Complications of Radiotherapy and Radiosurgery in the Brain and Spine

Abstract

Radiation therapy is an integral part of the standard of care for many patients with brain and spine tumors. Stereotactic radiation surgery is increasingly being used as an adjuvant therapy as well as a sole treatment. However, despite newer and more focused techniques, radiation therapy still causes significant neurotoxicity. In this article, we reviewed the scientific literature, presented cases of patients who had developed different complications related to conventional radiation therapy or radiosurgery (gamma knife), demonstrated the imaging findings, and discussed the relevant clinical information for the correct diagnoses. Radiation therapy can cause injury in different ways: directly damaging the structures included in the radiation portal, indirectly affecting the blood vessels, and increasing the chance of tumor development. We also divided radiation complications according to the time of occurrence: acute (0 to 4 weeks), early delayed (4 weeks to months), and late delayed (months to years). With the increasing application of radiation therapy for the treatment of CNS tumors, it is important for the neuroradiologist to recognize the many possible complications of radiation therapy. Although this may cause significant diagnostic challenges, understanding the pathophysiology, time course of onset, and imaging features may help institute early therapy and prevent possible deleterious outcomes.

Learning Objectives:

To recognize the main complications of radiation therapy and stereotactic radiosurgery in the brain and spine, and to highlight the imaging findings to improve the diagnostic process and treatment planning.

INTRODUCTION

In recent years, an increasing incidence of brain tumors has been reported.^1,2 Although this is well demonstrated for metastatic brain lesions, which represent the most common type of intracranial tumor, for primary brain neoplasms, it is still debated.³ Several recent studies report a significantly higher incidence of intracranial metastasis compared with that of half a century ago.^4–6 Currently, 10%–15% of people with cancer will develop metastatic disease, with an incidence of brain involvement that ranges from 10% to 40%.^4–9 Two elements play a major role in this phenomenon: the improvement in the control of systemic neoplastic diseases and the advances in diagnostic imaging methods. The former element leads to longer survival and, consequently, more time to develop brain metastasis; the latter allows better recognition and characterization of an increasing number of brain lesions. The Central Brain Tumor Registry of the United States reported a slight increase of overall average annual age-adjusted incidence rates for primary CNS neoplasms (from 21.42 per 100,000 in the 2007–2011 report¹⁰ to 22.36 per 100,000 in the 2009–2013 report¹¹). However, these results can be affected by many factors, such as the difference in diagnostic ability and access to medical care across time periods.

The management of brain tumors is continuously evolving, and many trials focus on finding the best balance between preventing disease progression and minimizing the development of life-threatening treatment-related complications. The patient’s quality of life is considered one of the primary goals of treatment. Radiation therapy (RT) is a mainstay treatment for brain tumors, especially in patients who cannot undergo surgery due to medical conditions or have lesions that are unresectable because of their multiplicity or location. Even if some types of RT, such as stereotactic radiosurgery (SRS), are more precise in delivering radiation specifically to the target and sparing the surrounding healthy tissue,¹² complications related to radiation are still a main concern that may negatively affect the patient’s quality of life. The information about adverse effects of RT and SRS is continuously increasing, but pathologic mechanisms and etiologic factors are still not fully understood. Moreover, the neuroradiologic features of these complications can be equivocal; therefore, advanced imaging techniques or more invasive procedures are sometimes necessary to reach the correct diagnosis.¹² In this article, we reported and discussed the main complications of RT and SRS in the brain and spine. In this pictorial review, we presented the clinical history and illustrated the imaging findings to demonstrate the various complications of radiation treatments.

COMPLICATIONS OF CONVENTIONAL RT

RT can cause injury both directly and indirectly. Direct damage involves structures included in the radiation field. Indirect damage affects blood vessels and increases the risk of tumor development. Radiation-induced neurotoxicities are classified according to the time of occurrence after the treatment: acute complications develop during or up to 1 month after irradiation; early delayed or subacute effects occur 1–6 months after irradiation; late delayed effects refer to complications that occur ≥6 months after radiation exposure and are often irreversible.¹³

Acute Complications

Acute Encephalopathy.

One of the most severe complications that may occur a few days after brain irradiation is acute encephalopathy. This condition is characterized by severe headache, nausea and vomiting, obtundation and alteration of consciousness, and focal neurologic defects. It is considered a consequence of the development of cerebral edema and of damage of the BBB. Neuroimaging studies show white matter edema and brain swelling. It is potentially fatal in the case of significantly elevated intracranial pressure, with resultant cerebral herniation. Fortunately, encephalopathy usually responds to corticosteroid treatment and antiemetics are useful for nausea and vomiting, and the prognosis is generally favorable. Early studies showed that the development of acute encephalopathy is dose-dependent^13–15 and, with current RT techniques, this complication is rare.

Fatigue.

The most common acute complication of brain RT is fatigue, which is encountered in >50% of patients.^16–19 Symptoms typically begin within 2 weeks of the start of RT, peak at approximately 6 weeks,¹⁶ and may persist for several months, with gradual improvement. Even if fatigue is often underestimated by clinicians,²⁰ it may affect not only the quality of life of patients but also their compliance with the treatment and, ultimately, the overall survival. Many factors have been correlated with the occurrence of fatigue, such as the type of cancer²¹ or the duration of the radiation treatment course.^22–24 Furthermore, results of recent studies indicate that the disruption of pathways that interconnect the basal ganglia, cerebellum, and higher cortical centers or a hormonal imbalance due to pituitary gland irradiation may play an important pathophysiologic role in the occurrence of fatigue after RT.^25–27 However, no neuroimaging or histologic findings were specifically found to be significantly associated with radiation-induced fatigue, and further studies are required to clarify this point.

