AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Background

Radiation necrosis, a focal structural lesion that usually occurs at the original tumor site, is a potential long-term central nervous system (CNS) complication of radiotherapy or radiosurgery. Edema and the presence of tumor render the CNS parenchyma in the tumor bed more susceptible to radiation necrosis. Radiation necrosis can occur when radiotherapy is used to treat primary CNS tumors, metastatic disease, or head and neck malignancies. It can occur secondary to any form of radiotherapy modality or regimen.

In the clinical situation of a recurrent astrocytoma (postradiation therapy), radiation necrosis presents a diagnostic dilemma. Astrocytic tumors can mutate to the more malignant glioblastoma multiforme. Glioblastoma multiforme's hallmark histology of pseudopalisading necrosis makes it difficult to differentiate radiation necrosis from recurrent astrocytoma using MRI.

Therapeutic effects of radiotherapy

Radiation creates ionized oxygen species that react with cellular DNA. Tumor cells have less ability than healthy cells for DNA repair. Thus, between fractionation doses, healthy cells have a greater probability than tumor cells of repairing themselves. With each subsequent mitosis, the cumulative effects of unrepaired DNA result in apoptosis (cell death) of these tumor cells.

Central nervous system syndromes secondary to radiotherapy

Radiation necrosis is part of a series of clinical syndromes related to CNS complications of radiotherapy. These syndromes occur in a distinct chronologic order and have characteristic pathophysiology. While the term radiation necrosis is used to refer to radiation injury, pathology is not limited to necrosis and a spectrum of injury patterns may occur.

Acute encephalopathy occurs during and up to 1 month after radiotherapy. This acute encephalopathy is due to disruption of the blood-brain barrier.

Early delayed complications occur 1-4 months after radiotherapy. Early delayed complications are caused by white matter injury characterized by demyelination and vasogenic edema. Early delayed changes may produce a somnolence syndrome in children, reappearance of the initial tumor's symptomatology, temporary decline in long-term memory, and encephalopathy. In early delayed complications, patients may have increased edema and contrast enhancement on MRI (both symptomatic and asymptomatic) that may resolve spontaneously over a few months. Both the acute and early delayed complications are steroid responsive.

Treatment-induced leukoencephalopathy is the leading toxicity after primary CNS lymphoma and may be seen both early and as a delayed consequence of treatment. It may be seen in greater than 90% of patients older than 60 years who have been successfully treated with combination chemotherapy and whole-brain radiation. A relationship between increased blood-brain barrier permeability and radiation therapy has been posited to contribute to this leukoencephalopathy and to methotrexate-induced vasculopathy. This also may be an etiology for the changes seen with radiation necrosis.

Radiation necrosis and diffuse cerebral atrophy are considered long-term complications of radiotherapy that occur from months to decades after radiation treatment. As opposed to the focal nature of radiation necrosis, diffuse cerebral atrophy is characterized by bihemispheric sulci enlargement, brain atrophy, and ventriculomegaly. Diffuse cerebral atrophy clinically is associated with cognitive decline, personality changes, and gait disturbances.

Pathophysiology

Radiation necrosis is coagulative and predominantly affects white matter. This coagulative necrosis is due to small artery injury and thrombotic occlusion. These small arteries demonstrate endothelial thickening, lymphocytic and macrophagic infiltrates, presence of cytokines, hyalinization, fibrinoid deposition, thrombosis, and finally occlusion.

The primary mechanism of the delayed injury in radiation associated with necrosis is secondary to vascular endothelial injury or direct damage to oligodendroglia. As a result, white matter tissue is often more affected than gray matter tissue. Radiation may have effects on fibrinolytic enzyme systems, with an absence of tissue plasminogen activator and an excess in urokinase plasminogen activator impacting tissue fibrinogen and extracellular proteolysis with subsequent cytotoxic edema and tissue necrosis. Whether immune-mediated mechanisms may also contribute to radiation-induced neurotoxicity is unclear, but an autoimmune vasculitis has been postulated as a secondary host response to tissue damage.

Animals exposed to radiation and given antibodies to cytokines (tumor necrosis factor, interleukin-1, tissue growth factor) have decreased survival compared to animals that do not receive these antibodies. These cytokines may be involved in initially protecting healthy tissue from the effects of radiation. With prolonged radiation exposure, these particular cytokines are overexpressed and result in a cascade of inflammatory events and vascular injury.

