Stroke-like migraine attacks after radiation therapy (SMART) syndrome: A call for standardized diagnostic criteria

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare but increasingly recognized delayed complication of cranial irradiation. Described in 1995, SMART syndrome primarily affects long-term survivors of brain tumors (1). Transient neurological deficits, migraine-like headaches and stroke-mimicking imaging findings characterize the syndrome (2–4). Despite its clinical importance, a standardized diagnostic criterion for SMART syndrome is still lacking in the International Classification of Headache Disorders, 3rd edition (ICHD-3), which hinders early recognition, appropriate management and comparative research. This editorial aims to highlight the key clinical and radiological features of SMART syndrome and propose diagnostic criteria that could be considered for inclusion in the next version of the ICHD to facilitate its identification and improve patient outcomes.

A recent case report describes a patient who underwent radiotherapy at age five years (5). At age 30 years, he developed confusion, dysarthria, right homonymous hemianopia and hemiparesis, with magnetic resonance imaging (MRI) findings typical of SMART syndrome. After some time, the neurological symptoms fully resolved.

A year later, he experienced left homonymous hemianopia and left-sided paresis, contralateral to the first episode, with new right hemisphere MRI changes. Both episodes were associated with migraine-like headaches.

This patient likely experienced two separate SMART syndrome episodes decades after early childhood radiotherapy. Performed mitochondrial tests were negative and cerebrospinal fluid (CSF) analysis showed no pleocytosis, supporting the diagnosis.

This case raises two possibilities: increased central nervous system susceptibility to radiation-induced injury in childhood or a genetic/environmental predisposition to develop lesions. Notably, an MRI performed one year before the second episode did not reveal any temporo-occipital abnormalities, indicating that imaging changes may not precede symptoms.

Diagnostic criteria for SMART syndrome have been previously established (3). Nevertheless, in the ICHD-3, the only headache type classified as possibly linked with radiation therapy was “6.8.3 Headache attributed to Moyamoya angiopathy”, defined as a chronic recurrent headache that may present with migraine-like characteristics (6).

Bartleson and coworkers (7) described two SMART syndrome cases, with a history of cranial irradiation for malignancy and long-standing migraine-like attacks, with and without aura. Over time, both patients experienced prolonged episodes resembling complicated migraine, sometimes with early seizure activity. MRI during episodes showed transient, intense gadolinium enhancement of the posterior cerebral gyri. Despite severe symptoms, both fully recovered, and follow-up imaging showed no tumor recurrence. Based on their description, Black and colleagues (3) proposed diagnostic criteria for SMART syndrome.

SMART syndrome typically emerges years or decades after cranial irradiation in pediatric and adult patients. Key features include recurrent migraine-like headaches, focal neurological deficits (e.g. hemiparesis, speech/language disturbances, hemianopia, hemisensory loss, hemineglect), seizures and occasional mental confusion (1–5,7,8). Symptoms can last days to months before resolving. Although its exact pathophysiology remains unclear, it likely stems from radiation-induced endothelial dysfunction, chronic neuroinflammation and cortical spreading depression. A recent study (9) analyzing four SMART cases confirmed preserved cortical architecture and normal neuronal cytology. Findings included gliosis, scattered neurons with tau/neurofibrillary protein accumulation and variable radiation-induced lesions, but no significant inflammation or consistent small vessel hyalinization, suggesting vascular dysregulation.

MRI findings include unilateral cortical T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities, typically in previously irradiated brain regions, with associated cortical swelling. Furthermore, MRI perfusion imaging may demonstrate increased perfusion in affected areas, differentiating it from hypoperfused ischemic lesions (8). In some cases, gadolinium-enhanced MRI reveals mild leptomeningeal enhancement (8). Follow-up imaging typically demonstrates the resolution of cortical abnormalities, reinforcing the transient nature of the syndrome (3,7). However, recurrent episodes may lead to long-term cortical atrophy and cognitive decline.

