Stroke-Like Migraine Attacks after Radiation Therapy (SMART) Syndrome Is Not Always Completely Reversible: A Case Series

Discussion

This series provides several new insights into the poorly understood and possibly under-recognized syndrome of SMART. Prior publications described a benign natural history with complete return to clinical baseline; however, in this series, 45% of patients had incomplete clinical recovery. All the patients in this series met the proposed diagnostic criteria of SMART, except for this unexpected incomplete recovery.¹ Permanent imaging sequelae from SMART were demonstrated in 27%, with MR imaging findings typical of cortical laminar necrosis developing as early as 17 days after symptom onset.

We demonstrated that the thick gyriform cortical enhancement characteristic of SMART develops only after 2–7 days, typically resolves in 14–35 days, but may last between 11–84 days. Diffusion-weighted abnormalities were minimal and primarily demonstrated T2 shine through without convincing evidence of restricted diffusion except in the 3 cases that had superimposed infarcts. The small occipital infarcts seen in patients 1 and 9 occurred after the more typical changes of gyral edema and enhancement had resolved, again suggesting that the mechanisms causing SMART are complex. A process driven by some form of cerebral hyperexcitability with impaired autoregulatory parameters and endothelial damage occurring as a consequence of remote radiation therapy seems plausible. Stabilizing seizure threshold and vascular reactivity are logical therapeutic interventions to consider.

The pathologic substrate for SMART is unknown, and biopsy in 4 of the 11 patients (36%) failed to demonstrate pathologic etiology. Also, 3 of 11 patients in this series had comorbid problems with high or low sodium or diabetes insipidus, but to what extent this may have contributed is not known.

Similar to previous reports, the interval between radiation and SMART diagnosis was on average 20 years, with an average age at diagnosis of 50.^1,3 All patients had somatosensory findings, 82% had various levels of evidence of seizure activity temporally and spatially correlated with imaging findings, 73% had migraine-like headaches, and all had unilateral, thick gyriform enhancement during their symptoms.

Limitations of this series include its retrospective nature. We did not actively recruit suspected cases but simply came across them during our daily practice. We saw 1–2 cases per year at our tertiary care center. Many of the subjects had received radiation therapy many years previously at other institutions; thus, radiation doses were largely unknown, though the radiation ports probably included regions affected by SMART in all cases.

Inherent to their history of cerebral irradiation and tumor, patients with SMART may have seizures as a premorbid condition and possible contributor to their neurologic problems. Many reports have demonstrated that nonconvulsive status epilepticus or frequent partial seizures may produce transient cortical edema, T2 hyperintensity, leptomeningeal or cortical enhancement, and permanent sequelae, including cortical laminar necrosis.^6⇓⇓–9 Postictal MR imaging findings in patients without prior radiation therapy appear different from SMART, suggesting that SMART may represent a unique syndrome with a complex poorly understood pathophysiology occurring in a subset of patients long after radiation therapy.^10,11

It may be that seizures in patients with SMART strain an already impaired brain because of the chronic endothelial vascular damage caused by remote radiation, and this “double hit” produces infarction in some instances in the affected cortical areas. Whether seizures initiate or are a consequence of SMART, the combination of radiation-induced vascular damage and clinical and subclinical seizure activity could explain cortical edema and impaired blood-brain barrier integrity with persisting contrast enhancement for days to weeks while patients' symptoms outlast any particular seizure activity and, at times, become permanent with evidence of cortical laminar necrosis.

Reports of what has been subsequently termed peri-ictal pseudoprogression (PIPG) demonstrate MR imaging findings similar to SMART but highlight absence of headache, less significant neurologic impairment, and more rapid clinical recovery as differentiating aspects.¹² Although PIPG probably represents the same spectrum of phenomena as SMART, reported cases tend to show more meningeal enhancement than the cortical enhancement seen in SMART.

Endothelial damage may also explain the interplay between too much or too little synaptic activity producing the migrainous headaches that occur in some patients with SMART as well as the unilaterality of the imaging findings that are similar to those reported in familial hemiplegic migraine.¹³ Cha et al¹⁴ reported identical twins with hemiplegic migraine without evidence of seizures who had MR imaging findings identical to SMART, though no history of radiation was mentioned. Therefore, vascular endothelial damage complicating radiation therapy may lower the threshold required to develop episodic symptoms of a hyperexcitable nervous system similar to the postulated mechanism of hemiplegic migraine and could contribute to the expression of symptoms consistent with migraine in these cases. Furthermore, it is plausible to consider that this syndrome occurs in individuals who survive radiation therapy and have a genetic predisposition similar to hemiplegic migraine.

Rapid control of seizure activity, if present, is important in treating patients with SMART. Intravenous fosphenytoin, oral or intravenous levetiracetam, and a short course of high-dose corticosteroids appear to be candidates for treatment.¹⁵ Because of the ischemic nature of the MR imaging findings that can progress to cortical laminar necrosis, verapamil appears to be an intuitive, though unproven, therapeutic option that may have the benefit of also preventing headaches. Although also unproven, some form of antiplatelet therapy or even statin therapy seem to be intuitive potential treatment options.

The possibility of recurrent tumor or loss of seizure control as a cause of symptoms is omnipresent in patients with prior radiation for brain tumors, and ongoing aggressive surveillance is required. Awareness and recognition of SMART syndrome signs, symptoms, imaging findings, and recurrent attacks should serve to guard against rendering an incorrect dire prognosis and prevent aggressive interventions such as brain biopsy or cerebral angiography. All 4 patients who underwent biopsy in this series experienced incomplete recovery, and only 1 of the 7 patients who did not undergo biopsy had an incomplete recovery. It should be noted that no new signs or symptoms were temporally correlated with the biopsy procedures; thus, the relation between biopsy and clinical outcome is unknown. It is unclear why the 14–3–3 protein was elevated in patient 1, who ultimately did not have CJD, but false-positives have been found with other nonspecific encephalopathies, especially with ischemia.¹⁶

For appropriate diagnosis and treatment, it is important for clinicians and radiologists to be aware of the characteristic imaging findings of SMART as well as their temporal evolution, the association with seizures, the possibility of permanent sequelae, and the lack of benefit and possible detriment from brain biopsy.