In addition to vessel occlusion with resultant tissue necrosis, telangiectatic vessels, which may hemorrhage, occasionally form. Demyelination, oligodendrocyte dropout, axonal swelling, reactive gliosis, and disruption of the blood-brain barrier also can be observed.

Frequency

United States

Natural history of the tumor in terms of prognosis and survival may affect the occurrence of radiation necrosis in a particular tumor population. In glioblastoma multiforme or metastatic disease with a poor long-term prognosis, the patient may not live long enough to develop radiation necrosis. Radiation necrosis can occur as soon as a few months or as long as decades after treatment. It generally occurs 6 months to 2 years after radiation therapy. Radiation injury may occur in 5-37% of patients treated for intracranial neoplasms.

Mortality/Morbidity

Radiation necrosis can be fatal. It also can cause problems associated with a mass lesion, such as seizures, focal deficits, increased intracranial pressure, and herniation syndromes.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

History

• Radiation necrosis is a focal process that occurs at the initial tumor site.
• • The history generally reflects a subacute or chronic re-emergence of the initial tumor symptoms.
  • Occasional reports exist of patients developing diffuse areas of necrosis away from the initial tumor site.
  • When obtaining a history, include questions to exclude stroke and infection, which can cause a tumorlike appearance on MRI.
• Breakthrough or new seizures may occur. These seizures may be partial, complex partial, or partial with secondary generalization (grand mal).
• Depending on the tumor location and rate of growth, radiation necrosis can present with signs of mass effect, elevated intracranial pressure, obstructive hydrocephalus, or one of the herniation syndromes.
• Hemorrhage in late radiation necrosis is a rare but described phenomenon.
• Radiation necrosis involving the frontal or temporal lobes may produce cognitive and personality changes.
• • In nasopharyngeal carcinoma, the anteromedial aspects of the temporal lobes are located in the radiation port.
  • A patient with radiation necrosis in this location may develop symptoms of personality change, memory loss, amnesia, and/or Klüver-Bucy syndrome.
  • Radiation necrosis resulting from radiotherapy for ocular and maxillary cancer can affect the frontal lobes. This can cause hemiparesis, apathy, and/or personality changes.

Physical

• Evaluate mental status and cortical functioning in patients with radiation necrosis who have a supratentorial lesion or signs of increased intracranial pressure. In cortical testing, examine for aphasia, apraxia, attention, neglect, visuospatial skills, recognition, short-term recall, and calculation.
• With the possibility of increased intracranial pressure, examine the fundus for possible papilledema and/or decreased or absent spontaneous venous pulsations.
• Since radiation necrosis is a focal lesion, tailor the neurologic exam to look carefully for focality, lateralization, or asymmetry in motor, sensory, or coordination testing.
• Since radiation necrosis occurs in the same region as the initial tumor bed, evaluate functions specific to that area of the CNS.

Causes

Occurrence generally is related to total radiation doses and fractionation size.

• Tolerable total radiation dose to the brain is 6500-7000 cGy.
• Patients who have received a total dose of 5500 cGy have a 3-5% occurrence of radiation necrosis.
• Fractionation daily dose exceeding 200 cGy also increases risk.
• Other predisposing factors include the following:
• • Other vasculopathic risk factors (eg, diabetes mellitus, hypercholesterolemia)
  • Intravenous chemotherapy

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Patients with a diagnosis of either a primary or metastatic brain tumor with a CNS event should undergo a meticulous review of their histories for other possible causes.

Sagittal sinus thrombosis
Neurologic complications related to antineoplastic treatments
Radiation-induced neoplasm
Brainstem syndromes
Complex partial status epilepticus
Increased intracranial pressure
Vascular dementia

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Lab Studies

• No specific tests of the serum or cerebrospinal fluid are indicated.