Based on a review of the literature and expert consensus, we propose the following diagnostic criteria:

Stroke-like migraine attacks after radiation therapy (SMART) syndrome

Description

The clinical manifestations include recurrent migraine-like headaches, focal neurological deficits, seizure activity and, in some cases, altered consciousness with mental confusion.

Diagnostic criteria

• Migraine-like headache, with or without aura, temporally associated with neurological deficits fulfilling criterion C.

• History of prior cranial irradiation, with an interval of at least one year between radiation exposure and symptom onset.

• Transient, stroke-like neurological symptoms lasting hours to weeks, with spontaneous resolution, including at least one of the following:

• Speech or language disturbances

• Hemianopia

• Hemisensory loss

• Hemineglect

• Epileptic seizures

• Mental confusion

• Other cerebral cortical clinical manifestations depending on the affected cortical regions

Neuroimaging findings: MRI showing unilateral cortical T2/FLAIR hyperintensities in previously irradiated regions, without signs of ischemic infarction (i.e. no restricted diffusion on diffusion-weighted imaging), and characteristic intense cortical ribbon enhancement. No evidence of residual or recurrent tumor.

Not better accounted for by another ICHD-3 diagnosis.

Comments

Epileptic seizures may occur during or shortly after the acute phase of SMART syndrome. Perfusion MRI typically shows increased perfusion in affected cortical areas, whereas gadolinium enhancement on MRI suggests transient blood–brain barrier disruption. Recurrence of similar episodes further supports the diagnosis in the absence of alternative explanations. The associated headache may not fully meet migraine criteria, and some patients may fulfill all diagnostic criteria without experiencing a headache attack. Exclusion criteria include alternative vascular causes such as ischemic stroke, transient ischemic attack or cerebral vasculitis, which must be ruled out through imaging and laboratory evaluation, as well as neoplastic progression or radiation necrosis affecting the symptomatic region. Additionally, metabolic, infectious or autoimmune encephalopathies that could mimic the clinical presentation should be considered and excluded. Many patients may report that after undergoing radiation therapy, they began to experience headache attacks with migraine-like features, with or without aura. “Complicated” SMART syndrome may be considered when radiological signs resolve but focal deficits with limited improvement persist.

Recently, modified diagnostic criteria for SMART syndrome were published based on the original criteria established by Black et al. (3). These updated criteria include the possibility that T2-weighted image and FLAIR hyperintensity in the cortex and subjacent white matter within irradiated areas may occur and persist (8).

Some patients may exhibit all the characteristic features of SMART syndrome, but without headache or with headache that does not fully meet the criteria for migraine (3). Additionally, the same patient may experience multiple episodes of transient focal deficits, although headache may not be present in each episode (3).

Another key differential diagnosis is headache and neurological deficits with CSF lymphocytosis (HaNDL) syndrome, a self-limiting condition with transient neurological deficits, migraine-like headaches and CSF pleocytosis (10). HaNDL typically presents with normal or mildly abnormal neuroimaging, whereas SMART syndrome shows more pronounced MRI changes in previously irradiated areas. CSF pleocytosis, a hallmark of HaNDL, is absent in SMART syndrome, making CSF analysis a key differentiator (10).

SMART syndrome remains underrecognized among non-radiologist specialists. With the increasing use of radiotherapy and radiosurgery for benign tumors (e.g. meningiomas, vestibular schwannomas) and non-neoplastic conditions (e.g. neuralgia, epilepsy), more patients may present with stroke-like episodes, seizures and headaches resembling migraine. Clinicians should always inquire about prior radiotherapy, even decades earlier because it may be key to diagnosing SMART syndrome. However, confirmation often requires follow-up to assess the reversibility of transient deficits. SMART syndrome is a delayed complication of cranial irradiation and warrants greater awareness. Proposed diagnostic criteria aim to enhance recognition, enable early intervention and support future research.