Published Ahead of Print on January 27, 2016 as 10.1212/WNL.0000000000002400
Clinical/Scientific Notes
Abby L. Olsen, MD, PhD Julie J. Miller, MD, PhD Shamik Bhattacharyya, MD P. Emanuela Voinescu, MD, PhD Joshua P. Klein, MD, PhD
CEREBRAL PERFUSION IN STROKE-LIKE MIGRAINE ATTACKS AFTER RADIATION THERAPY SYNDROME
Stroke-like migraine attacks after radiation therapy (SMART) syndrome is characterized by transient, focal neurologic symptoms occurring years after radiation,1 with focal or regional cortical thickening and gadolinium enhancement on MRI in the area of brain exposed to radiation. The pathophysiology of the syndrome is not well-understood. We present 2 patients with recurrent attacks of SMART syndrome with increased cerebral blood volume in affected regions and abnormal vascular reactivity on transcranial Doppler ultrasound, suggesting a potential mechanism. Case descriptions. Patient 1. A 68-year-old man with a history of 3,600 cGy prophylactic whole brain radiation 28 years ago for lung cancer presented with sudden right hemiparesis, aphasia, and leftward gaze preference. MRI 1 day after symptom onset showed abnormal T2 hyperintensity and avid enhancement in the left parieto-occipital cortex (figure, A and B). Perfusion MRI showed increased cerebral blood flow and volume in broader areas of the left hemisphere (figure, C and D). He developed seizures 4 days later (he had been monitored by EEG from the first day). Repeat MRI showed more diffuse abnormal T2 cortical hyperintensity in left frontal and temporal lobes (figure, E and F) as well as persistent increased blood flow and volume (figure, G and H). There was no diffusion abnormality on either scan. Autoregulatory measures of phase and coherence, assessed by analyzing oscillations in systemic blood pressure and cerebral blood flow using transcranial Doppler ultrasound,2 were significantly impaired in left middle cerebral artery compared to right. Notably, he had an identical presentation of SMART syndrome 15 years earlier. In the first instance, MRI abnormalities resolved over 1 week, while clinical symptoms took 8 months to resolve. In the second instance, both MRI abnormalities and symptoms resolved over 1 month. Patient 2. A 59-year-old woman with a history of skull base radiation (unknown dose) for osteosarcoma 14 years ago presented with headache, right-sided visual field deficit, and right hemiparesis. MRI showed abnormal T2 hyperintensity and avid
enhancement in the left parieto-occipital cortex (figure, I and J). There was no diffusion abnormality. Perfusion MRI demonstrated increased cerebral blood volume (figure, K). She had seizures and was treated with antiepileptics and methylprednisolone. Symptoms resolved over several weeks. This was her fourth episode of SMART syndrome and portions of this case were reported previously.3 Interestingly, the left and right cortices were alternately affected during different prior episodes (figure, L and M). Discussion. While diagnostic criteria for SMART syndrome have been proposed by Black et al.,4 the etiology remains unclear. Since attacks of SMART syndrome may be recurrent, there is likely an underlying predisposition. Hypothesized risk factors include male sex, time since radiation, and genetic susceptibility.5 The cases presented here are notable because they describe SMART syndrome in patients without intracerebral malignancy, suggesting that cranial radiation alone is sufficient for development. Others have reported the syndrome in patients with metastatic disease, also suggesting that a primary brain tumor is not required.6 Although headache and seizures are often present, they are not required for diagnosis. Imaging abnormalities in patient 1 preceded seizures, implying that seizures are not the sole explanation for the imaging abnormalities. Patient 2 additionally demonstrates that recurrent events can be multifocal. Impaired vascular reactivity is one proposed mechanism underlying SMART syndrome. Our findings of increased blood flow to affected cortex (patients 1 and 2) and impaired autoregulatory measures (patient 1) support this. While it is uncertain whether the perfusion abnormalities are causative or a consequence of the underlying pathology, the sequential scans in patient 1 show that increased perfusion precedes the T2 and enhancement changes. These findings complement a previous study using Tc-99m SPECT with acetazolamide challenge in the interictal period in patients with SMART syndrome, in which there was no evidence of impaired cerebrovascular reactivity during the interictal period.7 These findings suggest that SMART syndrome represents a transient period of cerebrovascular dysfunction. Like SMART syndrome, posterior reversible encephalopathy syndrome (PRES) is also hypothesized Neurology 86
February 23, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
Figure
Imaging
(A–H) Patient 1. Axial T2 fluid-attenuated inversion recovery (FLAIR) (A) and T1-post gadolinium (B) MRI of the brain shows abnormal hyperintensity and enhancement in the left parieto-occipital cortex. Perfusion images show abnormally elevated cerebral blood flow (CBF) (C) and cerebral blood volume (CBV) (D) in a wider area of the left hemispheric cortex (red/yellow). (A–D) were acquired on day 2 of symptoms. Repeat MRI shows confluent extension of the abnormal T2 hyperintensity (E) and enhancement (F) into the left frontal and temporal lobes. Perfusion images show persistently abnormal elevation of CBF (G) and CBV (H) in the left hemispheric cortex. (E–H) were acquired on day 5 of symptoms. (I–M) Patient 2. Axial T2 FLAIR (I) and T1 postgadolinium (J) MRI of the brain shows abnormal hyperintensity and enhancement in the left parieto-occipital cortex, with evidence of prior posterior craniotomy. A perfusion image shows abnormally elevated CBV (K) in the left hemisphere (red/yellow). MRI from a prior episode in the same patient shows abnormal hyperintensity (L) and enhancement (M) in the right parieto-occipital cortex; perfusion imaging was not performed at that time. (I–K) were acquired on day 3 of symptoms. (L–M) were acquired on day 5 of symptoms.
