertension, diabetes, preexisting neurologic disease, and nononcologic medications may affect prevalence and timing of CNS radiation toxicity.

Radiation-related white matter changes are common on CT and MRI scans (13), and as many as 20% of patients with the radiographic correlates of diffuse late brain injury develop frank radiation-induced dementia (14).

The dose-response relationship for brain toxicity is not straightforward due to the confounding factors discussed above and the challenges of evaluating complex dose distributions (30). As a rule, incidence increases and latency decreases with higher total doses, higher fraction size, and larger volumes of treated nervous system (39).

A significant determinant of cognitive injury is the volume and substructure of brain irradiated. Targeting the whole brain is more likely to cause cognitive injury and chronic fatigue, and is associated with greater severity of injury compared with partial brain irradiation. When whole brain radiation therapy is necessary, reducing dose to the hippocampi, which harbor neural stem cells and are thought to be play a key role in mediating radiation-induced cognitive toxicity, has been demonstrated to result in better cognitive preservation (08).

The incidence of radiation necrosis varies with dose per fraction and volume irradiated, among other factors. For stereotactic radiation, higher rates are reported with single-fraction stereotactic radiosurgery, around 20% with median of dose 20 Gy, compared with fractionated stereotactic radiotherapy, up to 8%. Limiting normal brain volume exposed to 12 Gy (V12Gy) is recommended to reduce the risk of necrosis with stereotactic radiosurgery (20). Quantec estimates a 5% risk of necrosis with a conventionally fractionated dose of 72 Gy (38). In the reirradiation setting, radiation-induced normal brain tissue necrosis is found to occur at normalized total dose of (cumulative) greater than 100 Gy (41).

Immune checkpoint inhibitors, given either concurrently or sequentially in combination with radiation, may increase risk for radionecrosis. Retrospective studies report conflicting results. Some studies have found an increased risk (11; 40), reporting radionecrosis rates as high as 20% of patients, whereas others have not (16).

Radiation-induced optic neuropathy is a rare phenomenon. With hypofractionated radiotherapy, the Qualitative Analysis of Normal Tissue Effects (QUANTEC) recommends a single-fraction radiotherapy limit of 12 Gy in 1 fraction, 19.5 Gy in 3 fractions (67), and 25 Gy in 5 fractions (AAPM Task Group 101), with which there is less than 1% risk of neuropathy (23). Incidence increases with higher biologically effective dose. With conventional fractionation radiotherapy, doses below 54 Gy are considered relatively safe (42). In a large retrospective study of mixed proton and photon radiotherapy, cumulative incidence of optic neuropathy was 1% with doses less than 59 Gy and 5.8% in patients receiving 60 Gy and above. Higher point dose to the optic pathway, female sex, and older age were associated with increased risk of optic neuropathy (36).

Based on 3D dose data, the risk of brainstem injury markedly increases above 54 Gy to the entire brainstem, and 59 Gy to more than 10 ml of the brainstem (43).

Because the symptoms of neuroendocrine dysfunction may be subtle or difficult to distinguish from other tumor-related symptoms, it may be underdiagnosed. At least one biochemical endocrine abnormality has been detected in two thirds to three quarters of children and adults at some point following radiotherapy (12; 03). In a case-control study, 26% of patients had biochemical evidence of hypothalamic hypothyroidism, 32% showed evidence of hypothalamic hypogonadism, and 29% had hyperprolactinemia (03). Children are more susceptible to radiation-related neuroendocrine dysfunction than adults. Increased activity of the hypothalamic or pituitary axis, concurrent cisplatin or nitrosourea chemotherapy, and higher radiation therapy doses (especially above 18 Gy) also predispose to hypopituitarism.

The QUANTEC working group provides an estimate for myelopathy when applying radiation to the full-thickness cord in conventional fractionation (1.8 to 2 Gy). It reports the risk of myelopathy of 1% for 54 Gy and 10% for 61 Gy. A strong fractionation dependency was shown with an estimated α/β of 0.87 Gy. For single fraction treatments, the dose should be kept below 13 Gy (28). Most clinicians apply far stricter dose constraints in the range of 40 to 45 Gy because of the devastating consequences if myelopathy should occur.

