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.^[8]

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

Multiple risk factors are thought to play a role in the development of radiation necrosis (RN). These include the cumulative radiation dose, fractionation size, treatment duration, treated volume, prior cranial radiation, and the use of adjuvant therapies. Additionally, probabilistic variables, such as the genetic profile of the radiated tumors or the host may also influence the risk of developing RN.^[9]

Brain lesions > 1cm in diameter exhibit the greatest risk of developing RN.^[9]Occurrence generally is related to total radiation doses and fractionation size. The risk increases with increasing doses and larger radiation fraction sizes.

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.
Cerebral necrosis is unlikely at doses less than 50 Gy in 25 fractions.^[10]
Hypofractionation is an effective strategy for treating recurrent high-grade gliomas without increasing the risk of RN.^[11]
A dose-dependent risk is also seen with stereotactic radiosurgery, where doses > 10 Gy to > 10.5 mL volume carry a 35% risk of RN,^{[12, 13]}and up to 50% risk with 13 Gy to > 10 mL surface area.^[13]
A systematic review showed no correlation between the duration from initial radiotherapy to re-irradiation and the risk of RN.^[14]

Other predisposing factors include the following:

Adjunctive therapies such as the use of BRAF inhibitors with SRS, which in one study caused a 22% risk of RN compared to 11% in SRS alone.^[15]
Other vasculopathic risk factors (eg, diabetes mellitus, hypercholesterolemia).
Chemotherapy: Chemotherapy increases the risks of necrosis even when adjusting for length of follow-up or initial radiation therapy dose.
A study of 5747 brain lesions by Miller et al. provided novel insight into the relationship between tumor biology and risk of RN. They found that metastatic renal and small-cell lung carcinomas were correlated with a greater likelihood of RN. Furthermore, HER2-amplification, BRAF V600+ mutational status, and ALK rearrangement appeared to be significantly associated with RN.^[16]
Individual risk factors, such as variations in genetic radiosensitivity, also contribute to the risk of RN. Wang et al. identified the gene Cep128 as a radiation injury susceptibility gene.^[17]

Differential Diagnoses

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Media Gallery

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.
T1-weighted contrast imaging shows left frontoparietal enhancing mass lesion with significant perilesional edema and midline shift. Peripheral wavy frond-like enhancement is typical of radiation necrosis.
T1-weighted contrast imaging after the corticosteroid administration showing a significant reduction in enhancement, swelling, and mass effect with reversal of midline shift.

of 4

Author

Gaurav Gupta, MD, FAANS, FACS Associate Professor of Neurosurgery, System Co-Director, Cerebrovascular and Endovascular Neurosurgery, Fellowship Director, Endovascular Neurosurgery Fellowship (Site), Department of Surgery, Division of Neurosurgery, Rutgers RWJ Barnabas Healthcare, Rutgers Robert Wood Johnson Medical School

Gaurav Gupta, MD, FAANS, FACS is a member of the following medical societies: American Academy of Neurology, American Association for the Advancement of Science, American Association of Neurological Surgeons, American College of Surgeons, American Heart Association, American Medical Association, Congress of Neurological Surgeons, Facial Pain Association, Society for Neuroscience, Society of NeuroInterventional Surgery

Disclosure: Nothing to disclose.

Coauthor(s)

Fareed R Jumah, MBBS Postdoctoral Research Fellow, Department of Neurosurgery, RWJ University Hospital, Rutgers Robert Wood Johnson Medical School

Disclosure: Nothing to disclose.

Bharath Raju, MBBS, MCh Postdoctoral Research Fellow, Department of Neurosurgery, RWJ University Hospital, Rutgers Robert Wood Johnson Medical School

Bharath Raju, MBBS, MCh is a member of the following medical societies: AOSpine, Bangalore Neurological Society, European Association of Neurosurgical Societies, Neurological Society of India, Neurotrauma Society of India

Disclosure: Nothing to disclose.

Sudipta Roychowdhury, MD Clinical Associate Professor of Radiology, Department of Radiology, Rutgers Robert Wood Johnson Medical School; Attending Radiologist/Neuroradiologist, University Radiology Group, PC

Sudipta Roychowdhury, MD is a member of the following medical societies: American College of Radiology, American Medical Association, American Society of Neuroradiology, Medical Society of New Jersey, Radiological Society of New Jersey, Radiological Society of North America, Society of NeuroInterventional Surgery

Disclosure: Nothing to disclose.

Anil Nanda, MD, MPH, FACS Professor and Chairman, Department of Neurosurgery, Rutgers University Robert Wood Johnson Medical School and Rutgers New Jersey Medical School; Peter W Carmel, MD, Endowed Chair of Neurological Surgery, Senior Vice President of Neurosurgical Services, RWJBarnabas Health

Anil Nanda, MD, MPH, FACS is a member of the following medical societies: American Academy of Neurological Surgery, American Association of Neurological Surgeons, American Medical Association, Brain Attack Coalition, Congress of Neurological Surgeons, John C McDonald Surgical Society, Louisiana Neurosurgical Society, Louisiana State Medical Society, North American Skull Base Society, Shreveport Medical Society, Society of Neurological Surgeons, Society of University Neurosurgeons, Southern Neurosurgical Society

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.

Chief Editor

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Medical Association, American Neurological Association, The Society of Federal Health Professionals (AMSUS), Child Neurology Society, Southern Pediatric Neurology Society

Disclosure: Nothing to disclose.

Additional Contributors

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, Neurocritical Care Society, Stroke Council of the American Heart Association

Disclosure: Nothing to disclose.

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.

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.

Acknowledgements

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.