2
Neurology 86
February 23, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
to result from cerebrovascular autoregulatory dysfunction and endothelial injury. Both have a predilection for affecting the posterior cerebral hemispheres and have similar findings on magnetic resonance spectroscopy consistent with neuronal injury.8 PRES, however, is characterized by decreased rather than increased cerebral blood volume,9 greater white matter involvement, and no enhancement. More recently, acute late-onset encephalopathy after radiotherapy was described as a syndrome of impaired consciousness with transient bilateral areas of abnormal subcortical T2 hyperintensity with patchy enhancement and reduced diffusivity.10 The etiology of this syndrome is also speculated to be related to endothelial injury. SMART syndrome is associated with regional hyperperfusion preceding both seizures and MRI cortical abnormalities, suggesting a transient period of impaired cerebrovascular autoregulation. From Brigham and Women’s Hospital (A.L.O., J.J.M., S.B., P.E.V., J.P.K.), Massachusetts General Hospital (A.L.O., J.J.M., S.B., P.E.V.), and Harvard Medical School (A.L.O., J.J.M., S.B., P.E.V., J.P.K.), Boston, MA. Author contributions: Abby L. Olsen: drafting/revising the manuscript, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. Julie J. Miller: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. Shamik Bhattacharyya: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. P. Emanuela Voinescu: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. Joshua P. Klein: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, contribution of vital reagents/tools/patients, acquisition of data, statistical analysis, study supervision. Study funding: No targeted funding reported. Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Received July 15, 2015. Accepted in final form October 27, 2015. Correspondence to Dr. Joshua P. Klein: [email protected] © 2016 American Academy of Neurology 1.
2.
3. 4.
5.
6.
7.
8.
9.
10.
Shuper A, Packer RJ, Vezina LG, et al. “Complicated migraine-like episodes” in children following cranial irradiation and chemotherapy. Neurology 1995;45: 1837–1840. Otite F, Mink S, Tan CO, et al. Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage. Stroke 2014; 45:677–682. Wang N, Prasad S. SMART syndrome. Neurol Clin Pract 2014;4:530–531. Black DF, Bartleson JD, Bell ML, Lachance DH. SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia 2006;26:1137–1142. Armstrong AE, Gillan E, DiMario FJ. SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients. J Child Neurol 2014;29: 336–341. Black DF, Morris JM, Lindell EP, et al. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series. Am J Neuroradiol 2013;34:2298–2303. Farid K, Meissner WG, Samier-Foubert A, et al. Normal cerebrovascular reactivity in stroke-like migraine attacks after radiation therapy syndrome. Clin Nucl Med 2010; 35:583–585. Gómez-Cibeira E, Calleja-Castaño P, Gonzalez de la Aleja J, et al. Brain magnetic resonance spectroscopy findings in the stroke-like migraine attacks after radiation therapy (SMART) syndrome. J Neuroimaging 2015;25: 1056–1058. Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. Am J Neuroradiol 2008;29: 447–455. Di Stefano AL, Berzero G, Vitali P, et al. Acute late-onset encephalopathy after radiotherapy: an unusual lifethreatening complication. Neurology 2013;81:1014–1017.