Alopecia and Dermatitis.

Another extremely common acute adverse effect of cranial irradiation is alopecia. The severity and permanence of alopecia are directly dependent on the radiation dose, and scalp-sparing irradiation techniques have been shown to be able to prevent alopecia.²⁸ Radiation dermatitis is a common mild complication that may occur 1–3 weeks after RT. The treatment can include soothing moisturizing ointments. Bacteriostatic topical treatments should be added in the case of dry or moist desquamation, usually in areas of the skin that received particularly high doses of radiation. The prognosis is generally good. In patients who have recently begun phenytoin or carbamazepine anticonvulsant therapy, Stevens-Johnson syndrome should be suspected if a severe skin reaction occurs or if a skin reaction that extends beyond the RT fields occurs.²⁹

Mucositis and Myelosuppression.

Among the complications related to craniospinal irradiation, mucositis and myelosuppression are relevant. The risk of their occurrence is significantly increased in patients who receive concomitant chemotherapy. Although these complications are temporary and usually resolve in less than a month, they have an important impact on patients’ quality of life. Pharyngeal mucositis is commonly associated with dysphagia, secondary malnutrition, and increased complication rates.^30–32 Recently, a model to identify patients at high risk for the need of artificial nutrition has been proposed, and it could help the clinician to optimally select patients who could benefit from prophylactic percutaneous endoscopic gastrostomy tube insertion.³³ Ultimately, both of these complications can lead to the interruption of therapy, which results in a worse survival rate.

Early Delayed Complications

This subtype of complications usually occurs between 1 and 6 months after RT.

Pseudoprogression.

Pseudoprogression is frequently found in patients with high-grade gliomas (HGGs), which occur in roughly 15%–30%^34–38 of patients treated with RT and concomitant temozolomide chemotherapy; it also seems to be frequent in patients with low-grade gliomas (LGGs) after RT, even if its incidence is largely unknown, and only 2 studies investigated it.^39,40 This complication most likely occurs because of endothelial damage and the increased permeability of the tumor vasculature induced by chemoradiation treatment, which leads to tissue hypoxia.³⁶ Although in patients with HGG, pseudoprogression usually develops within 12 weeks after RT,⁴¹ in patients with LGG, a longer latency period has been reported, with a median of 12 months.³⁹ This finding drove some researchers to hypothesize a different pathophysiologic mechanism of pseudoprogression in LGG, which involves asymptomatic small enhancing ischemic infarctions due to radiation-induced microvascular injury.³⁹

However, contrary to radiation necrosis or radionecrosis (RN), pseudoprogression is a mild and self-limited form of necrosis⁴² and appears earlier on MR imaging.⁴¹ Pseudoprogression is characterized by contrast enhancement on MR imaging (Fig 1), and this feature, without any other specific imaging finding, makes it difficult to reliably differentiate pseudoprogression from true disease progression. However, the use of advanced MR imaging techniques can aid in diagnosis. MRS can give valuable support to diagnose pseudoprogression; increases in lipid and lactate signal intensities, together with reductions in total Cho and the Cho:NAA ratio indicate the transformation of viable cells into necrosis, which thus suggests underlying pseudoprogression.⁴³ However, an increase in total Cho has been found to be associated with tumor progression.⁴⁴ Also, dynamic MR imaging can be helpful in distinguishing these 2 entities because of their different perfusion patterns; relative CBF (rCBF) has been found to be decreased in the case of pseudoprogression, whereas it may be increased in the case of progressing viable tumor cells.⁴¹

Fig 1.

Pseudoprogression. T1WI post-gadolinium (Gd) (top row) and T2WI FLAIR (bottom row) show a glioblastoma multiforme that underwent surgical resection followed by RT; the initial postoperative MR imaging shows T1 shortening from blood products; there was a development of new enhancement along the margins of the surgical cavity 2 months after RT, which regressed on the follow-up scans, compatible with pseudoprogression.

Some molecular markers may be useful for the evaluation and prediction of pseudoprogression in patients with HGG. It has been reported that promoter methylation of the O6-methylguanine methyltransferase gene is associated with improved overall survival of patients with HGG and the development of pseudoprogression.^36,45 Overexpression of tumor protein P53⁴⁶ and isocitrate dehydrogenase 1 (IDH1) mutation⁴⁷ have also been associated with the development of pseudoprogression.

From a clinical point of view, even if pseudoprogression is asymptomatic in most patients,^48,49 the worsening of symptoms cannot reasonably exclude pseudoprogression in favor of true progression.⁵⁰ Although the scientific community made a great effort in developing standardized criteria that could be helpful in distinguishing these 2 conditions, pseudoprogression is still a challenging diagnosis, and novel diagnostic methods need to be identified to avoid potentially harmful surgical interventions.⁵¹

Somnolence Syndrome and Neurocognitive Deficits.

