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Radiation: CNS complications …
- Updated 05.01.2025
- Released 03.24.1999
- Expires For CME 05.01.2028
Radiation: CNS complications
Introduction
Overview
Radiation therapy is an effective therapy for many malignancies and benign conditions. However, radiation therapy can potentially cause early and late toxicities in the central nervous system. These include radiation necrosis, cerebrovascular disease, cognitive deficits, endocrinopathies, encephalopathy, myelopathy, plexopathy, radiculopathy, neuropathy, and secondary tumors. This article discusses in detail radiation complications in the central nervous system, prevention of radiation toxicity, diagnosis, and therapeutic options.
With more advanced imaging techniques and the widespread adoption of conformal intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), particle therapy, and stereotactic radiation approaches, it is more possible to limit and prevent radiation toxicity. Novel ways to provide effective treatment while optimally sparing normal tissue have been and are being explored. NRG Oncology CC001 showed that hippocampal-sparing whole brain radiation therapy decreases neurocognitive injury compared to conventional whole brain radiation therapy. Prospective studies are investigating the role of sparing other important structures involved in neurocognition, such as the fornix, corpus callosum, and amygdala.
Spine stereotactic body radiotherapy (SBRT) has become more prevalent in the treatment of spinal osseous metastases and has been demonstrated to be safe, with no difference in toxicity, including in rates of myelopathy, when compared with conventionally fractionated radiation therapy in recently published prospective trials.
The diagnosis and treatment of radiation necrosis continues to improve, with more imaging techniques and treatment options available. Advancements in diagnosis include the application of perfusion magnetic resonance imaging (MRI) to determine relative cerebral blood volume (rCBV) and newer imaging modalities like amino acid positron emission tomography (PET). Treatment options for radiation necrosis now include bevacizumab and laser-interstitial thermal therapy (LITT). Boswellia serrata is a dietary supplement that may be considered as an adjunct or alternative to corticosteroids.
Treatment of late cognitive impairment due to central nervous system radiation continues to be an elusive goal. Cognitive rehabilitation and behavioral intervention are under investigation.
Key points
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• When radiation therapy is used to treat primary or metastatic central nervous system (CNS) diseases, or non-CNS targets located close to neural structures, side effects to the normal neural tissues can occur. | |
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• When practicing within accepted constraints, the acute and subacute complications of radiation therapy are generally mild, transient, or treatable with corticosteroids. | |
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• In contrast, the late complications of radiation therapy are generally progressive and often permanent. | |
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• The incidence and severity of radiation-induced CNS complications varies with the radiation dose, fractionation scheme, volume of tissue irradiated, and target location; patient age; underlying diseases (malignant and nonmalignant); concomitant treatments; comorbidities; and length of survival after completion of radiation treatment. | |
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• In general, the risks of radiation-related CNS side effects are balanced against the risk of progressive or recurrent disease. |
Historical note and terminology
Older radiation therapy techniques for treating primary or metastatic nervous system diseases, or structures adjacent to neural structures, were associated with increased risk damage to the nervous system. The most dramatic example of this type of injury, brain radiation necrosis, was first recognized in 1930, soon after radiation was first used therapeutically for brain tumors (21). Since that time, a spectrum of injuries throughout the central and peripheral nervous system has been identified, and some of the details of specific syndromes have been elucidated. Despite this heightened awareness, the neurologic complications of radiation therapy continue to occur because individual tolerances to radiation are variable, safe radiation thresholds are not precisely known, latency to development of injury range between days to years, and risks are altered by use of chemotherapy, other systemic therapies, or preexisting disease. Conventional and stereotactic radiation treatment cause similar toxicities, though dose per fraction, volume irradiation, location, and other dosimetric factors may affect severity and timing of injury. Despite increasing understanding and ability to prevent CNS radiation toxicity, the incidence of radiation-related nervous system side effects are likely to increase as patients survive longer.
