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Relationship between ischemic lesion volume and functional status in the second week after middle cerebral artery stroke

SK Schiemanck1,2, MWM Post1,2,3, ThD Witkamp2,4, LJ Kappelle2,5, AJH Prevo1,2

(1)  Center of Excellence for Rehabilitation Medicine, Rehabilitation Center De Hoogstraat Utrecht (2)  Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (3)  Institute for Rehabilitation Research, Hoensbroek (4)  Department of Radiology, University Medical Center, Utrecht (5)  Department of Neurology and Neurosurgery, University Medical Center Utrecht, The Netherlands

Neurorehabilitation and Neural Repair, 2005 Jun;19(2):133-8

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Abstract
Objective- To examine the relationship between the volume of the middle cerebral artery stroke lesion and functional status in the subacute phase of stroke. Methods- Infarct volumes of 94 patients with a first middle cerebral artery stroke assessed on conventional MRI scans obtained in the second week poststroke were related to a clinical measure of stroke severity (National Institutes of Health Stroke Scale, NIHSS) and to functional status: motor impairment (Motricity Index, MI) and limitation in activities (Barthel Index and modified Rankin Scale). Separate correlations were computed for patients with large (>30 ml) and small (30 ml) lesions and to investigate the influence of lesion location on the relationship between volume and functional status, correlations were computed for patients with left and right hemisphere lesions and for patients with cortical and subcortical lesions. Results- Lesion volume correlated strongly with NIHSS scores (R=0.61) and moderately with the patients functional status (Motricity Index (R between -0.42 and -0.49), Barthel Index (R=-0.43) and Modified Rankin Scale (R=0.45)). Right hemisphere lesions and cortical lesions had a stronger correlation with functional status. In patients with small lesion volumes (0-30 ml) no relationship between lesion volumes and functional status was seen at all. Conclusions- Lesion volume is moderately to strongly related to the functional status in the second week poststroke.

Introduction
The relationship between lesion volume and stroke severity and between lesion volume and functional outcome in stroke has been described before1-17. Few studies have assessed the correlation between lesion volume and stroke severity at an early stage poststroke3,10,17, but only one small study has evaluated the correlation between lesion volume and the patients functional status at an early stage poststroke10. Leinonen and colleagues found significant correlations between lesion volume (MRI scans) and NIHSS (R=0.57) and with the Barthel Index (R=-0.41) assessed at a mean of 2.2 days poststroke in 22 patients with acute stroke10. In the current study we assessed the correlation between the volume of the ischemic lesion and a clinical measure of stroke severity and with functional status (motor impairment and dependency in activities of daily living (ADL)) of patients with their first-ever middle cerebral artery infarction in the early phase of stroke. Furthermore, we examined whether the correlation between lesion volume and functional status was different for patients with small and with large infarcts. Finally, we explored the influence of lesion site on the correlation of lesion volume and functional status.

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Methods
Subjects
Patients admitted to the stroke units of six regional hospitals (one university and five general hospitals) in the period of 1999-2001 in the Netherlands were asked to participate. After informed consent, an MRI scan was made. Data about stroke severity were retrieved from medical files. Included were patients with their first-ever stroke, aged between 18 and 85 years, having a premorbid Barthel Index (BI) 18 and with a stable neurological condition one week after stroke. The criterion of 18 or higher on the Barthel Index was used because patients with these scores generally require only minimal or no assistance with daily activities18. All patients had a visible middle cerebral artery lesion on the MRI scan made in the second week poststroke. Excluded were patients with other lesions, infarctions other than MCA infarctions, borderzone infarctions, multiple infarctions and lacunar infarctions. Lacunar infarctions were defined as infarctions in the deep white matter of the brain, caused by an occlusion of small perforating arteries, with a diameter ranging from 3-4 mm to a diameter of 15-20 mm located at the site of the basal ganglia, the internal capsule or corona radiata19,20. Furthermore, patients with premorbid cognitive limitations (stated by patient or family) or co-morbidity influencing functional outcome at the time of stroke (such as progressive neurological, orthopaedic, rheumatologic, psychiatric or cardio-pulmonary disorders) were excluded.

Instruments
Stroke severity at the time of admittance to the hospital was assessed with the National Institutes of Health Stroke Scale (NIHSS)21. This information was retrospectively taken from the patient file22-24. Other measures of functional status were part of a physical examination. An experienced research assistant tested patients about six days poststroke. Motor impairment was measured with the Motricity Index (MI)25. Dependency in ADL was assessed with the Barthel Index26 and global level of functioning with the modified Rankin Scale27.

