ISSN 0017-8748 doi: 10.1111/j.1526-4610.2011.01963.x Published by Wiley Periodicals, Inc. Headache © 2011 American Headache Society Brief Communication Hemiplegic Migraine Aura Begins With Cerebral Hypoperfusion: Imaging in the Acute Phase head_1963 1289..1296 Jakob M. Hansen, MD, PhD; Henrik W. Schytz, MD, PhD; Vibeke A. Larsen, MD, PhD; Helle K. Iversen, MD, DrMSc; Messoud Ashina, MD, PhD, DrMSc Imaging studies of spontaneous migraine aura have proved challenging because of the episodic and unpredictable nature of migraine attacks. Two patients with signs of acute ischemic stroke were evaluated for thrombolysis and turned out to suffer from familial hemiplegic migraine. It was possible to record the early phase of the hemiplegic aura with computed tomography with perfusion sequences and magnetic resonance imaging. We found cerebral hypoperfusion in the relevant cortical areas within the first hour after onset of aura symptoms. This report supports the concept that migraine aura across the migraine spectrum is caused by similar mechanisms. In a setting with efficient cooperation between headache and stroke neurologists, thrombolysis centers provide the set-up and opportunity to record aura symptoms at an early phase. Furthermore, in the time of ready access to acute systemic thrombolysis treatment, these cases underscore the importance of an accurate headache history, especially in younger patients. Key words: familial hemiplegic migraine, migraine aura, cortical spreading depression, magnetic resonance imaging, computed tomography (Headache 2011;51:1289-1296) INTRODUCTION Imaging studies of spontaneous migraine aura have proved challenging because of the episodic and Address all correspondence to J.M. Hansen, Danish Headache Center, Department of Neurology N01, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Nordre Ringvej 57, DK-2600 Glostrup, Copenhagen, Denmark, email: jmh@dadlnet.dk. unpredictable nature of migraine attacks. Two patients with signs of acute ischemic stroke were evaluated for thrombolysis and turned out to suffer from familial hemiplegic migraine. It was possible to record the early phase of the hemiplegic aura with computed tomography (CT) with perfusion sequences and magnetic resonance imaging (MRI). We found cerebral hypoperfusion in the relevant cortical areas within the first hour after onset of aura symptoms. This report supports the concept that migraine aura across the migraine spectrum is caused by similar mechanisms. In a setting with efficient cooperation between headache and stroke neurologists, thrombolysis centers provide the set-up and opportunity to record aura symptoms at an early phase. Furthermore, in the time of ready access to acute systemic thrombolysis Accepted for publication April 3, 2011. Conflict of Interest: None From Danish Headache Center, Department of Neurology, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (J.M. Hansen, H.W. Schytz, and M. Ashina); Glostrup Stroke Center, Department of Neurology, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (H.K. Iversen); Radiology and Functional Imaging Unit, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (V.A. Larsen). Patient confidentiality: All patients gave informed consent. 1289 1290 September 2011 NCCT CBF CBV Fig 1.—Non-contrast computed tomography (NCCT) and CT perfusion of patient 1 performed 70 minutes after onset of symptoms. NCCT shows no signs of infarcts. CT perfusion study performed with a 64 multi-detector CT scanner. Sixteen 5-mm slices were performed using 50 mL Iomeron 400 mg I/mL with an injection rate of 5 mL/second. The images show a perfusion defect in the right frontal lobe with decreased cerebral blood flow (CBF) and cerebral blood volume (CBV), indicating a vascular event in that region. treatment, these cases underscore the importance of an accurate headache history, especially in younger patients. CASE 1 A 33-year-old man, non-smoker, noted acute onset of anesthesia and paresthesia in the left part of the face and neck. After a few minutes, the symptoms spread to the left arm. Paramedics arrived 10 minutes later and noted reduced motor response of the left leg on ambulation. The patient was referred to the Stroke Center and arrived 55 minutes after onset of symptoms. On admission, the patient was alert and fully cooperative and reported aggravation of the paresthesia in the left part of the face and arm, but no headache. Physical examination revealed a discrete reduction in the motor