The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–5, 2020 Ó 2020 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter https://doi.org/10.1016/j.jemermed.2019.12.019 Selected Topics: Emergency Radiology A HELPFUL TOOL IN DIAGNOSING STROKE MIMICS: ARTERIAL SPIN LABELED PERFUSION MAGNETIC RESONANCE IMAGING Michael U. Antonucci, MD and Milad Yazdani, MD Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, South Carolina Reprint Address: Michael U. Antonucci, MD, Department of Radiology and Radiological Science, Medical University of South Carolina, 96 Jonathan Lucas Street, MSC 323, Charleston, SC 29425 , Abstract—Background: Prompt and effective management of acute ischemic stroke in the emergency setting requires a high level of suspicion and accurate diagnosis. Conversely, identifying stroke mimics can be challenging, given the similarity of their clinical symptomatology, the necessary rapid assessment and triage, and the overall frenetic pace inherent in the goal of rapid thrombolysis (‘‘time is brain’’). Case Report: We describe a case that involves an elderly patient with acute hemiplegia and dysarthria. Given these concerning symptoms, and multiple preexisting cerebrovascular risk factors (including paroxysmal atrial fibrillation), a ‘‘stroke alert’’ was issued. Imaging was negative for infarct and she was ultimately diagnosed with hemiplegic migraine based on her symptoms and impressive findings on a novel magnetic resonance sequence called arterial spin labeled (ASL) perfusion. Why Should an Emergency Physician Be Aware of This?: Identifying a nonischemic etiology in a presumed stroke patient, while often difficult, can obviate unnecessary treatment, improve patient care, and promote appropriate resource allocation. As imaging and treatment of cerebrovascular disease advances, the optimization of multidisciplinary care should incorporate neuroradiologists informing and availing their clinical colleagues of applications of an everexpanding imaging armamentarium. This case is an excellent example of both a common challenging stroke mimic and the potential benefits of ASL perfusion imaging in refining and expediting accurate diagnosis. In addition, it serves as a more general introduction to the particular strengths of this noninvasive, noncontrast magnetic resonance technique, which can be employed to assess varied emergent neuropathology. reserved. Ó 2020 Elsevier Inc. All rights , Keywords—stroke; stroke mimics; migraine; arterial spin labeled perfusion; MRI INTRODUCTION Stroke remains the fifth leading cause of death in the United States (1,2). The rate of long-term disability and financial burden associated with ischemic infarct further underscore its substantial effect on public health (3). Fortunately, advances in neuroimaging, availability of and familiarity with intravenously administered tissue plasminogen activator, and continually evolving endovascular techniques have produced dramatic improvements in stroke care (4–6). In the emergency setting, rapid diagnosis optimizes care and affords patients timesensitive treatment options. The diagnostic process necessarily involves excluding intracranial hemorrhage, an absolute contraindication to thrombolysis. It may also include components of the more arduous assessment for other entities that can produce stroke-like symptoms. Identifying these ‘‘mimics’’ can be challenging, given the similarity of their clinical presentation, coupled with the diagnostic alacrity needed for rapid thrombolysis. However, the emergency physician will encounter these processes quite frequently. For example, recent analyses revealed 30% of 8187 and 38.2% of 1881 suspected RECEIVED: 5 April 2018; FINAL SUBMISSION RECEIVED: 10 December 2019; ACCEPTED: 16 December 2019 1 2 M. U. Antonucci and M. Yazdani stroke patients ultimately had an alternative diagnosis (7,8). These comprise both non-neurologic systemic and nonischemic neurologic processes. Common examples of the latter include seizure, space-occupying lesions, and migraine (9,10). If unrecognized, these mimics may be treated unnecessarily with thrombolytic agents. While the risk of complications in this situation is fortunately low, hemorrhage can occur and there is a substantial increase in excess health care costs (11–14). As such, improving diagnostic assessment by utilizing novel techniques to recognize nonischemic entities can optimize treatment paradigms and improve resource utilization. The case we present demonstrates the potential utility of arterial spin labeled (ASL) perfusion, a noninvasive, noncontrast magnetic resonance sequence, in confirming the diagnosis of hemiplegic migraine. It also serves as a