Power analysis
The Barthel Index is the most crucial assessed variable in this study. It is possible to detect a clinically relevant difference of 3 points on the Barthel Index28, with an alpha=0.05 and a beta=0.80 with 45 patients in each group.

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Image analysis
About 10 days poststroke Magnetic Resonance Imaging was performed. Scans were obtained at this time point because T2-weighted MRI in the first few days after stroke can reflect local edema as well as ischemic and infarcted tissue resulting in an overestimation of the lesion volume. In the second week poststroke lesion volume is stable1,29,30. MRI studies were performed using 0.5 Tesla, 1.0 Tesla or 1.5 Tesla MRI scans (Philips Medical Systems). A standard scanning protocol was performed in all hospitals: a saggital T1-weighted sequence (survey), an axial T2-weighted (T2-W) sequence, Slice Thickness (S.Th) 6 mm, gap 1.2 mm; a transversal Fluid Attenuated Inversion Recovery (FLAIR) sequence; a transversal gradient echo T2-W sequence. Scans were digitally stored on an Optical Disc and further analyzed using a Philips Easy Vision Workstation. For logistic reasons, the scans from one hospital were delivered on hard copies only. These hard copies were digitized and analyzed afterwards31. Areas of abnormal hyperintensity were traced on each slice of the T2-weighted and/or FLAIR images (cortical lesions). These areas of abnormal hyperintensity were summed and multiplied with the slice thickness (6 mm) and interslice gap (1.2 mm) to calculate the volumes of the cerebral lesions. If patients had 2 or more ischemic lesions in the same hemisphere, the volumes of these lesions were summed. Lesions that affected grey matter were described as cortical lesions; lesions were described as purely subcortical if cortex was not affected at all. Lesions were divided into left hemisphere and right hemisphere lesions. Subgroups of patients with small (0-30 ml) and large (>30 ml) lesions were obtained. Measurement of the infarct volume13,31 was performed de-identified and blinded for the patients clinical status on admittance by a research fellow (SKS) in co-operation with an experienced neuro-radiologist (ThDW)31. Since both digital analysis (using optical discs) and analysis of digitized hard copies were used, an inter-method analysis was performed for 24 MRI scans that were delivered digitally as well as on hard copies, giving an intra-class correlation coefficient of 0.97 (95% CI: 0.94-0.99). Because of this high agreement, all results were put together for further statistical analysis.

Statistical analysis
As neither the functional status scores, nor the MRI lesion volumes were normally distributed, the Spearman rank order correlation coefficient was used for statistical analysis. All statistical analyses were carried out using SPSS 11.5 for Windows.

Results
From a total of 115 included patients, 21 patients were excluded because of the findings on the MRI scan: old lesions (4 patients); infratentorial lesions (10 patients); multiple infarctions (left and right hemisphere) (5 patients); borderzone infarction

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(1 patient); and in one patient the MRI scan could not be evaluated because of movement artifacts due to claustrophobia of the patient. Therefore 94 patients were available for further analysis. 85% of these patients were admitted to the hospital at the day of stroke onset. Patients were investigated in the first week poststroke (mean 6 days; 95% Confidence Interval (CI) 5.5-6.5). MRI scans were obtained at a mean of 11 days poststroke (CI 10.2-11.9). The study population consisted of 46 men and 48 women. The mean age at the time of inclusion was 63 years (CI 59.9-66.1). Patients showed a wide range of lesion volume (Table 1).

Table 1. Lesion volume (ml) and functional status in the subacute phase of stroke.
N 94 94 92 93 92 94 94 All lesions Median IQR 35.11 6.51-89.26 11.00 6.75-15.00 109.50 14.00-191.00 38.00 0.00-92.00 75.00 14.00-100.00 7.50 2.75-16.25 4.00 3.00-4.00 N 45 45 44 45 44 45 45 Lesions 0-30 ml Median IQR 6.40 3.01-13.54 7.00 5.00-10.50 163.50 75.25-192.00 75.00 14.50-100.00 91.00 46.25-100.00 11.00 5.00-17.00 3.00 2.00-4.00 N 49 49 48 48 48 49 49 Lesions > 30 ml Median IQR 82.27 45.90-146.71 15.00 12.00-16.50 33.50 0.00-168.25 0.00 0.00-81.50 33.50 0.00-91.00 4.00 2.00-11.50 4.00 3.00-5.00