Somnolence syndrome (SS) is an early delayed complication that usually occurs during the second month after irradiation and lasts for approximately 2 weeks. It is mainly diagnosed in children, especially after prophylactic cranial irradiation for acute lymphoblastic leukemia.^52–61 The incidence of SS has decreased because cranial irradiation is now predominantly replaced by chemotherapy. Even though it is much less common, there are a few cases of SS reported in adults.^16,62,63 As suggested by its name, the main symptom of this syndrome is excessive sleepiness, often accompanied by drowsiness, a low-grade fever, and anorexia. Although SS was reported for the first time in 1929,⁶⁴ the etiologic mechanism that explains its development is still unknown; however, the most influential theory attributes SS to radiation-induced transient demyelination of nerve fibers.^63,65,66 No significant neuroimaging findings have been associated with this syndrome. Treatment is usually not required, but steroids may be useful for symptomatic relief and for prevention as well.^54,58

Among the early delayed complications, reversible neurocognitive deficits were also reported.⁶⁵ Armstrong et al^67,68 observed a temporary decline in “short-term memory” and, specifically, in verbal and visual memory, with a full recovery within a year after RT. In their studies, these early delayed effects did not predict the occurrence of late delayed neurocognitive complications, and no specific neuroimaging findings were linked to these symptoms.^67,68 Moreover, these findings seemed consistent with the theorized periods of radiation-induced demyelination and remyelination that some researchers proposed as a potential mechanism that causes the early delayed transitory effects of RT.^13,61,69,70

Transient Myelopathy.

With regard to complications of the spine, a transient myelopathy was described in patients undergoing RT treatment for head and neck cancer.^71–73 It mainly occurs at 4 to 6 months after RT, and it is characterized only by the Lhermitte phenomenon, an electrical sensation that runs down the back and, frequently, into the limbs. The symptom may be elicited by neck flexion and usually resolves after several months. The remainder of the neurologic examination is normal, and, on MR images, there are no specific findings. Transient radiation-induced demyelination of the posterior columns has been proposed as the cause of the phenomenon, even if histologic proof is lacking.⁷⁴

Late Delayed Complications

RN.

RN is one of the most serious complications of RT. From a pathologic point of view, a combination of direct glial injury, endothelial cell and BBB damage, and immunologic responses may be responsible for the tissue death that occurs in RN.¹³ It typically occurs 1 to 2 years after radiation, but RN can occur as early as 3 months or as late as several years after treatment. The accurate incidence of intracranial RN remains unknown because many factors could influence it, such as the type of treatment (RT alone or combined with chemotherapy), the clinical and radiologic follow-up duration, the dose delivered, the type of neuro-imaging examination used to diagnose RN, and the provision or lack of histologic confirmation. However, it has been reported that the incidence may range from 5% to 50%.¹²

Among the risk factors, the total radiation dose and fraction size are important^13,75,76; in patients who undergo SRS, the irradiated volume is relevant as well.⁷⁷ Results of some studies also indicate that the concomitant use of chemotherapy can increase the risk of the development of RN, but definitive evidence is still required.^13,78–81 More recently, interindividual variability in the occurrence of RN among patients treated with comparable radiation doses and administration protocols for similar pathologies in similar locations supported the hypothesis that genetic factors may influence tissue sensitivity to radiation exposure.^82,83 “Radiogenomics” (not to be confused with “imaging genomics”) is the branch of genomics involved in the research of these factors, and one of its most significant goals is to tailor the treatment dose by individual genotype.^84,85 Symptoms related to RN are strictly dependent on location rather than on the size of the necrosis: patients may present with a large region of RN while remaining completely clinically asymptomatic. Patients who are symptomatic most commonly present with neurocognitive impairment. Short-term memory and personality are mostly affected, but focal neurologic defects may also appear. Moreover, symptoms of increased intracranial pressure, such as headaches, seizures, and confusion, may occur.⁸⁶

The RN appearance in conventional imaging is often indistinguishable from tumor recurrence.^87,88 In both cases, white matter high signal intensity and perilesional edema with or without mass effect are common findings on T2WI FLAIR. However, Kumar et al⁸⁹ reported some characteristics that make RN more probable than recurrence; these include a new focus of contrast enhancement in a previously nonenhancing lesion or at a distant site within the radiation field, the presence of a “soap-bubble” or a “Swiss-cheese” enhancing pattern, and changes in the periventricular white matter. Mullins et al⁹⁰ described RN as being usually focal, whereas the involvement of the corpus callosum with extension across the midline or the presence of multiple or diffuse lesions should be considered as more suggestive of tumor progression.

DWI and ADC are less helpful in distinguishing RN from tumor recurrence because of the lack of a specific pattern of presentation.⁹¹ Advanced imaging, such as MRS, can show decreased Cho, NAA, and creatine, and elevated lactate in RN; however, tumors usually have increased Cho and decreased NAA.⁹² MR perfusion imaging can show rCBF in RN because of the decreased metabolic activity and vascularization of the necrotic tissue. However, sometimes both neoplastic and necrotic tissues can coexist within the area of recurrent tumor.⁹³ FDG-PET, which measures glucose metabolism within the brain, may be able to detect increased radiotracer uptake in highly metabolically active cells of tumor recurrence and minimal or no radiotracer uptake in hypometabolic RN⁹⁴ (Figs 2–4).

Fig 2.