response of the left arm and leg (strength 4 of 5), no dysarthria or aphasia (National Institutes of Health Stroke Scale [NIHSS] 1-2). The patient was cardiorespiratory stabile. In 2004, the patient was diagnosed with hemiplegic migraine. He described his usual hemiplegic attacks as acute right-sided migraine headache followed by a left-sided hemiparesis lasting up to 1 hour. The previous diagnostic work-up, including cerebral CT, MRI, lumbar puncture tab and ultrasound of the heart, revealed no pathology. The last attack was 6 years before the current admission. As the patient described a different quality to the symptoms than his previous attacks of hemiplegic migraine, he was taken to acute CT with perfusion sequences (Fig. 1). Computed tomography was performed 70 minutes after start of symptoms and showed a small perfusion defect in the right frontal lobe with increased cerebral blood volume (CBV), reduced cerebral blood flow (CBF), and increased mean transit time (MTT) (Fig. 1). Based on imaging, headache history and the gradual evaluation of symptoms, no thrombolysis was given. Ninety minutes after onset, the symptoms remitted gradually over 30 minutes. Approximately 3 hours after onset, the patient reported a bilateral mild and pressing headache (Intensity 2 on visual analog scale). The patient needed no analgesic treatment, and reported no nausea, photo, or phonophobia. Two days after ictus, the headache had resolved spontaneously. The MRI with diffusion and angio sequences 3 days after ictus showed no signs of stroke or other pathology. Ultrasound of the carotid arteries was normal. CASE 2 A 25-year-old non-smoking man noted foggy vision and dizziness quickly followed by acutely beginning anesthesia and paresthesia in the right hand spreading slowly proximally. After 10 minutes the patient noted aphasia and difficulties controlling Headache 1291 Fig 2.—Diffusion-weighted imaging and fluid-attenuated inversion recovery magnetic resonance imaging (MRI) performed 20 minutes after onset of symptoms in patient 2 is normal without signs of ischemia or infarct. MR perfusion measurement with time-to-peak map showing delayed arrival of the contrast bolus in the left occipitoparietal region. The measurement was performed on a 3T Philips scanner with the dynamic susceptibility contrast MRI. the right arm. The patient was near the hospital and was rushed there for an acute evaluation. Twenty minutes after start of symptoms, the patient underwent 3 Tesla dynamic susceptibility contrast MRI (Fig. 2). Magnetic resonance imaging showed normal diffusion and no signs of infarction; diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) were normal but MR perfusion showed increased time to peak (TTP) in an area posteriorly in the left hemisphere, indicating hypoperfusion in this area (Fig. 2). The aura symptoms gradually resolved within 20 minutes. Fifty minutes after start of symptoms, the patient reported left-sided headache, described as pressing and aggravated after physical strain, intensity 7 on visual analog scale.The headache was associated with photophobia only. The headache resolved spontaneously within 12 hours. The patient had never previously experienced similar episodes and only suffered from episodic tension-type headache less than 2 days per month. His mother, however, has had several similar episodes and had been diagnosed with hemiplegic migraine. DISCUSSION We describe 2 cases of spontaneous hemiplegic migraine aura, where imaging was carried out in the acute phase 20-70 minutes after symptom onset. We found signs of acute cerebral hypoperfusion similar to what has been reported in migraine with typical aura. Cortical spreading depression (CSD), described by Leão,1 has been linked to migraine aura pathogenesis in both observational,2 animal,3 and human studies.4-6 In patients with migraine with typical aura (MA), the regional cerebral blood flow (rCBF) has been measured during the aura by single-photon emission computed tomography (SPECT), MRI, and positron emission tomography (PET).7-9 During the aura, spreading oligemia moves from posterior to anterior brain areas,7-9 with a focal blood flow decrease of 16-53% compared with the symmetrical contralateral region.9-11 During the ensuing headache phase, regional CBF gradually changes from abnormally low to abnormally high without apparent parallel changes in headache,6 but the hyperperfusion often persists beyond the duration of the clinical headache.12 Cerebral imaging