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The 2015 International Stroke Conference

September 2015

By Ben Best

A stroke is characterized by a blocked or broken blood vessel in the brain or carotid artery and is a major cause of physical disability, dementia, and death.1

With improvements in the quality of medical care, stroke death rates have declined since 1990, but stroke-related disabilities have increased 40%.2

More than one-third of those who have a stroke after age 80 become demented as a consequence.1 Roughly half of surviving stroke victims have difficulty swallowing or suffer fecal incontinence,3 and more than one-tenth experience seizures within five years.4 Urinary tract infections3 and pneumonia5 commonly occur in stroke survivors as well.

Most stroke survivors have difficulty grasping and manipulating objects,6,7 and many require assistance with basic daily activities due to having trouble walking or impaired vision, which can lead to falls (nearly a quarter of stroke survivors suffer falls).8,9 Intriguingly, a pooled analysis of data from several studies suggested that vitamin D supplementation might reduce falls in some stroke survivors, possibly by increasing muscle strength.10

The 2015 International Stroke Conference  

Stroke is classified as either an ischemic or hemorrhagic stroke.

Ischemic stroke accounts for about 85% of strokes11,12 and is caused by blockage of a blood vessel, preventing or severely reducing blood flow in the brain. Blood vessel blockage is typically caused by narrowing and hardening of arteries due to atherosclerosis, or blockage of a blood vessel by a blood clot or dislodged piece of atherosclerotic plaque.13

Up to 15% of strokes are hemorrhagic,12 in which a blood vessel in the brain has burst or broken. Hemorrhagic strokes are fatal much more often than ischemic strokes.14

The most effective treatment for ischemic stroke is the clot-dissolving medication tissue-type plasminogen activator (tPA) and clot-removing intra-arterial surgical procedures, which should be initiated promptly. The therapeutic benefit of tPA is greatest when administered within three- to four-and-a-half hours after ischemic stroke onset.15 However, tPA is often not given because prompt CT or MRI diagnostics are not provided to rule out hemorrhagic stroke.16 Intra-arterial clot removing devices have shown efficacy as long as 12 hours after onset of stroke symptoms.

High blood pressure is the greatest risk factor for stroke,17 and stroke risk increases sharply as blood pressure exceeds 115/75 mm Hg.18,19 It is especially important for aging individuals to avoid high blood pressure and take steps to maintain good vascular health, as more than two-thirds of strokes occur in those over age 65.20

Life Extension® has outlined a variety of important strategies for reducing stroke risk in our Disease Prevention and Treatment protocols: Stroke, Atherosclerosis and Cardiovascular Disease, and Blood Pressure Management.

This article will summarize some of the most interesting discussions and presentations from the International Stroke Conference held in Nashville, Tennessee, February 11-13, 2015.

White Matter Hyperintensities

Dufouil
Dufouil

Carole Dufouil, PhD, (Epidemiologist, National Institute of Health and Medical Research, Paris, France) spoke about the prevalence of various brain afflictions related to stroke.

Visualization of blood vessels in the brain with modern medical imaging equipment has revealed blockage of blood vessels even when there are no overt symptoms of stroke. Between the ages of 50 and 75, the incidence of these “silent infarcts” increases from about 5 to 20%.21

The brain consists of both gray matter (neurons, axons, dendrites, synapses) and white matter (myelin coverings of axons that facilitate communication between neurons).22 Areas of the brain that have a concentration of lines of communication between neurons are dominated by white matter.23

Imaging of the brain has revealed bright areas in the white matter described as white matter hyperintensities, which are thought to be due to various abnormalities.24 Over a four-year period, persons with severe white matter hyperintensities are over eight times more likely to suffer severe cognitive deterioration than those with no white matter hyperintensities.25 White matter hyperintensities are predictive of both Alzheimer’s disease and stroke.26-29 Because white matter hyperintensities can be so reliably quantified, they can serve as a means of assessing the effectiveness of treatments for stroke or dementia.28 Lowering blood pressure has been shown to slow the progression of white matter hyperintensities.30

The March 2014 issue of this publication described in detail the effects of white matter hyperintensities and ways to minimize them that include getting more physical activity and lowering homocysteine. The title of this article is “Leukoaraiosis: A Hidden Cause of Brain Aging.” Leukoaraiosis is the medical term used to describe white matter hyperintensities in the brain.

