Neurologic complications of radiation therapy

Radiation therapy is a mainstay of cancer treatment, particularly for patients with nervous system tumors. Like most cancer treatments, radiation is nonspecifically cytotoxic. As a result, when radiation therapy is used to treat primary or metastatic nervous system cancers or non-nervous system malignancies located close to neural structures (eg, head and neck cancers or mediastinal Hodgkin disease), treatment must be carefully crafted and doses and fraction sizes curtailed to prevent injury to the adjacent normal nervous system. A dramatic example of radiation-related nervous system injury, cerebral radionecrosis, was originally described in 1930, soon after radiation was first used therapeutically for brain tumors [1]. Since that time, a spectrum of injuries involving central and peripheral nervous system structures has been identified. 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 (and may be altered by concurrent chemotherapy, pre-existing disease, and variations in tumor anatomy), and intentional "overdoses" may be given with curative or long-term palliative intent. The incidence of radiation-related nervous system injury seems to be increasing as conventional radiation therapy techniques are being applied more aggressively, new approaches (such as hyperfractionated radiation therapy, concurrent chemo- and radiotherapy, and radiosurgery) are becoming commonplace, and patients are surviving longer. Accurate diagnosis based on clinical manifestations is critical to exclude other potentially treatable total doses, higher fraction size, and larger volumes of treated nervous system [2]. Among the acute complications, acute radiation encephalopathy is now uncommon because of careful radiation treatment planning and the judicious use of corticosteroids. In contrast, fatigue and other nonspecific side effects associated with conventional and stereotactic cranial irradiation (Box 1) occur in the majority of patients. Except for subacute myelopathy, which is seen in up to 15% of patients treated with mantle irradiation for Hodgkin disease, the subacute complications of nervous system irradiation are also uncommon. In contrast to the acute and subacute complications of radiation, late radiation effects are relatively common. Delayed cerebral radionecrosis occurs in approximately 5% of patients receiving more than 5000 cGy of cranial irradiation, although the actual incidence is dose and fraction size dependent (Fig. 1A, B; Fig. 2A, B). Hypertension, diabetes, concomitant chemotherapy (particularly with known radiosensitizing agents) [3-7], accelerated hyperfractionated radiation [8], stereotactic radiosurgery, and interstitial brachytherapy increase the frequency and accelerate the time course of this form of late-radiation-related injury. Up to 20% of patients receiving stereotactic radiosurgery [9] and as many as 80% of patients undergoing interstitial brachytherapy develop symptomatic radionecrosis, usually 3 to 12 months after treatment [10]. Radiation-related white matter changes are extremely common on CT and MRI scans [11,12], and as many as 20% of patients with these radiographic correlates of diffuse late brain injury develop frank radiation-induced dementia [ 13] (Fig. 3A-D). The incidence is greatest in patients receiving whole-brain radiation therapy with fractions greater than 200 cGy and in patients surviving more than I year. Concurrent methotrexate or nitrosourea chemotherapy may increase the risk. Subtle, nonprogressive personality and cognitive changes are even more frequent and are more pronounced in children and in those over 60 years of age. The manifestations of radiation-induced endocrine dysfunction are often subtle and difficult to distinguish from other treatment- and tumor-related with regard to prognosis and therapeutic options, and competing diagnoses with very different natural histories and therapies often mask or mimic the signs and symptoms of radiation-related nervous system injury. The ability to efficiently negotiate this complicated differential diagnostic landscape allows for early diagnosis of tumor recurrence or an alternative etiology, prompt institution of appropriate therapy, avoidance of unnecessary diagnostic studies, and confident prognostication for patients and families. Even after the diagnosis of a radiation-related complication is made, continued vigilance for additional sites or manifestations of radiation injury is mandatory. Meanwhile, further research into treatment, prevention, and the causes of individual susceptibility to radiation injury are essential.