SMART syndrome: a case report

Stroke-like migraine attacks after radiation therapy (SMART) syndrome, is a late complication of brain radiotherapy (1). Symptoms are commonly subacute in onset and involve migraine type of headache, seizures, focal neurologic deficits (2). Magnetic resonance imaging (MRI) findings are usually unilateral and posterior predominant cortical-subcortical hyperintensity, swelling and prominent gyriform (cortical and leptomeningeal) gadolinium enhancement in the areas of the brain that underwent irradiation with or without diffusion restriction (1). There is no standard treatment protocol for SMART syndrome. Antiepileptics and corticosteroids are commonly used drugs. A 65 years old woman was diagnosed with breast cancer with brain metastases and treated with more than 50 Gy brain radiotherapy. The patient presented with acute right-sided weakness and numbness, episodic myoclonic jerking of the right arm and leg, and gait instability five months later. MRI and magnetic resonance angiography of the brain with gadolinium revealed left parietooccipital cortical diffusion restriction and accompanying dilatation of the left posterior cerebral artery as new findings. Computed tomography (CT) perfusion revealed increased perfusion in the affected area. The patient was diagnosed with SMART syndrome. The patient was treated with dexamethasone (16 mg/day) and anticonvulsant therapy. Myoclonic seizures had almost completely remitted. However, her cognitive impairment persisted, then the patient was arrested because of aspiration a month later. Besides confirming SMART syndrome, diagnostic investigations are also important to exclude other etiologies. Posterior reversible encephalopathy syndrome, post-ictal changes, meningoencephalitis, and cerebrovascular diseases are radiological differential diagnoses considered (3). Proper and early diagnosis of SMART syndrome is significant in preventing unnecessary aggressive approaches and appropriate treatment to avoid lesions of sequela.


Introduction
Stroke-like migraine attacks after radiation therapy (SMART) syndrome, is a rare syndrome and delayed complication of brain radiotherapy. SMART syndrome was first defined in 1995 [1]. Symptoms of SMART syndrome are commonly subacute in onset. They involve migraine type of headache, seizures, focal neurologic signs such as aphasia, hemianopsia, hemiparesis, sensory deficits, which can be seen in stroke [2]. These findings are generally reversible; however, neurological deficits and imaging sequelae may become permanent in described cases [4]. In a case series including 11 patients, five patients (45%) were recovered partially after treatment, and laminar cortical necrosis was seen in 3 of them (27%) [4].
The examination of magnetic resonance imaging (MRI) is necessary to detect SMART-specific findings and rule out other etiological reasons. MRI pattern of SMART syndrome usually presents unilateral and posterior predominant cortical-subcortical hyperintensity, swelling and prominent gyriform (cortical and leptomeningeal) gadolinium enhancement in the brain areas that underwent irradiation with or without diffusion restriction [1].
SMART syndrome is a clinical and radiological diagnosis and must be based on a coherent medical history. Even though there is no targeted treatment of SMART syndrome, corticosteroids may improve neurological deficits. There are reports of patients with partial or complete recovery of symptoms after pulse therapy with corticosteroids [1].
This report presents a case of SMART syndrome with characteristic clinical and radiological findings, which was treated with corticosteroids and anticonvulsant therapy.

