Stroke-like migraine attacks after radiation therapy (SMART) syndrome presenting as a migraine copycat: A case report

Abstract

Background:

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a possible long term consequence of cranial beam radiation therapy and may present as a perfect mimic of migraine with or without aura.

Methods and Results:

We present a 57-year-old man suffering from diffuse astrocytoma and presenting with SMART syndrome perfectly mimicking his antecedent migraine with visual aura. He was treated with intravenous steroid therapy inducing rapid response.

Conclusion:

SMART syndrome is a rare complex delayed complication of brain radiation therapy, which may present as an isolated migraine with or without aura even decades after cranial radiation. Thus, a sudden intensification or relapse of a previous migraine in a patient with remote cranial radiotherapy constitutes a red flag even decades after cranial irradiation and cured or stable tumor disease on a recent brain MRI. Moreover, SMART syndrome adds to the list of secondary headaches not yet listed in the current International Classification of Headache Disorders, 3rd edition (ICHD3).

Introduction

External beam cranial radiation therapy is effective for treatment, prophylaxis and palliation in different intracranial malignancies, but can also result in early and delayed toxic effects on brain tissue and intracranial vasculature. Shuper et al. ¹ were the first to describe Stroke-Like Migraine Attacks after Radiation Therapy (SMART) syndrome in 1995. The etiology of SMART syndrome appears to be multifactorial and is considered to be due to cerebrovascular autoregulation impairment and neuronal dysfunctions due to former radiation therapy. ² It was subsequently described both in pediatric and adult patients with a male predominance. ³ SMART syndrome may occur 1–32 years after brain radiation therapy ⁴ and present with migraine-like headaches, focal neurologic symptoms and seizures. ² Although clinical symptoms may vary significantly, migraine-like headaches are considered to be one of the clinical hallmarks of SMART syndrome ^1,2,5 and may either as the only symptom or in combination with other neurological symptoms, imitate migraine with or without aura possibly leading to misdiagnosis and wrong treatment. Here we present a patient, whose SMART syndrome presented as a migraine mimic, perfectly imitating the patient’s antecedent migraine with visual aura.

Patient information and clinical findings

A 57-year-old man was admitted to the emergency department because of a disabling, unilateral, throbbing headache, localized in the neck and the right occiput, as well as photophobia, phonophobia, nausea and flickering waves and zigzag lines in the left visual field causing blurred vision and left homonymous hemianopsia. In the beginning, the symptoms imitated the patient’s migraine with visual aura with the visual symptoms preceding the migraine-like headaches. But later on, symptoms appeared simultaneously, could last from minutes to hours and reoccur up to several times a day several days at a stretch finally leading to the patient’s admittance to the emergency department.

His past medical history (Figure 1) was remarkable for diffuse astrocytoma in the right temporal lobe. The tumor had been diagnosed 12 years ago due to temporal lobe epilepsy with focal seizures with impairment of consciousness. Initial watch and wait strategy was followed by surgery due to progression (4 years ago) and by radiotherapy targeting the tumor bed (59.4 Gy/33 fractions) as well as chemotherapy (temozolomide) due to a more malignant appearance on the magnet resonance imaging (MRI) (2 years ago). Since then, brain MRI every 3rd month had shown stable disease in the temporal and normal appearance in the occipital lobe and the patient was neurologically unremarkable apart from a left homonymous upper quadrant anopsia. Moreover, he was suffering from a migraine without and with visual aura according to the International Classification of Headache Disorders, 3rd edition (ICHD3) classification. Migraine aura was mild, exclusively visual, presenting with slowly spreading flickering spots and zigzag lines in the periphery of the patient’s visual field preceding a disabling, unilateral, throbbing headache, localized in the neck and the right occiput, as well as photo- and phonophobia and nausea. Migraine had been most frequent in adolescence fading out in adulthood with 7–8 attacks over the past decades (< 1 attack / year) not requiring any prophylactic treatment.

Figure 1.

Timeline.

Timeline

Diagnostic assessment

In the emergency department, acute brain MRI showed a cortical gyral hyperintensity (fluid attenuated inversion recovery, FLAIR) in the right occipital lobe with diffusion restriction and contrast enhancement (Figure 2(a) and (b)) as well as changes after former operation in the right temporal lobe without any tumor progression. At discharge, the MRI-based diagnosis was suspected stroke and antiplatelet treatment initiated. After 2 weeks, clinical symptoms had disappeared. Control brain MRI showed an overall decrease in signal changes on diffusion-weighted images and complete remission of contrast enhancement (Figure 2(c) and (d)). However, even if some small areas with diffusion restriction were still detectable on control brain MRI (Figure 2(d)), no defect in the brain tissue occurred, challenging the primary stroke diagnosis.

Figure 2.

Gadolinium-enhanced T1-weighted (a) and diffusion-weighted (b) MRI during the first SMART attack; gadolinium-enhanced T1-weighted (c) and diffusion-weighted (d) MRI after clinical symptoms of the first SMART attack had disappeared. Gadolinium-enhanced T1-weighted (e) and diffusion-weighted (f) MRI during the fourth SMART attack (3rd reoccurance); gadolinium-enhanced T1-weighted (g) and diffusion-weighted (h) MRI after the patient had received a four-day prednisolone-pulse treatment and clinical symptoms of the fourth SMART attack had disappeared.

