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3 Introduction Stroke is the second leading cause of death and the leading cause of disability in Western society 1. The stroke syndrome is clinically defined as a rapid development of focal neurological deficits of vascular origin 2. Stroke can be distinguished in ischemic stroke and hemorrhagic stroke 3. Ischemic stroke (infarction) is the most common type of cerebrovascular accident (80%), and occurs when a blood clot blocks an artery and interrupts the brain s blood supply, depriving the brain cells of oxygen and other nutrients. Hemorrhagic stroke is caused by rupture of a blood vessel resulting in the infiltration of blood into the surrounding tissue, either inside the brain tissue (intracerebral hemorrhage: 15%) or in the subarachnoid space surrounding the brain (subarachnoid hemorrhage: 5%). In the Netherlands, the incidence rate of stroke is estimated at 170 to 190 in 100,000 inhabitants per year. This incidence will increase due to ageing of the population and epidemiological transitions 4. About 120,000 to 140,000 stroke survivors are living in the Netherlands at present 5. It has been estimated that the number of stroke survivors in the Netherlands will increase with 27% over the period Functional outcome after stroke The clinical presentation of stroke varies from minor neurological symptoms to severe deficits, depending on the location and volume of the brain lesion Neurological deficits or impairments such as hemiparesis (80% 90%) 11, communication disorders and disorders in visuo-spatial perception often cause disabilities such as diminished mobility and Activities of Daily Living (ADL) 11, 12. At 6-months poststroke, 20 30% of patients have died, whereas 20 30% of stroke survivors are moderately to severely disabled, 20 25% are mildly disabled, and others have no deficits at all 13. In 2001, the World Health Organization published the International Classification of Functioning, Disability and Health (ICF) as a model for the description of the components of health 12, 14 (Figure 1). This model is widely used as a theoretical framework for outcome research. Functional outcome (and recovery) can be classified into levels of body functions and structures (i.e., impairments), activities (functional impact of impairment) and participation (social impact of the disease). Patients show a more or less functional recovery in time 12, 15, 16. Functional recovery is affected by a variety of biological and environmental factors and recovery profiles are characterized by a high inter-individual variability 12, Chapter 1 11 Schiemanck_totaal_v4.indd :13:14

4 Health condition Body functions Activities Participation Personal factors Environmental factors Figure 1. Schematic representation of the framework of the International Classification of Functioning, Disability and Health. Prediction of outcome Early prediction of functional outcome after stroke is an important topic in stroke management and related research 17, 20, 21. For the rehabilitation physician as well as for the neurologist, a valid early prognosis of functional outcome for the individual stroke patient is required to inform the patient and his relatives adequately, to facilitate discharge planning 19, and to initiate an optimal rehabilitation program with realistic therapeutic goals 15, 16. Over the last decade, several studies have evaluated determinants that might be used to forecast functional outcome of stroke patients early after stroke 18, 21, 22. A critical review of the literature 21 indicated that several clinical and demographic variables might be valid predictors of general functional recovery, including factors such as consciousness at onset, disorientation in time and place, sitting balance and severity of motor deficits. For example, urine continence status, initial level of Activities of Daily Living (ADL), and age are valid predictors of Activities of Daily Living (ADL) at 6-months poststroke 18. Many prediction models for outcome of stroke patients have been proposed since, but their predictive validity appeared to be rather poor 10, 13, 18, 21, Furthermore, previous research studies have assessed functional outcome at different levels of outcome using the ICF, thereby making a comparison between these studies difficult. Ischemic lesion characteristics and functional outcome A stroke lesion is characterized by its volume and its neuro-anatomic localization in the brain. The development of new neuro-imaging methods has made it possible 12 Chapter 1 Schiemanck_totaal_v5.indd :55:57

5 to easily and accurately determine infarct volume and localization 10, 25, 27. Neuroimaging techniques such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are crucial for differentiating between hemorrhagic and ischemic strokes. Brain CT shows the relevant infarct in 50 60% of patients with an ischemic stroke 28. However, absence of a visible infarct does not mean that the patient did not have a stroke 29. MRI more often than CT shows cortical involvement of infarctions and reveals more silent lesions 28. Neuro-imaging characteristics of the ischemic brain lesion are known to relate to the patient s neurological deficits 30, 31. The neuro-anatomic localization of the brain lesion and its volume are believed to be an important parameter reflecting the primary pathological condition, since a larger lesion volume means more destruction of brain tissue, and the extent of this pathological condition relates to neurological deficits and therefore functional outcome The modesty of the correlation between CT infarct volume and standard measures of clinical outcome suggested that CT volume could be considered a somewhat useful but imperfect auxiliary outcome marker for ischemic stroke studies 34. MRI techniques have provided better early biological markers of treatment effectiveness. For example, T2-weighted MRI measures have greater spatial resolution and sensitivity to ischemic injury than CT attenuation 35. Few studies have compared conventional MR measures of infarct volume and clinical end points, but the largest of these supported the hypothesis that MR measures correlate more closely with functional outcome 36. A better understanding of the impact of the volume and localization of the brain lesion by its disruption of neuro-anatomic structures, leading to neurological deficits and therefore to specific loss of body functions such as physical and cognitive impairments, might give the physician a tool to directly relate neurological deficits to a patient s activity limitations and to better forecast the long-term functional outcome of the individual stroke patient 34. From previous studies it was concluded that prognostic research should measure functional outcome beyond 6-months poststroke, since functional improvement may extent beyond 6 months 15, 37 after the stroke incident. In order to increase the accuracy of prediction models, prognostic studies should restrict their patient selection to more homogeneous groups in terms of lesion location and stroke subtype 20, 38. Furthermore, it has been recommended that studies should enroll sufficient numbers of patients to improve the precision of the prediction model they derive and to reveal the added value of MRI volume measurements compared with clinical determinants 34 Scope of this thesis The research in this thesis focused on gaining a better understanding of the relationship between ischemic lesion characteristics and long-term functional outcome of the stroke survivor. A homogeneous group of stroke survivors with a first-ever supratentorial middle cerebral artery infarct was investigated. Functional outcome of stroke survivors was assessed after two weeks and after 1-year poststroke. Functional outcome was Chapter 1 13 Schiemanck_totaal_v4.indd :13:15