more general illustration of the advantages of this imaging method in the emergency setting, including in the overall diagnostic assessment of patients presenting with cerebrovascular symptoms. then performed, with diffusion-weighted imaging (Figure 1B) excluding acute infarct. The MRI included an ASL perfusion sequence, which revealed asymmetrically elevated cerebral blood flow (CBF) in the right peri-Sylvian region (Figure 1C). While localizing to the clinically suspected MCA territory, the detection of hyperemia (in contrast to the expected finding of ischemic hypoperfusion), prompted a reassessment of the underlying etiology of her symptomatology. Significantly, the patient and her family noted that her symptom onset was temporally related to a severe headache. In addition, she reported prior similar episodes, each of which had prompted emergency department visits, extensive diagnostic workups (including the electroencephalographic exclusion of seizure), and multiple neuroimaging studies. Although prior MRIs were negative for acute infarct, they predated the inclusion of ASL perfusion, which represented the only imaging with an explanatory finding on the current presentation. Specifically, the increased CBF, coupled with a history of recurrent headaches and associated stereotypical symptoms, supported a diagnosis of hemiplegic migraine. CASE REPORT DISCUSSION An 88-year-old woman with paroxysmal atrial fibrillation, hypertension, hyperlipidemia, and a remote left thalamic lacunar infarct, presented with transient dysarthria and left-sided weakness. Given her medical history and significant symptomatology, a right middle cerebral artery (MCA) territory infarct was suspected. Initial brain computed tomography with angiography (CTA) (Figure 1A) demonstrated no arterial occlusion or stenosis. Magnetic resonance imaging (MRI) of the brain was Hemiplegic migraine is a known, but diagnostically challenging, stroke mimic, in which motor dysfunction is presumed to reflect the sequela of cortical spreading depression (15,16). Even when a history of headache is elicited, the exclusion of ischemia on clinical examination is difficult, and standard neuroimaging is often unrevealing or nonspecific. In addition, while there has long been appreciation of the potential alterations in CBF in Figure 1. Computed tomography (CT) and magnetic resonance imaging (MRI) obtained in the setting of suspected infarct. In this elderly patient with a history of paroxysmal atrial fibrillation and acute symptoms suggestive of right middle cerebral artery (MCA) stroke, oblique maximum intensity projection reconstruction of a brain CT angiogram (A) demonstrates no vessel occlusion or significant stenosis with a widely patent right MCA. MRI diffusion-weighted (B-1000) imaging demonstrates no evidence of acute infarct (B). Processed arterial spin labeled (ASL) color perfusion map demonstrates asymmetrically increased cerebral blood flow (CBF) in the right MCA territory (C, arrows). Coupled with a history of headache, exclusion of seizure by electroencephalography, and prior similar episodes, this suggests a diagnosis of hemiplegic migraine. (For reference, note that a right MCA stroke would typically be evident on CT angiogram with vessel stenosis or occlusion, on MRI with abnormal diffusion signal in infarcted parenchyma, and with decreased CBF ASL perfusion.) Arterial Spin Labeled Perfusion MRI the setting of migraine, initial reports described heterogeneous findings, depending on timing of imaging relative to headache/aura (17). More recently, several studies have assessed the pattern of cerebral perfusion on ASL MRI and have noted several specific findings, including areas of focal cortical hyperperfusion during migraine (18–20). This suggests a potentially valuable role for ASL in this setting. In our patient, CT, CTA, and standard MRI sequences demonstrated no acute finding to explain the patient’s dramatic symptomatology. The only sequence with a referable abnormality was ASL perfusion, which demonstrated focal increased perfusion in the right MCA territory (rather than low CBF, which would be expected in the setting of ischemia). Coupled with her reported headache and the electroencephalographic exclusion of seizure, this confirmed a diagnosis of hemiplegic migraine. ASL is a noninvasive technique that, unlike other perfusion studies, requires no contrast (see Supplementary Figure 1). Instead, the MR machine imparts a magnetic spin on blood traversing the neck. After a short delay to allow for intracranial arterial transit, this spin is detected as a subtle change in brain signal. The intensity difference between the post-labeling scan