Stroke And Infection Risk

Veltkamp
Veltkamp

Roland Veltkamp, MD, (Professor, Imperial College London, England) discussed infection resulting from stroke.

Immediately after a stroke, high levels of inflammatory proteins and cells are present, but within four days there is a profound suppression of the immune system.31 The size of the stroke corresponds to the amount by which the immune system is suppressed.32

Suppression of the immune system is due to massive release of corticosterone and related hormones.33,34 One result is that stroke victims often suffer from urinary tract infections, and pneumonia contributes to the death of many stroke survivors.34,35 A very large study of stroke victims showed an infection rate of 30%, but for stroke victims in the intensive care unit, the infection rate was 45%.35

Microinfarcts And Microbleeds

van Buchem
van Buchem

Mark van Buchem, MD, PhD, (Professor, Leiden University Medical Center, Leiden, The Netherlands) is an expert in imaging of the brain.

Brain imaging techniques have revealed that tiny blood vessel blockages (microinfarcts) and tiny blood vessel hemorrhages (microbleeds) are common in many apparently healthy people who have no obvious symptoms. Microbleeds are very common in the elderly, and have been suggested to be predictive of hemorrhagic stroke.36

Viswanathan
Viswanathan

A recent study found evidence of microbleeds in 99% of subjects aged 65 or older, and that increasing the imaging strength increased the number of detectable microbleeds.37 The amyloid-beta protein, which is implicated in Alzheimer’s disease, can accumulate in blood vessel walls as well as on neurons.38,39 But Alzheimer’s disease patients show a higher-than-normal incidence of microinfarcts, independent of the amyloid-beta deposition in their blood vessels.40

Anand Viswanathan, MD, PhD, (Associate Director, Telestroke Program, Massachusetts General Hospital) has shown that ischemic stroke victims are twice as likely to have disruptive control of their cognitive processes (executive dysfunction) if they exhibited high levels of microbleeds in the cerebral cortex of the brain.41 Cerebral microbleeds are also associated with high blood pressure and statin use.42

Carotid Endarterectomy

Brown
Brown

Martin Brown, MD, (Professor of Stroke Medicine, University College London, England) spoke on the subject of carotid endarterectomy for prevention of ischemic stroke.

Endarterectomy refers to making incisions in blood vessels to remove atherosclerotic plaque.43 Endarterectomy is a surgical procedure that has a small risk of immediate death, but in the great majority of cases, the benefits exceed the risks.44 A 10-year study of more than 1,500 patients with substantial carotid artery narrowing showed that endarterectomy of the carotid artery greatly reduced the risk of stroke.45 The benefits are greatest for those under age 75.45,46 Stroke risk reduction is substantially higher (about 70%) for those in whom the carotid artery narrowing is greatest.47

Plaque Composition In Stroke

Hatsukami
Hatsukami

Thomas Hatsukami, MD, (Professor of Surgery, University of Washington, Seattle) has used imaging of blood vessels in the brain to distinguish the types of atherosclerotic plaques that are likely to rupture.

Often, the amount of blood vessel narrowing produced by atherosclerotic plaque is less indicative that a plaque is going to rupture than the composition of the plaque. Plaques composed of fat rather than collagen fiber are more vulnerable to rupture.48 Plaques showing signs of inflammation are also more likely to rupture.49 A blood test called the PLAC® test can help assess the stability of arterial plaque by measuring levels of an inflammatory enzyme called Lp-PLA2.

Modern imaging of blood vessels to detect the composition of atherosclerotic plaque can be used to determine when carotid endarterectomy is advisable.50 Placing a stent (tube) in the carotid artery can be less invasive than endarterectomy, but stents have some risk of themselves causing ischemic stroke.51

Migraine Headache And Stroke

Rist
Rist

Pamela Rist, ScD, (Instructor, Harvard School of Public Health, Boston) studies the prevalence of migraine headache, with or without aura.