The incidence of radiation-induced secondary tumors is directly related to the radiation dose and volume of tissue irradiated and inversely related to the age of radiation exposure. Excess relative risk (ERR) has been estimated at 0.2 to 6 per Gy for any secondary brain tumor, 0.6 to 5 per Gy for meningioma and 0.08 to 0.6 per Gy for glioma (07).

Prevention

Preventive strategies have mostly been the result of improvements in radiation delivery technology. These include advancements in imaging defining targets for irradiation, and more conformal treatment planning and precise targeting. Greater knowledge of clinical radiation tolerances helps to guide future treatments. Specifically, reductions in overall radiation dose, fraction size, treatment volume, and the application of particle therapy or modern radiation techniques such as stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT), IMRT, or VMAT; aggressive control of increased intracranial pressure; modifications in radiation dose when concurrent chemotherapy is being used; and exploration of alternatives to irradiation in the very young and very old have led to reduced radiation associated toxicities.

Memantine has shown some promise in providing neuroprotection when given concurrently with radiotherapy. In one randomized clinical trial, memantine delayed time to cognitive decline and patients receiving memantine had improved executive function and processing speed, and a trend toward improved memory recall, compared to patients receiving placebo (09).

Hippocampal-avoidance whole brain radiotherapy (HA-WBRT), conformal avoidance of bilateral hippocampi during whole brain radiotherapy, has been shown to reduce the long-term cognitive toxicity of whole brain irradiation. A phase 2 clinical trial initially demonstrated less decline in memory recall and quality of life compared to historical controls (21). The phase 3 clinical trial NRG Oncology CC001 demonstrated that patients receiving HA-WBRT and memantine had significantly lower rates of and longer time to neurocognitive decline than patients receiving standard whole brain radiotherapy and memantine (08).

Retrospective studies have suggested that sparing brain tissue using proton therapy may also help to preserve cognitive function and other physiological processes (72; 22; 65). Ongoing clinical trials are investigating this possibility. There is emerging evidence from in vivo animal studies that FLASH radiation therapy (FLASH-RT), ie, treatment delivered in fractions of a second using high dose rates of greater than 100 Gy/second, may spare normal tissues without compromising tumor control. In studies of mice, high therapeutic doses could be delivered while minimizing neurocognitive toxicity with FLASH-RT (06; 64; 48). The mechanism of this superior normal tissue sparing has not been fully elucidated but may be related to a protective effect of radiochemical oxygen depletion, decreased generation of reactive oxygen species, and modification of the immune response to radiation (47; 69).

In the setting of increasing use of immunotherapy and possible increased radionecrosis with concurrent immunotherapy, ongoing studies are examining if reduced-dose stereotactic radiosurgery with immunotherapy provides comparable efficacy with decreased toxicity. Interim analysis of one such trial, on which patients received 18 Gy for lesions 0 to 2 cm, 14 Gy for lesions 2.1 to 3 cm, and 12 Gy for lesions 3.1 to 4 cm, has demonstrated excellent local control rates with no radiographic radionecrosis at six months (44).

Preoperative stereotactic radiosurgery as a strategy to maintain the local control provided by postoperative stereotactic radiosurgery while reducing radionecrosis and iatrogenic leptomeningeal spread is also under investigation. Retrospective studies report low rates of radionecrosis (5% to 7%) and leptomeningeal spread (3% to 7%) with lower dose preoperative stereotactic radiosurgery (53; 55). Phase III randomized clinical trials comparing pre- and postoperative stereotactic radiosurgery are underway.

Differential diagnosis

Confusing conditions

In general, the most frequent and most pressing diagnosis competing with radiation-related nervous system injury is recurrent tumor. For specific syndromes, however, other neurologic and nonneurologic conditions may complicate the differential (Table 4).

