SMART (Stroke-Like Migraine Attacks After Radiation Therapy) Syndrome: A Case Study with Imaging Supporting the Theory of Vascular Dysfunction

Background

SMART (Stroke-like Migraine Attacks after Radiation Therapy) syndrome is an uncommon delayed complication of cerebral radiotherapy, occurring on average about 20 years after treatment. Less than 50 cases have been reported in the literature worldwide.

Its pathophysiology remains poorly understood, and patients commonly present with headaches, complex seizures, and stroke-like symptoms.

MRI is the imaging modality of choice for investigation. Our case study stands out as it includes serial MRI perfusion imaging from the time of current presentation through to resolution of symptoms, demonstrating the temporal evolution of the disease and its associated vascular dysfunction appreciated on imaging.

SMART syndrome is self-limiting, and better understanding of the condition by clinicians will help prevent performance of unnecessary interventions such as brain biopsies.

Case Report

SERIAL MRI IMAGING WITH PERFUSION STUDIES:

Figures 1–5 presents a temporal series of MRI images including MRI perfusion studies. All MRI perfusion imaging was obtained using standardized contrast volumes, timing, and acquisition parameters on a Siemens 1.5T Aera. Figure 1 (1 year prior), Figure 2A–2C (on day 2), Figure 3A and 3B (9 days later), Figure 4 (4 weeks later) and Figure 5 (4 months later).

Discussion

SMART syndrome is an uncommon delayed complication of cerebral radiotherapy, typically occurring many years after treatment [1–3]. Less than 50 cases have been reported in the literature since it was first described in 1995 [4]. A large range has been reported, but presentation on average is 20 years after radiotherapy. Patients commonly present with headaches, complex seizures, and stroke-like symptoms [5,6].

The exact pathophysiology of the disease remains poorly understood. Some of the proposed theories include radiation-induced vascular dysfunction leading to a faulty autoregulatory state and neuronal dysfunction with impairment or a lowered threshold for cortical spreading depression [7].

MRI is the imaging modality of choice for investigation. Our patient demonstrated the hallmarks of SMART syndrome: cortical thickening, high T2 signal with mild mass effect, and prominent unilateral gyral enhancement in the expected field of previous radiotherapy [1,8].

In 2006, Black et al. proposed the revised diagnostic criteria for SMART syndrome [8]. This included:Remote history of cranial radiation;Prolonged, reversible unilateral cortical signs and symptoms beginning years after radiation with manifestations including visuo-spatial deficit, confusion, hemiparesis, aphasia, seizures, headaches, and antecedent migraine with or without aura;Transient, diffuse, unilateral cortical gray matter enhancement sparing white matter;Not attributed to any other disorder.

SMART syndrome is usually self-limiting, and most patients achieve complete recovery of symptoms. This is, however, not always the case. One case series of 11 patients reported complete recovery in only about 55% at the 2-month mark [2]. Patients with incomplete recovery in this series were noted to have areas of cortical laminar necrosis and infarction/gliosis on follow-up MRI. Our patient had complete resolution of neurologic symptoms, but there were persisting waxing and waning subtle foci of enhancement up until the 4-month mark.

The diagnosis of SMART syndrome is in general a clinical one in tandem with typical imaging appearances. However, the presentation and particularly the imaging in SMART syndrome has considerable overlap with those of patients without a history of previous radiotherapy presenting with seizures or hemiplegic migraines. In addition, differentiation from recurrent tumor and associated new seizures is important to avoid unnecessary interventions, including biopsy. While there are other case reports of SMART syndrome which include both CT and MRI perfusion studies, to the best of our knowledge, this is one of the few to include serial MRI perfusion imaging from the time of current presentation through to resolution of symptoms.

In our case, the patient’s neurologic symptoms were maximal within the first 5 days, at which point gyral enhancement and cortical thickening were noted to be most marked on day 2. This agreed with other imaging case series, but, interestingly, marked gyral enhancement was not associated with a significant relative increase in cerebral blood volume. After 9 days, the patient’s symptoms had improved, at which time there was far less gyral enhancement and cortical swelling on the follow-up MRI. Despite this reduction in enhancement, there was a 4-fold increase in cerebral blood volume on the affected side, far more marked compared to imaging at initial presentation (day 2) when there was more prominent enhancement. On further follow-up at 4 weeks and 4 months, the patient’s neurologic symptoms had completely resolved, while imaging demonstrated small persisting foci of enhancement but symmetrical cerebral blood volume.

Seizures are well documented to cause alterations in cerebral perfusion, likely related to vasodilation, often with an increase in cerebral blood flow and cerebral blood volume in the acute phase [9]. In the post-ictal phase, there may be reduced cerebral blood volume with cerebral hypoperfusion [10]. While the initial imaging appearances in our case may be attributed to the single documented seizure prior to presentation, the later prolonged enhancement over weeks despite resolution of symptoms and increased cerebral blood volume at 9 days are atypical for seizure. There are also case reports of SMART syndrome in patients who have presented with headache, cerebral hyperperfusion, and gyral enhancement, but without prior seizures [11].

Hemiplegic migraine has also been reported to be associated with alterations in cerebral perfusion. Cerebral hypoperfusion is more often documented, thought to be due to spreading cortical depression with reduced cerebral blood flow and cerebral blood volume [12,13]. There are, however, also reports of hyperperfusion in this condition, likely related to vasodilation [14].

Absence of increased cerebral hyperperfusion in the presence of marked enhancement makes high-grade tumor recurrence less likely, unless imaging findings are attributed solely to coexisting seizures.

Conclusions

Our patient had previously been provisionally diagnosed with a terminal illness, only to make a complete recovery. Better understanding of the temporal evolution of imaging findings and cerebral perfusion in SMART syndrome may help differentiate the entity from tumor recurrence, averting unnecessary interventions such as brain biopsies, with their possible risks and complications. It may also better elucidate the underlying pathophysiology of the disease, which remains poorly understood. Because the diagnosis of this condition portends a significantly better prognosis and substantially alters patient expectation and management, it is important that clinicians are aware of the usual delayed presentation, symptomology, and imaging findings.