Imaging Studies

• A fundamental problem in diagnosis is that most imaging studies do not preclude the need for surgical brain biopsy or craniotomy for diagnosis. The typical appearance of brain radiation injury is similar to that of brain tumors, with a contrast-enhancing mass surrounded by edema and mass effect.
• • With conventional MRI, CT scan, positron emission tomography with [¹⁸F]-labeled fluorodeoxyglucose (PET-FDG), and thallium 201 spectroscopy (single-photon emission CT [SPECT]), differentiating radiation necrosis from recurrent tumor is difficult.
  • Most of the research has been focused on recurrent astrocytoma.
• MRI
• • MRI signal changes in radiation necrosis cannot be differentiated from tumor-related changes.
  • In a study by Asao et al, diffusion-weighted MRI sequences of radiation necrosis were associated with marked and spotty hypointensity compared with recurrent tumors, with maximal apparent diffusion coefficient values in each lesion being smaller for recurrent tumors versus radiation necrosis.
  • T1, T1 with gadolinium, T2, T2- fluid-attenuated inversion recovery (FLAIR), and proton density do not adequately enable differentiation of radiation necrosis from tumors.
  • Previously, radiation necrosis was believed to have greater peripheral than central enhancement with gadolinium. However, this peripheral enhancement pattern is not a consistent finding in radiation necrosis. Tumors also may display a greater peripheral than central enhancement.
  • MRI patterns that may signal but are not diagnostic for the possibility of radiation necrosis include the following:
    • Nonenhancing tumors prior to surgery that have enhancing foci that subsequently develop within and circumscribed to the tumor bed may represent necrosis rather than progression to higher-grade tumor.
    • Enhancing lesions that develop some distance from a primary glioma but within the radiation field may be indicative of radiation necrosis.
    • Enhancing focus in the periventricular white matter, particular within the corpus callosum or the top of the ventricles, may represent necrosis because the periventricular white matter is highly susceptible to radiation necrosis.
    • Consider radiation necrosis if a new MRI enhancing lesion has a soap-bubble or Swiss-cheese appearance.
• CT scan
• • CT scan is not helpful in making the diagnosis of radiation necrosis.
  • It is most useful in the acute, clinical decline of a patient with brain tumor to differentiate acute hemorrhage from increased intracranial pressure, obstructive hydrocephalus, or a herniation syndrome.
• Dynamic testing
• • Dynamic testing (eg, PET-FDG, SPECT) detects differences in tissue metabolism.
  • Tumors have greater metabolism (ie, increased uptake of PET-FDG and SPECT) than healthy brain parenchyma and areas of radiation necrosis.
  • Radiation necrosis is hypometabolic (ie, decreased uptake of FDG and thallium) compared to healthy brain parenchyma.
  • PET-FDG uses glucose transport and glycolysis as markers of metabolic activity.
  • Thallium metabolic activity is due to its similarity to potassium.
  • Thallium SPECT reflects metabolic activity of sodium/potassium ATP-dependent membrane transport, chloride transport, and calcium channels.
  • In dynamic testing, a region of interest (ROI) is compared to a similar area of healthy brain. A ROI located in one hemisphere is compared to a similar area in the contralateral hemisphere.
  • For bihemispheric lesions, a ROI is compared to an equivalent region in the anterior-posterior or posterior-anterior areas of brain parenchyma.
  • Most medical centers use qualitative assessments of ROI rather than quantitative assessments.
  • Despite diagnostic benefits and limitations of dynamic testing, histology often demonstrates mixed findings of malignant cells and radiation necrosis.
• Advantages of PET-FDG
• • PET-FDG correlates with prognosis and survival for newly diagnosed astrocytoma. Astrocytoma research has demonstrated that increased FDG uptake correlates with decreased survival.
  • Increased FDG activity on PET is more indicative of higher-grade astrocytoma such as anaplastic astrocytoma or glioblastoma multiforme.
  • PET-FDG also has assisted in guiding brain biopsy sites. Since brain biopsies are subject to sampling error, PET-FDG can assist the surgeon in obtaining the most metabolically active tissue to allow more accurate tumor staging.
  • PET-FDG is diagnostically useful in evaluating a tumefactive lesion (ie, structural lesion on MRI that suggests tumor) when clinical history suggests another diagnosis (eg, stroke, demyelination, abscess).
  • Despite the potential of this tool in a newly diagnosed brain tumor, PET-FDG becomes problematic when differentiating radiation necrosis from tumor recurrence.
• Disadvantages of PET-FDG
• • Its sensitivity and specificity in differentiating radiation necrosis from tumor recurrence are related to various factors. Overall, the sensitivity of FDG-PET has been reported as 80-90%, but the specificity is lower (50-90% depending on the series).
  • A ROI less than 1.6 cm lowers sensitivity and specificity in the differentiation of radiation necrosis from tumor recurrence.
  • A ROI located in the temporal lobes and brain stem may have poor resolution due to artifact from nearby bony structures.
  • Inflammatory cells in areas of radiation necrosis may show increased metabolic activity, which falsely can indicate tumor recurrence.
  • Tumor cells also may be present in areas of low glucose activity on PET-FDG.
  • Brain tissue used for comparison to the ROI can become depressed metabolically from radiotherapy and/or chemotherapy.
  • Carbon C 11–methionine PET scanning may be a complementary study to FDG-PET. In one series, 31 of 35 brain tumors showed increased ¹¹C-methionine despite isometabolsim or hypometabolism on FDG-PET scans, and 10 benign lesions (of which 2 were cases of radiation necrosis) showed decreased or normal uptake of ¹¹C-methionine.
• Thallium single-photon emission CT scan
• • Except for being more readily available at more medical centers than PET-FDG, thallium SPECT has the same limitations in dynamic testing.
  • A thallium index greater than 1.5 generally correlates with an anaplastic astrocytoma, glioblastoma multiforme, primary CNS lymphoma, or metastasis.
• Magnetic resonance spectroscopy
• • Magnetic resonance spectroscopy (MRS) offers a new, quantitative approach to help differentiate radiation necrosis from tumor recurrence.
  • A few studies with histologic confirmation demonstrate the potential of MRS in differentiating radiation necrosis from tumor recurrence.
  • Future studies will determine the usefulness of MRS in avoiding biopsy or craniotomy for definitive diagnosis. MRS measures various brain metabolic markers, as follows:
    • Creatine is indicative of cellular bioenergetics.
    • Choline (Cho) compounds reflect membrane metabolism.
    • Lactate (Lac) reflects anaerobic metabolism.
    • N-acetylaspartate (NAA) is an amino acid marker of neurons.
    • Gliomas have high peaks in Cho and even higher peaks in creatine when compared to healthy brain tissue.
    • Radiation necrosis has decreased peaks in Cho, NAA, and creatine compared to healthy brain tissue.
    • MRS may be of particular use in distinguishing pure tumor from pure necrosis. Knowledge of the choline/creatine and lipid-lactate/choline ratios may allow one to distinguish between tumor and necrosis; good correlation between MRS and lesion biopsy findings was reported from a study by Rock et al.
• Overall, imaging studies provide additional information, but they cannot provide a definitive diagnosis (ie, to avoid biopsy or craniotomy).