Table 4. Cancer-Related Disorders Mimicking the Symptoms of Radiation Toxicity

When new symptoms develop over days or weeks, are mild, or improve over the weekend break from radiation therapy, a presumptive diagnosis of acute radiation encephalopathy and an empirical increase of steroid dose are reasonable. Marked or abrupt deterioration or fluctuating symptoms raise the possibilities of tumor progression, tumor-associated hemorrhage or increased edema, obstructive hydrocephalus, unrecognized seizures, or infection (intracranial or systemic).

In the context of radiation-related nervous system injury, the most common diagnostic quandary arises when a patient presents with a recurrent mass in the same location as the original tumor. When the new lesion develops within 8 to 12 months of the completion of standard radiation therapy, the presumption of recurrent tumor can be made with fair certainty, but the possibility of delayed radiation necrosis must be considered (even after many years). PET or MRI may differentiate the process. MR spectroscopy and Technetium-99 SPECT may also be useful in deciphering etiology.

Diffuse late brain injury can also present both a clinical and radiographic diagnostic dilemma. Clinically, leptomeningeal disease, encephalitis (infectious or paraneoplastic), concurrently administered drugs (anticonvulsants, steroids, and analgesics), metabolic abnormalities, systemic infection, and depression may be considered in the differential diagnosis. Chemotherapy alone, particularly high-dose chemotherapy, can produce cognitive, neurophysiological, and radiographic changes that mimic the effects of radiation (46; 61). One smaller, prospective trial (GLIO-CMV-01 study) suggested encephalopathy caused by cytomegalovirus viremia may be an overlooked and underdiagnosed condition (18). Rarely, radiographic confusion with periventricular small vessel disease, multiple sclerosis, progressive multifocal leukoencephalopathy, or transependymal CSF resorption in the setting of hydrocephalus can occur. Ideally, a diagnosis should not be made based on radiographic findings alone.

However, hemorrhages occurring in the brain parenchyma are more commonly caused by bleeding tumor or coagulopathies related to a patient’s malignancy or antineoplastic therapy.

Associated or underlying disorders

Underlying patient conditions that predispose to radiation injury, such as lupus, connective tissue disease, or radiation sensitivity syndromes (ie, ataxia, telangiectasia, and NF1), may increase the risk of CNS radiation toxicity.

Diagnostic workup

A CT or MRI scan is an appropriate first diagnostic step when symptoms suggest the possibility of acute radiation encephalopathy. The finding of increased edema supports the diagnosis.

In early delayed encephalopathy, the CT or MRI may show increased edema, diffuse or focal increases in white matter T2 signal, and sometimes enhancement (13). Progressive space occupying radiation necrosis has the appearance of ring enhancing mass lesion on neuroimaging studies (27). A biopsy is performed only if the scan and severity of symptoms suggests the possibility of treatment failure and makes the need for alternative therapy an urgent consideration. Another very useful tool in the differentiation of recurrent tumor versus radiation necrosis is amino acid PET imaging, which seems to be superior to conventional FDG PET imaging; among these, MET and FET are most frequently used, and the use of FET is more convenient due to its longer half-life (01). These tracers are of limited availability, but increased experience with them may broaden their availability and routine use. MRI and CT perfusion and SPECT studies are also under investigation as methods to help with noninvasive diagnosis (70).

In the absence of a confounding neurologic disease, such as multiple sclerosis, or if tumor recurrence is not a concern, additional diagnostic investigations in cases of subacute myelopathy are unnecessary. Spinal cord atrophy or fusiform enlargement of irradiated segments of spinal cord are occasionally seen on MRI or myelography in patients with radiation myelopathy, but MRI reliably differentiates tumor involvement of the epidural from the intramedullary space and from leptomeningeal metastases, which are the chief competing diagnoses. The CSF protein may be elevated in all four disorders, but a pleocytosis, a hypoglycorrhachia, and a positive cytology distinguish leptomeningeal spread of tumor.

