====== SMART syndrome ====== SMART syndrome, an [[acronym]] for [[stroke]]-like [[migraine]] attacks after [[radiation therapy]], is an uncommon delayed [[complication]] of brain [[radiotherapy]]. It is probably a more severe manifestation of peri-ictal pseudoprogression ([[PIPG]]). ===== Epidemiology ===== Since the first case of stroke-like migraine attacks after radiation therapy (SMART) syndrome was described by Shuper et al. ((Shuper A, Packer RJ, Vezina LG, Nicholson HS, Lafond D. 'Complicated migraine-like episodes' in children following cranial irradiation and chemotherapy. Neurology. 1995 Oct;45(10):1837-40. doi: 10.1212/wnl.45.10.1837. PMID: 7477978.)) in 1995, nearly one hundred cases have been reported worldwide ((Di Stefano AL, Berzero G, Ducray F, Eoli M, Pichiecchio A, Farina LM, Cuccarini V, Brunelli MC, Diamanti L, Condette Auliac S, Salmaggi A, Silvani A, Giometto B, Pace A, Vidiri A, Bourdain F, Bastianello S, Ceroni M, Marchioni E. Stroke-like events after brain radiotherapy: a large series with long-term follow-up. Eur J Neurol. 2019 Apr;26(4):639-650. doi: 10.1111/ene.13870. Epub 2019 Jan 10. PMID: 30471162.)) Although SMART syndrome is extremely rare, improvements in cancer survival rates are very likely to result in an increase in the frequency of this entity. ===== Pathophysiology ===== The pathophysiology of SMART syndrome is poorly understood. In all the cases reported, patients had previously received brain radiation therapy. Although the syndrome was initially associated with high doses (>50Gy), cases have also been reported in patients receiving lower doses ((Bartleson JD, Krecke KN, O'Neill BP, Brown PD. Reversible, strokelike migraine attacks in patients with previous radiation therapy. Neuro Oncol. 2003 Apr;5(2):121-7. doi: 10.1093/neuonc/5.2.121. PMID: 12672284; PMCID: PMC1920675.)) ((Farid K, Meissner WG, Samier-Foubert A, Barret O, Menegon P, Rouanet F, Fernandez P, Orgogozo JM, Allard M, Tison F, Sibon I. Normal cerebrovascular reactivity in Stroke-like Migraine Attacks after Radiation Therapy syndrome. Clin Nucl Med. 2010 Aug;35(8):583-5. doi: 10.1097/RLU.0b013e3181e4db6f. PMID: 20631504.)) all cases occurred after doses ranging from 15 to 64Gy ((Singh AK, Tantiwongkosi B, Moise AM, Altmeyer WB. Stroke-like migraine attacks after radiation therapy syndrome: Case report and review of the literature. Neuroradiol J. 2017 Dec;30(6):568-573. doi: 10.1177/1971400917690009. Epub 2017 Jun 23. PMID: 28643603; PMCID: PMC5703131.)). Neurotoxicity disrupts the blood-brain barrier, damages endothelial cells, and causes vascular smooth muscle cell proliferation and vascular fibrinoid necrosis, ultimately leading to vascular occlusion. This explains why the pathogenesis of SMART syndrome was attributed to these factors. However, in the series published by Black et al., ((Black DF, Morris JM, Lindell EP, Krecke KN, Worrell GA, Bartleson JD, Lachance DH. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series. AJNR Am J Neuroradiol. 2013 Dec;34(12):2298-303. doi: 10.3174/ajnr.A3602. Epub 2013 Jun 20. PMID: 23788601; PMCID: PMC7965219.)) brain biopsy studies did not identify vascular alterations, but rather nonspecific gliosis. Proposed causes of SMART syndrome include disruption of the trigeminovascular system and radiation-induced neuronal dysfunction, which suggests that the syndrome may bear a greater resemblance to migraine or epilepsy than to cerebrovascular disease ((Farid K, Meissner WG, Samier-Foubert A, Barret O, Menegon P, Rouanet F, Fernandez P, Orgogozo JM, Allard M, Tison F, Sibon I. Normal cerebrovascular reactivity in Stroke-like Migraine Attacks after Radiation Therapy syndrome. Clin Nucl Med. 2010 Aug;35(8):583-5. doi: 10.1097/RLU.0b013e3181e4db6f. PMID: 20631504.)). ===== Clinical features ===== Patients usually present with seizures and subacute stroke-like episodes with symptoms such as [[hemiplegia]], [[aphasia]], and [[hemianopia]] ((Black DF, Morris JM, Lindell EP, Krecke KN, Worrell GA, Bartleson JD, Lachance DH. