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Pontine Warning Syndrome: Case Series and Review of Literature
Pontine Warning Syndrome: Case Series and Review of Literature Sombat Muengtaweepongsa, MD,* Niranjan N. Singh, MD, DM,† and Salvador Cruz-Flores, MD‡
Crescendo transient ischemic attacks (TIAs) are defined as repeated frequent shortlasting episodes of focal neurologic deficit due to cerebral ischemia. The capsular warning syndrome, a subset of crescendo TIA, consists of repetitive episodes of motor dysfunction due to ischemia in the region of internal capsule. It is not clear that patients with ischemia in the pons can have a similar clinical presentation and course. We report 11 cases presenting with crescendo TIA in the form of pure motor hemiparesis or ataxic hemiparesis that later proved to have a paramedian pontine infarct. The presumed mechanism of these infarcts is penetrating basilar artery branch occlusion at their origin, also called basilar branch disease. Key Words: Pontine warning syndrome—capsular warning syndrome—paramedian pontine infarction—basilar branch disease—motor fluctuation. Ó 2010 by National Stroke Association
Crescendo transient ischemic attacks are defined as repeated frequent short-lasting episodes of focal neurologic deficit due to cerebral ischemia.1 The capsular warning syndrome (CWS), a subset of crescendo transient ischemic attack, consists of repetitive episodes of motor dysfunction due to ischemia in the region of internal capsule. In the original case series of CWS, 42% of cases had subsequent capsular infarcts demonstrated by computed tomography (CT).2 Ischemia involving pyramidal tract below the capsule was postulated as an alternative site in those with negative CT scan results. With the advent of magnetic resonance (MR) imaging (MRI), there are now few reports of cases presenting with CWS that proved to have a pontine infarct.3-6 All those cases had From the *Division of Neurology, Department of Medicine, Thammasat University, Bangkok, Thailand; †Department of Neurology, University of Missouri, Columbia; and ‡Souers Stroke Institute, Department of Neurology and Psychiatry, Saint Louis University School of Medicine. Received March 30, 2009; revision received May 31, 2009; accepted June 16, 2009. Address correspondence to Sombat Muengtaweepongsa, MD, Division of Neurology, Department of Medicine, Thammasat University, Raugsit Campus, Paholyothin Rd., Klonglaung Pathaam Thani, Thailand 12120. 1052-3057/$ - see front matter Ó 2010 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2009.06.008
a paramedian pontine infarct that is characterized by extension of the lesion to the basal surface. The presumed mechanism of these infarcts is penetrating basilar artery branch occlusion at their origin, also called basilar branch disease.7-14 These cases with paramedian pontine infarct show certain uniformity in their clinical presentation and resemble the original CWS. We report 11 patients who presented with CWS in whom the MRI showed a paramedian pontine infarct. Given the location of the final lesion we name the clinical presentation ‘‘pontine warning syndrome.’’
Methods We reviewed the medical records and neuroimaging studies of 11 consecutive patients admitted to the stroke unit at Saint Louis University Hospital between 2004 and 2007 with the CWS and pontine infarction. We sought to describe the clinical features, course, and neuroimaging characteristics.
Results We identified 11 patients (5 men), mean age 62 years (42-89) (Table 1). Seven of them were African American. Five patients presented with dysarthria and pure motor hemiparesis, 3 with dysarthria and ataxic hemiparesis,
Journal of Stroke and Cerebrovascular Diseases, Vol. 19, No. 5 (September–October), 2010: pp 353-356
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Table 1. Baseline and symptom characteristics of patients
Case 1 2 3 4 5 6 7 8 9 10 11
Age (y)/sex
Risk factors
Clinical features
50/F 42/F 79/M 62/F 58/M 88/M 61/F 76/F 44/M 51/F 71/M
HTN, DM, TIA HTN, DM, HLP HTN, CAD HTN, DM, CAD HTN, HLP HTN HTN, DM HTN HTN HTN HTN, DM, HLP
AH PMH, dysarthria PMH, dysarthria AH, dysarthria AH AH, dysarthria PMH PMH, dysarthria PMH, dysarthria PMH, dysarthria AH, dysarthria
Period of symptomatic fluctuation, d
Frequency of symptomatic fluctuation
Worsening with head-up position
7 4 3 5 1 3 5 4 1 2 2
4-15/d 3-4/d 2-3/d 2-5/d 4/d .3/d 2-3/d 1-3/d 10/d 1-2/d 1-2/d
Yes No No No Yes No Yes No No No No
Abbreviations: AH, ataxic hemiparesis; CAD, coronary artery disease; DM, diabetes mellitus; F, female; HLP, hyperlipidemia; HTN, hypertension; M, male; PMH, pure motor hemiparesis; TIA, transient ischemic attack.