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
|
Brain |
• Acute encephalopathy |
|
Neuroendocrine |
• Hypothalamic, pituitary, and thyroid hypofunction |
|
Cranial neuropathies (including optic neuropathy) | |
|
Spinal cord |
• Subacute (transient) myelopathy |
|
Brachial and lumbosacral plexuses |
• Transient brachial plexopathy |
|
Peripheral nerves |
• Perineural fibrosis |
|
Cerebral vascular disease |
• Intracranial arterial occlusive disease |
Table 2. Temporal Classification of Radiation-Related Nervous System Side Effects
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Acute (early) |
• Acute encephalopathy |
|
Subacute |
• Subacute ("early delayed") encephalopathy |
|
Late (chronic) |
• Delayed cerebral radiation necrosis |
Accurate diagnosis based on clinical manifestations is critical 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.
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.
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 2 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 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 neck flexion, may be the sole symptom and 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. Imaging findings consistent with radiation necrosis are discussed in the Diagnostic workup section below. Rarely, the presentation is fulminant, and even less commonly, established radiation necrosis may be complicated by acute hemorrhage (12).
A more diffuse late brain injury manifests clinically in progressive cognitive impairment, characterized by deficits in memory, learning, 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 (60; 54).
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 decades (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 (26; 81). 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 paresthesia, dysesthesia, 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 possible, as is disturbance of sphincter function. Symptoms begin 3 to 30 months or more (median 20 months) after radiation 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. Onset may be 10 or more years following radiation exposure, necessitating long-term surveillance (79). 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 (61; 39). Radiation-induced cavernous malformations are another manifestation of radiation-related cerebrovascular disease, associated with brain doses in the range of 45 to 60 Gy (63). Moyamoya syndrome is a rare complication of cranial irradiation, particularly in children who received higher doses to the circle of Willis (88). Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare late complication, associated with radiotherapy greater than or equal to 50 Gy, and characterized by migraine-like headaches, stroke-like deficits, and seizures. MRI findings include cortical gyriform enhancement with corresponding T2-FLAIR hyperintensity and diffusion restriction inconsistent with vascular territories (92). Clinical symptoms and radiologic signs are reversible though incomplete recovery or recurrent episodes may occur (65). 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 (86; 24). NF2 gene rearrangements, which appear to be specific to radiation-induced meningiomas, have been described in approximately half of patients with such tumors (01).
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
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• Hair loss |
Prognosis and complications
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 (03), 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 multifactorial, with endothelial and glial cell injury involved in the resultant edema and inflammation. This theory is supported by neuroimaging data and the clinical observation of steroid responsiveness. Newer data suggest that unchecked 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 (46; 41).
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 (42).
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 (17). 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, particularly in the hippocampi (46; 41), which is thought to play a key role in mediating radiation-induced cognitive toxicity. 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 (33; 72).
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 (43).
Epidemiology
The rate and severity 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, whereas latency decreases, 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 further complicated 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.
Another significant determinant of cognitive injury is the 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. In patients receiving whole brain radiation therapy, over 90% demonstrate diffuse white matter changes (57) and over 50% demonstrate neurocognitive decline on the Hopkins verbal learning test or other learning and memory assessments by 4 to 6 months (10).
The incidence of radiation necrosis varies with dose per fraction and volume irradiated, among other factors. Quantec estimates a 5% risk of necrosis with a conventionally fractionated dose of 72 Gy (47). For stereotactic radiation, higher rates of up to 20% with a median dose of 20 Gy are reported with single-fraction stereotactic radiosurgery, compared to up to 8% with fractionated stereotactic radiotherapy. Limiting normal brain volume exposed to 12 Gy (V12Gy) is recommended to reduce the risk of necrosis with stereotactic radiosurgery (27). In the reirradiation setting, radiation-induced normal brain tissue necrosis occurs at normalized total dose of (cumulative) greater than 100 Gy (49). A model based on patients receiving multiple courses of stereotactic radiosurgery suggested a 50% risk of radionecrosis associated with maximum point dose (defined as 0.2 cc) of sum EQD2 of 165 Gy and a logarithmic time factor for repair (82).
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 (13; 48), whereas others have not (20).
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 one fraction, 19.5 Gy in three fractions (87), and 25 Gy in five fractions (AAPM Task Group 101), with which there is less than 1% risk of neuropathy (30). Incidence increases with higher biologically effective dose. With conventional fractionation radiotherapy, doses below 54 Gy are considered relatively safe (51). 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 (45).