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series. AJNR Am J Neuroradiol. 2013 Dec;34(12):2298-303. doi: 10.3174/ajnr.A3602. Epub 2013 Jun 20. PMID: 23788601; PMCID: PMC7965219.)) These episodes have been associated with headaches and are often preceded by a migraine-like aura ((Louis Caplan, MD. Caplan's Stroke. (2009) ISBN: 9781416047216)) ((Bartleson JD, Krecke KN, O'Neill BP, Brown PD. Reversible, strokelike migraine attacks in patients with previous radiation therapy. Neuro Oncol. 2003 Apr;5(2):121-7. doi: 10.1093/neuonc/5.2.121. PMID: 12672284; PMCID: PMC1920675.)). ---- Involves complex migraines with focal neurologic findings in patients following [[cranial irradiation]] for [[central nervous system]] malignancies. ---- In most instances, patients have a history of seizures ---- SMART syndrome is characterised by subacute onset of neurological symptoms (aphasia, hemianopsia or complete vision loss, hemiparesis, hemiparaesthesia, hearing loss), seizures, migraine-like headache, and encephalopathy of varying severity, ranging from mild psychomotor retardation to severely impaired consciousness ((Q. Zheng, L. Yang, L.M. Tan, L.X. Qin, C.Y. Wang, H.N. Zhang. Stroke-like migraine attacks after radiation therapy syndrome. Chin Med J (Engl), 128 (2015), pp. 2097-2110)).1 In the largest series published to date, ((Di Stefano AL, Berzero G, Ducray F, Eoli M, Pichiecchio A, Farina LM, Cuccarini V, Brunelli MC, Diamanti L, Condette Auliac S, Salmaggi A, Silvani A, Giometto B, Pace A, Vidiri A, Bourdain F, Bastianello S, Ceroni M, Marchioni E. Stroke-like events after brain radiotherapy: a large series with long-term follow-up. Eur J Neurol. 2019 Apr;26(4):639-650. doi: 10.1111/ene.13870. Epub 2019 Jan 10. PMID: 30471162.)) the most frequent symptoms were neurological deficits and headache. SMART syndrome completely resolved in most cases, but some patients were left with sequelae or even experienced relapses. The course of the syndrome seems to be relapsing-remitting. ===== Pathology ===== The precise mechanism that underlies SMART syndrome is uncertain and biopsies obtained from some patients do not reveal specific abnormalities above and beyond those expected in previously irradiated brain ((Black DF, Morris JM, Lindell EP, Krecke KN, Worrell GA, Bartleson JD, Lachance DH. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series. AJNR Am J Neuroradiol. 2013 Dec;34(12):2298-303. doi: 10.3174/ajnr.A3602. Epub 2013 Jun 20. PMID: 23788601; PMCID: PMC7965219.)) It is hypothesized that SMART syndrome represents an exacerbation of normal post-ictal phenomena due to prior radiotherapy ((Black DF, Morris JM, Lindell EP, Krecke KN, Worrell GA, Bartleson JD, Lachance DH. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series. AJNR Am J Neuroradiol. 2013 Dec;34(12):2298-303. doi: 10.3174/ajnr.A3602. Epub 2013 Jun 20. PMID: 23788601; PMCID: PMC7965219.)) ===== Diagnosis ===== They can be generally summarized as follows: patient: history of cranial irradiation (typically years ago) with no residual/recurrent tumor clinical: prolonged (usually reversible) symptoms referrable to a unilateral cortical area that has been irradiated imaging: prominent gyral enhancement (usually transient) within an area of previously irradiated brain ---- Mean time from brain radiation therapy to diagnosis of SMART syndrome was 10 years (range, 1-35) ((Di Stefano AL, Berzero G, Ducray F, Eoli M, Pichiecchio A, Farina LM, Cuccarini V, Brunelli MC, Diamanti L, Condette Auliac S, Salmaggi A, Silvani A, Giometto B, Pace A, Vidiri A, Bourdain F, Bastianello S, Ceroni M, Marchioni E. Stroke-like events after brain radiotherapy: a large series with long-term follow-up. Eur J Neurol. 