two with ataxic hemiparesis only, and one patient with pure motor hemiparesis only. All patients had hypertension, 4 had diabetes, and 3 had hyperlipidemia. Six patients were current smokers. During the period of fluctuation, the symptoms were similar to those leading to the initial presentation. All patients were symptom free between each episode. The period of symptomatic fluctuation lasted from 1 to 7 days. The typical duration of the symptoms was less than 1 hour. The frequency of symptomatic fluctuation ranged from 1 to 14 episodes per day. Three patients had worsening of the symptoms with head-up position (Table 1). MRI showed a paramedian pontine infarction by diffusion-weighted imaging (DWI) and apparent diffusion coefficient in all patients. Six patients had their MRI during the episode of symptomatic fluctuation. MR angiography showed some degree of basilar artery stenosis in two patients and dolichoectasia of basilar artery in 3 patients (Fig 1). All patients were treated with antiplatelet agents. Two patients treated with volume expansion, Trendelenburg position, and dual antiplatelet agents with aspirin and clopidogrel did not develop hemiplegia. No patient was treated with vasopressor or high-dose statin. One patient received intravenous thrombolysis without resolution of the symptomatic fluctuation; the patient developed permanent hemiplegia 24 hours later.
Discussion In the original case series of the CWS, the diagnosis was made by the typical clinical features and the associated capsular infarction demonstrated by brain CT. However, brain CT failed to identify the capsular infarct in about 60% of patients. Pontine location was postulated in those with negative CT results.2 The hypothesis was later supported by case reports of pontine infraction demonstrated
by MRI in patients presenting with CWS.3-6 The pontine location of the lesions led to the name ‘‘pontine warning syndrome.’’5 Our case series adds to the current literature and emphasizes the pontine location of the lesion in patients presenting with CWS. It could be argued that the pontine location is as common as or more common than the capsular location. Patients with pontine infarction sometimes present with progressive motor deficit.15-17 Our case series probably represents a subset of patients with stroke with a fluctuating course. They showed a remarkable uniformity of clinical pattern such that the symptomatic fluctuation is possibly an important clinical feature of this stroke subtype. It is clear that the clinical findings could not definitely distinguish between CWS and pontine warning syndrome. Paramedian pontine infarction probably results from an occlusion of a penetrating branch from the basilar artery at their origin known as basilar branch disease.7-9 The diagnosis of basilar branch disease is usually made by the exclusion of large artery stenosis or a cardiac source of emboli.10-12 However, high-resolution MRI might be able to identify basilar artery plaque at the origin of basilar artery branch.13 The cause of basilar artery branch occlusion is usually atherosclerosis and differs from lipohyalinosis that typically leads to lacunar infarct, which is an isolated ‘‘island’’ infarction far from the basal surface of the pons.8,18 The occlusion at the penetrating branch at its origin likely explains infarct extension to the surface.9,19 Interestingly, although DWI restriction is said to represent irreversible tissue damage and thus permanent neurologic deficit,20,21 DWI restriction was demonstrated in some patients during the symptomatic fluctuation that was followed by improvement. This finding suggests that DWI restriction may not always indicate irreversible injury.22
PONTINE WARNING SYNDROME
Figure 1.
355
DWI, Apparent diffusion coefficient (ADC), and MR angiography (MRA) of all 11 cases.
The worsening of symptoms in head-up position in some of our patients suggests hemodynamic failure that is further supported by the clinical observation that induced hypertension, Trendelenburg, and volume expansion has helped some patients.23-26 However, this claim can only raise questions that need to be answered in a clinical trial. In summary, we presented a case series of pontine warning syndrome, a clinical phenomenon likely resulting from hemodynamic failure due to penetrating branch
artery occlusion resulting in a fluctuating clinical course frequently ending with a fixed deficit and that awaits definite therapy.
References 1. Rothrock JF, Lyden PD, Yee J, et al. ‘Crescendo’ transient ischemic attacks: Clinical and angiographic correlations. Neurology 1988;38:198-201.