RN developed 1 year after radiation for lung adenocarcinoma metastasis. The (A) T2WI shows a hypointense lesion associated with edema, central diffusion restriction on the ADC map (red arrow in D), thick rim enhancement on (B) T1WI post-Gd, and foci of susceptibility artifacts related to blood products on T2* (red arrows in E). The advanced imaging provides additional information that shows decreased rCBF on the dynamic susceptibility contrast MR perfusion (white arrow in C) and elevated lactate on MRS (red arrow in F).

Fig 4.

Pathologically proven cervical spinal cord RN. The patient presented with increased gait instability and right-hand clumsiness and dexterity changes after 1 year of surgical resection and 2 cycles of radiation for chondrosarcoma. The (A) T2WI shows a hypointense lesion (white arrow). The (B) axial and (D) sagittal T1WI fat-saturated post-Gd contrast enhancement shows the enhancing radionecrotic lesion (white arrow in B and white circle in D). The (C) STIR image demonstrates hyperintensity within the spinal cord (white circle).

However, some tumors may not take up radiotracers as expected,⁹⁵ and mixed efficacy of FDG-PET in differentiating tumor recurrence from RN has been reported in the literature.^96–107 Amino acid analogs, including 3,4-dihydroxy-6–¹⁸F-fluoro-L-phenylalanine, O-2-¹⁸F-fluoroethyl-L-tyrosine, and L-methyl-¹¹C-methionine, have also been investigated as potential radiotracers for detecting tumor recurrence and RN.^108,109 Because the active uptake of amino acids in viable tumor cells is different from that in RN, wherein only passive diffusion across the damaged BBB occurs,^110–113 the feasibility and usefulness of aminoacid PET for this critical diagnostic issue have been demonstrated in several studies.^114–118 In some cases, neuroimaging cannot provide a definitive diagnosis, and a biopsy of the lesion is required, especially in patients whose clinical and radiologic findings are indicative of a worsening condition. Treatment is necessary when patients are symptomatic, and steroids can improve symptoms by reducing cerebral edema.

Leukoencephalopathy.

The most common late delayed complication of cranial RT is leukoencephalopathy.¹¹⁹ It occurs within months to years after treatment,¹²⁰ and the risk factors include a higher radiation dose, a large irradiated volume (eg, whole-brain RT), older age, and combined radiochemotherapy.¹²¹ This complication typically manifests as mild neurocognitive impairment; short-term memory and frontal functions are mainly affected.¹²² It is very common in children, who also manifest learning difficulties.^120,123 Other symptoms include seizure and motor abnormalities. Symptoms are usually irreversible and can either remain stable or slowly get worse. However, in some patients, especially those with combined radiochemotherapy, severe dementia may develop, which eventually leads to death.¹¹⁹ Clinical symptoms are not definitively correlated with the degree of neuroimaging findings, and patients may be asymptomatic even if they show significant involvement of white matter on MR imaging.^123,124

The diagnosis is based on neuroradiologic imaging. Both CT and MR imaging can be used. The main finding is diffuse injury to the white matter of the cerebral hemispheres, which appears as hyperintensity on T2WI FLAIR sequences on MR imaging and as hypoattenuation on CT, especially in the periventricular area. Cortical atrophy with prominent sulci and ventricular dilatation may be observed as well¹²¹ (Fig 5). The pathogenesis of the ventriculomegaly associated with radiation leukoencephalopathy is not fully understood.¹²⁵ Although results of some studies indicate that the observed ventricular dilatation is primarily ex vacuo because CSF diversion failed to produce a sustained benefit or changes in ventricular diameter,^126–128 in many patients, ventriculomegaly is often disproportionate to the degree of cortical atrophy, and clinical symptoms strongly resemble idiopathic normal pressure hydrocephalus, with ataxia, cognitive impairment, and urinary incontinence.^129–131

Fig 5.

Leukoencephalopathy after whole-brain RT. In this patient treated for metastatic melanoma, the T2WI FLAIR in 2011 shows edema and mass effect; eventually, rapidly progressing white matter hyperintensities develop on the T2WI FLAIR sequences, along with progressive marked brain atrophy.

Indeed, ventriculoperitoneal shunt surgery has been reported to partially and temporarily improve these symptoms, despite minimal or no changes in ventricular size.^125,129,132 It is possible that cranial RT produces fibrosis of the arachnoid granulations that inhibit CSF reabsorption.¹³³ However, marked parenchymal damage is also apparent throughout the white matter, which explains the incomplete resolution of symptoms after ventriculoperitoneal shunt surgery.¹²⁹ Ultimately, no specific treatment has been found to be able to reverse or prevent the occurrence of hydrocephalus associated with radiation leukoencephalopathy.¹²⁵ Leukoencephalopathy has been studied from a histologic point of view in fatal cases: this analysis revealed myelin and axonal loss together with vascular lesions.^128,134 Methylphenidate and donepezil have been proposed as treatments to improve cognitive function and mood in patients with leukoencephalopathy.^135,136

Radiation-induced Myelopathy.