and a previously acquired baseline brain MRI is proportional to CBF (21). Depending on manufacturer and institutional capabilities, specific methods can be utilized to generate either relative qualitative or quantitative perfusion imaging to assess varied neuropathology. Its use in the setting of cerebrovascular disease is well established, and its inclusion in stroke imaging permits a thorough assessment for ischemia. Importantly, it allows for noncontrast assessment of perfusion–diffusion mismatch and, as in this case, can assist in diagnosing stroke mimics like seizure and migraine (22–24). It is imperative to note that MRI is not necessary prior to thrombolytic administration. However, as treatment options may be based on the concept of salvageable brain—rather than solely limited by strict timing—the ability to identify abnormally perfused, but not yet infarcted, brain becomes increasingly desirable. In this regard, ASL represents the main sequence in which a perfusion–diffusion mismatch can be calculated using noncontrast and nonirradiating technique. Depending on the parameters used in interpretation, studies have shown sensitivity and specificity of up to 92% and 85%, respectively, compared with contrasted perfusion technique (25). While ASL is not considered a first-line assessment before stroke treatment, it holds unique potential, as it can comprise a portion of a single noncontrasted MRI that can provide: 1) an assessment of penumbra through a comparison of perfusion and diffusion imaging; 2) a determination of completed infarct 3 through identification of the core tissue with restricted diffusion; 3) arterial vessel imaging using noncontrast time-of-flight MR angiography; 4) and a more thorough evaluation for other etiologies/mimics compared with CT scan. While ASL has been an established MR technique for more than 20 years, it has only recently become more widely used in the clinical setting (26). The inertia regarding its use stems, in part, from an overall lack of awareness of the technique outside of the neuroradiology community. A central motivation here is to introduce the technique to a group of clinicians who might otherwise be unaware of the potential benefits it can offer in everyday practice. Indeed, the desirability of incorporating this sequence into MR protocols is being emphasized in the radiology and stroke literature, with a recent consensus white paper providing practical guidelines for expanding its utilization and simplifying the technical and processing considerations associated with its use (26). The use of ASL in the emergency department setting carries significant potential advantages. For instance, as no contrast is required, a perfusion assessment can be performed in those with contrast allergies or renal impairment, which might preclude other methods of evaluation (21,24). Additionally, the placement of a dedicated i.v. capable of handling bolus contrast dosing is not needed (which would be of benefit for children and patients with difficult venous access). Unlike standard perfusion imaging methodologies, which require accurate timing of imaging relative to contrast administration, noncontrast ASL can be repeated. The parameters utilized to obtain perfusion imaging can also be adapted for those with known chronic cerebrovascular disease, including chronic steno-occlusive disease and those with unusual entities, such as moyamoya disease (27,28). The use of MR also avoids the relatively highdose radiation associated with CT perfusion. From a logistical standpoint, it should be noted that the sequence can simply be added to any given protocol, as long as contrast has not been administered and provided the patient can remain still within the scanner or is sedated. A standard, high-quality ASL sequence can be obtained in approximately 4 min under routine situations. Should expedited imaging be desired, a usable perfusion map can be obtained in approximately 2 min of scan time (26). While ASL is optimal at 3 Tesla, diagnostic imaging can be performed at 1.5 Tesla as well, increasing the number of facilities at which the sequence can be implemented. Arterial spin labeling can be technically challenging, particularly for institutions not yet accustomed to its use and cautious about initiating the novel protocol. However, MR manufacturers have increasingly recognized its desirability and can provide simplified paradigms or 4 instruction on its incorporation. At present, ASL sequences are available from all major MRI vendors, and it can be performed at either 3 or 1.5 Tesla (26,29). Radiologists are increasingly familiar with its use, and international guidelines to establish protocols