356 2. Donnan GA, O’Malley HM, Quang L, et al. The capsular warning syndrome: Pathogenesis and clinical features. Neurology 1993;43:957-962. 3. Farrar J, Donnan GA. Capsular warning syndrome preceding pontine infarction. Stroke 1993;24:762. 4. Oliveira-Filho J, Ay H, Koroshetz WJ, et al. Localization of clinical syndromes using DWI: Two examples of the ‘‘capsular’’ warning syndrome. J Neuroimaging 2001;11:44-47. 5. Benito-Leon J, Alvarez-Linera J, Porta-Etessam J. Detection of acute pontine infarction by diffusion-weighted MRI in capsular warning syndrome. Cerebrovasc Dis 2001;11:350-351. 6. Staaf G, Geijer B, Lindgren A, et al. Diffusion-weighted MRI findings in patients with capsular warning syndrome. Cerebrovasc Dis 2004;17:1-8. 7. Fisher CM, Caplan LR. Basilar artery branch occlusion: A cause of pontine infarction. Neurology 1971;21:900-905. 8. Caplan LR. Intracranial branch atheromatous disease: A neglected, understudied, and underused concept. Neurology 1989;39:1246-1250. 9. Toyoda K, Saku Y, Ibayashi S, et al. Pontine infarction extending to the basal surfaces. Stroke 1994;25:2171-2178. 10. Bogousslavsky J, Regli F, Maeder P, et al. The etiology of posterior circulation infarcts: A prospective study using magnetic resonance imaging and magnetic resonance angiography. Neurology 1993;43:1528-1533. 11. Kumral E, Bayulkem G, Evyapan D. Clinical spectrum of pontine infarction: Clinical-MRI correlations. J Neurol 2002;249:1659-1670. 12. Kataoka S, Hori A, Shirakawa T, et al. Paramedian pontine infarction: Neurological/topographical correlation. Stroke 1997;28:809-815. 13. Klein IF, Lavallee PC, Schouman-Claeys E, et al. Highresolution MRI identifies basilar artery plaques in paramedian pontine infarct. Neurology 2005;64:551-552. 14. Kim JS, Lee JH, Im JH, et al. Syndromes of pontine base infarction: A clinical-radiological correlation study. Stroke 1995;26:950-955.
S. MUENGTAWEEPONGSA ET AL. 15. Kaps M, Klostermann W, Wessel K, et al. Basilar branch disease presenting with progressive pure motor stroke. Acta Neurol Scand 1997;96:324-327. 16. Kunz S, Griese H, Busse O. Etiology and long-term prognosis of unilateral paramedian pontine infarction with progressive symptoms. Eur Neurol 2003;50:136-140. 17. Fisher CM. The ‘‘herald hemiparesis’’ of basilar artery occlusion. Arch Neurol 1988;45:1301-1303. 18. Helgason CM, Wilbur AC. Basilar branch pontine infarction with prominent sensory signs. Stroke 1991;22:1129-1136. 19. Montaner J, Molina C, Alvarez-Sabin J, et al. ‘‘Herald hemiparesis’’ of basilar artery occlusion: Early recognition by transcranial Doppler ultrasound. Eur J Neurol 2000;7:91-93. 20. Wiener JI, King JT Jr, Moore JR, et al. The value of diffusion-weighted imaging for prediction of lasting deficit in acute stroke: An analysis of 134 patients with acute neurologic deficits. Neuroradiology 2001;43: 435-411. 21. Oppenheim C, Lamy C, Touze E, et al. Do transient ischemic attacks with diffusion-weighted imaging abnormalities correspond to brain infarctions? AJNR Am J Neuroradiol 2006;27:1782-1787. 22. Donnan GA, O’Malley HM, Quang L, et al. The capsular warning syndrome: The high risk of early stroke. Cerebrovasc Dis 1996;6:202-207. 23. Schwarz S, Georgiadis D, Aschoff A, et al. Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke. Stroke 2002; 33:497-501. 24. Wojner-Alexander AW, Garami Z, Chernyshev OY, et al. Heads down: Flat positioning improves blood flow velocity in acute ischemic stroke. Neurology 2005;64:1354-1357. 25. Hillis AE, Ulatowski JA, Barker PB, et al. A pilot randomized trial of induced blood pressure elevation: Effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis 2003;16:236-246. 26. Belayev L, Pinard E, Nallet H, et al. Albumin therapy of transient focal cerebral ischemia: In vivo analysis of dynamic microvascular responses. Stroke 2002;33:1077-1084.