Another rare but severe complication that typically occurs 1 to 2 years after RT is radiation-induced myelopathy. The main risk factor is the radiation dose; the spinal cord tolerance is considered to be a total dose of 50 Gy in daily fractions of 1.8–2 Gy. Myelopathy has also been reported when the radiation dose was within the accepted tolerance limits in the case of concurrent administration of chemotherapy and RT.¹³⁷ Delayed radiation myelopathy symptoms include an initial presentation with dysesthesia and paresthesia, followed by motor weakness and progressing to paraplegia and, sometimes, quadriplegia. These conditions are usually irreversible.⁷⁴ On MR imaging, T2WI sequences may show an abnormality in signal intensity, and the affected cord may appear widened. After contrast injection, an irregular or ring-enhancing pattern can be observed. These abnormalities usually persist and may extend beyond the radiation field. After many years, spinal cord atrophy eventually becomes evident.¹³⁸

Histopathologic analyses from patients who were autopsied revealed both white matter parenchymal and vascular lesions, alone or combined, with a variable predominance of one or the other.¹³⁹ In the samples in which vascular lesions were preponderant, a high immune response was also reported.¹³⁹ This finding has been proposed to occur because of radiation-induced capillary endothelial damage and disruption of the BBB.¹⁴⁰ The immune mechanism can explain, in part, the extension of changes beyond the radiation field.¹³⁹ Limited treatment options are available for patients with radiation-induced myelopathy. Steroids may prevent symptoms from worsening. In some patients, partial improvement was reported after warfarin or heparin,¹⁴¹ and hyperbaric oxygen seems to be helpful for clinical and radiologic improvement,^142,143 though further studies need to validate these therapeutic options. In addition, late delayed complications include those related to an indirect effect of radiation, such as cerebrovascular disorders, radiation-induced tumors (RIT), and endocrine dysfunction. Among cerebrovascular disorders, we reviewed accelerated atherosclerosis, mineralizing microangiopathy, moyamoya disease, and vascular malformations.

Radiation-induced Atherosclerosis.

The first symptoms of atherosclerosis, such as TIA or ischemic strokes, range from 6 months to >20 years after irradiation.^144,145 On histologic examination, the disease is comparable with spontaneous atherosclerosis, even if the atherogenic risk factors play a limited role in its occurrence.¹⁴⁶ The radiation dose and patient age at the time of RT seem to considerably influence the incidence of this complication.¹⁴⁷ MR imaging and MR angiography can be useful both for the diagnosis and for screening in patients with radiation-induced cerebrovascular disease.¹⁴⁷ The affected vessels are inside the irradiated area and may show multiple sites of stenosis. Patients with radiation-induced carotid atherosclerosis may benefit from percutaneous transluminal angioplasty and carotid endarterectomy as well, even if these procedures are more difficult because of perivascular and cutaneous sclerosis. With regard to preventative pharmacotherapy, the use of prophylactic antiplatelet or anticoagulant drugs is still debated.¹⁴⁸

Mineralizing Microangiopathy.

Mineralizing microangiopathy is characterized by dystrophic calcification, mainly within the basal ganglia (the putamen is particularly affected), the dentate nuclei, the cerebral gray-white matter junction, and sometimes in the cerebral cortex.^74,123,149 This complication is usually, but not exclusively, seen in children with cancer after chemoradiotherapy,^150–152 even at low doses (15 Gy) of radiation.¹⁵² On histologic analysis, deposition of calcium appears in small blood vessels, surrounded by calcified necrotic tissue. The relationship between these findings and clinical manifestations is not entirely clear.¹⁵² Calcifications may be easily detected on CT, often associated with cortical atrophy and white matter hypoattenuation.^149,153,154 These calcifications may also be revealed on T1WIs on MR imaging, which show signal hyperintensity (Fig 6).

Fig 6.

Mineralizing microangiopathy. The (A and B) CT images show extensive calcifications (white arrows) that affect the deep cerebellar nuclei and basal ganglia in this 29-year-old patient treated with RT for craniopharyngioma. The (C) basal ganglia exhibit signal hyperintensity on the T1WI (white arrows).

Moyamoya Syndrome.

Another vasculopathy that may occur after irradiation is moyamoya syndrome. It is more frequent in patients who receive RT for tumors that encompass the circle of Willis, for example, optic pathway gliomas, and in patients with type 1 neurofibromatosis.^155–158 It is usually diagnosed 5 years after RT.⁷⁴ This syndrome is caused by a gradual occlusion of the distal part of the internal carotid artery or involves the vessels of the circle of Willis, and leads to the proliferation of small, abnormal collateral vessels that are prone to hemorrhage. On pathologic examination, the occlusion is due to the proliferation of endothelial and myointimal cells. Fibrosis may be found in the intimal layer as well.⁷⁴ The clinical manifestations of moyamoya syndrome are variable and include multiple ischemic and hemorrhagic strokes, recurrent TIA, headaches, seizures, and progressive cognitive impairment.⁷⁴ Cerebral angiography is the criterion standard for the diagnosis, which sometimes shows the typical “puff of smoke,” but MR imaging may also be supportive. On T1WIs and T2WIs, signal intensity voids in the basal ganglia may indicate the abnormal collaterals of lenticulostriate and thalamostriate arteries. Moreover, the slow flow inside the leptomeningeal collateral vessels appears as serpentine sulcal signal hyperintensity on T2WI FLAIR. This finding is called the “ivy sign,” and it is also evident on T1WI postcontrast enhanced sequences.^159,160 Treatment is mainly based on surgical revascularization and is aimed to bypass the occluded portions of the irradiated vasculature.^147,161,162

Cavernous Malformation.