Migraine aura refers to symptoms (usually in vision) that occur before or during the headache, such as seeing zigzag lines or flash spots.52 In the United States, 18% of females and 6% of males have migraine headaches, with prevalence highest between the ages of 25 and 55.53 People with migraine, especially with aura, are more likely to smoke or have diabetes,54 as well as have high blood pressure and high blood cholesterol.55 Only those who have migraine with aura are at increased risk of ischemic stroke, which is approximately doubled.56 But among all those with migraine, there is nearly a 50% greater chance of hemorrhagic stroke.57

Increasing frequency of migraines corresponds with increasing area of white matter intensities in women, but not in men.58 A significant correlation has been seen between the duration of aura and the increase in white matter hyperintensities seen over a period of nearly three years.59

Dalkara
Dalkara

Turgay Dalkara, MD, PhD, (Professor, Hacettepe University, Ankara, Turkey) wants to know the biological basis of migraine so that he can find therapies. Migraine is a disorder affecting both the central nervous system and the blood vessels of the brain. Dr. Dalkara suggested that reduced blood flow can trigger a wave of electrical discharge (cortical spreading depolarization) in the brain,60,61 which causes headache and aura.62 A defect in brain blood vessels (an incomplete Circle of Willis) is especially common in people who have migraine with aura.63 On the other hand, brain tissue hyperexcitability, such as seen in epilepsy, may result in migraine and increased risk of stroke.64 Anti-epileptic drugs and drugs that block adrenalin-like substances (like beta-blocker drugs such as propranolol) have been used to prevent migraine.65-67

About one-in-four people have a hole in their heart (patent foramen ovale) that failed to close after birth.68 The prevalence of this condition is up to twice as common in people with migraine, and up to three times as common in people having migraine aura.69 Dr. Dalkara has demonstrated that an air microembolism from a patent foramen ovale can cause brain electrical disturbance and headache.70 Surgical closure of the patent foramen ovale has been shown to significantly reduce the severity and frequency of migraine headaches.71

Preventing A Second Ischemic Stroke

Salman
Salman

Rustam Salman, PhD, (Professor, University of Edinburgh, Scotland) discussed therapy for preventing a subsequent ischemic stroke.

Acute stroke is treated as soon as possible with agents that dissolve blood clots. Aspirin is useful at any time following an ischemic stroke, as late as up to 48 hours after the stroke, but the sooner aspirin is given, the more effective the aspirin will be in preventing subsequent stroke.72 One-quarter of ischemic strokes are lacunar, meaning they occur in blood vessels that penetrate deep into the brain.73 The use of the anticlotting drug clopidogrel with aspirin soon after lacunar stroke was shown to be no more effective at preventing a subsequent stroke than aspirin alone, but significantly increased the risk of bleeding and death.74

Brain Recovery After Stroke

Carmichael
Carmichael

Thomas Carmichael, MD, PhD, (Professor, Brain Research Institute, UCLA, California) described the effect of stroke on brain cells.

The immediate effect of stroke is cell death, but within a few days growth factors promote recovery.75 Experiments in rodents and monkeys indicate considerable sprouting of new neuron connections following an ischemic stroke, although there is less sprouting in older people.76-79 There are currently no approved drug treatments that facilitate this process of brain recovery, but it is hoped that studying the natural growth factors causing brain recovery can lead to drug treatment.75

Maharaj
Maharaj

Dipnarine Maharaj, MD, a member of Life Extension®’s Scientific Advisory Board, suggests that prompt administration of a drug called Neupogen® (granulocyte-colony stimulating factor) might lead to faster neuronal recovery. Dr. Maharaj has seen improvements in long-term stroke victims when properly administering this drug (Neupogen®) that mobilizes stem cells from the bone marrow that then migrate to the brain.

Quality Of Life After Stroke

Dhamoon
Dhamoon

Mandip Dhamoon, MD, (Assistant Professor Neurology, Mount Sinai Hospital, New York) studies quality of life for stroke survivors.