Crescendo transient ischemic attacks (TIAs) are defined as repeated frequent shortlasting episodes of focal neurologic deficit due to cerebral ischemia. The capsular warning syndrome, a subset of crescendo TIA, consists of repetitive episodes of motor dysfunction due to ischemia in the region of internal capsule. It is not clear that patients with ischemia in the pons can have a similar clinical presentation and course. We report 11 cases presenting with crescendo TIA in the form of pure motor hemiparesis or ataxic hemiparesis that later proved to have a paramedian pontine infarct. The presumed mechanism of these infarcts is penetrating basilar artery branch occlusion at their origin, also called basilar branch disease. Key Words: Pontine warning syndrome—capsular warning syndrome—paramedian pontine infarction—basilar branch disease—motor fluctuation. Ó 2010 by National Stroke Association
Crescendo transient ischemic attacks are defined as repeated frequent short-lasting episodes of focal neurologic deficit due to cerebral ischemia.1 The capsular warning syndrome (CWS), a subset of crescendo transient ischemic attack, consists of repetitive episodes of motor dysfunction due to ischemia in the region of internal capsule. In the original case series of CWS, 42% of cases had subsequent capsular infarcts demonstrated by computed tomography (CT).2 Ischemia involving pyramidal tract below the capsule was postulated as an alternative site in those with negative CT scan results. With the advent of magnetic resonance (MR) imaging (MRI), there are now few reports of cases presenting with CWS that proved to have a pontine infarct.3-6 All those cases had From the *Division of Neurology, Department of Medicine, Thammasat University, Bangkok, Thailand; †Department of Neurology, University of Missouri, Columbia; and ‡Souers Stroke Institute, Department of Neurology and Psychiatry, Saint Louis University School of Medicine. Received March 30, 2009; revision received May 31, 2009; accepted June 16, 2009. Address correspondence to Sombat Muengtaweepongsa, MD, Division of Neurology, Department of Medicine, Thammasat University, Raugsit Campus, Paholyothin Rd., Klonglaung Pathaam Thani, Thailand 12120. 1052-3057/$ - see front matter Ó 2010 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2009.06.008
a paramedian pontine infarct that is characterized by extension of the lesion to the basal surface. The presumed mechanism of these infarcts is penetrating basilar artery branch occlusion at their origin, also called basilar branch disease.7-14 These cases with paramedian pontine infarct show certain uniformity in their clinical presentation and resemble the original CWS. We report 11 patients who presented with CWS in whom the MRI showed a paramedian pontine infarct. Given the location of the final lesion we name the clinical presentation ‘‘pontine warning syndrome.’’
Methods We reviewed the medical records and neuroimaging studies of 11 consecutive patients admitted to the stroke unit at Saint Louis University Hospital between 2004 and 2007 with the CWS and pontine infarction. We sought to describe the clinical features, course, and neuroimaging characteristics.
Results We identified 11 patients (5 men), mean age 62 years (42-89) (Table 1). Seven of them were African American. Five patients presented with dysarthria and pure motor hemiparesis, 3 with dysarthria and ataxic hemiparesis,
Journal of Stroke and Cerebrovascular Diseases, Vol. 19, No. 5 (September–October), 2010: pp 353-356
353
S. MUENGTAWEEPONGSA ET AL.
354
Table 1. Baseline and symptom characteristics of patients
Case 1 2 3 4 5 6 7 8 9 10 11
Age (y)/sex
Risk factors
Clinical features
50/F 42/F 79/M 62/F 58/M 88/M 61/F 76/F 44/M 51/F 71/M
HTN, DM, TIA HTN, DM, HLP HTN, CAD HTN, DM, CAD HTN, HLP HTN HTN, DM HTN HTN HTN HTN, DM, HLP
AH PMH, dysarthria PMH, dysarthria AH, dysarthria AH AH, dysarthria PMH PMH, dysarthria PMH, dysarthria PMH, dysarthria AH, dysarthria
Period of symptomatic fluctuation, d
Frequency of symptomatic fluctuation
Worsening with head-up position
7 4 3 5 1 3 5 4 1 2 2
4-15/d 3-4/d 2-3/d 2-5/d 4/d .3/d 2-3/d 1-3/d 10/d 1-2/d 1-2/d
Yes No No No Yes No Yes No No No No
Abbreviations: AH, ataxic hemiparesis; CAD, coronary artery disease; DM, diabetes mellitus; F, female; HLP, hyperlipidemia; HTN, hypertension; M, male; PMH, pure motor hemiparesis; TIA, transient ischemic attack.