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 (52).
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 (15; 02). In a case-control study, 26% of patients had biochemical evidence of hypothalamic hypothyroidism, 32% showed evidence of hypothalamic hypogonadism, and 29% had hyperprolactinemia (02). 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. Most clinicians apply far stricter dose constraints in the range of 45 to 50 Gy because of the devastating consequences if myelopathy should occur.
Spine stereotactic body radiation therapy (SBRT) has been increasing in utilization. Prospective studies have reported no significant difference in myelopathy, plexopathy, or vertebral compression fracture between patients treated with spine stereotactic body radiation therapy and those treated with conventionally fractionated radiation therapy (78; 76; 95). The following spinal cord point maximum doses are estimated to be associated with 1% to 5% risk of radiation myelopathy: 12.4 to 14 Gy in one fraction, 17 Gy in two fractions, 20.3 Gy in three fractions, 23.0 Gy in four fractions, and 25.3 Gy in five fractions (77).
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 (09).
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 with IMRT/VMAT, stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT), and/or particle therapy. Greater knowledge of clinical radiation tolerances helps to guide future treatments. Additionally, aggressive control of increased intracranial pressure, modifications in radiation dose when concurrent systemic therapy 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 randomized clinical trials, 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 (11; 28).
Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) utilizing conformal IMRT/VMAT radiation therapy has been shown to reduce the long-term cognitive toxicity of whole brain irradiation. 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 bilateral standard whole brain radiotherapy and memantine (10; 28). Unilateral HA-WBRT, particularly sparing of the left hippocampus, has also shown promise and may be appropriate for patients who are not candidates for bilateral HA-WBRT (32). Avoidance of additional brain structures involved in memory and cognition like the amygdala, corpus collosum, and fornix is another active area of investigation for further preserving neurocognitive function (14; 68).
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 (66; 69). Lower doses can also be employed when utilizing preoperative stereotactic radiosurgery (70). Phase III randomized clinical trials comparing pre- and postoperative stereotactic radiosurgery are underway.
For glioblastoma, efforts have been made to optimize treatment volumes, including studies investigating reducing standardized target volume expansions (56; 71) and utilizing novel radiotracer positron emission tomography (PET) or multiparametric MRI techniques to better delineate target volumes (35; 40).
Retrospective studies have suggested that sparing brain tissue using proton therapy may help to preserve cognitive function and other physiological processes (94; 29; 85). Ongoing clinical trials are investigating this possibility. Data from in vivo animal studies suggest 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 (08; 84; 59). 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 (58; 91).
Given concern for the safety of concurrent immunotherapy and stereotactic radiation, trials are investigating de-escalating radiation treatment in this setting to reduce the risk of radionecrosis. Prospective studies are exploring reduced-dose stereotactic radiosurgery (53) or holding radiation and monitoring brain metastases while patients are on immunotherapy (04).
Differential diagnosis
Confusing conditions
In general, the most frequent and serious alternative diagnosis for radiation-related CNS toxicity is recurrent tumor. Other neurologic and non-neurologic conditions corresponding with specific toxicity syndromes are listed in Table 4.
Table 4. Cancer-Related Disorders Mimicking the Symptoms of Radiation Toxicity
|
Radiation-related sequelae |
Alternative etiologies |
|
Acute and subacute encephalopathy and myelopathy |
• Metabolic encephalopathy |
|
Radiation necrosis |
• Tumor recurrence |
|
Diffuse late brain injury |
• Tumor recurrence |
|
Neuroendocrine dysfunction |
• Psychiatric disorders |
|
Optic neuropathy |
• Drug effect |
|
Cranial neuropathy |
• Tumor recurrence |
|
Chronic progressive myelopathy |
• Epidural or intramedullary metastasis |
|
Motor neuronopathy |
• Effects of chemotherapy |
|
Plexopathy |
• Metastatic tumor |
|
Cerebrovascular disease |
• Nonbacterial thrombotic endocarditis |
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 toxicity and an empirical trial of steroids 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).
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 later, greater than 6 months to years after the completion of radiation therapy, recurrent tumor is most likely, but the possibility of delayed radiation necrosis must be considered (even years later) particularly in the context of new systemic therapy with CNS activity, such as immunotherapy or targeted therapies. MRI or other imaging studies described in the next section may help to identify the process.