In one five-year study, he found a slight annual improvement in quality of life in the younger lacunar stroke victims.80 In another study, however, he found a marked decline in quality of life in the years following the stroke, but this decline was restricted to persons lacking medical insurance or only having access to Medicaid.81,82

Driving A Car After Stroke

George
George

Stacey George, PhD, (Associate Professor, Flinders University, Australia) is interested in the prospect of rehabilitating stroke victims so they can drive an automobile.

Driving is an important aspect of daily living for many people. For about a third of stroke survivors there is no possibility of driving, but about a third can drive without retraining, and a third would be able to drive after retraining and rehabilitation.83 In a review of the literature, Dr. George found that there is not sufficient evidence to prove that driving simulators or other existing methods of retraining adequately address the needs of stroke victims.84

Devos
Devos

Hannes Devos, PhD, (Assistant Professor, Georgia Regents University, Augusta, Georgia) is also interested in methods of assessment and retraining of stroke survivors wishing to resume driving.

Dr. Devos favors virtual reality driving simulators that could simulate very risky conditions.85 He also wants to see intelligent cars with brain-computer interface systems for shared control over driving86 before we get self-driving cars. Dr. Devos and colleagues have developed a set of three tests that can be administered in a physician’s office that predict how likely a person is to fail a road test.87

Conclusions

New medical imaging technologies are providing much more information about stroke risk. At present, however, these techniques are not being used extensively to guide stroke treatment.

Hopefully, future technological advances will better be able to distinguish between ischemic and hemorrhagic stroke in a timely manner. Stroke can be horrifyingly debilitating, which makes it an important affliction to avoid. A healthy lifestyle emphasizing practices that reduce atherosclerosis and blood pressure is the best way to avoid stroke.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