are now readily accessible (26). Additionally, it should be noted that the ASL presented here was performed shortly after its incorporation at our facility, at a time when there was little institutional familiarity with the sequence. This particular example is also a relatively uncomplicated qualitative sequence. Nonetheless, it illustrates nicely the pathologic process in a manner in which multiple prior CT and MRIs could not. This patient now carries a diagnosis of hemiplegic migraine and is followed in the outpatient clinic setting. Her numerous prior ‘‘negative’’ examinations, acquired before our institution’s incorporation of ASL, illustrate the sequence’s potential diagnostic value in this setting. Its utilization can help optimize resource allocation— for instance, should this patient again present with similar symptoms, the initial ordered study might be a limited noncontrast MRI to exclude the presence of infarct (given her risk factors), while confirming a recurrent hemiplegic migraine by establishing the presence of stereotypical perfusion findings. While such a workup would not be appropriate for every patient, those with a lower risk for cerebrovascular disease (including young patients in whom minimizing radiation dose would be of benefit), those whose medical conditions that preclude other imaging (for instance, patients in acute renal failure in whom contrast should be avoided), and those with known alternative diagnoses, might particularly benefit from an MRI with ASL perfusion as the initial imaging study. While further research will help solidify the role of ASL in the assessment of stroke mimics, this case demonstrates its potential benefit in the treatment of a challenging subset of patients in the emergency department. M. U. Antonucci and M. Yazdani obvious abnormality on routine brain CT and MRI. This case demonstrates the utility of ASL perfusion imaging, which confirmed the migrainous etiology of the patient’s symptoms. This technique has a number of advantages, particularly in the assessment of emergent neuropathology. Its use in clinical imaging is continually expanding. In addition to migraines, ASL has been shown to have characteristic findings in patients with seizures and can help identify perfusion changes associated with tumors, hydrocephalus, and other scenarios in which patients with chronic neurologic pathology can present with acute exacerbations (21,23,30). More generally, it can be utilized in any scenario in which perfusion imaging is desired, and provides results that are consistent with standard contrasted perfusion studies, including dynamic susceptibility contrast-enhanced MRI (31). In addition, ASL can uncover pathologic perfusion abnormalities that are otherwise ‘‘silent’’ on standard imaging, including the hemiplegic migraine in this case, and perfusion abnormalities associated with imaging-negative transient ischemic attacks (32). However, to maximize the potential benefit of this sequence, radiologists must familiarize their clinical colleagues with its existence and advantages. Thus, this case represents an exemplary illustration of hemiplegic migraine presenting as a stroke mimic and, just as importantly, affords an opportunity to discuss ASL and its potential benefits in both this specific case and, more generally, in the emergency physician’s workup of varied neuropathology. SUPPLEMENTARY DATA Supplementary data related to this article can be found at https://doi.org/10.1016/j.jemermed.2019.12.019. REFERENCES WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? A large number of patients who present to the emergency department with signs and symptoms concerning for cerebral ischemia are ultimately diagnosed with a stroke mimic. This presents a significant challenge to the emergency physician who must rapidly assess the patient with a primary goal of prompt thrombolysis. While inadvertently treating a mimic carries relatively low risk, techniques to improve diagnostic accuracy can improve patient care, minimize complication, decrease overall cost, and optimize resource allocation. While some stroke mimics, such as a space-occupying lesion, are readily visible on standard imaging, migraines present a diagnostic challenge and are frequently without 1. Kochanek KD, Xu JQ, Murphy SL, Arias E. Mortality in the United States, 2013. NCHS Data Brief, No. 178. Hyattsville, MD: National Center for Health Statistics, Centers for Disease Control and Prevention, Department of Health and Human Services; 2014. 2. Mozzafarian D, Benjamin EJ, Go AS, et al., on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation 2016; 133:e38–360. 