in the acute phase of the aura in MA show cerebral hypoperfusion.8,13,14 Most perfusion abnormalities have been reported in the occipital cortex, corresponding with visual aura symptoms, whereas aphasic aura is likely a symptom of CSD in the parietal lobe.14,15 Subtle differences in disease mechanisms may, however, exist across the migraine spectrum.16 Hemiplegic migraine is a rare subtype of migraine with transient hemiplegia during the aura phase.17 Hemiplegic migraine is a very rare disease with prevalence of 0.01%,18 and therefore imaging studies in these patients are mostly single cases. Most observations of spontaneous aura have been carried MR perfusion; day 1 MR perfusion; 47 hours MR perfusion; 1 week MR perfusion; day 2 MR perfusion, DWI; 6 hours SPECT; during the attack, ND SPECT; during the attack, ND MR perfusion, DWI; day 2 MR perfusion, DWI; during the attack, ND MRI; within the time limit for lytic therapy, timing not disclosed CT; on admission, ND CT; within the time limit for lytic therapy, timing not disclosed Hsu et al20 Masuzaki et al21 Jacob et al22 Oberndorfer et al23 Lindahl et al24 Friberg et al19 Cheng et al27 Yilmaz et al28 Altinok et al29 Chen et al30 Pettersen et al31 Mjaset and Russell26 Acute Imaging; Timing Reference Reduced perfusion Normal DWI normal Hypoperfusion, small area of restricted diffusion Hypoperfusion DWI normal During aura: hypoperfusion During headache: hyperperfusion Hypoperfusion, preceded by focal hyperperfusion Hyperperfusion DWI normal Hyperperfusion Hyperperfusion Hyperperfusion Hyperperfusion Perfusion 3 days SPECT; day 22 DWI; day 9 ND MR perfusion; 3 days MR perfusion, DWI; 12 months SPECT; 10 days ND MR perfusion; 4 days and 3 months MR perfusion; days 9 and 24 3 months MR perfusion; 1 month CT perfusion; days 6 and 14 Follow-Up; Timing Normal DWI DWI: ischemia without infarction SPECT: reduced perfusion ND Normal Near normal Normal ND Hyperperfusion; day 4 Normal follow-up at 3 months Hyperperfusion; day 9 Normal; day 24 Almost complete resolution Normal Hyperperfusion Perfusion Table.—Neuroimaging in Patients With Hemiplegic Migraine or Suspected Hemiplegic Migraine DWI 3 days after onset was normal Readmitted on day 55: MRI normal SPECT: reduced perfusion Evaluated for, but not given, thrombolysis — Diagnosed with “headache with neurological deficits and CSF lymphocytosis (HaNDL)” — Triggered by angiography — SPECT showed increased (day 2) and normal (day 24) tracer uptake — Initial imaging carried out during headache phase Two clonic seizures during admission Comment 1292 September 2011 DWI and MR perfusion: normal PET: reduced relative tracer uptake CT normal DWI high signal DWI; day 1 MR perfusion; day 2 PET; day 6 Contrast CT (1st visit); ND DWI (2nd visit); 3 weeks CTC; 1 hour DWI; 9 hours MRI, DWI; 48 hours MRA; 2 days MRI and MRA; 2 days Gutschalk et al33 Butteriss et al34 Toldo et al35 Kumar et al36 Gonzalez-Alegre & Tippin37 Barbour et al25 PET decrease cortical metabolic activity DWI normal SPECT on day 6 hypoperfusion of the left cerebral hemisphere compared with the right FLAIR; high signal throughout the cortex of the right cerebral hemisphere SPECT; hyperperfusion of the right cerebral hemisphere PET; 14 days SPECT; 14 days MRI-FLAIR; day 8 MRI, DWI; 5 days SPECT; 6 days MRA; 5 days SPECT; 13 days Diffuse cortical edema on FLAIR that was reduced at day 15; SPET on day 27; showed a marked hemispheric hypoperfusion MRA showed increased flow SPECT normal perfusion Normal Normal Normal DWI Diffuse cortical edema on FLAIR ND MRI on days 4,11 and 15; SPET on day 27; showed a marked left hemispheric hypoperfusion MRI (1st visit); day 6 MRI (2nd visit); 6 months DWI, MR perfusion; day 98 Day 10; MRI ND Left-sided hemiparesis. Patient 36 weeks pregnant Left-sided hemiparesis. Patient 38 weeks pregnant — SHM MRI and SPET at 6 months was normal Same patient examined on 2 episodes — SHM Two cases evaluated for, but not given, thrombolysis CSF = cerebrospinal fluid; CTC = computed tomography colonography; DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; ND = not described; PET = positron emission tomography; SHM = spontaneous hemiplegic migraine; SPECT = single-photon emission computed tomography; SPET = single-photon emission tomography; — = inconclusive results. Normal MRA normal DWI normal CT normal DWI normal MRA, DWI were normal MRA, DWI; not disclosed De Sanctis et al32 Hypoperfusion DWI normal MR perfusion, DWI; within the time limit for lytic therapy, timing