A cavernous malformation (also called cavernous hemangioma) is an increasingly recognized sequel to cranial RT, and children who are irradiated are at a higher risk.^163–165 Its cumulative incidence is >3% within 10 years after RT,^163,164 and the reported latency period for the development of this complication after RT ranges from 1 to 26 years.¹⁶⁴ A cavernous hemangioma is a vascular lesion composed of thin-walled, dilated capillary spaces surrounded by hemosiderin, with no intervening brain tissue.¹⁶⁶ It is different from capillary telangiectasias, which are thin-walled ectatic capillaries with intervening normal brain parenchyma and usually occur 3–9 months after irradiation.^167,168 Nevertheless, some researchers noticed that capillary telangiectasias and cavernous hemangiomas may be sequential variations of the same pathologic process triggered by radiation injury to the cerebral microcirculation.^169,170

Radiation-induced cavernous hemangiomas are generally asymptomatic, but it is important to diagnose and monitor these because they can expand in volume and can become symptomatic, which potentially leads to neurologic defects and seizures due to a risk of hemorrhage. On MR imaging, a cavernous malformation appears as a well-defined nodule, with a rim of decreased signal intensity due to a deposition of hemosiderin surrounding a reticulated core of mixed hyper- and hypointense signal on T2WIs. Gradient recalled-echo T2* sequences and SWI show higher sensitivity in the detection of cavernous hemangiomas and appear as foci of signal intensity loss (Fig 7). However, SWI may sometimes overestimate the size of the lesion due to paramagnetic hemosiderin from chronic vascular stasis or previous hemorrhage.¹⁷¹ Lesion contrast enhancement is not common, but it can be observed.¹⁷² Cavernous malformations can be classified based on MR imaging findings,¹⁷³ even if their clinical relevance is still debated.¹⁷⁴

Fig 7.

Vascular malformations. The (A) T2* and (B and C) SWI of a patient treated with RT for anaplastic astrocytoma show progressive development of foci of susceptibility (white arrows in B and C), compatible with telangiectasias and/or cavernous malformations.

RITs.

RITs represent an uncommon late delayed complication of RT, especially in patients who, at a young age, received cranial irradiation for cancer. Because of an improvement in treatments and better survival rates, in the past decades, the incidence of RIT has become more significant.¹⁷⁵ However, Bhatia et al¹⁷⁶ showed that a reduction of RIT occurrence in the brain may be expected in children with acute lymphoblastic leukemia due to the lower number of patients who receive prophylactic irradiation. However, the true incidence is still unclear, mainly because of the long incubation time before the development of RITs.¹⁷⁷ The most common RITs of the brain are meningiomas and gliomas: the former accounts for approximately 70% of RITs and the latter for 20%.^175,178 They also differ in the median latency period: 19 years for the development of meningioma versus 9.1 years for glioma.¹⁷⁵ The risk of glioma in childhood cancer survivors significantly and progressively decreases after this period.¹⁷⁹ However, cases of meningioma were also reported many years after the median latency period, so a lifetime risk for radiation-induced meningioma development has been proposed.^179,180

The correlation between the radiation dose and RIT is not fully understood.^180–183 There are some studies that showed that RIT may develop at some distance from the maximal irradiation area.^177,180 This finding could be related to the fact that cell death occurs where the highest dose is delivered, whereas genetic damage affects viable cells in the surrounding lower-dose irradiation area.¹⁸⁴ This may also explain why RIT is much less common after radiosurgery, which is characterized by more focused radiation delivery and a reduced amount of involvement of normal tissue.¹⁸⁵ Younger age at the time of RT has been reported as a significant risk factor for the occurrence of RIT because the developing nervous tissue in children is more sensitive to radiation, which results in more extensive genetic injury.^{180,182,186–188} However, other predisposing factors are likely involved in the pathogenesis of RIT because this complication affects only the minority of patients who were irradiated.¹⁷⁷

Radiation-induced meningiomas are recognized as separate entities, and specific features distinguish them from primary meningiomas. Indeed, radiation-induced meningiomas are more likely to occur in a multifocal pattern, they often show an anaplastic grade on histology, and they are generally recurrent after surgical resection^181,189,190 (Fig 8). Female patients who received irradiation are at a higher risk than male patients for meningioma development, even if the preponderance of radiation-induced meningiomas is less significant in female patients than that observed for meningiomas in the general population.¹⁸⁰ A higher radiation dose has been found to increase the risk of tumor development, though its ability to influence the latency period is still debated.^{175,179–181,190}

Fig 8.

Radiation-induced meningiomas. This patient underwent RT for leukemia during childhood. The initial scan (top row) shows multiple dural-based masses, compatible with meningiomas. The follow-up after 9 months (bottom row) shows the marked growth of the right temporal convexity lesion with increasing mass effect and edema. The lesion was resected and on pathologic examination proved to be a meningioma. This case highlights the unpredictable behavior of RITs.

Surgical removal is the treatment of choice, and an exceptionally wide bone and dural margin resection should be performed if possible because of the higher rate of local recurrence of radiation-induced meningiomas after surgery.^181,191 This increased recurrence rate may, in part, be attributed to the propensity of these tumors for bone invasion,^192,193 a characteristic that has been associated with a high risk of recurrence.¹⁹⁴ When surgery is contraindicated, other treatment options, for example, radiosurgery, should be considered.^195,196

Radiation-induced gliomas are mainly high-grade lesions and are often multifocal. They do not exhibit any distinctive feature: both radiologic and histopathologic appearances do not allow differentiation from spontaneous gliomas (Fig 9). However, the clinical course of radiation-induced glioblastomas in children who were previously irradiated is more aggressive and treatment-refractive than the spontaneous pediatric patients.¹⁹⁷ In the past decade, analyses of gene expression profiles performed on radiation-induced glioblastomas demonstrated that their molecular characteristics differ from those commonly found in glioblastomas,^197,198 and further studies may be helpful to find a more specialized treatment for this RT complication. Other RITs include sarcoma and schwannoma. Sarcoma is rare; it may occur with various pathologic subtypes that arise within dura or cranial bones, and the prognosis is poor.¹⁹⁹ Schwannoma may present as a painful, enlarging lesion and is usually malignant on histology.²⁰⁰ Patients rarely develop many RITs of different types simultaneously (Fig 10).