Case report
A 65 years old woman was diagnosed with breast carcinoma. The patient was treated with neoadjuvant chemotherapy, surgery and breast irradiation.
Three years later, MRI showed irregular metastatic lesions with microhemorrhages in the left parietooccipital and right cerebellar lobes. Following tumor excision, the pathology result was compatible with breast cancer metastasis. Antiepileptic treatment was started after surgery. The patient received focal brain radiation. Left occipital cavity, residual tumor and right cerebellar lesion were irradiated with 30 Gy in 6 fractions by stereotactic body radiotherapy (SBRT). After radiotherapy, MRI showed reduction of multiple brain metastases compared to the previous result, and there was no newly developing lesion.
A follow-up visit two years later, MRI demonstrated increased metastatic lesions, progressing the disease. The patient was treated with whole-brain radiotherapy (WBRT) at 30 Gy in 12 fractions. In control MRI, a significant reduction in the diffuse edema in the posterior part of the right cerebellar and left hemisphere, a considerable decrease of the left lesion enhancement, and stable right cerebellar contrast enhancement were observed.
Five months after WBRT, the patient presented with a two-day history of acute right-sided weakness and numbness, episodic myoclonic jerking of the right arm, and especially right leg and gait instability. She had speech difficulty. Physical examination was unremarkable. On neurologic examination, she had confusion, and she was agitated and not oriented. Her speech was meaningless. Pupils were symmetric and reactive. Direct and indirect pupillary reflexes were positive. Poor cooperation limited the cerebellar testing, motor, sensory and cranial nerve examinations. Initial laboratory results were all unremarkable except for thrombocytopenia. The platelet count was 63 (× 10 3 /µL).
A computed tomography (CT) scan of the head did not demonstrate any acute abnormalities, showed chronic stable left occipital postsurgical changes. Lumbal punction was not performed due to a lack of evidence of meningeal irritation. MRI and magnetic resonance angiography (MRA) of the brain with gadolinium revealed left parietooccipital cortical diffusion restriction and accompanying dilatation of the left posterior cerebral artery as new findings. Initial necrotic-metastatic lesions in the right cerebellum and left parietooccipital lobes and diffuse T2 hyperintensity were also demonstrated. Previous necrotic-metastatic lesions were stable compared to after-WBRT MRI.
Computed tomography perfusion (CTP) demonstrated increased cerebral blood flow (CBF) and cerebral blood volume (CBV) and reduced mean transit time (MTT) at the posterior cerebral artery (PCA) territory of the left hemisphere.
The patient was diagnosed with SMART syndrome based on radiologic findings, clinical features, and a history of brain irradiation.
Electroencephalogram (EEG) showed diffuse theta wave and epileptiform discharges in the left parietooccipital lobe. She was treated with dexamethasone (16 mg/day) and a loading dose of phenytoin (1000 mg). Levetiracetam could not be performed due to a history of rash with levetiracetam. The patient received pregabalin (1 × 75 mg/day) and clonazepam (2 × 5 drops/day).
During follow-up in the oncology department, EEG was performed to rule out nonconvulsive status epilepticus because of ongoing myoclonic jerking of the right upper and lower extremities. There were no significant changes in EEG.
The patient was not treated with valproate due to thrombocytopenia and with diphenylhydantoin due to the risk of interaction with current chemotherapy. Lacosamide (2 × 50 mg/day) was given, and control EEG demonstrated no epileptiform discharges. After all treatment, myoclonic seizures had almost completely remitted. However, her cognitive impairment persisted. At follow-up, the patient was arrested because of aspiration a month later, and follow-up imaging could not be done.