not disclosed Kraus et al13 Headache 1293 1294 out over a large time span with respect to onset of symptoms. Cerebral blood flow studies during a hemiplegic aura provoked by angiography showed a spreading cortical hypoperfusion,19 similar to migraine with aura,10 which suggest that CSD is the most likely mechanism of hemiplegic aura.7,11 Most reports of spontaneous hemiplegic migraine aura, however, report cortical hyperperfusion,20-25 possibly because imaging in these patients has been carried out late in the aura phase, where blood flow is abnormally high (see also the Table). Reduced perfusion long after onset of symptoms26 and even hypoperfusion in the right thalamus during the aura phase with SPECT27 have been reported. In a case of headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) with left-sided deficits, MRI was performed 30 minutes after onset of symptoms and showed focal hypoperfusion in the brain regions corresponding to the focal neurological deficits.28 A recent paper reported cerebral hypoperfusion contralateral to the side of hemiplegic aura on perfusion MRI performed during the aura phase (timing, however, not disclosed).29 Concomitant susceptibilityweighted MRI showed prominent vessels in the left cerebral hemisphere, likely caused by venous stasis raising the possibility of stroke or vasculitis. In these 2 cases of spontaneous hemiplegic migraine attacks, the location of the perfusion defects in the relevant cortical areas may explain the clinical presentation with hemiplegia and aphasia (Figs. 1 and 2). Apart from the location, it seems that the cerebrovascular changes in hemiplegic migraine aura are similar to the aura of typical migraine. Both patients were evaluated for acute systemic thrombolysis treatment. Migraine aura is a wellknown differential diagnosis to stroke and because of the march of symptoms and taking into account the patient’s family and headache history, thrombolysis treatment was not indicated. CONCLUSION The 2 cases underscore the importance of an accurate headache history, especially in younger patients. In a streamlined set-up for admission and evaluation of stroke patients for thrombolysis, some September 2011 patients who actually suffer from migraine with aura will be referred. Given an efficient cooperation between headache and stroke neurologists, this offers unique opportunities to study the early aura phase. STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Jakob M. Hansen; Henrik W. Schytz; Vibeke A. Larsen; Helle K. Iversen; Messoud Ashina (b) Acquisition of Data Jakob M. Hansen; Vibeke A. Larsen (c) Analysis and Interpretation of Data Jakob M. Hansen; Henrik W. Schytz; Vibeke A. Larsen; Helle K. Iversen; Messoud Ashina Category 2 (a) Drafting the Article Jakob M. Hansen; Henrik W. Schytz; Messoud Ashina (b) Revising It for Intellectual Content Jakob M. Hansen; Henrik W. Schytz; Vibeke A. Larsen; Helle K. Iversen; Messoud Ashina Category 3 (a) Final Approval of the Completed Article Jakob M. Hansen; Henrik W. Schytz; Vibeke A. Larsen; Helle K. Iversen; Messoud Ashina REFERENCES 1. Leão AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7:359-390. 2. Milner PM. Note on a possible correspondence between the scotomas of migraine and spreading depression of Leao. Electroencephalogr Clin Neurophysiol Suppl. 1958;10:705. 3. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain. 1994;117: 199-210. 4. Lauritzen M, Skyhoj Olsen T, Lassen NA, Paulson OB. Changes in regional cerebral blood flow during the course of classic migraine attacks. Ann Neurol. 1983;13:633-641. 5. Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687-4692. Headache 6. Olesen J, Friberg L, Olsen TS, et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol. 1990;28: 791-798. 7. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9:344-352. 8. Woods RP, Iacoboni M, Mazziotta JC. Brief report: Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. 1994;331:1689-1692. 9. Cutrer FM, Sorensen AG, Weisskoff RM, et al. Perfusion-weighted imaging defects during spontaneous migrainous aura. Ann Neurol. 1998;43:25-31. 10. Sanchez del Rio M, Bakker D, Wu O, et al. Perfusion weighted imaging during migraine: Spontaneous visual aura and headache. Cephalalgia. 1999;19:701707. 11. Lauritzen M, Olesen J. Regional cerebral blood flow during migraine attacks by Xenon-133 inhalation and emission tomography. Brain. 1984;107:447-461. 