Fig 9.

Radiation-induced glioma. The patient underwent RT for treatment of a pineal parenchymal tumor of intermediate differentiation and developed a glioblastoma 4 years after treatment. The (A) T2WI FLAIR and (B) T2WI show a hyperintense lesion centered in the right cerebral peduncle, with (C) restricted diffusion and an irregular rim enhancement on (D) T1WI post-Gd. The (E and F) MRS shows a pattern compatible with neoplasm, with reduced NAA and increased Cho (white arrow and red arrow in F, respectively).

Fig 10.

RITs. This 31-year-old patient treated with RT for retinoblastoma in infancy presented with 3 different pathologically proven tumors: schwannoma (upper arrow in B), meningioma (lower arrow in B), and sarcoma (arrow in C). Note the different signal intensity on the (A) T2WI and the different enhancing patterns seen on the (B and C) T1WI post-Gd.

Endocrine Dysfunction.

Endocrine dysfunction is a common late delayed RT complication due to either pituitary gland or hypothalamic-pituitary tract damage. Its incidence is correlated with the radiation dose, which also influences the length of the latency period between RT and the onset of the hormonal deficit.²⁰¹ A dose of 20 Gy has been shown to be sufficient for the occurrence of this complication.²⁰² Moreover, the true prevalence of this complication is often underestimated because of the different tests and cutoff values used in endocrine evaluation. The mechanisms of radiation damage may include either direct injury to the hormone-secreting cells or vasculature involvement, with subsequent cell necrosis, or prevention of the hormones from reaching the blood.²⁰³

Growth hormone deficiency is the most common, and its effects may be profound in children who were irradiated.²⁰⁴ Other common abnormalities include gonadotropin deficiency, hyperprolactinemia, corticotropin deficiency, and central hypothyroidism. Changes in hormonal serum levels usually precede the symptoms. Clinical presentations of endocrine dysfunction are well known, but they may develop insidiously after RT. Before typical manifestations appear, the symptoms are often subtle or nonspecific, and they may significantly affect quality of life in these patients as well.²⁰⁵ Early diagnosis may also be challenging because neuroradiologic imaging does not reveal any significant alteration. Close clinical and endocrinologic assessments should become part of the standard of care in the follow-up of patients undergoing RT, to identify and eventually treat this complication. Hormonal replacement therapy is often effective in symptom control.¹⁷⁸

COMPLICATIONS OF SRS

Different from conventional RT, whose dose fractionation schemes for intracranial lesions typically consist of 1.8 to 2 Gy in daily sessions, with cumulative doses of 30 to 60 Gy, SRS delivers high doses of ionizing radiation, which usually range from 11 to 70 Gy, in a single session or a very limited number of fractions when targets are large or are near critical normal tissues (ie, “hypofractionation”).^206–209 Furthermore, in conventional RT, the entire brain receives the defined radiation dose, while in SRS, the beams of ionizing radiation are precisely focused to a radiographically discrete treatment volume, thereby minimizing injury to adjacent structures.

The 2 main radiosurgery systems are gamma knife and linear accelerator machines. SRS is a valuable, minimally invasive alternative to surgery, especially for patients at a high risk for complications after surgical procedures, for tumors that are inaccessible to the neurosurgeon, for tumors with multiple locations, or for lesions that are adjacent to regions of critical brain function or important vascular structures. In addition to its use for many types of benign and malignant tumors, SRS is used for the treatment of AVMs and of functional neurologic conditions, for example, trigeminal neuralgia. Even though less volume is irradiated when compared with conventional RT, complications may still develop after SRS. Some of these, including fatigue,²¹⁰ alopecia,²¹⁰ leukoencephalopathy,²¹¹ pseudoprogression,²¹² and RITs,^213,214 were previously described in this article. In this section, we focused on RN, hemorrhage, and tumefactive cysts.

RN

The most common complication of SRS is RN, which occurs in up to 50% of patients^77,215–219 and leads to neurologic complications in up to 30% of patients.^220–232 Although necrosis of the tumor and reduction of enhancement are expected effects of gamma knife radiation surgery (GKRS), sometimes a significant inflammatory response can ensue. Fortunately, RN from SRS usually has a good response to corticosteroids (Fig 11). The most important predictive variables of brain necrosis after SRS include the radiation dose, tumor volume and location, and the brain volumes that surround the target lesions that receive at least 10 Gy and 12 Gy of radiation as an adverse effect.^{77,216–219,233} The other clinical and pathologic characteristics of RN were discussed elsewhere in this article.

Fig 11.