Neurology 86
February 23, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
3
Cerebral perfusion in stroke-like migraine attacks after radiation therapy syndrome Abby L. Olsen, Julie J. Miller, Shamik Bhattacharyya, et al. Neurology published online January 27, 2016 DOI 10.1212/WNL.0000000000002400 This information is current as of January 27, 2016 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2016/01/27/WNL.0000000000 002400.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cerebrovascular disease/Stroke http://www.neurology.org//cgi/collection/all_cerebrovascular_disease_ stroke All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology MRI http://www.neurology.org//cgi/collection/mri Radiation therapy-tumor http://www.neurology.org//cgi/collection/radiation_therapytumor
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Clinical/Scientific Notes
Abby L. Olsen, MD, PhD Julie J. Miller, MD, PhD Shamik Bhattacharyya, MD P. Emanuela Voinescu, MD, PhD Joshua P. Klein, MD, PhD
CEREBRAL PERFUSION IN STROKE-LIKE MIGRAINE ATTACKS AFTER RADIATION THERAPY SYNDROME
Stroke-like migraine attacks after radiation therapy (SMART) syndrome is characterized by transient, focal neurologic symptoms occurring years after radiation,1 with focal or regional cortical thickening and gadolinium enhancement on MRI in the area of brain exposed to radiation. The pathophysiology of the syndrome is not well-understood. We present 2 patients with recurrent attacks of SMART syndrome with increased cerebral blood volume in affected regions and abnormal vascular reactivity on transcranial Doppler ultrasound, suggesting a potential mechanism. Case descriptions. Patient 1. A 68-year-old man with a history of 3,600 cGy prophylactic whole brain radiation 28 years ago for lung cancer presented with sudden right hemiparesis, aphasia, and leftward gaze preference. MRI 1 day after symptom onset showed abnormal T2 hyperintensity and avid enhancement in the left parieto-occipital cortex (figure, A and B). Perfusion MRI showed increased cerebral blood flow and volume in broader areas of the left hemisphere (figure, C and D). He developed seizures 4 days later (he had been monitored by EEG from the first day). Repeat MRI showed more diffuse abnormal T2 cortical hyperintensity in left frontal and temporal lobes (figure, E and F) as well as persistent increased blood flow and volume (figure, G and H). There was no diffusion abnormality on either scan. Autoregulatory measures of phase and coherence, assessed by analyzing oscillations in systemic blood pressure and cerebral blood flow using transcranial Doppler ultrasound,2 were significantly impaired in left middle cerebral artery compared to right. Notably, he had an identical presentation of SMART syndrome 15 years earlier. In the first instance, MRI abnormalities resolved over 1 week, while clinical symptoms took 8 months to resolve. In the second instance, both MRI abnormalities and symptoms resolved over 1 month. Patient 2. A 59-year-old woman with a history of skull base radiation (unknown dose) for osteosarcoma 14 years ago presented with headache, right-sided visual field deficit, and right hemiparesis. MRI showed abnormal T2 hyperintensity and avid
enhancement in the left parieto-occipital cortex (figure, I and J). There was no diffusion abnormality. Perfusion MRI demonstrated increased cerebral blood volume (figure, K). She had seizures and was treated with antiepileptics and methylprednisolone. Symptoms resolved over several weeks. This was her fourth episode of SMART syndrome and portions of this case were reported previously.3 Interestingly, the left and right cortices were alternately affected during different prior episodes (figure, L and M). Discussion. While diagnostic criteria for SMART syndrome have been proposed by Black et al.,4 the etiology remains unclear. Since attacks of SMART syndrome may be recurrent, there is likely an underlying predisposition. Hypothesized risk factors include male sex, time since radiation, and genetic susceptibility.5 The cases presented here are notable because they describe SMART syndrome in patients without intracerebral malignancy, suggesting that cranial radiation alone is sufficient for development. Others have reported the syndrome in patients with metastatic disease, also suggesting that a primary brain tumor is not required.6 Although headache and seizures are often present, they are not required for diagnosis. Imaging abnormalities in patient 1 preceded seizures, implying that seizures are not the sole explanation for the imaging abnormalities. Patient 2 additionally demonstrates that recurrent events can be multifocal. Impaired vascular reactivity is one proposed mechanism underlying SMART syndrome. Our findings of increased blood flow to affected cortex (patients 1 and 2) and impaired autoregulatory measures (patient 1) support this. While it is uncertain whether the perfusion abnormalities are causative or a consequence of the underlying pathology, the sequential scans in patient 1 show that increased perfusion precedes the T2 and enhancement changes. These findings complement a previous study using Tc-99m SPECT with acetazolamide challenge in the interictal period in patients with SMART syndrome, in which there was no evidence of impaired cerebrovascular reactivity during the interictal period.7 These findings suggest that SMART syndrome represents a transient period of cerebrovascular dysfunction. Like SMART syndrome, posterior reversible encephalopathy syndrome (PRES) is also hypothesized Neurology 86
February 23, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
Figure
Imaging
(A–H) Patient 1. Axial T2 fluid-attenuated inversion recovery (FLAIR) (A) and T1-post gadolinium (B) MRI of the brain shows abnormal hyperintensity and enhancement in the left parieto-occipital cortex. Perfusion images show abnormally elevated cerebral blood flow (CBF) (C) and cerebral blood volume (CBV) (D) in a wider area of the left hemispheric cortex (red/yellow). (A–D) were acquired on day 2 of symptoms. Repeat MRI shows confluent extension of the abnormal T2 hyperintensity (E) and enhancement (F) into the left frontal and temporal lobes. Perfusion images show persistently abnormal elevation of CBF (G) and CBV (H) in the left hemispheric cortex. (E–H) were acquired on day 5 of symptoms. (I–M) Patient 2. Axial T2 FLAIR (I) and T1 postgadolinium (J) MRI of the brain shows abnormal hyperintensity and enhancement in the left parieto-occipital cortex, with evidence of prior posterior craniotomy. A perfusion image shows abnormally elevated CBV (K) in the left hemisphere (red/yellow). MRI from a prior episode in the same patient shows abnormal hyperintensity (L) and enhancement (M) in the right parieto-occipital cortex; perfusion imaging was not performed at that time. (I–K) were acquired on day 3 of symptoms. (L–M) were acquired on day 5 of symptoms.