12. Andersen AR, Friberg L, Olsen TS, Olesen J. Delayed hyperemia following hypoperfusion in classic migraine. Single photon emission computed tomographic demonstration. N Engl J Med. 1988;45: 154-159. 13. Kraus J, Golaszewski S, Luthringshausen G, et al. [Prolonged migrainous aura and acute ischemic insult. Differential diagnosis by diffusion- and perfusion-weighted cMRI]. Nervenarzt. 2007;78: 1420-1424. 14. Nieuwkamp DJ, van der Schaaf IC, Biessels GJ. Migraine aura presenting as dysphasia with global cognitive dysfunction and abnormalities on perfusion CT. Cephalalgia. 2010;30:1007-1009. 15. Linn J, Freilinger T, Morhard D, et al. Aphasic migraineous aura with left parietal hypoperfusion: A case report. Cephalalgia. 2007;27:850-853. 16. Hansen JM. Familial hemiplegic migraine. Dan Med Bull. 2010;57:B4183. 17. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(Suppl. 1):9-160. 18. Thomsen L, Eriksen M, Faerch Romer S, et al. An epidemiological survey of hemiplegic migraine. Cephalalgia. 2002;22:361-375. 19. Friberg L, Olsen TS, Roland PE, Lassen NA. Focal ischaemia caused by instability of cerebrovascular 1295 tone during attacks of hemiplegic migraine. A regional cerebral blood flow study. Brain. 1987;110: 917-934. 20. Hsu DA, Stafstrom CE, Rowley HA, et al. Hemiplegic migraine: Hyperperfusion and abortive therapy with intravenous verapamil. Brain Dev. 2008;30:8690. 21. Masuzaki M, Utsunomiya H, Yasumoto S, Mitsudome A. A case of hemiplegic migraine in childhood: Transient unilateral hyperperfusion revealed by perfusion MR imaging and MR angiography. AJNR Am J Neuroradiol. 2001;22: 1795-1797. 22. Jacob A, Mahavish K, Bowden A, et al. Imaging abnormalities in sporadic hemiplegic migraine on conventional MRI, diffusion and perfusion MRI and MRS. Cephalalgia. 2006;26:1004-1009. 23. Oberndorfer S, Wober C, Nasel C, et al. Familial hemiplegic migraine: Follow-up findings of diffusion-weighted magnetic resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAOSPECT in a patient with prolonged hemiplegic aura. Cephalalgia. 2004;24:533-539. 24. Lindahl AJ, Allder S, Jefferson D, et al. Prolonged hemiplegic migraine associated with unilateral hyperperfusion on perfusion weighted magnetic resonance imaging. J Neurol Neurosurg Psychiatry. 2002;73:202-203. 25. Barbour PJ, Castaldo JE, Shoemaker EI. Hemiplegic migraine during pregnancy: Unusual magnetic resonance appearance with SPECT scan correlation. Headache. 2001;41:310-316. 26. Mjaset C, Russell MB. Intravenous nimodipine worsening prolonged attack of familial hemiplegic migraine. J Headache Pain. 2008;9:381-384. 27. Cheng MF, Wu YW, Tang SC. Cerebral perfusion changes in hemiplegic migraine: Illustrated by Tc-99m ECD brain perfusion scan. Clin Nucl Med. 2010;35:456-458. 28. Yilmaz A, Kaleagasi H, Dogu O, et al. Abnormal MRI in a patient with “headache with neurological deficits and CSF lymphocytosis (HaNDL).” Cephalalgia. 2009;30:615-619. 29. Altinok D, Agarwal A, Ascadi G, et al. Pediatric hemiplegic migraine: Susceptibility weighted and MR perfusion imaging abnormality. Pediatr Radiol. 2010;40:1958-1961. 30. Chen Y, Bogosavljevic V, Leys D, et al. Intravenous thrombolytic therapy in patients with stroke mimics: Baseline characteristics and safety profile. Eur 1296 J Neurol. 2011; DOI: 10.1111/j.1468-1331.2011. 03367.x. 31. Pettersen JA, Aviv RI, Black SE, et al. Global hemispheric CT hypoperfusion may differentiate headache with associated neurological deficits and lymphocytosis from acute stroke. Stroke. 2008; 39:492-493. 32. De Sanctis S, Grieco GS, Breda L, et al. Prolonged sporadic hemiplegic migraine associated with a novel de novo missense ATP1A2 gene mutation. Headache. 2011;51:447-450. 33. Gutschalk A, Kollmar R, Mohr A, et al. Multimodal functional imaging of prolonged neurological deficits in a patient suffering from familial hemiplegic migraine. Neurosci Lett. 2002;332:115-118. September 2011 34. Butteriss DJ, Ramesh V, Birchall D. Serial MRI in a case of familial hemiplegic migraine. Neuroradiology. 2003;45:300-303. 35. Toldo I, Cecchin D, Sartori S, et al. Multimodal neuroimaging in a child with sporadic hemiplegic migraine: A contribution to understanding pathogenesis. Cephalalgia. 2011;31:751-756. 36. Kumar G, Topper L, Maytal J. Familial hemiplegic migraine with prolonged aura and multimodality imaging: A case report. Headache. 2009;49:139142. 37. Gonzalez-Alegre P, Tippin J. Prolonged cortical electrical depression and diffuse vasospasm without ischemia in a case of severe hemiplegic migraine during pregnancy. Headache. 2003;43:72-75.