two with ataxic hemiparesis only, and one patient with pure motor hemiparesis only. All patients had hypertension, 4 had diabetes, and 3 had hyperlipidemia. Six patients were current smokers. During the period of fluctuation, the symptoms were similar to those leading to the initial presentation. All patients were symptom free between each episode. The period of symptomatic fluctuation lasted from 1 to 7 days. The typical duration of the symptoms was less than 1 hour. The frequency of symptomatic fluctuation ranged from 1 to 14 episodes per day. Three patients had worsening of the symptoms with head-up position (Table 1). MRI showed a paramedian pontine infarction by diffusion-weighted imaging (DWI) and apparent diffusion coefficient in all patients. Six patients had their MRI during the episode of symptomatic fluctuation. MR angiography showed some degree of basilar artery stenosis in two patients and dolichoectasia of basilar artery in 3 patients (Fig 1). All patients were treated with antiplatelet agents. Two patients treated with volume expansion, Trendelenburg position, and dual antiplatelet agents with aspirin and clopidogrel did not develop hemiplegia. No patient was treated with vasopressor or high-dose statin. One patient received intravenous thrombolysis without resolution of the symptomatic fluctuation; the patient developed permanent hemiplegia 24 hours later.
Discussion In the original case series of the CWS, the diagnosis was made by the typical clinical features and the associated capsular infarction demonstrated by brain CT. However, brain CT failed to identify the capsular infarct in about 60% of patients. Pontine location was postulated in those with negative CT results.2 The hypothesis was later supported by case reports of pontine infraction demonstrated
by MRI in patients presenting with CWS.3-6 The pontine location of the lesions led to the name ‘‘pontine warning syndrome.’’5 Our case series adds to the current literature and emphasizes the pontine location of the lesion in patients presenting with CWS. It could be argued that the pontine location is as common as or more common than the capsular location. Patients with pontine infarction sometimes present with progressive motor deficit.15-17 Our case series probably represents a subset of patients with stroke with a fluctuating course. They showed a remarkable uniformity of clinical pattern such that the symptomatic fluctuation is possibly an important clinical feature of this stroke subtype. It is clear that the clinical findings could not definitely distinguish between CWS and pontine warning syndrome. Paramedian pontine infarction probably results from an occlusion of a penetrating branch from the basilar artery at their origin known as basilar branch disease.7-9 The diagnosis of basilar branch disease is usually made by the exclusion of large artery stenosis or a cardiac source of emboli.10-12 However, high-resolution MRI might be able to identify basilar artery plaque at the origin of basilar artery branch.13 The cause of basilar artery branch occlusion is usually atherosclerosis and differs from lipohyalinosis that typically leads to lacunar infarct, which is an isolated ‘‘island’’ infarction far from the basal surface of the pons.8,18 The occlusion at the penetrating branch at its origin likely explains infarct extension to the surface.9,19 Interestingly, although DWI restriction is said to represent irreversible tissue damage and thus permanent neurologic deficit,20,21 DWI restriction was demonstrated in some patients during the symptomatic fluctuation that was followed by improvement. This finding suggests that DWI restriction may not always indicate irreversible injury.22
PONTINE WARNING SYNDROME
Figure 1.
355
DWI, Apparent diffusion coefficient (ADC), and MR angiography (MRA) of all 11 cases.
The worsening of symptoms in head-up position in some of our patients suggests hemodynamic failure that is further supported by the clinical observation that induced hypertension, Trendelenburg, and volume expansion has helped some patients.23-26 However, this claim can only raise questions that need to be answered in a clinical trial. In summary, we presented a case series of pontine warning syndrome, a clinical phenomenon likely resulting from hemodynamic failure due to penetrating branch
artery occlusion resulting in a fluctuating clinical course frequently ending with a fixed deficit and that awaits definite therapy.
References 1. Rothrock JF, Lyden PD, Yee J, et al. ‘Crescendo’ transient ischemic attacks: Clinical and angiographic correlations. Neurology 1988;38:198-201.
