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. Lethargy is the predominant feature of acute radiation encephalopathy and may be 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.

Subacute myelopathy is a common form of radiation neurotoxicity and usually follows radiation therapy to the cervical (less often thoracic or thoracolumbar) spinal cord. Lhermitte sign may be the sole symptom. The neurologic exam is normal. Symptom onset peaks at 4 to 6 months (range one to 30 months) after radiation exposure.

Late (chronic) complications. Delayed cerebral radiation necrosis is the best described late complication of cranial irradiation. It occurs following intentional irradiation of the intracranial contents or after inadvertent exposure of the brain to radiation. The risk of brain necrosis depends at least on the chosen fractionation schedule, the exposed volume, and the applied dose; the inherent risk may be minimized by applying highly conformal techniques used in precision radiotherapy. In the reirradiation setting, radiation-induced normal brain tissue necrosis is found to occur at normalized total dose of (cumulative) greater than 100 Gy (38).

Headache, personality change, focal deficits, and seizures 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 (09). Although late-delayed radiation complications are often permanent, asymptomatic transient brain lesions often appear radiographically and completely resolve without long-term imaging findings or neurologic sequelae.

A more diffuse late brain injury manifests clinically by gradual intellectual decline, short term memory loss, fatigue, and personality change, culminating (after 6 months to several years) in dementia. Age at irradiation is one primary determinant of this sequelae. The negative impact on neurocognition is well shown and more pronounced in children and more diffuse in adults. Symptoms are more notable for patients of age greater than 50 years and dramatically more severe in those irradiated at age greater than 70 years.

Even with the relatively low doses of cranial irradiation given for prophylaxis in children with acute lymphoblastic leukemia or in adults with small-cell lung cancer, significant declines in IQ and academic achievement are common, as are memory deficits, fine motor and visual-spatial dysfunction, and psychological disturbances (44; 29).

Another significant determinant of cognitive injury is the volume 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 (07).

Risk of deficits after cranial irradiation is associated with high radiation therapy dose, large 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, tumor characteristics, tumor progression, concurrent medical illnesses, neurologic comorbidity, and medications that can contribute to neurocognitive deficits.

Neurocognitive impairment can be minimized with combined efforts of using modern conformal radiation therapy with avoidance of high total dose exposure to the brain (less than 54 Gy), reducing dose to the hippocampi in particular (to less than 16 Gy), using conventional fractionation, and applying advanced planning imaging and software (28).

The same types of radiation therapy that predispose to cerebral injury can result in endocrine dysfunction. Among adults, endocrine dysfunction can occur insidiously, developing over months to years and often undiagnosed. Given the ability to correct for most pituitary deficiencies, patients should be counseled on the importance of regular endocrine evaluation if their radiation therapy will involve the parasellar or hypothalamic regions. Children irradiated for brain tumors are even more vulnerable. The most common radiation-induced endocrinopathies are hypothyroidism and growth hormone deficiency.

Postirradiation optic neuropathy can occur after conventional or stereotactic radiation therapy to the optic apparatus, for tumors involving the retina, optic nerve, chiasm, and pituitary region, or intracranial tumors proximal to the visual system. 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 3 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; 54). 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. Delayed myelopathy after radiosurgery has been reported (17).

The cerebral vasculature itself may be damaged by radiation to the brain, sellar region, head and neck, or thorax. Depending on the portion of the vascular tree affected and the type of vascular lesion, transient ischemia, strokes, or hemorrhage may occur. However, hemorrhages occurring in the brain parenchyma are most commonly caused by metastatic tumor or coagulopathies related to a patients malignancy or antineoplastic therapy. Radiation that is administered to the neck can result in delayed carotid atherosclerosis. Tumor embolization to the brain is a rare cause of stroke. Neuroimaging studies, measurement of coagulation function, and echocardiography are the most useful modalities to identify the cause of stroke (50).

Radiation-induced cavernous malformations are another possible complication following therapeutic irradiation, commonly with brain doses in the range of 45 to 60 Gy. They have an inherent bleeding risk of approximately 1% per year. Their appearance is not different from other cavernous malformations (46).