2019 Apr;26(4):639-650. doi: 10.1111/ene.13870. Epub 2019 Jan 10. PMID: 30471162.)) Diagnostic criteria for stroke-like migraine attacks after radiation therapy syndrome. (1) History of brain radiation therapy for malignancy (2) Prolonged, reversible clinical manifestations (mostly years after radiation therapy), which may include migraine, seizures, hemiparesis, hemisensory deficits, visuospatial defect, aphasia, etc. (3) Reversible, transient, unilateral cortical gadolinium enhancement, associated with abnormal T2-weighted and FLAIR signal of the affected cerebral region (4) Eventual complete or partial recovery, with the duration of recovery ranging from hours to weeks (5) No evidence of residual or recurrent tumour (6) Not attributable to another disease ((Q. Zheng, L. Yang, L.M. Tan, L.X. Qin, C.Y. Wang, H.N. Zhang. Stroke-like migraine attacks after radiation therapy syndrome. Chin Med J (Engl), 128 (2015), pp. 2097-2110)). ==== Radiographic features ==== === CT === On initial imaging, a region of relatively minor low density with mass effect can be seen. Features of laminar necrosis in the involved territory, such as cortical calcifications, can be seen following the initial episode. === MRI === MRI is the modality of choice to investigate SMART syndrome. Importantly, imaging abnormalities do not precede or coincide with symptom onset; rather, it takes 2-7 days for imaging abnormalities to develop ((Black DF, Morris JM, Lindell EP, Krecke KN, Worrell GA, Bartleson JD, Lachance DH. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series. AJNR Am J Neuroradiol. 2013 Dec;34(12):2298-303. doi: 10.3174/ajnr.A3602. Epub 2013 Jun 20. PMID: 23788601; PMCID: PMC7965219.)) As such, if imaging is performed early, a repeat scan is advisable a week later to have a better chance of identifying abnormalities. ---- MRI typically shows unilateral cortical hyperintensities on T2-weighted and FLAIR sequences, with gyriform enhancement, predominantly in the temporal, parietal, and occipital lobes. Diagnosis of SMART syndrome is clinical and radiological and must be based on a compatible medical history. In 2015, Zheng et al. ((Q. Zheng, L. Yang, L.M. Tan, L.X. Qin, C.Y. Wang, H.N. Zhang. Stroke-like migraine attacks after radiation therapy syndrome. Chin Med J (Engl), 128 (2015), pp. 2097-2110)) reviewed the criteria established by Black et al. ((D.F. Black, J.D. Bartleson, M.L. Bell, D.H. Lachance. SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia, 26 (2006), pp. 1137-1142)) and proposed a new set of diagnostic criteria. Alternative diagnoses include brain radiation necrosis. Although brain radiation necrosis may occur at any time, it has been reported to present at 10 to 16 months post-treatment in several series ((D.F. Black, J.D. Bartleson, M.L. Bell, D.H. Lachance. SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia, 26 (2006), pp. 1137-1142)) ((S. Telera, A. Fabi, A. Pace, A. Vidiri, V. Anelli, C.M. Carapella, et al. Radionecrosis induced by stereotactic radiosurgery of brain metastases: results of surgery and outcome of disease. J Neurooncol, 113 (2013), pp. 313-325 http://dx.doi.org/10.1007/s11060-013-1120-8)) ((D. Boothe, R. Young, Y. Yamada, A. Prager, T. Chan, K. Beal. Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. Neuro Oncol, 15 (2013), pp. 1257-1263 http://dx.doi.org/10.1093/neuonc/not085)) ((J.D. Ruben, M. Dally, M. Bailey, R. Smith, C.A. McLean, P. Fedele. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys, 65 (2006), pp. 499-508 http://dx.doi.org/10.1016/j.ijrobp.2005.12.002 ((B. Carangelo, A. Cerillo, A. Mariottini, G. Peri, G. Rubino, V. Mourmouras, et al. Therapeutic strategy of late cerebral radionecrosis. A retrospective study of 21 cases. J Neurosurg Sci, 54 (2010), pp. 21-28)) Although no pathognomonic radiological signs of brain radiation necrosis have been described, MRI typically reveals necrotic lesions, usually with surrounding oedema and mass effect. These findings are described as having a “Swiss cheese” or “soap bubble” appearance ((Boothe D, Young R, Yamada Y, Prager A, Chan T, Beal K. Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. Neuro Oncol. 2013 Sep;15(9):1257-63. doi: 10.1093/neuonc/not085. Epub 2013 Jun 27. PMID: 23814264; PMCID: PMC3748921.)) ((Chao ST, Ahluwalia MS, Barnett GH, Stevens GH, Murphy ES, Stockham AL, Shiue K, Suh JH. Challenges with the diagnosis and treatment of cerebral radiation necrosis. Int J Radiat Oncol Biol Phys. 2013 Nov 1;87(3):449-57. doi: 10.1016/j.ijrobp.2013.05.015. Epub 2013 Jun 19. PMID: 23790775.)) ((Hoefnagels FW, Lagerwaard FJ, Sanchez E, Haasbeek CJ, Knol DL, Slotman BJ, Vandertop WP. Radiological progression of cerebral metastases after radiosurgery: assessment of perfusion MRI for differentiating between necrosis and recurrence. J Neurol. 2009 Jun;256(6):878-87. doi: 10.1007/s00415-009-5034-5. Epub 2009 Mar 10. PMID: 19274425; PMCID: PMC2698975.)). ===== Treatment ===== Little is known about the mechanisms behind the disorder, making successful treatment challenging. ---- No targeted treatment is available; management of these patients focuses on symptom control. While corticosteroids may improve neurological deficits, their use continues to be controversial ((Farid K, Meissner WG, Samier-Foubert A, Barret O, Menegon P, Rouanet F, Fernandez P, Orgogozo JM, Allard M, Tison F, Sibon I. Normal cerebrovascular reactivity in Stroke-like Migraine Attacks after Radiation Therapy syndrome. Clin Nucl Med. 2010 Aug;35(8):583-5. doi: 10.1097/RLU.0b013e3181e4db6f. PMID: 20631504.)) ((D.F. Black, J.D. Bartleson, M.L. Bell, D.H. Lachance. SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia, 26 (2006), pp. 1137-1142)) ((M. Tomek, S.V. Bhavsar, D. Patry, A. Hanson. The syndrome of stroke-like migraine attacks after radiation therapy associated with prolonged unresponsiveness in an adult patient. Neurologist, 19 (2015), pp. 49-52 http://dx.doi.org/10.1097/NRL.0000000000000003)) ((P.R. Maloney, A.A. Rabinstein, D.J. Daniels, M.J. Link. Surgically induced SMART syndrome: case report and review of the literature. World Neurosurg, 82 (2014), pp. 7-12 http://dx.doi.org/10.1016/j.wneu.2014.04.062)) ((J. Bradshaw, L. Chen, M. Saling, G. Fitt, A. Hughes, A. Dowd. Neurocognitive recovery in SMART syndrome: a case report. Cephalalgia, 31 (2011), pp. 372-376 http://dx.doi.org/10.1177/0333102410388436)) ((A.E. Armstrong, E. Gillan, F.J. DiMario Jr.. SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients. J Child Neurol, 29 (2014), pp. 336-341 http://dx.doi.org/10.1177/0883073812474843)). SMART syndrome was initially thought to be self-limiting with gradual and complete resolution over the course of several weeks; typically occurring within 2-5 weeks but can take up to 3 months 4,6. However, incomplete clinical recovery is not uncommon (up to ~45% of subjects in one series 6). In a smaller proportion of patients (~27%) permanent imaging sequelae are also encountered consistent with cortical laminar necrosis, visible within a few weeks of presentation ===== Case reports ===== Armstrong et al. reported 2 new cases of SMART syndrome in pediatric patients as well as review all documented cases of the syndrome. Each of our 2 pediatric patients suffered multiple episodes. Attacks were characterized by severe headache, visual disturbance, aphasia, and weakness. Recovery occurred over several days to weeks. The data from all documented reports of SMART syndrome indicate a greater prevalence for male gender. An age-dependent pattern of onset was also observed, with a greater variability of syndrome onset in patients who received cranial irradiation at a younger age. SMART appears to be a reversible, recurrent long-term complication of radiation therapy with possible age- and gender-related influences ((Armstrong AE, Gillan E, DiMario FJ Jr. SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients. J Child Neurol. 2014 Mar;29(3):336-41. doi: 10.1177/0883073812474843. Epub 2013 Jan 29. PMID: 23364656.)).