6 evaluated at the levels of body functions, activities, participation (ICF) and quality of life 14. Neuro-imaging characteristics were obtained from Magnetic Resonance Images (MRI). A standardized scanning protocol using conventional MRI scanning method for all participating hospitals and a valid and reliable assessment for estimating the volume and localization of infarcts was used 27, 30. Research Questions 1) What is the methodological quality of MRI studies evaluating the predictive value of hemispheric infarct volume for neurological deficits and poststroke functional outcome? (Systematic Review, Chapter 2) 2) What is the relationship between lesion volume and functional outcome of the stroke survivor? a. In the subacute phase poststroke (i.e., second week after stroke) (Chapter 3) b. In the long-term poststroke (i.e., 1 year after stroke) (Chapter 4) 3) Does neuro-imaging information from MRI scans have an added value next to clinical variables, in predicting independency in ADL of stroke survivors at 1-year poststroke? (Chapter 5) 4) Is there a relationship between lesion localization and long-term functional recovery of the stroke survivor? a. With respect to motor deficits, i.e. isolated motor hand function (Chapter 6) b. With respect to cognitive disorders, i.e. episodic (verbal and visual) memory performance (Chapter 7) 14 Chapter 1 Schiemanck_totaal_v4.indd :13:15

7 References 1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997 May 3;349(9061): Stroke Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. Stroke 1989 October;20(10): Hankey GJ, Wardlaw JM. Vascular diseases of the nervous system. In: Hankey GJ, Wardlaw JM, editors. Clinical Neurology. 1st edition. London: Manson Publishing Ltd.; p Hollander M, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, Breteler MM. Incidence, risk, and case fatality of first ever stroke in the elderly population. The Rotterdam Study. J Neurol Neurosurg Psychiatry 2003 March;74(3): van Oers JAM. Gezondheid op koers? Volksgezondheid Toekomstverkenning. Rijksinstituut voor Volksgezondheid en Milieu; Struijs JN, van Genugten ML, Evers SM, Ament AJ, Baan CA, van den Bos GA. Modeling the future burden of stroke in The Netherlands: impact of aging, smoking, and hypertension. Stroke 2005 August;36(8): Beloosesky Y, Streifler JY, Burstin A, Grinblat J. The importance of brain infarct size and location in predicting outcome after stroke. Age Ageing 1995 November;24(6): Hertanu JS, Demopoulos JT, Yang WC, Calhoun WF, Fenigstein HA. Stroke Rehabilitation: Correlation and Prognostic Value of Computerized tomography and Sequential Functional Assessments. Arch Phys Med Rehabil 1984;65: Olsen TS. Outcome following occlusion of the middle cerebral artery. Acta Neurol Scand 1991 April;83(4): van Everdingen KJ, van der Grond J, Kappelle LJ, Ramos LM, Mali WP. Diffusion-weighted magnetic resonance imaging in acute stroke. Stroke 1998 September;29(9): Kotila M, Waltimo O, Niemi ML, Laaksonen R, Lempinen M. The profile of recovery from stroke and factors influencing outcome. Stroke 1984 November;15(6): Herman B, Leyten AC, van Luijk JH, Frenken CW, Op de Coul AA, Schulte BP. Epidemiology of stroke in Tilburg, the Netherlands. The population-based stroke incidence register: 2. Incidence, initial clinical picture and medical care, and three-week case fatality. Stroke 1982 September;13(5): Baird AE, Dambrosia J, Janket S, Eichbaum Q, Chaves C, Silver B, Barber PA, Parsons M, Darby D, Davis S, Caplan LR, Edelman RE, Warach S. A three-item scale for the early prediction of stroke recovery. Lancet 2001 July 30;357(9274): WHO. ICF: International Classification of Functioning, Disability and Health Geneva. 15. Kwakkel G, Kollen B, Lindeman E. Understanding the pattern of functional recovery after stroke: facts and theories. Restor Neurol Neurosci 2004;22(3-5): Chapter 1 15 Schiemanck_totaal_v4.indd :13:15

