Stroke-Like Migraine Attacks After Radiation Therapy Syndrome and Radiation Necrosis After Cerebral Proton Beam Radiation: A Case Report of Dual Radiotherapy Complications

Abstract

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare, delayed complication of cranial radiation therapy that consists of migraine-like headaches and focal neurologic deficits such as visual loss, aphasia, hemiparesis, hemisensory loss, and unconsciousness. SMART syndrome may be mistaken for tumor recurrence, radiation necrosis, and stroke. Timely recognition of SMART syndrome prevents unnecessary brain biopsies and enables appropriate anticipatory guidance. We present a 38 year-old right handed male with new headaches, vertigo, visual symptoms, and left-sided paresthesias. Neuroimaging revealed a heterogeneously enhancing mass with invasion into the transverse sinus, diagnosed as an epithelioid hemangioendothelioma by surgical pathology. After resection, the patient underwent proton beam radiation for maximal tissue-sparing. Six months later, he developed radiation necrosis. After another year, he developed recurrent headaches with transient language difficulties and blurry vision during each headache. Neuroimaging was consistent with SMART syndrome, and the patient was started on valproate. Verapamil was added after a second attack. The patient’s headaches improved, but he remains dyslexic. Subsequent imaging shows resolution of gyriform contrast enhancement and continued left temporo-occipital T2/FLAIR hyperintensity. We present a case of early SMART syndrome following proton beam radiotherapy, as well as the dual occurrence of radiation necrosis and SMART syndrome in this individual. Radiation necrosis and SMART syndrome are known complications of radiotherapy, with the latter less well-described. We discuss a possible shared pathophysiology involving endothelial cell dysfunction and impaired cerebrovascular autoregulation, and we question whether proton RT increases risk of early SMART syndrome development.

Introduction

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare complication of cranial radiation therapy that consists of migraine-like headaches accompanied by focal neurologic deficits such as visual loss, aphasia, hemiparesis, hemisensory loss, seizures, and unconsciousness.^1,2 While it remains a diagnosis of exclusion, SMART syndrome has a characteristic magnetic resonance imaging (MRI) appearance of unilateral gyral enhancement and T2 fluid attenuated inversion recovery (FLAIR) hyperintensity, with or without diffusion restriction. Magnetic resonance perfusion imaging demonstrates hyper-perfusion in the affected region. Clinical improvement coincides with resolution of radiographic findings, though patients may experience recurrent attacks. SMART syndrome can be mistaken for tumor recurrence, radiation necrosis, and stroke—the latter two resulting in edema and hypo-perfusion on MR perfusion imaging. Recognition of this clinical and radiographic syndrome avoids unnecessary brain biopsy and allows for initiation of appropriate therapy.

Case Description

A 38 year-old right handed male with no significant medical history developed frequent headaches, vertigo, blurry vision, left face and arm paresthesias, and nosebleeds. MRI of the brain revealed a left parieto-occipital, extra-axial, heterogeneously enhancing mass with invasion of the transverse sinus and adjacent occipital bone (Figure 1A-B). Tumor pathology from gross total resection was consistent with epithelioid hemangioendothelioma, a rare malignant vascular tumor of the epithelial lining within blood vessels which most frequently invades the liver, lungs, and bones, but can also involve lymph nodes, brain, meninges, and spine. ³ Staging scans were unremarkable. Proton beam radiotherapy (RT) was chosen to limit radiation to sensitive cranial structures and administered at a dosage of 66.8 Gray (Gy) divided into 33 fractions. The patient’s symptoms improved after treatment but returned six months later. MRI brain showed a peripherally enhancing lesion with extensive vasogenic edema (Figure 1C-D) corresponding to radiation target volume, consistent with radiation necrosis. Treatment with corticosteroids and bevacizumab led to clinical and radiographic improvement. The patient endorsed mild headaches afterwards but no neurologic deficits.

Figure 1.

Pre-operative MRI T1 with gadolinium (A) and FLAIR sequences (B) demonstrating an extra axial lesion (arrows) in the left occipital lobe. Six months post-resection, MRI T1 with gadolinium (C) and FLAIR (D) demonstrate irregularly shaped parenchymal enhancement in the left occipital-temporal region with extensive associated vasogenic edema consistent with radiation necrosis.

One year later, the patient developed severe left-sided headaches accompanied by language difficulties and blurry vision at the peak of each headache. Neurologic exam was notable for right hemianopia and dyslexia. MRI brain demonstrated new T2 FLAIR hyperintensity and abnormal contrast enhancement within the left temporal and occipital gyriform cortices, without vasogenic edema or diffusion restriction (Figure 2A-D). Continuous electroencephalography (EEG) monitoring and infectious workup were unremarkable. The patient declined lumbar puncture. Severe headaches, neurologic deficits, and history of cranial irradiation raised suspicion for SMART syndrome. The patient was started on valproate with symptom improvement over several months, as well as decreased cortical enhancement on MRI (Figure 2E-H).

Figure 2.

MRI of the brain 1 year later. (A) T1 sequence with gadolinium showing serpiginous gyriform linear enhancement (white star) with associated cortical FLAIR hyperintensity (B, black star) in the left occipital and temporal lobe consistent with SMART syndrome. Similar findings more superiorly within the left posterior temporal lobe (C and D, arrows). Resolution of previously seen enhancement and cortical FLAIR hyperintensity on follow up imaging after several months (E-H).