Procedures

• The similarities of radiation necrosis and tumor recurrence in clinical presentation and diagnostic imaging make performing a brain biopsy critical for diagnosis.
• • Diagnosing radiation necrosis is problematic. The diagnosis depends on obtaining adequate biopsy findings and is prone to sampling error.
  • A brain biopsy sample must be large enough to exclude tumor recurrence without causing clinically significant neurologic deficits. Areas to avoid include the deep central areas of the thalamus, the motor strip, occipital lobe, and speech centers.

Histologic Findings

• Radiation necrosis tissue samples demonstrate necrotic tissue without predominance of malignant cells.
• Irradiated tumor may contain necrosis, which does not necessarily signify radiation necrosis.
• Some biopsy findings of radiation necrosis show both malignant cells and radiation necrosis.
• A hallmark of radiation necrosis is involvement of the white matter with demyelination and oligodendrocyte dropout.
• In addition to necrotic tissue, biopsy findings of radiation necrosis may demonstrate thickened vessels with endothelial proliferation and/or hyalinization with fibrosis and moderate infiltration of lymphocytes and macrophages.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Medical Care

Probably the most important factor in providing good care is the clinician's confidence of diagnosis. Exposing a patient with radiation necrosis to unwarranted antineoplastic treatment is not desirable.

• A conservative option in treating a patient with radiation necrosis is observation. This may be appropriate for a patient found to have an asymptomatic necrotic mass on follow-up MRI. If the patient is asymptomatic and definitive diagnosis of radiation necrosis or recurrent glioma does not make a difference in clinical management, the patient should be monitored clinically and with serial MRI scans.
• For patients with signs and symptoms of mass effect, increased intracranial pressure, or neurologic disability, consider other treatment options. Consider surgical evaluation, steroids, anticoagulation, or hyperbaric oxygen therapy separately or in combination.
• Hyperbaric oxygen promotes perfusion and angiogenesis.
• • Oxygen is delivered at 20-24 atm for 20-30 sessions. Each session lasts approximately 90-120 minutes.
  • Hyperbaric oxygen therapy is expensive, time-consuming, and not readily available at most medical centers.
  • Efficacy is not well documented.
  • Small case studies exist, but many of these patients also were receiving concomitant steroid therapy. These clinical series showed resolution of a lesion on MRI.
  • Hyperbaric oxygen can be provided in conjunction with anticoagulation.

