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Radiation Necrosis

  • Author: Michael J Schneck, MD, MBA; more...
Updated: Nov 18, 2015


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. See Medscape Reference articles Neurologic Manifestations of Glioblastoma Multiforme and Low-Grade Astrocytoma.

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[1] 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.

Recent studies

Liu et al reported that in children with pontine gliomas, a nearly always fatal brain tumor, bevacizumab may provide both therapeutic benefit and diagnostic information. They note that although radiation therapy can provide some palliation in such patients, it can also result in radiation necrosis and neurologic decline. In a study of 4 children, 3 children showed significant clinical improvement with bevacizumab and were able to discontinue steroid use, which, according to the authors, can have numerous side effects that significantly compromise a patient's quality of life. In 1 child who continued to decline on bevacizumab, it was later determined that the patient had disease progression, not radiation necrosis. In all cases, according to the investigators, bevacizumab was well tolerated.[2]

Barajas et al attempted, in a study of 57 patients, to determine whether T2-weighted dynamic susceptibility-weighted contrast material-enhanced (DSC) MRI can differentiate radiation-therapy-induced necrosis from glioblastoma multiforme. They found that mean, maximum, and minimum relative peak height and relative cerebral blood volume were significantly higher in patients with recurrent glioblastoma multiforme than in patients with radiation necrosis. In addition, they determined that mean, maximum, and minimum relative percentage of signal intensity recovery values were significantly lower in patients with recurrent glioblastoma multiforme than in patients with radiation necrosis.[3]

Levin et al designed a class 1 double-blind study to compare the treatment of cerebral radiation necrosis with bevacizumab or placebo in 14 patients. Their protocol use, clinical, imaging, and other measures clearly demonstrated a beneficial effect of bevacizumab. They used 4 cycles at 3-week intervals. The dose was 7.5 mg/kg. Theoretically, bevacizumab blocks the effect of vascular endothelial growth factor (VGEF) and decreases vascular permeability, a critical component of radiation-mediated injury in the brain. The long-term benefit is not known. One of the study patients required an additional dose.[4]

Plimpton et al used MRI to retrospectively study 101 children with solid brain tumors. Median follow-up for all patients was 13 months (range 3-51 mo). They concluded that findings in pediatric patients treated with radiotherapy for solid brain tumor suggests children may have an increased likelihood to develop radiation necrosis compared with adults.[5]



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.[6]

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.




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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.[7]


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.

Contributor Information and Disclosures

Michael J Schneck, MD, MBA Vice Chair and Professor, Departments of Neurology and Neurosurgery, Loyola University, Chicago Stritch School of Medicine; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center

Michael J Schneck, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Society of Neuroimaging, Stroke Council of the American Heart Association, Neurocritical Care Society

Disclosure: Received honoraria from Boehringer-Ingelheim for speaking and teaching; Received honoraria from Sanofi/BMS for speaking and teaching; Received honoraria from Pfizer for speaking and teaching; Received honoraria from UCB Pharma for speaking and teaching; Received consulting fee from Talecris for other; Received grant/research funds from NMT Medical for independent contractor; Received grant/research funds from NIH for independent contractor; Received grant/research funds from Sanofi for independe.


Anna Janss, MD, PhD Associate Professor of Pediatric Neuro-oncology, Emory University School of Medicine; Consulting Neuro-oncologist, Children's Healthcare of Atlanta

Anna Janss, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Association for Cancer Research, American Medical Association, International Association for the Study of Pain, Pennsylvania Medical Society, Society for Neuroscience, Children's Oncology Group, Society for Neuro-Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Jorge C Kattah, MD Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria

Jorge C Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Frederick M Vincent, Sr, MD Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Frederick M Vincent, Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners Institute, American College of Legal Medicine, American College of Physicians

Disclosure: Nothing to disclose.


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

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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.
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.
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