The term pseudoprogression refers to increased or new areas of enhancement of treated areas on MRI within months after radiation therapy or systemic treatments with CNS activity such as chemotherapy or immunotherapy, due to transient blood-brain barrier disruptions. Patients are often asymptomatic or minimally symptomatic despite imaging changes. The imaging changes usually shrink or resolve spontaneously within a few months. It is often difficult to distinguish pseudoprogression from radionecrosis and true progression, though imaging changes over time, radiation dose to the areas involved, and novel imaging techniques may help with diagnosis (18; 06).
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 (55; 80). One smaller, prospective trial (GLIO-CMV-01 study) suggested encephalopathy caused by cytomegalovirus viremia may be an overlooked and underdiagnosed condition (25). 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, neurofibromatosis type 1- and neurofibromatosis type 2-related schwannomatosis), may increase the risk of CNS radiation toxicity.
Diagnostic workup
In general, a focused history and physical, review of medications particularly those with sedative or psychoactive properties, CNS imaging, and laboratory studies such as comprehensive metabolic panel and complete blood count, should be part of the initial diagnostic work up.
A CT or MRI scan is an appropriate first diagnostic step when symptoms suggest the possibility of radiation acute setting; CNS imaging can reveal edema or intracranial bleeding.
Radiation necrosis has the appearance of ring enhancing mass lesion on neuroimaging studies (36) and may be rapidly progressive. T1 and T2-weighted imaging, diffusion weighted imaging (DWI), and apparent diffusion coefficient (ADC) are recommended conventional MRI sequences for diagnosis. Highly cellular tumors may exhibit lower ADC due to relatively restricted motion of water, compared with radiation necrosis. With standard MRI neuroimaging, the radiographic appearance of radiation necrosis may be indistinguishable from primary or secondary brain tumors.
Efforts have been made to better identify radiation necrosis using advanced imaging techniques (06; 07; 50). Perfusion MRI with relative cerebral blood volume (rCBV) can show tumor angiogenesis and neovascularization, increased with tumor growth but decreased with radiation necrosis. MR spectroscopy using ratios of metabolites such as increased lipid/choline, increased lactate/creatine, or decreased choline/creatine has shown some promise in diagnosing radiation necrosis. Positron emission tomography (PET) using L-3,4-dihydroxy-6-[18F]-fluorophenylalanine (F-DOPA), [11C]-methyl-L-methionine (C-MET), O‐(2‐[18F]fluoroethyl)‐L‐tyrosine (18F‐FET), 18F-fluciclovine, and other radiotracers have been demonstrated to aid diagnosis. Generally, amino acid PET has been found to be superior to fluorodeoxyglucose (FDG) PET in sensitivity and specificity of diagnosing radiation necrosis. Single photon emission tomography (SPECT) using thallium-201 or technetium-99 may be another nuclear medicine modality that can aid diagnosis. Algorithms and guidelines are available that take into account multi-modality imaging results to help establish a diagnosis of radiation necrosis (06; 50). Radiomics-based prediction models, some employing artificial intelligence, have also been proposed to help improve diagnostic accuracy (67; 19; 64). Biopsy is ultimately the gold standard for diagnosis of radiation necrosis but is often reserved for persistent or severe symptoms despite nonsurgical treatments.
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 evaluation, are important. A characteristic MRI appearance for radiation-induced optic neuropathy consists of discrete focal areas of enhancement along the intracranial optic nerve. 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 utilizing a cranial nerve protocol may be required.
Furthermore, when 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 screen routinely, typically annually, thereafter for radiation-induced neuroendocrine deficits.
As with non-radiation-associated cerebral vascular disease, CT or MRI can uncover infarcts, and conventional or MR angiography helps distinguish among potential etiologies. MR angiography may also help diagnose accelerated carotid 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) (62).
For patients with suspected late cognitive decline due to radiation therapy, neuropsychiatric and neurocognitive evaluation are useful tools for diagnosis and monitoring. Standardized tests for evaluating distinct neurocognitive domains include the Trail Making Test Parts A and B, Hopkins Verbal Learning Test-Revised, the Controlled Oral Word Association Test, the Digit Span, the Boston Naming Test, and the Wechsler Adult Intelligence Scale, 4th edition (16).