References

  1. Leys D, Henon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol. Nov 2005;4(11):752-9.
  2. Murray CJ, Atkinson C, Bhalla K, et al. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA. Aug 14 2013;310(6):591-608.
  3. Kumar S, Selim MH, Caplan LR. Medical complications after stroke. Lancet Neurol. Jan 2010;9(1):105-18.
  4. Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project. BMJ (Clinical research ed.). Dec 13 1997;315(7122):1582-7.
  5. Hannawi Y, Hannawi B, Rao CP, Suarez JI, Bershad EM. Stroke-associated pneumonia: major advances and obstacles. Cerebrovasc Dis. 2013;35(5):430-43.
  6. Lai SM, Studenski S, Duncan PW, Perera S. Persisting consequences of stroke measured by the Stroke Impact Scale. Stroke. 2002 Jul;33(7):1840-4.
  7. Urban PP, Wolf T, Uebele M, et al. Occurence and clinical predictors of spasticity after ischemic stroke. Stroke. 2010 Sep;41(9):2016-20.
  8. Davenport RJ, Dennis MS, Wellwood I, Warlow CP. Complications after acute stroke. Stroke. 1996 Mar;27(3):415-20.
  9. Langhorne P, Stott DJ, Robertson L, et al. Medical complications after stroke: a multicenter study. Stroke. 2000 Jun;31(6):1223-9.
  10. Batchelor F, Hill K, Mackintosh S, Said C. What works in falls prevention after stroke?: a systematic review and meta-analysis. Stroke. 2010 Aug;41(8):1715-22.
  11. Pandya RS, Mao L, Zhou H, et al. Central nervous system agents for ischemic stroke: neuroprotection mechanisms. Cent Nerv Syst Agents Med Chem. 2011Jun 1;11(2):81-97.
  12. Paolucci S, Antonucci G, Grasso MG, et al. Functional outcome of ischemic and hemorrhagic stroke patients after inpatient rehabilitation: a matched comparison. Stroke. 2003 Dec;34(12):2861-5.
  13. Available at: http://www.mayoclinic.org/diseases-conditions/stroke/symptoms-causes/dxc-20117265 Accessed June 3, 2015.
  14. Bilic I, Dzamonja G, Lusic I, Matijaca M, Caljkusic K. Risk factors and outcome differences between ischemic and hemorrhagic stroke. Acta Clinica Croatica. 2009 Sep;48(4):399-403.
  15. Del Zoppo GJ, Saver JL, Jauch EC, Adams HP, Jr. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009 Aug;40(8):2945-8.
  16. Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation. 2011 Feb 22;123(7):750-8.
  17. Faraco G, Iadecola C. Hypertension: a harbinger of stroke and dementia. Hypertension. 2013 Nov;62(5):810-17.
  18. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002 Dec 14;360(9349):1903-13.
  19. Lawes CM, Bennett DA, Feigin VL, Rodgers A. Blood pressure and stroke: an overview of published reviews. Stroke. 2004 Apr;35(4):1024.
  20. Kelly-Hayes M. Influence of age and health behaviors on stroke risk: lessons from longitudinal studies. J Am Geriat Soc. 2010 Oct;58 Suppl 2:S325-8.
  21. Fanning JP, Wong AA, Fraser JF. The epidemiology of silent brain infarction: a systematic review of population-based cohorts. BMC Med. 2014;12:119.
  22. Wen Q, Chklovskii DB. Segregation of the brain into gray and white matter: a design minimizing conduction delays. PLoS. 2005 Dec;1(7):e78.
  23. Schmahmann JD, Smith EE, Eichler FS, Filley CM. Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates. Ann New York Acad Scis. 2008 Oct;1142:266-309.
  24. Raz N, Yang Y, Dahle CL, Land S. Volume of white matter hyperintensities in healthy adults: contribution of age, vascular risk factors, and inflammation-related genetic variants. BBA. 2012 Mar;1822(3):361-9.
  25. Dufouil C, Godin O, Chalmers J, et al. Severe cerebral white matter hyperintensities predict severe cognitive decline in patients with cerebrovascular disease history. Stroke. 2009 Jun;40(6):2219-21.
  26. Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015 Mar;11(3):157-65.
  27. Provenzano FA, Muraskin J, Tosto G, et al. White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease? JAMA Neurol. 2013 Apr;70(4):455-61.
  28. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ (Clin Res Ed). 2010;341:c3666.
  29. Jeerakathil T, Wolf PA, Beiser A, et al. Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke. 2004 Aug;35(8):1857-61.
  30. Dufouil C, Chalmers J, Coskun O, et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation. 2005 Sep 13;112(11):1644-50.
  31. Offner H, Subramanian S, Parker SM, et al. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol. 2006 Jun 1;176(11):6523-31.