2
Neurology 86
February 23, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
to result from cerebrovascular autoregulatory dysfunction and endothelial injury. Both have a predilection for affecting the posterior cerebral hemispheres and have similar findings on magnetic resonance spectroscopy consistent with neuronal injury.8 PRES, however, is characterized by decreased rather than increased cerebral blood volume,9 greater white matter involvement, and no enhancement. More recently, acute late-onset encephalopathy after radiotherapy was described as a syndrome of impaired consciousness with transient bilateral areas of abnormal subcortical T2 hyperintensity with patchy enhancement and reduced diffusivity.10 The etiology of this syndrome is also speculated to be related to endothelial injury. SMART syndrome is associated with regional hyperperfusion preceding both seizures and MRI cortical abnormalities, suggesting a transient period of impaired cerebrovascular autoregulation. From Brigham and Women’s Hospital (A.L.O., J.J.M., S.B., P.E.V., J.P.K.), Massachusetts General Hospital (A.L.O., J.J.M., S.B., P.E.V.), and Harvard Medical School (A.L.O., J.J.M., S.B., P.E.V., J.P.K.), Boston, MA. Author contributions: Abby L. Olsen: drafting/revising the manuscript, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. Julie J. Miller: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. Shamik Bhattacharyya: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. P. Emanuela Voinescu: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval. Joshua P. Klein: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, contribution of vital reagents/tools/patients, acquisition of data, statistical analysis, study supervision. Study funding: No targeted funding reported. Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
Received July 15, 2015. Accepted in final form October 27, 2015. Correspondence to Dr. Joshua P. Klein: [email protected] © 2016 American Academy of Neurology 1.
2.
3. 4.
5.
6.
7.
8.
9.
10.
Shuper A, Packer RJ, Vezina LG, et al. “Complicated migraine-like episodes” in children following cranial irradiation and chemotherapy. Neurology 1995;45: 1837–1840. Otite F, Mink S, Tan CO, et al. Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage. Stroke 2014; 45:677–682. Wang N, Prasad S. SMART syndrome. Neurol Clin Pract 2014;4:530–531. Black DF, Bartleson JD, Bell ML, Lachance DH. SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia 2006;26:1137–1142. Armstrong AE, Gillan E, DiMario FJ. SMART syndrome (stroke-like migraine attacks after radiation therapy) in adult and pediatric patients. J Child Neurol 2014;29: 336–341. Black DF, Morris JM, Lindell EP, et al. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series. Am J Neuroradiol 2013;34:2298–2303. Farid K, Meissner WG, Samier-Foubert A, et al. Normal cerebrovascular reactivity in stroke-like migraine attacks after radiation therapy syndrome. Clin Nucl Med 2010; 35:583–585. Gómez-Cibeira E, Calleja-Castaño P, Gonzalez de la Aleja J, et al. Brain magnetic resonance spectroscopy findings in the stroke-like migraine attacks after radiation therapy (SMART) syndrome. J Neuroimaging 2015;25: 1056–1058. Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. Am J Neuroradiol 2008;29: 447–455. Di Stefano AL, Berzero G, Vitali P, et al. Acute late-onset encephalopathy after radiotherapy: an unusual lifethreatening complication. Neurology 2013;81:1014–1017.
Neurology 86
February 23, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
3
Cerebral perfusion in stroke-like migraine attacks after radiation therapy syndrome Abby L. Olsen, Julie J. Miller, Shamik Bhattacharyya, et al. Neurology published online January 27, 2016 DOI 10.1212/WNL.0000000000002400 This information is current as of January 27, 2016 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2016/01/27/WNL.0000000000 002400.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cerebrovascular disease/Stroke http://www.neurology.org//cgi/collection/all_cerebrovascular_disease_ stroke All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology MRI http://www.neurology.org//cgi/collection/mri Radiation therapy-tumor http://www.neurology.org//cgi/collection/radiation_therapytumor
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