356 2. Donnan GA, O’Malley HM, Quang L, et al. The capsular warning syndrome: Pathogenesis and clinical features. Neurology 1993;43:957-962. 3. Farrar J, Donnan GA. Capsular warning syndrome preceding pontine infarction. Stroke 1993;24:762. 4. Oliveira-Filho J, Ay H, Koroshetz WJ, et al. Localization of clinical syndromes using DWI: Two examples of the ‘‘capsular’’ warning syndrome. J Neuroimaging 2001;11:44-47. 5. Benito-Leon J, Alvarez-Linera J, Porta-Etessam J. Detection of acute pontine infarction by diffusion-weighted MRI in capsular warning syndrome. Cerebrovasc Dis 2001;11:350-351. 6. Staaf G, Geijer B, Lindgren A, et al. Diffusion-weighted MRI findings in patients with capsular warning syndrome. Cerebrovasc Dis 2004;17:1-8. 7. Fisher CM, Caplan LR. Basilar artery branch occlusion: A cause of pontine infarction. Neurology 1971;21:900-905. 8. Caplan LR. Intracranial branch atheromatous disease: A neglected, understudied, and underused concept. Neurology 1989;39:1246-1250. 9. Toyoda K, Saku Y, Ibayashi S, et al. Pontine infarction extending to the basal surfaces. Stroke 1994;25:2171-2178. 10. Bogousslavsky J, Regli F, Maeder P, et al. The etiology of posterior circulation infarcts: A prospective study using magnetic resonance imaging and magnetic resonance angiography. Neurology 1993;43:1528-1533. 11. Kumral E, Bayulkem G, Evyapan D. Clinical spectrum of pontine infarction: Clinical-MRI correlations. J Neurol 2002;249:1659-1670. 12. Kataoka S, Hori A, Shirakawa T, et al. Paramedian pontine infarction: Neurological/topographical correlation. Stroke 1997;28:809-815. 13. Klein IF, Lavallee PC, Schouman-Claeys E, et al. Highresolution MRI identifies basilar artery plaques in paramedian pontine infarct. Neurology 2005;64:551-552. 14. Kim JS, Lee JH, Im JH, et al. Syndromes of pontine base infarction: A clinical-radiological correlation study. Stroke 1995;26:950-955.
S. MUENGTAWEEPONGSA ET AL. 15. Kaps M, Klostermann W, Wessel K, et al. Basilar branch disease presenting with progressive pure motor stroke. Acta Neurol Scand 1997;96:324-327. 16. Kunz S, Griese H, Busse O. Etiology and long-term prognosis of unilateral paramedian pontine infarction with progressive symptoms. Eur Neurol 2003;50:136-140. 17. Fisher CM. The ‘‘herald hemiparesis’’ of basilar artery occlusion. Arch Neurol 1988;45:1301-1303. 18. Helgason CM, Wilbur AC. Basilar branch pontine infarction with prominent sensory signs. Stroke 1991;22:1129-1136. 19. Montaner J, Molina C, Alvarez-Sabin J, et al. ‘‘Herald hemiparesis’’ of basilar artery occlusion: Early recognition by transcranial Doppler ultrasound. Eur J Neurol 2000;7:91-93. 20. Wiener JI, King JT Jr, Moore JR, et al. The value of diffusion-weighted imaging for prediction of lasting deficit in acute stroke: An analysis of 134 patients with acute neurologic deficits. Neuroradiology 2001;43: 435-411. 21. Oppenheim C, Lamy C, Touze E, et al. Do transient ischemic attacks with diffusion-weighted imaging abnormalities correspond to brain infarctions? AJNR Am J Neuroradiol 2006;27:1782-1787. 22. Donnan GA, O’Malley HM, Quang L, et al. The capsular warning syndrome: The high risk of early stroke. Cerebrovasc Dis 1996;6:202-207. 23. Schwarz S, Georgiadis D, Aschoff A, et al. Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke. Stroke 2002; 33:497-501. 24. Wojner-Alexander AW, Garami Z, Chernyshev OY, et al. Heads down: Flat positioning improves blood flow velocity in acute ischemic stroke. Neurology 2005;64:1354-1357. 25. Hillis AE, Ulatowski JA, Barker PB, et al. A pilot randomized trial of induced blood pressure elevation: Effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis 2003;16:236-246. 26. Belayev L, Pinard E, Nallet H, et al. Albumin therapy of transient focal cerebral ischemia: In vivo analysis of dynamic microvascular responses. Stroke 2002;33:1077-1084.