Management
Acute radiation toxicity is often managed with corticosteroids. Corticosteroids may hasten improvement in some patients with early delayed encephalopathy. 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.
No treatment is necessary for either subacute myelopathy or transient brachial plexopathy, both of which are self-limited.
Delayed radiation injury is often irreversible and treatment is largely aimed at symptom control. The preventative strategies described in the Prevention section above are generally more successful than management strategies.
In many cases, radiation necrosis can be managed conservatively without intervention. In more severe cases, corticosteroids can be helpful in reducing the mass effect and associated deficits caused by edema or inflammation associated with cerebral radiation necrosis. Additional treatments to consider include bevacizumab, surgical resection, and laser-interstitial thermal therapy (LITT). Hyperbaric oxygen, high-dose multivitamins, anticoagulation, and antiplatelet therapy have not been established to be efficacious, but are utilized at times.
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. 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 (44; 93). However, other studies have reported worsening symptoms with bevacizumab (83; 34); 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 (36). Laser-interstitial thermal therapy (LITT) has been proposed as a minimally invasive alternative to open craniotomy (74; 31). This technique requires only a small burr hole to enable probe access to the brain and may be more tolerable for patients. However, systemic literature reviews suggest that bevacizumab may outperform LITT in managing radiation necrosis in terms of both clinical and radiographic outcomes (22; 90).
A possible adjunct or alternative to corticosteroids for managing cerebral edema and radionecrosis is Boswellia serrata, an extract of the Indian frankincense plant. Small prospective studies, including one placebo-controlled, double-blind randomized clinical trial, and retrospective studies suggest that this dietary supplement can help to reduce cerebral edema and treat radionecrosis (38; 89).
For patients with late cognitive impairment due to radiation, limited treatment options are available and of largely unproven benefit. Pharmacologic interventions include the Alzheimer drug donepezil (75) and stimulants like methylphenidate or modafinil. Cognitive rehabilitation and behavioral intervention are under investigation as treatment for late cognitive impairment (23; 16; 73; 37).
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.
Outcomes
Acute radiation toxicity is often self-limited, and corticosteroids may hasten improvement.
The outcome of treatment of radiation necrosis with steroids, bevacizumab, and other treatments is highly variable. Surgical resection is the most definitive option and is used for salvage when other methods fail.
Delayed radiation injury is often irreversible, but treatment described in Management may help to address symptoms.
Media
References
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Puyao Li MD
Dr. Li of University of Vermont Medical Center has no relevant financial relationships to disclose.
See Profile -
Alexander Schrager
Mr. Schrager of Larner College of Medicine has no relevant financial relationships to disclose.
See Profile
Editor
-
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Jazz Therapeutics, Novocure, and Servier for speaking engagements, honorariums from Cardinal Health, Catalyx, Merck, and Novocure for advisory board membership, research support from BMS as principal investigator, and an honorarium from GT Medical Technologies for DSMB membership.
See Profile
Former Authors
- Michael J Glantz MD
- Zubair A Shaikh MD
- Edward J Dropcho MD
- Maximilian Niyazi MD MSc
- Helen A Shih MD MPH MS
Patient Profile
- Age range of presentation
-
- 2 to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Exposure to ionizing radiation: W88
- Exposure to man-made visible and ultraviolet light: W89
- Exposure to other nonionizing radiation: W90
- Exposure to unspecified type of radiation: W91
- Other specified disorders of the skin and subcutaneous tissue related to radiation: L59.8
- Other cerebrovascular disease: 167.89
- Radiological procedure and radiotherapy as the cause of abnormal reaction of the patient, or of later complication, without mention of misadventure at the time of the procedure: Y84.2
- Radiation sickness: T66.XXXA
- Other specified intracranial injury without loss of consciousness, initial encounter: S06. 890A
- ICD-11
-
- Exposure to radiation: XE60C
- Effects of radiation, not elsewhere classified: NF00
- Other specified injury, poisoning or certain other consequences of external causes: NF2Y
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