  32. Hug A, Dalpke A, Wieczorek N, et al. Infarct volume is a major determiner of post-stroke immune cell function and susceptibility to infection. Stroke. 2009 Oct;40(10):3226-32.
  33. Mracsko E, Liesz A, Karcher S, Zorn M, Bari F, Veltkamp R. Differential effects of sympathetic nervous system and hypothalamic-pituitary-adrenal axis on systemic immune cells after severe experimental stroke. Brain Behav Immun. 2014 Oct;41:200-9.
  34. Liesz A, Ruger H, Purrucker J, et al. Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases. PloS One. 2013;8(9):e74839.
  35. Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de Beek D. Post-stroke infection: a systematic review and meta-analysis. BMC. 2011;11:110.
  36. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009 Feb;8(2):165-74.
  37. Janaway BM, Simpson JE, Hoggard N, et al. Brain haemosiderin in older people: pathological evidence for an ischaemic origin of magnetic resonance imaging (MRI) microbleeds. Neuropathol Appl Neurobiol. 2014 Apr;40(3):258-69.
  38. Smith EE, Greenberg SM. Beta-amyloid, blood vessels, and brain function. Stroke. 2009 Jul;40(7):2601-6.
  39. Kadowaki H, Nishitoh H, Urano F, et al. Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death Differ. 2005 Jan;12(1):19-24.
  40. Van Rooden S, Goos JD, van Opstal AM, et al. Increased number of microinfarcts in Alzheimer disease at 7-T MR imaging. Radiology. 2014 Jan;270(1):205-11.
  41. Martinez-Ramirez S, Greenberg SM, Viswanathan A. Cerebral microbleeds: overview and implications in cognitive impairment. Alzheimer’s Res Ther. 2014;6(3):33.
  42. Romero JR, Preis SR, Beiser A, et al. Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke. 2014 May;45(5):1492-4.
  43. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063016/. Accessed June 2, 2015.
  44. Barnett HJ, Meldrum HE, Eliasziw M. The appropriate use of carotid endarterectomy. CMAJ. 2002 Apr 30;166(9):1169-79.
  45. Halliday A, Harrison M, Hayter E, et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet. 2010 Sep 25;376(9746):1074-84.
  46. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet. 2004 May 8;363(9420):1491-1502.
  47. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet. 2003 Jan 11;361(9352):107-16.
  48. Cai J, Hatsukami TS, Ferguson MS, et al. In vivo quantitative measurement of intact fibrous cap and lipid-rich necrotic core size in atherosclerotic carotid plaque: comparison of high-resolution, contrast-enhanced magnetic resonance imaging and histology. Circulation. Nov 29 2005;112(22):3437-44.
  49. Mauriello A, Sangiorgi GM, Virmani R, et al. A pathobiologic link between risk factors profile and morphological markers of carotid instability. Atherosclerosis. 2010 Feb;208(2):572-80.
  50. Altaf N, Daniels L, Morgan PS, et al. Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with mild to moderate carotid stenosis predicts recurrent neurological events. J Vasc Surg. 2008 Feb;47(2):337-42.
  51. Yoshimura S, Yamada K, Kawasaki M, et al. High-intensity signal on time-of-flight magnetic resonance angiography indicates carotid plaques at high risk for cerebral embolism during stenting. Stroke. 2011 Nov;42(11):3132-7.
  52. Kurth T, Schurks M, Logroscino G, Gaziano JM, Buring JE. Migraine, vascular risk, and cardiovascular events in women: prospective cohort study. BMJ. 2008;337:a636.
  53. Lipton RB, Bigal ME. The epidemiology of migraine. Am J Med. 2005 Mar;118 Suppl 1:3S-10S.
  54. Stam AH, Weller CM, Janssens AC, et al. Migraine is not associated with enhanced atherosclerosis. Cephalalgia. 2013 Mar;33(4):228-35.
  55. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology. 2005 Feb 22;64(4):614-20.
  56. Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ. 2009;339:b3914.
  57. Sacco S, Ornello R, Ripa P, Pistoia F, Carolei A. Migraine and hemorrhagic stroke: a meta-analysis. Stroke. 2013 Nov;44(11):3032-8.
  58. Kruit MC, van Buchem MA, Hofman PA, et al. Migraine as a risk factor for subclinical brain lesions. JAMA. 2004 Jan 28;291(4):427-34.
  59. Dinia L, Bonzano L, Albano B, et al. White matter lesions progression in migraine with aura: a clinical and MRI longitudinal study. J Neuroimaging. 2013 Jan;23(1):47-52.
  60. Erdener SE, Dalkara T. Modelling headache and migraine and its pharmacological manipulation. Br J Pharmacol. 2014 Oct;171(20):4575-94.