Discussion
We report a patient with typical anamnesis; clinical and radiological picture is compatible with the SMART syndrome. SMART syndrome is a unique, rare neurologic complication of brain radiation and includes temporary, reversible neurological dysfunction, which may present with migrainous headaches, seizures [5]. Among the cases of delayed up to 35-years, our case is one of the 'early-onset' SMART cases.
The pathophysiology of the SMART syndrome is not unknown. It is known that radiation may cause vasculopathy, which leads to disruption of blood-brain barrier [5,6]. Radiation causes neurotoxic effects over time, causing necrosis and myelopathy [2].
On the other hand, the trigeminovascular system is affected by radiation, resulting in the impairment of homeostasis [5,6]. The development of SMART syndrome is related to radiation dosage exceeding 50 Gy; however, some cases of SMART syndrome have been described with radiation dosage less than 50 Gy [6,7]. Our patient was treated with more than 50 Gy.
MRI findings may include typical gyriform, unilateral cortical gadolinium enhancement, and minimal leptomeningeal enhancement [4]. In our case, slight cortical diffusion restriction was the main MRI finding without cortical enhancement. Perfusion CT revealed increased perfusion in the affected area (Fig. 1). Previous reports also documented increased perfusion with perfusion CT, MR perfusion [8], single-photon emission tomography, and positron emission tomography in SMART syndrome [9]. In our patient's MR, there were no visible lesions or globular contrast enhancement in corresponding areas on T2WI and postcontrast T1WI, respectively. It is important to rule out tumor progression.
Besides confirming SMART syndrome, diagnostic investigations are also important to exclude other etiologies. Neuroimaging with gadolinium-enhanced brain MRI and MR or CT angiography, lumbar puncture for CSF analysis, EEG, serum lactic acid level could be beneficial to rule out other etiologies which have similar presentations with SMART syndrome [10].
Posterior reversible encephalopathy syndrome (PRES) has a similar clinical presentation consisting of headaches, neurological deficits, and seizures with SMART syndrome. Gyral enhancement is a radiological finding which may be seen in PRES [3]. The underlying mechanism of PRES is thought to be vascular pathology related to altered integrity of blood-brain barrier, neuroradiological changes in PRES tend to be seen in bilateral hemispheres [11]. PRES also has underlying conditions like cytotoxic medication, sepsis, autoimmune disorders. There were no such conditions in our case, and MRI findings were unilateral. Because the patient had seizures, post-ictal effects on MRI were thought to be a differential diagnosis. Post-ictal changes are frequently Fig. 1 Heterogeneous T2 hyperintense necrotic lesion (thin arrows) (a T2WI) with contrast enhancement (b, postcontrast T1WI) did not demonstrate diffusion restriction (c, d; DWI and ADC map) or increased perfusion (f, CBF map). Left parietooccipital cortical slight diffusion is seen as hyperintensity on DWI and hypointensity on ADC map (thick arrows). Note the PCA dilatation on TOF-MRA (e, black arrow). Areas with diffusion restriction showed prominent increased perfusion (f, CBF map) without any visible lesion or GLOBULAR contrast enhancement in corresponding regions on T2WI and postcontrast T1WI, respectively associated with hippocampal involvement [12], but in our case parietooccipital region was affected. Symptom presentation may be attributable to meningoencephalitis or cerebrovascular events [3], but the examination was negative for meningeal irritation, and MRI did not detect specific lesions for stroke.
There is no standard treatment protocol for SMART syndrome. Antiepileptics and corticosteroids are commonly used drugs. There are cases recovered without corticosteroid treatment, at least partially [13]. However, steroid therapy should be considered as spare unnecessary invasive procedures [13]. Moreover, in some cases [1], corticosteroids have shown encouraging outcomes. Because of vasoreactivity involved in pathophysiology, calcium-channel blocker verapamil was used in some cases [13,14].
Although SMART syndrome is named as ''stroke-like'', it is also a predisposing factor for stroke [15]. Vascular damage and abnormal vascular reactivity may be causing a stroke.
Most cases reported in the literature had complete recovery, but about 15% exhibited permanent sequelae in a large case series [1]. Despite high-dose corticosteroid therapy, the expected benefit from the treatment could not be seen in our patient due to the advanced stage of malignancy.

Conclusion
This report highlights a rare but reversible late complication of brain radiation. Clinical suspicion and neuroimaging findings are significant to diagnose the SMART syndrome. SMART syndrome should be considered in all patients with a history of radiation therapy who present neurological deficits and parietooccipital MRI alterations. Proper and early diagnosis of SMART syndrome is significant in preventing unnecessary aggressive approaches, such as brain biopsy, and appropriate treatment to prevent sequela lesions, including cortical laminar necrosis, hence neurologic deficit and stroke.
Take-home points: 1. SMART syndrome diagnosis made by suspicion: the most important clue in the history of brain radiation. It is also the most valuable for differential diagnosis. 2. Characteristic MRI findings include typical gyriform, unilateral cortical gadolinium enhancement, and minimal leptomeningeal enhancement. 3. Although there are no controlled studies, therapy includes steroids and calcium-channel blockers for vasoreactivity and seizure control. 4. Rapid diagnosis prevents to make invasive procedures from investigating other etiologies.

Declarations
Research ethics and patient consent The patient's legally authorized representative provided written informed consent for patient information and images to be published.