Radionecrosis. The (A) pre-GKRS T1WI post-Gd shows a homogeneously enhancing meningioma of the anterior falx. After GKRS, the lesion exhibits signs of RN, with decreased enhancement on the (B) T1WI post-Gd, associated with edema and mass effect on the (C) T2WI FLAIR. The (D) follow-up T2WI FLAIR after corticosteroids shows a good response with decreased edema and mass effect.

Hemorrhage

Hemorrhage is an extremely rare complication of SRS. It has been described in meningiomas, brain metastases, cavernous malformations, and AVMs, and it can occur immediately or after weeks.^234–238 It is most commonly seen after the treatment of AVMs.²³⁹ Yamamoto et al²⁴⁰ found that it was associated with incomplete obliteration of the nidus, even if delayed hemorrhage occurred after complete angiographic occlusion of AVMs.^239,240 Nevertheless, Karlsson et al²⁴¹ do not support the idea of a higher risk for hemorrhage immediately after GKRS for AVMs. In meningiomas, the rate of spontaneous hemorrhage is similar to the rate of hemorrhage after GKRS, so this occurrence should be considered sporadic and not related to the treatment.²³⁷ However, there are some cases in the literature that reported an acute hemorrhage developing a few hours after GKRS, and it has been hypothesized that GKRS-induced changes in the vasculature may play a contributing role in this complication.^236,242

Spontaneous hemorrhage may occur inside brain metastases, with metastases from malignant melanoma harboring the highest risk.²³⁴ Although the main studies that reported the incidence of intratumoral hemorrhage before and after GKRS showed a decrease in posttreatment bleeding^243–245 (the radiation dose does not seem to affect the risk of hemorrhage²³⁴), the possibility of an acute hemorrhage during or immediately after SRS in brain metastases exists and may also be fatal for the patient (Fig 12).^234,246

Fig 12.

Hemorrhage after GKRS in melanoma metastasis. The (A) pre-GKRS T2WI shows a mildly hyperintense tumor centered in the left cerebellopontine angle, with no focus of susceptibility artifacts on (B) SWI and homogenous enhancement on (C) T1WI post-Gd. Immediately after GKRS, the patient presented with multiple cranial nerve palsies and altered mental status. The (D) T2WI and (E) SWI show enlargement of the lesion (white arrow in D), now hypointense, and markedly hypointense on SWI (asterisk in E), compatible with hemorrhage. The (F) T1WI post-Gd demonstrates no enhancement (white arrow).

Tumefactive Cyst

Tumefactive cyst formation is a late complication of GKRS-treated AVMs that usually occurs 2–8 years after treatment. This long latency period together with the lack of follow-up imaging in patients with resolved AVMs and without neurologic symptoms make the incidence of this complication difficult to determine. Tumefactive cysts may show malignant features, such as a complex structure, a thin enhancing wall, white matter T2 hyperintensity, and adjacent vasogenic edema or heterogeneous nodular enhancement (Fig 13). Moreover, these cysts may present with significant mass effect and cause neurologic symptoms. However, they are benign lesions, and treatment with shunt surgery or excision should be limited to patients who are symptomatic. Neuroimaging findings and a clinical history are sufficient for the diagnosis.²⁴⁷

Fig 13.

Tumefactive cyst. This patient was treated for an AVM 10 years earlier and presented with progressive headache. The (A) T2 and (B) T2* show multiple cysts with blood-fluid levels as well as marked superficial siderosis. The (C) T1WI and (D) T1WI post-Gd show the enhancing tangle of vessels (white arrows in C and D), related to the residual and/or recurrent nidus of the AVM. The differential diagnosis includes hemorrhage and an unusual cavernous malformation.

CONCLUSION

With the increasing application of RT and SRS for treatment of CNS tumors and AVMs, it is important for the neuroradiologist to recognize and be aware of the many possible radiation-related complications. Understanding the pathophysiology, typical time to onset, and imaging features allows for prompt diagnosis, appropriate treatment decisions, and increased probability of better patient outcomes.

Fig 3.

Temporal lobe RN after external beam radiation in 2012 for nasopharyngeal carcinoma; (A) 2013 and (B) 2017 axial T2WI FLAIR, and (C) 2017 coronal STIR images in a patient treated for nasopharyngeal carcinoma demonstrate interval development of white matter hyperintensity in the temporal lobes (red circles in B and C), which corresponds to the radiation treatment portal; 2017 (D) axial and (E) coronal T1WI post-Gd demonstrate patchy enhancement in the temporal lobes (red arrows in D and E); 2017 (F) FDG-PET shows relative hypometabolic activity (red circles in F) associated with RN in the temporal lobes.

CME Credit.

The American Society of Neuroradiology (ASNR) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ASNR designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To obtain Self-Assessment CME (SA-CME) credit for this activity, an online quiz must be successfully completed and submitted. ASNR members may access this quiz at no charge by logging on to eCME at http://members.asnr.org. Nonmembers may pay a small fee to access the quiz and obtain credit via https://members.asnr.org/webcast/content/course_list.asp?srcNeurographics. Activity Release Date: June 1, 2018. Activity Termination Date: June 1, 2021.

ABBREVIATION KEY

¹⁸F

¹⁸fluorine

Gd

gadolinium

GKRS

gamma knife radiation surgery

HGG

high-grade glioma

LGG

low-grade glioma

rCBF

relative CBF

RIT

radiation-induced tumor

RN

radiation necrosis

RT

radiation therapy

SRS

stereotactic radiosurgery

SS

somnolence syndrome