  61. Dalkara T, Nozari A, Moskowitz MA. Migraine aura pathophysiology: the role of blood vessels and microembolisation. Lancet Neurol. 2010 Mar;9(3):309-17.
  62. Karatas H, Erdener SE, Gursoy-Ozdemir Y, et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science. 2013 Mar 1;339(6123):1092-5.
  63. Cucchiara B, Wolf RL, Nagae L, et al. Migraine with aura is associated with an incomplete circle of willis: results of a prospective observational study. PloS One. 2013;8(7):e71007.
  64. Eikermann-Haerter K, Lee JH, Yalcin N, et al. Migraine prophylaxis, ischemic depolarizations, and stroke outcomes in mice. Stroke. 2015 Jan;46(1):229-36.
  65. Capuano A, Vollono C, Mei D, Pierguidi L, Ferraro D, Di Trapani G. Antiepileptic drugs in migraine prophylaxis: state of the art. Clin Ter. 2004 Feb-Mar;155(2-3):79-87.
  66. Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev. 2004(2):CD003225.
  67. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol. 2009 Jul;8(7):643-53.
  68. Ailani J. Migraine and patent foramen ovale. Curr Neurol Neurosci Rep. 2014 Feb;14(2):426.
  69. Lip PZ, Lip GY. Patent foramen ovale and migraine attacks: a systematic review. The Am J Med. 2014 May;127(5):411-20.
  70. Sevgi EB, Erdener SE, Demirci M, Topcuoglu MA, Dalkara T. Paradoxical air microembolism induces cerebral bioelectrical abnormalities and occasionally headache in patent foramen ovale patients with migraine. J Am Heart Assoc. 2012 Dec;1(6):e001735.
  71. Vigna C, Marchese N, Inchingolo V, et al. Improvement of migraine after patent foramen ovale percutaneous closure in patients with subclinical brain lesions: a case-control study. JACC Cardiovasc Interv. 2009 Feb;2(2):107-13.
  72. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: A combined analysis of 40,000 randomized patients from the Chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke. 2000 Jun;31(6):1240-9.
  73. Bailey EL, Smith C, Sudlow CL, Wardlaw JM. Pathology of lacunar ischemic stroke in humans--a systematic review. Brain Pathol. 2012 Sep;22(5):583-91.
  74. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, Pearce LA. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. New Engl J Med. 2012 Aug 30;367(9):817-25.
  75. Clarkson AN, Overman JJ, Zhong S, Mueller R, Lynch G, Carmichael ST. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci. 2011 Mar 9;31(10):3766-75.
  76. Brown CE, Aminoltejari K, Erb H, Winship IR, Murphy TH. In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites. J Neurosci. 2009 Feb 11;29(6):1719-34.
  77. Carmichael ST, Chesselet MF. Synchronous neuronal activity is a signal for axonal sprouting after cortical lesions in the adult. J Neurosci. 2002 Jul 15;22(14):6062-70.
  78. Li S, Overman JJ, Katsman D, et al. An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat Neurosci. 2010 Dec;13(12):1496-1504.
  79. Dancause N, Barbay S, Frost SB, et al. Extensive cortical rewiring after brain injury. J Neurosci. 2005 Nov 2;25(44):10167-79.
  80. Dhamoon MS, McClure LA, White CL, Lau H, Benavente O, Elkind MS. Quality of life after lacunar stroke: the Secondary Prevention of Small Subcortical Strokes study. J Stroke Cerebrovasc Dis. 2014 May-Jun;23(5):1131-7.
  81. Dhamoon MS, Moon YP, Paik MC, et al. Quality of life declines after first ischemic stroke. Neurology. 2010 Jul 27;75(4):328-34.
  82. Dhamoon MS, Moon YP, Paik MC, et al. Long-term functional recovery after first ischemic stroke: the Northern Manhattan Study. Stroke. 2009 Aug;40(8):2805-11.
  83. Akinwuntan AE, Wachtel J, Rosen PN. Driving simulation for evaluation and rehabilitation of driving after stroke. J Stroke Cerebrovasc Dis. 2012 Aug;21(6):478-86.
  84. George S, Crotty M, Gelinas I, Devos H. Rehabilitation for improving automobile driving after stroke. Cochrane Database Syst Rev. 2014;2:CD008357.
  85. Hird MA, Vetivelu A, Saposnik G, Schweizer TA. Cognitive, on-road, and simulator-based driving assessment after stroke. J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):2654-70.
  86. Khaliliardali Z, Chavarriaga R, Andrei Gheorghe L, Millan Jdel R. Detection of anticipatory brain potentials during car driving. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference. 2012;2012:3829-32.
  87. Devos H, Akinwuntan AE, Nieuwboer A, Truijen S, Tant M, De Weerdt W. Screening for fitness to drive after stroke: a systematic review and meta-analysis. Neurology. 2011 Feb 22;76(8):747-56.