In the following 13 months, the symptoms reoccurred 2 times lasting 3–6 weeks followed by an asymptomatic interval of 3–4 months. Every time, brain MRI presented with stable disease in relation to the tumor localization in the right temporal lobe but gyral hyperintensity (FLAIR), diffusion restriction and contrast-enhancement localized in the right occipital cortex. Hyperintensity (FLAIR) and diffusion restriction were increasing and decreasing simultaneously with the clinical symptoms even if they did not completely disappear in the periods of clinical remission. Contrast-enhancement, however, concomitantly appeared and completely disappeared with the clinical symptoms disproving tumorprogression, meningeosis carcinomatosa and apoplexy. 18F-Fluoroethyl-thyrosine-positron emission tomography (F18-FET PET) presented with elevated signal but the dynamic of the uptake did not suggest tumorprogression. Ictal long-term electroencephalogram (EEG) disproved epileptic seizures. A multidisciplinary team conference concluded that lumbar puncture would be without additional diagnostic value. At this time the patient’s left quadrant anopsia had progressed to a left homonymous hemianopsia, confirmed by an ophthalmologist excluding an underlying ophthalmological cause.

Based on these findings and the fact, that the affected area was part of the former beam radiation field, the diagnosis SMART syndrome was made.

Therapeutic intervention

After 13 months, the symptoms reoccurred for the 3rd time, visual disturbances additionally presented with pallinopsia in the disturbed left visual fields. Brain MRI presented with stable disease according to the tumor site but gyral hyperintensity (FLAIR), diffusion restriction and contrast-enhancement in the right occipital cortex were spreading to an increasing area of the ipsilateral occipital, temporal and parietal cortex. Moreover, small defects in the brain tissue and gliosis were suspected to present sequelae of former SMART episodes (Figure 2(e) and (f)). The multidisciplinary team conference recommended biopsy of the contrast-enhanced gyral occipital area in addition to a 4-day prednisolone-pulse treatment with 500mg/day.

Follow-up and outcomes

From second day of the prednisolone treatment, the patient became asymptomatic and his brain MRI normalized apart from the tumor site (Figure 2(g) and (h)). Biopsy was cancelled. Since then, no SMART episodes reoccurred (18 months).

Discussion

SMART syndrome is a rare, late complication of remote cranial radiotherapy. Due to its rarity and delayed occurrence, it is not feasible to perform prospective clinical studies, and evidence is mainly based on case series. In line, there is no consensus diagnostic criteria for SMART syndrome. However, our patient fulfilled the revised diagnostic criteria proposed by Black et al. ² presented in Table 1.

Table 1.

The revised diagnostic criteria proposed by Black et al. ²

Presence of all of the following findings can confirm SMART diagnosis:  Remote history of external beam cranial irradiation and no evidence of residual/recurrent neoplasm  Prolonged, reversible signs/symptoms referable to a unilateral cortical region beginning years after radiation, such as visuo-spatial deficits, confusion, hemisensory deficits, hemiparesis, aphasia, seizures, headache with attacks, antecedent migraine with or without aura starting after irradiation  Transient, diffuse and unilateral cortical gadolinium enhancement of the cerebral gyri sparing white matter within a previous radiation field  No other better explanation.

Although it has been considered to be reversible, incomplete resolution ⁶ has been reported and increased risk of recurrent SMART episodes has been associated to female sex and absence of electrographic seizure discharges during initial symptoms, ⁶ and recently, abnormal susceptibility signal, restricted diffusion and subcortical white matter (WM) changes on MRI. ⁷

There are no guidelines for the treatment of SMART syndrome. Steroids have been described to be effective in resolving neurological impairments and radiological findings. ⁸ Their effects on edema and inflammation due to radiation induced vascular damage, resulting in blood-brain barrier disruption, have been discussed as a possible mechanism. ^{9 –11} However, contradictory results concerning the use of steroids have been published and further studies are needed. ^4,6 Seizures and migraine headache have been addressed respectively with anti-seizure and anti-migraine medications. ^4,6

The diagnosis is challenging and should be differentiated from tumor progression, meningeosis carcinomatosa, epileptic seizures, apoplexy, inflammatory diseases, posterior reversible encephalopathy syndrome (PRES), mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL).

Migraine-like headache has been considered to be one of the clinical hallmarks of SMART syndrome, ^1,2,5 and may, as in our patient, perfectly imitate the patient’s antecedent migraine with or without aura and therefore adds to the list of secondary headaches not yet listed in the current ICHD3. Thus, a sudden intensification or relapse of a previous migraine in a patient with remote cranial radiotherapy even decades after cranial irradiation and evidence for cured or stable tumor disease on a recent brain MRI, should rise the suspicion for SMART syndrome.

Patient perspective

The patient was fearful of increasing neurological deficits and hoped to obtain a clinical steady state or improvement. He tolerated the prednisolone-pulse without side effects and was relieved when he realized the prompt response.

Clinical implications

SMART syndrome is a rare complex delayed complication of brain radiation therapy, which may present as an isolated migraine with or without aura even decades after cranial radiation.

SMART syndrome can sometimes imitate a patient’s antecedent migraine.

A sudden intensification or relapse of a previous migraine in a patient with remote cranial radiotherapy constitutes a red flag even decades after cranial irradiation and cured or stable tumor disease on a recent brain MRI.

SMART syndrome adds to the list of secondary headaches not yet listed in the current ICHD3 classification.