Surgical Care

In addition to providing potential histologic diagnosis, surgery has other therapeutic benefits. Surgical debulking of the lesion can relieve increased intracranial pressure and improve disability. Patients with obstructive hydrocephalus may require a shunting procedure. Surgery, however, is associated with a high risk of complications or neurologic deficit and should be reserved for symptomatic patients in whom medical therapy fails.

MEDICATION

Section 7 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Medical therapy focuses on 2 mechanisms: controlling vasogenic edema and/or controlling vessel thrombosis.

Drug Category: Corticosteroids

Steroid therapy has only a temporary role in relieving neurologic decompensation and deficits. It relieves any symptomology related to vasogenic edema and disruption of the blood-brain barrier. While administering steroid therapy, the clinician must implement another medical or surgical therapy to treat radiation necrosis and to protect the patient from long-term complications.

Drug Category: Anticoagulants

Because radiation necrosis pathophysiology involves vessel thrombosis and subsequent occlusion, anticoagulant use has been proposed. To date, few case studies have addressed use in this condition; the evidence for anticoagulation is very limited. Patients with radiation necrosis may also be at risk of intracranial hemorrhage, further limiting the presumptive benefits of this therapy. In most of these studies, histologic verification of radiation necrosis was present. Patients received 6 mo of IV heparin, then warfarin with aPTT and PT adjusted to 1.5 times the control. Patients had significant resolution of deficits. When anticoagulation was stopped, symptoms reemerged. Almost immediate resolution of symptoms occurred when anticoagulation was restarted. Before starting anticoagulation therapy, careful diagnostic evaluation and management are needed.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Consider the special medical needs of immobilized patients with a decreased level of consciousness and paralysis. They are more susceptible to deep venous thrombosis, pulmonary embolism, pneumonia, sepsis, malnutrition, and skin breakdown.
• Depending on lesion site and treatment effects, patients with brain tumors may be more predisposed to cognitive difficulties and dementia, which in turn increase the risk of delirium and cognitive difficulties. Prevention and treatment of delirium includes reorientation techniques, frequent interactions with familiar personal contacts (eg, family members), minimal or no exposure to psychotropic medications, control of noxious visual and auditory stimuli, correction of underlying metabolic derangements, and maintenance of a normal sleep-wake schedule.

Further Outpatient Care

• Many neurooncology patients have significant cognitive and neurologic disabilities. These may require physical therapy, occupational therapy, social work support, and home nursing.

Prognosis

• Prognosis is related to the natural history of underlying tumor and the idiosyncratic nature of radiation necrosis. Some lesions may show no interval growth while others require multiple resections to relieve disability.

ACKNOWLEDGMENTS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Robert Wilson, MD to the development and writing of this article.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

Media file 1:  MRI of a patient with symptoms of gait unsteadiness 1 year after being diagnosed with a posterior fossa primitive neuroectodermal tumor (PNET). Treatment during the 1-year interval prior to this MRI consisted of surgical resection, craniospinal radiation of 2340 cGy, boost dose given to the posterior fossa for a total of 5500 cGy, chemotherapy (vincristine, cis-platinum, and cyclohexylchloroethylnitrosurea [CCNU]), and dexamethasone therapy.
	View Full Size Image
Media type:  MRI

Media file 2:  Positron emission tomography with [18F]-labeled fluorodeoxyglucose (PET-FDG) performed following the MRI of a patient with symptoms of gait unsteadiness 1 year after being diagnosed with a posterior fossa primitive neuroectodermal tumor (PNET). Treatment during the 1-year interval prior to these studies consisted of surgical resection, craniospinal radiation of 2340 cGy, boost dose given to the posterior fossa for a total of 5500 cGy, chemotherapy (vincristine, cis-platinum, and cyclohexylchloroethylnitrosurea [CCNU]), and dexamethasone therapy. PET-FDG demonstrates hypometabolism consistent with probable radiation necrosis. Four years later, the patient is stable and without evidence of tumor progression.
	View Full Size Image
Media type:

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Oct 4, 2006