Lesion volume NIHSS, adm MI (total) MI (arm) MI (leg) Barthel Index Mod. Rankin

Lesion volume NIHSS, adm MI (total) MI (arm) MI (leg) Barthel Index Mod. Rankin

N 51 51 50 50 50 51 51

Left hemisphere Median IQR 31.90 4.84-69.19 11.00 5.00-16.00 102.00 17.00-192.00 29.00 0.00-100.00 75.00 14.00-100.00 8.00 2.00-16.00 4.00 3.00-5.00

N 43 43 42 43 42 43 43

Right Hemisphere Median IQR 37.00 9.76-124.00 12.00 7.00-15.00 116.50 9.00-177.00 50.00 0.00-91.00 75.00 6.75-100.00 7.00 4.00-17.00 4.00 3.00-4.00

Lesion volume NIHSS, adm MI (total) MI (arm) MI (leg) Barthel Index Mod. Rankin Abbreviations IQR: NIHSS, adm MI: Mod. Rankin:

N 58 58 57 57 57 58 58

Cortical lesion Median IQR 60.15 26.95-139.98 12.50 7.00-16.00 128.00 4.50-196.00 38.00 0.00-100.00 75.00 0.00-100.00 7.00 2.00-17.00 4.00 3.00-5.00

N 36 36 35 36 35 36 36

Subcortical lesion Median IQR 6.47 2.96-27.35 9.00 6.00-14.00 106.00 27.00-166.00 36.50 0.00-75.75 75.00 27.00-91.00 8.00 4.25-11.75 4.00 3.00-4.00

Interquartile Range (25%-75%) National Institutes of Health Stroke Scale at admission into hospital Motricity Index Modified Rankin Scale

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Mean lesion volume was 60 ml (CI 44.5-77.5), while the median was 35.1 (IQR, 1st and 3rd percentile, 6.5-89.3). At the time of admission to the hospital all patients were conscious; median NIHSS was 11, indicating that the patients showed moderate neurological deficits. To analyze the relationship between the volume and the functional status in subgroups of patients with small and large lesions, we divided the patients into two groups using a cut-off point of lesion volume of 30 ml. A receiver operating characteristic analysis was used to calculate lesion volume which determines independent functional status assessed with the Barthel Index (19 and 20)28. Since no optimum sensitivity and specificity could be estimated, the arbitrary cut-off point of 30 ml was used to get two equally sized groups of patients. Furthermore, patients were divided on the basis of the lesion localization into subgroups of patients with left and right hemisphere lesions, cortical and subcortical lesions. No significant differences were found for gender between these subgroups. The patients in the 0-30 ml lesion group were significantly older than in the >30 ml lesion group (mean 66 years and 61 years respectively; p=0.05); No significant mean age differences were found between the other subgroups. Spearman rank correlations between lesion volume and functional status of the patient in the early phase of stroke are shown in Table 2.

Table 2. Spearman rank correlation coefficients between the volume of ischemic lesion and functional status.
NIHSS MI (total) MI (arm) MI (leg) Barthel Index Mod. Rankin Abbreviations NIHSS: MI: Mod. Rankin: All lesions 0.61** -0.46** -0.42** -0.49** -0.43** 0.45** Lesion 0-30 ml 0.28 -0.09 -0.06 -0.24 -0.15 0.10 Lesion >30 ml 0.28 -0.52** -0.52** -0.45** -0.35* 0.29* Left hemisphere 0.62** -0.36* -0.36* -0.37** -0.37** 0.48** Right hemisphere 0.56** -0.54** -0.47* -0.61** -0.49** 0.46** Cortical lesion 0.60** -0.66** -0.65** -0.63** -0.47** 0.55** Subcortical lesion 0.67** -0.49** -0.42* -0.52** -0.65** 0.52**

National Institutes of Health Stroke Scale Motricity Index Modified Rankin Scale

*Correlation is significant at the 0.05 level (2-tailed) **Correlation is significant at the 0.01 level (2-tailed)

There was a strong correlation between lesion volume and NIHSS score (R=0.61). Non-linear correlation coefficients were computed, but were not higher than the linear correlation of 0.61. Lesion volume moderately correlated with the Motricity Index, Barthel Index and Modified Rankin Scale scores. Spearman rank correlations for the volume of ischemic lesion and the functional status in the subgroups of patients are also shown in Table 2. Neither the 0-30 ml lesion group nor the >30 ml lesion group showed a significant correlation between lesion volume and stroke severity assessed with

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NIHSS scores. All measures of functional status showed a significant relationship with lesion volume in the >30 ml lesion group, but not in the small lesion group. In the right hemisphere group, the correlation coefficients between lesion volume and NIHSS were comparable to those in the left hemisphere group. Correlation coefficients between lesion volume and functional status (motor impairments and activity limitations) were not significantly different in the right hemisphere group compared to the left hemisphere group (p=0.19-0.58). Comparing the correlation coefficients of the cortical lesion group and the subcortical lesion group, the correlation coefficients between lesion volume and NIHSS and Modified Rankin Scale were similar; correlation coefficient between lesion volume and physical impairment was stronger in the cortical lesion group, but did not differ significantly (p=0.11); correlations between lesion volume and Barthel Index were not-significantly stronger in the subcortical lesion group (p=0.09). All these correlation coefficients were also calculated corrected for the age-difference in the subgroups, showing no significant differences with the correlation coefficients presented here.