Radiation-induced CNS tumors constitute a small but serious risk for subjects 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 8 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 (47; 58). 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 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 4 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 extensively described, their etiologies are still not well understood. Acute toxicity (occurring within hours to weeks of treatment) is probably related to increased edema. This theory is supported by neuroimaging data and the clinical observation of steroid responsiveness. Release of excitotoxic neurotransmitters has also been postulated as a contributory mechanism. Subacute damage (occurring within weeks to months of treatment) may reflect demyelination (04). Late injuries (occurring months to decades after treatment) constitute a more diverse group of disorders with multiple hypothesized etiologies, including neurovascular damage, progressive fibrosis, autoimmunogenesis, and disruption of cellular DNA (51).

Cerebral radiation necrosis and radiation myelopathy are the best characterized radiation-related syndromes from a histopathologic standpoint. From histopathologic studies it has been deduced that fibrinoid necrosis, endothelial proliferation, hyalinization and thickening of vessel walls, adventitial fibroblast proliferation, thrombosis, telangiectasias, and multinucleated astrocytes all contribute to the picture of coagulative white matter necrosis.

Reversible radiation myelopathy is characterized by prominent demyelination with axonal loss but only minimal vascular injury (32).

The histologic alterations in diffuse late brain injury with dementia are less dramatic and less specific. Gliosis, neuronal loss, and white matter spongiform changes predominate (14).

Radiation-induced optic neuropathy is thought to be due to free radical-induced damage to endothelium and neuroglial cell progenitors leading to vaso-occlusion, demyelination, and neuronal degeneration (33).

Epidemiology

The incidence of radiation-induced nervous system complications varies with the radiation dose, volume of tissue irradiated, and fractionation scheme; degree of edema; patient age; underlying diseases (malignant and nonmalignant); concomitant treatments; and length of survival after completion of radiation treatment. As a rule, incidence increases and latency decreases with higher total doses, higher fraction size, and larger volumes of treated nervous system (37).

Radiation-related white matter changes are extremely common on CT and MRI scans (12), and as many as 20% of patients with the radiographic correlates of diffuse late brain injury develop frank radiation-induced dementia (13). The incidence of radiation necrosis is greatest in patients receiving higher doses per fraction and higher biologically effective dose (52), and in those surviving more than one year. Concurrent methotrexate or nitrosourea chemotherapy may increase the risk. There is a hypothesized increased risk for radionecrosis with immune checkpoint inhibitors in combination with radiation, either concurrently or sequentially. Retrospective studies have found conflicting results, with some studies demonstrating an increased risk (10) whereas others have not (15). Subtle, nonprogressive personality and cognitive changes are even more frequent and are more pronounced in children and those over 60 years.

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 (59), 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 (39). 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 (35).

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 (40).

Data on brain toxicity are limited by failure to evaluate complex dose distributions (30). Hypertension, diabetes, concomitant chemotherapy (particularly with known radiosensitizing agents), stereotactic radiosurgery, and interstitial brachytherapy increase the frequency and accelerate the time course of this form of late-radiation-related injury.

Because the symptoms of neuroendocrine dysfunction may be subtle or difficult to distinguish from other tumor-related symptoms, this type of radiation-related disorder is 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 (11; 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 (27). 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.

Prevention

Preventive strategies have mostly been the result of improvements in radiation delivery technology. This includes advancements in imaging, defining target for irradiation, and more conformal treatment planning and targeting of radiation to designated target. 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 SBRT, 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. Studies suggest that variations in lymphocyte or skin fibroblast radiosensitivity may additionally predict the occurrence of radiation-related nervous system toxicity (36).

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 (08).

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 (20; 07).

Several retrospective studies have suggested that sparing brain tissue using proton therapy may also help to preserve cognitive function and other physiological processes (63; 22; 57). Multiple ongoing clinical trials are investigating this possibility, with some directly comparing proton therapy and photon IMRT.

Finally, 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; 56; 43). 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 (42; 60).

Differential diagnosis

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 (41; 53). 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.

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 (12). Progressive space occupying radiation necrosis has the appearance of ring enhancing mass lesion on neuroimaging studies (26). 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 (61).

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 4 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) (45). 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 associated with cerebral radiation necrosis, but they are not usually beneficial in radiation myelopathy (51; 31). A small randomized study demonstrated that behavioral intervention may be of benefit in improving executive functioning (48).

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 (34; 62). However, other studies have reported worsening symptoms with bevacizumab (55; 25); 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 (26). Laser-interstitial thermal therapy (LITT) has been proposed as a minimally invasive alternative to open craniotomy (49; 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.