Several months later, the patient began to exhibit episodes of aphasia, felt to represent another SMART syndrome attack. EEG showed slowing over the left temporal-occipital region without epileptiform discharges. MRI brain revealed reappearance of focal gyriform enhancement. MR spectroscopy was not consistent with tumor recurrence. Verapamil was added to valproate for SMART syndrome therapy, with improvement in the patient’s severe headaches. He unfortunately remained dyslexic. MRI brain six months later continued to show mild T2/FLAIR hyperintensity along the left temporal-occipital gyri, but prior areas of gyriform enhancement have resolved.

Discussion

SMART syndrome most frequently affects the temporal, parietal, and occipital lobes. MRI findings in SMART syndrome are characteristically unilateral, cortical, T2/FLAIR hyperintensities that enhance with gadolinium administration. Diffusion restriction is usually absent. Clinical symptoms and MRI findings typically resolve within weeks to months, though rates of incomplete clinical and radiologic recovery are described to be as high as 45% and 27%, respectively. ¹ Interestingly, a recent case series of seven patients with SMART syndrome noted almost exclusively left hemispheric involvement. ⁴ SMART syndrome has a higher prevalence in males and occurs after high radiation doses (>50 Gy). ⁵ Many patients received radiation as children or adolescents but experience symptom onset in adulthood. ² Age at time of irradiation may influence the speed of onset, with younger age predisposing to faster onset. ⁶ The delay until SMART syndrome onset ranges from 1-35 years post-radiation, with a mean delay of 10-20 years in multiple case series.^1,2 There are no established guidelines for treatment of SMART syndrome. Aspirin, verapamil, and anticonvulsant medications such as valproate and levetiracetam are sometimes used for prophylaxis, with mixed studies on the efficacy of each therapy. Corticosteroids do not consistently show benefit in treatment of acute attacks. ⁵

We describe one of the first accounts of SMART syndrome following proton RT. Our patient developed SMART syndrome within two years of receiving proton RT. Two patients within the case series by Winter et al, the only other report of SMART syndrome following proton RT, experienced a similarly accelerated onset of SMART syndrome after proton RT (14 months and 4 years). ⁴ Uniquely, our patient developed radiation necrosis in the same cortical region as his first SMART syndrome attack, one year prior. The dual occurrence of radiation necrosis and SMART syndrome in our patient raises the question of whether a shared pathophysiology drives the development of both RT complications.

SMART syndrome is postulated to result from cerebral hyperexcitability and impaired cerebrovascular autoregulation within regions of prior radiation-induced endothelial damage. ⁷ Two hypotheses regarding the pathophysiology of radiation necrosis strike a similar note—firstly, regional vascular injury leads to small vessel necrosis and cell death, and secondly, glial cell damage causes VEG-F production and inflammation, with resultant disruption of the blood-brain barrier. ⁸ Breakdown of the blood-brain barrier leads to the radiographic hallmark of contrast enhancement and vasogenic edema in radiation necrosis. While we cannot draw conclusions from a case report, it is worth considering a related pathophysiology between SMART syndrome and radiation necrosis, as both invoke vascular injury and impairment of cerebrovascular regulation. Another consideration is whether our patient’s radiation necrosis lowered the threshold for later development of SMART syndrome.

Combining our case with observations by Winter et al, it seems that proton beam RT predisposes patients to early SMART syndrome development. ⁴ RT of intracranial malignancy may be applied widely, for example in whole-brain RT, or to focal lesions. ⁹ Proton beam radiotherapy allows for precise targeting and a lower radiation burden on surrounding tissue; therefore, it has gained popularity in the treatment of specific brain and skull-base tumors to reduce damage to sensitive neighboring structures, though tissues within and immediately surrounding the target region still receive a high dose of radiation.^10,11 For its targeting precision, proton RT gained early traction in the treatment of pediatric brain tumors, with limited studies on the risks of cerebral proton RT in adults. ⁸ Amongst pediatric patients, proton RT may induce a higher rate of radiation necrosis and moyamoya physiology, when compared to traditional photon RT.^12,13 With moyamoya representing one of the most extreme examples of secondary vasculopathy, the increased incidence of moyamoya following proton RT suggests that proton RT causes a more potent vascular injury, compared to photon RT. A separate observation of earlier pseudoprogression in oligodendrogliomas treated with proton RT compared to photon RT (48 days vs 131 days, respectively) mirrors our observation of early SMART syndrome development following proton RT. ¹⁴ Lastly, a comparison of post-RT radiographic appearance in patients with meningioma of any grade, who received proton vs photon RT following resection, showed higher rates of T1 post-contrast enhancement in patients who underwent proton RT (26.8% vs 5.3%). ¹⁵

Conclusion

SMART syndrome is a rare complication of cranial irradiation that classically occurs after a delay of several years. We present a patient who developed SMART syndrome and radiation necrosis within two years of RT. We briefly review the risk factors for SMART syndrome and describe one of the first reports of accelerated SMART syndrome following proton beam RT. The dual occurrence of SMART syndrome and radiation necrosis in our patient raises the question of a shared pathophysiology rooted in endothelial dysfunction and impaired cerebrovascular autoregulation. We also offer the suggestion that proton RT uniquely increases the risk of early SMART syndrome development, as seen in our patient and observed in a recent case series. ⁴ We support this hypothesis with a small but growing number of observations on the clinical and radiographic effects of this highly specialized and thus increasingly utilized form of RT.

ORCID iD

Deborah Huang https://orcid.org/0000-0002-2658-912X