Discussion
In this study, a strong relationship between lesion volume and NIHSS was demonstrated, as well as moderate correlations between lesion volume and functional status assessed with measures of physical impairments (Motricity Index) and activity limitations (Barthel Index and Rankin Scale). The correlations between lesion volume and functional status were stronger in the subgroups of patients with large lesions and with right hemisphere lesions. Strong features of this study are the large and relatively homogenous group of patients included, the focus on a broad range of outcomes, using valid and reliable test material and the precise volume measurements using both T2-weighted and FLAIR Magnetic Resonance Images obtained in the second week poststroke. It is known that T2-weighted MR measures have greater spatial resolution and sensitivity to ischemic injury than CT attenuation29. MRI scanning was performed in the second week after stroke because T2-weighted MRI in the first few days after stroke can reflect local edema as well as ischemic and infarcted tissue32 resulting in an overestimation of the lesion volume. In this study FLAIR images were used next to T2-weighted images, to measure lesion volume for cortical lesions because on the T2-weighted images there was not always a clear differentiation visible between cortical lesions and cerebrospinal fluid. Our study showed some limitations. First, the T2-weighted MRI slices used for lesion segmentation were relatively thick at 6 mm. This could have resulted in an underestimation of the lesion volume, particularly when lesions were small. However, a study in patients with multiple sclerosis showed that the computed lesion volume did not increase much if lesion slice-thickness of 6 mm was further minimized33 and it appears unlikely that minimization of the lesion slice-thickness would lead to different results in our study. Second, patients were tested about 5 days before the neuro-imaging procedure (mean day 11 poststroke). In this time period, patients

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could show an improvement (or deterioration) in functioning. Third, the influence of lesion location within the hemisphere might be an important determinant of outcome but was ignored in this study. The correlation of 0.61 between lesion volume and NIHSS found in our study falls well within the range of correlations (0.57-0.74) found in other studies that were performed in the acute phase of stroke3,10,17. In addition, our results showed a substantial correlation between the lesion volume and the functional status on the levels of impairment and limitation in activities. The group of patients with large lesions (>30 ml) showed a strong correlation between lesion volume and motor impairment and limitation in activities whereas patients with small lesions did not. This lack of a relationship between lesion volume and functional status in the group of patients with a small ischemic lesion could be a result of lack of sensitivity of the chosen test material for minor differences in functional status in the acute phase of stroke. However, a more plausible reason might be that in this group the lesion volume differences between patients are small and that therefore the location differences will be of greater influence on the functional outcomes. For patients with lacunar lesions this strong effect of localization on functional status has earlier been shown11,34. Our study showed stronger relationships between lesion volume and outcomes in patients with right hemisphere lesions than in patients with left hemisphere lesions, although these differences were not significant. From the IQR values in Table 1 it can be inferred that lesion volumes in the group of patients with left hemisphere lesions were smaller than lesion volumes in the group of patients with right hemisphere lesions. This might explain the lower correlations between lesion volume and the functional status in the left hemisphere group when compared to the right hemisphere group. Differences between the group of patients with cortical and with subcortical lesions were less pronounced and not consistent for the various outcome measures used. This might be the result of combinations of influences working in opposite directions. One explanation might be that volume differences in subcortical lesions have stronger influence on outcome because these lesions affect the motor descending pathways. Another explanation is that lesion volumes in the cortical group are substantially larger than lesion volumes in the subcortical group (Table 1) and that the relationship between lesion volume and outcome is much stronger in the large lesion group (Table 2). In the early phase of stroke, predictions about future level of functioning and decisions about most appropriate types of care are made. Knowledge about lesion volume and its relationship with functional status and later functional outcome might support these predictions and decisions, provided that the relationship between lesion volume and outcome does not diminish on the long term.

Clinical Implications
Ischemic lesion volume is strongly correlated with stroke severity and moderately correlated with motor impairment and activity limitations. Knowledge about lesion volume might support predictions about future level of functioning and decisions about types of care in stroke.

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