8 16. Kwakkel G, Kollen B, Twisk J. Impact of time on improvement of outcome after stroke. Stroke 2006 September;37(9): Meijer R, Ihnenfeldt DS, van Limbeek J, Vermeulen M, de Haan RJ. Prognostic factors in the subacute phase after stroke for the future residence after six months to one year. A systematic review of the literature. Clin Rehabil 2003 August;17(5): Meijer R, Ihnenfeldt DS, de Groot IJ, van Limbeek J, Vermeulen M, de Haan RJ. Prognostic factors for ambulation and activities of daily living in the subacute phase after stroke. A systematic review of the literature. Clin Rehabil 2003 April;17(2): Meijer R, van Limbeek L, Kriek B, Ihnenfeldt D, Vermeulen M, de HR. Prognostic social factors in the subacute phase after a stroke for the discharge destination from the hospital stroke-unit. A systematic review of the literature. Disabil Rehabil 2004 February 18;26(4): Jongbloed L. Prediction of function after stroke: a critical review. Stroke 1986 July;17(4): Kwakkel G, Wagenaar RC, Kollen BJ, Lankhorst GJ. Predicting disability in stroke--a critical review of the literature. Age Ageing 1996 November;25(6): Woldag H, Gerhold LL, de Groot M, Wohlfart K, Wagner A, Hummelsheim H. Early prediction of functional outcome after stroke. Brain Inj 2006 September;20(10): Chamorro A, Vila N, Ascaso C, Saiz A, Montalvo J, Alonso P, Tolosa E. Early prediction of stroke severity. Role of the erythrocyte sedimentation rate. Stroke 1995 April;26(4): Johnston KC, Connors AF, Jr., Wagner DP, Knaus WA, Wang X, Haley EC, Jr. A predictive risk model for outcomes of ischemic stroke. Stroke 2000 February;31(2): Thijs VN, Lansberg MG, Beaulieu C, Marks MP, Moseley ME, Albers GW. Is early ischemic lesion volume on diffusion-weighted imaging an independent predictor of stroke outcome? A multivariable analysis. Stroke 2000 November;31(11): Weimar C, Kurth T, Kraywinkel K, Wagner M, Busse O, Haberl RL, Diener HC. Assessment of functioning and disability after ischemic stroke. Stroke 2002 August;33(8): van der Worp HB, Claus SP, Bar PR, Ramos LM, Algra A, van Gijn J, Kappelle LJ. Reproducibility of measurements of cerebral infarct volume on CT scans. Stroke 2001 February;32(2): Lindgren A, Norrving B, Rudling O, Johansson BB. Comparison of clinical and neuroradiological findings in first-ever stroke. A population-based study. Stroke 1994 July;25(7): Lindgren A, Roijer A, Rudling O, Norrving B, Larsson EM, Eskilsson J, Wallin L, Olsson B, Johansson BB. Cerebral lesions on magnetic resonance imaging, heart disease, and vascular risk factors in subjects without stroke. A population-based study. Stroke 1994 May;25(5): Chapter 1 Schiemanck_totaal_v4.indd :13:16

9 30. Saunders DE, Clifton AG, Brown MM. Measurement of infarct size using MRI predicts prognosis in middle cerebral artery infarction. Stroke 1995 December;26(12): Tong DC, Yenari MA, Albers GW, O Brien M, Marks MP, Moseley ME. Correlation of perfusion- and diffusion-weighted MRI with NIHSS score in acute (<6.5 hour) ischemic stroke. Neurology 1998 April;50(4): Brott T, Marler JR, Olinger CP, Adams-HP J, Tomsick T, Barsan WG, Biller J, Eberle R, Hertzberg V, Walker M. Measurements of acute cerebral infarction: lesion size by computed tomography. Stroke 1989 July;20(7): Chua MG, Davis SM, Infeld B, Rossiter SC, Tress BM, Hopper JL. Prediction of functional outcome and tissue loss in acute cortical infarction. Arch Neurol 1995 May;52(5): Saver JL, Johnston KC, Homer D, Wityk RJ, Koroshetz W, Truskowski LL, Clarke Haley E. Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials. Stroke 1999;30: Kinkel WR. Classification of stroke by neuroimaging technique. Stroke 1990 September;21(9 Suppl):II7-II Lovblad KO, Baird AE, Schlaug G, Benfield A, Siewert B, Voetsch B, Connor A, Burzynski C, Edelman RR, Warach S. Ischemic lesion volumes in acute stroke by diffusion-weighted magnetic resonance imaging correlate with clinical outcome. Ann Neurol 1997 August;42(2): Ferrucci L, Bandinelli S, Guralnik JM, Lamponi M, Bertini C, Falchini M, Baroni A. Recovery of functional status after stroke. A postrehabilitation follow-up study. Stroke 1993;24: Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991 June 22;337(8756): Chapter 1 17 Schiemanck_totaal_v4.indd :13:16

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