3. Benjamin EJ, Blaha MJ, Chiuve SE, et al., on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation 2017; 135:e229–445. 4. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–7. 5. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better stroke outcome: the NINDS rt-PA stroke study. Neurology 2000;55:1649–55. Arterial Spin Labeled Perfusion MRI 6. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11–20. 7. Merino JG, Luby M, Benson RT, et al. Predictors of acute stroke mimics in 8187 patients referred to a stroke service. J Stroke Cerebrovasc Dis 2013;22:e397–403. 8. Faiz KW, Labberton AS, Thommessen B, Rønning OM, Dahl FA, Barra M. The burden of stroke mimics: present and future projections. J Stroke Cerebrovasc Dis 2018;27:1288–95. 9. Long B, Koyfman A. Clinical mimics: an emergency medicinefocused review of stroke mimics. J Emerg Med 2017;52:176–83. 10. Hand PJ, Kwan J, Lindley RI, Dennis MS, Wardlaw JM. Distinguishing between stroke and mimic at the bedside: the brain attack study. Stroke 2006;37:769–75. 11. Nguyen PL, Chang JJ. Stroke mimics and acute stroke evaluation: clinical differentiation and complications after intravenous tissue plasminogen activator. J Emerg Med 2015;49:244–52. 12. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis. Stroke 2015;46:1281–7. 13. Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. Stroke 2013;44:1080–4. 14. Goyal N, Male S, Al Wafai A, Bellamkonda S, Zand R. Cost burden of stroke mimics and transient ischemic attack after intravenous tissue plasminogen activator treatment. J Stroke Cerebrovasc Dis 2015;24:828–33. 15. Ridolfi M, Granato A, Polverino P, et al. Migrainous aura as strokemimic: the role of perfusion-computed tomography. Clin Neurol Neurosurg 2018;166:131–5. 16. Tfelt-Hansen PC. History of migraine with aura and cortical spreading depression from 1941 and onwards. Cephalalgia 2010; 30:780–92. 17. Friberg L, Olesen J, Lassen NA, Olsen TS, Karle A. Cerebral oxygen extraction, oxygen consumption, and regional cerebral blood flow during the aura phase of migraine. Stroke 1994;25:974–9. 18. Kato Y, Araki N, Matsuda H, Ito Y, Suzuki C. Arterial spin-labeled MRI study of migraine attacks treated with rizatriptan. J Headache Pain 2010;11:255–8. 19. Wolf ME, Okazaki S, Eisele P, et al. Arterial pin labeling cerebral perfusion magnetic resonance imaging in migraine aura: an observational study. J Stroke Cerebrovasc Dis 2018;27:1262–6. 5 20. Pollock JM, Deibler AR, Burdette JH, et al. Migraine associated cerebral hyperperfusion with arterial spin-labeled MR imaging. AJNR Am J Neuroradiol 2008;29:1494–7. 21. Telischak NA, Detre JA, Zaharchuk G. Arterial spin labeling MRI: clinical applications in the brain. J Magn Reson Imaging 2015;41: 1165–80. 22. Zaharchuk G. Arterial spin-labeled perfusion imaging in acute ischemic stroke. Stroke 2014;45:1202–7. 23. Kim BS, Lee ST, Yun TJ, et al. Capability of arterial spin labeling MR imaging in localizing seizure focus in clinical seizure activity. Eur J Radiol 2016;85:1295–303. 24. Grade M, Hernandez Tamames JA, Pizzini FB, Achten E, Golay X, Smits M. A neuroradiologist’s guide to arterial spin labeling MRI in clinical practice. Neuroradiology 2015;57:1181–202. 25. Bivard A, Krishnamurthy V, Stanwell P, et al. Arterial spin labeling versus bolus-tracking perfusion in hyperacute stroke. Stroke 2014; 45:127–33. 26. Alsop DC, Detre JA, Golay X, et al. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: a consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia. Magn Reson Med 2014;73:102–16. 27. Wang R, Yu S, Alger JR, et al. Multi-delay arterial spin labeling perfusion MRI in moyamoya disease—comparison with CT perfusion imaging. Eur Radiol 2014;24:1135–44. 28. Fan AP, Guo J, Khalighi MM, et al. Long-delay arterial spin labeling provides more accurate cerebral blood flow measurements in moyamoya patients: a simultaneous positron emission tomography/MRI study. Stroke 2017;48:2441–9. 29. Mutsaerts HJ, van Osch MJ, Zelaya FO, et al. Multi-vendor reliability of arterial spin labeling perfusion MRI using a nearidentical sequence: implications for multi-center studies. Neuroimage 2015;113:143–52. 30. Yeom KW, Lober RM, Alexander A, Cheshier SH, Edwards MS. Hydrocephalus decreases arterial spin-labeled cerebral perfusion. AJNR Am J Neuroradiol 2014;35:1433–9. 31. Wang DJ, Alger JR, Qiao JX, et al. The value of arterial spin-labeled perfusion imaging in acute ischemic stroke: comparison with dynamic susceptibility contrast-enhanced MRI. Stroke 2012;43: 1018–24. 32. Qiao XJ, Salamon N, Wang DJ, et al. Perfusion deficits detected by arterial spin-labeling in patients with TIA with negative diffusion and vascular imaging. AJNR Am J Neuroradiol 2013;34:2125–30.