In patients with radiation-induced optic neuropathy, careful review of the radiation treatment plan, in conjunction with neuroradiographic imaging and neuroophthalmology are important. A characteristic MRI appearance for radiation-induced optic neuropathy consisting of discrete focal areas of enhancement along the intracranial optic nerve are classically described. Ophthalmic examination may uncover loss of visual acuity and color vision, visual field defects, and pallor of the optic discs on fundoscopy.

In the setting of possible radiation-induced cranial neuropathy, CT scanning may be diagnostic of tumor recurrence at the skull base, although prolonged and careful observation is frequently required. Because leptomeningeal disease, sarcoidosis, Lyme disease, basilar meningitis, and paraneoplastic encephalomyelitis can also present with cranial neuropathies, a lumbar puncture and brain MRI are also required.

Furthermore, where there is radiation dose exposure to the pituitary/hypothalamic axis, it is advisable to routinely perform a baseline screening (T3U, T4, TSH, FSH, LH, prolactin, testosterone, and in children, GH) prior to radiation therapy, and screened routinely, typically annually, thereafter for radiation-induced neuroendocrine deficits.

As with nonradiation-associated cerebral vascular disease, CT or MRI is used to document infarcts, and conventional or MR angiography helps select among potential etiologies. In patients with accelerated carotid atherosclerosis, there is concern for increased susceptibility to atherosclerosis in irradiated segments of vasculature not otherwise commonly involved (eg, the proximal common carotid artery, internal carotid artery distal to the bifurcation, and small and medium-sized intracranial arteries) (51). In the typical case of nonspecific radiation-related side-effects, necessary diagnostic studies are limited to an examination, a routine blood count and electrolyte determination, and a review of medications (anticonvulsants, especially phenobarbital, and analgesics, frequently have a pronounced sedating effect on patients with brain tumors, particularly during radiation treatment).

Management

Increasing doses of corticosteroids usually ameliorate the symptoms of acute radiation encephalopathy and may hasten improvement in some patients with early delayed encephalopathy. No treatment is necessary for either subacute myelopathy or transient brachial plexopathy, both of which are self-limited.

Most forms of delayed radiation injury are irreversible and treatment is largely aimed at symptom control. In many cases, radiation necrosis can be managed conservatively without intervention. In more severe cases, corticosteroids are sometimes helpful in reducing the mass effect and associated deficits caused by edema and/or inflammation associated with cerebral radiation necrosis, but they are not usually beneficial in radiation myelopathy (59; 31). A small randomized study demonstrated that behavioral intervention may be of benefit in improving executive functioning (57).

Bevacizumab has been utilized with success in select cases of radiation necrosis and is under further investigation as a treatment for radiation necrosis and radiation-induced optic neuropathy. Two small prospective trials in addition to retrospective studies have found that anti-VEGF therapy offered symptomatic relief and radiographic response in patients with radiation necrosis and low risk of cerebral hemorrhage (35; 71). However, other studies have reported worsening symptoms with bevacizumab (63; 26); further investigations to establish the safety and optimal patient cohort are needed.

Resection of progressive space occupying radiation necrosis may be considered after failure of conservative therapy if there is evidence for persistent or progressive neurologic symptoms (27). Laser-interstitial thermal therapy (LITT) has been proposed as a minimally invasive alternative to open craniotomy (58; 24). This technique requires only a small burr hole to enable probe access to the brain and is a far less difficult procedure for patients to tolerate.

Hyperbaric oxygen, high-dose multivitamins, anticoagulation, and antiplatelet therapy have not been established to be efficacious, but are utilized at times.

Most radiation-related tumors are histologically and clinically aggressive. Treatment does not differ from the standard of care for any CNS malignancy, though the risks of reirradiation and cumulative dose need to be considered.

Patients suffering from the nonspecific side effects of radiation, such as fatigue, may benefit from rest. A slow corticosteroid taper and temporary return to higher doses in patients who were previously prescribed this for cerebral edema or other reasons may be necessary.

Outcomes

The outcome of treatment of radiation necrosis with steroids, bevacizumab, surgical resection, and LITT is highly variable. Surgical resection is the most effective option and is used for salvage when other methods fail.