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(Stroke. 1999;30:2355-2359.)
© 1999 American Heart Association, Inc.

Original Contributions

Does the National Institutes of Health Stroke Scale Favor Left Hemisphere Strokes?

Daniel Woo, MD; Joseph P. Broderick, MD; Rashmi U. Kothari, MD; Mei Lu, PhD; Thomas Brott, MD; Patrick D. Lyden, MD; John R. Marler, MD; James C. Grotta, MD for the NINDS t-PA Stroke Study Group

From the Departments of Neurology (D.W., J.P.B.) and Emergency Medicine (R.U.K.), University of Cincinnati, Cincinnati, Ohio; Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit Mich (M.L.); the Department of Neurology, Mayo Clinic, Jacksonville, Fla (T.B.); the Department of Neurology, University of California–San Diego, San Diego, Calif (P.D.L.); the Division of Stroke and Trauma, NINDS, Bethesda, Md (J.R.M.); and the Department of Neurology, University of Texas Medical School, Houston, Tex (J.C.G.).

Correspondence to Daniel Woo, MD, University of Cincinnati College of Medicine, Department of Neurology, 231 Bethesda Ave, ML 0525, Cincinnati, OH 45220. E-mail daniel.woo{at}uc.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion Appendix I Appendix II References

 
Background and Purpose—The National Institutes of Health Stroke Scale (NIHSS) is a valid, reproducible scale that measures neurological deficit. Of 42 possible points, 7 points are directly related to measurement of language compared with only 2 points related to neglect.

Methods—We examined the placebo arm of the NINDS t-PA stroke trial to test the hypothesis that the total volume of cerebral infarction in patients with right hemisphere strokes would be greater than the volume of cerebral infarction in patients with left hemisphere strokes who have similar NIHSS scores. The volume of stroke was determined by computerized image analysis of CT films and CT images stored on computer tape and optical disks. Cube-root transformation of lesion volume was performed for each CT. Transformed lesion volume was analyzed in a logistic regression model to predict volume of stroke by NIHSS score for each hemisphere. Spearman rank correlation was used to determine the relation between the NIHSS score and lesion volume.

Results—The volume for right hemisphere stroke was statistically greater than the volume for left hemisphere strokes, adjusting for the baseline NIHSS (P<0.001). For each 5-point category of the NIHSS score <20, the median volume of right hemisphere strokes was approximately double the median volume of left hemisphere strokes. For example, for patients with a left hemisphere stroke and a 24-hour NIHSS score of 16 to 20, the median volume of cerebral infarction was 48 mL (interquartile range 14 to 111 mL) as compared with 133 mL (interquartile range 81 to 208 mL) for patients with a right hemisphere stroke (P<0.001). The median volume of a right hemisphere stroke was roughly equal to the median volume of a left hemisphere stroke in the next highest 5-point category of the NIHSS. The Spearman rank correlation between the 24-hour NIHSS score and 3-month lesion volume was 0.72 for patients with left hemisphere stroke and 0.71 for patients with right hemisphere stroke.

Conclusions—For a given NIHSS score, the median volume of right hemisphere strokes is consistently larger than the median volume of left hemisphere strokes. The clinical implications of our finding need further exploration.

Key Words: dominance, cerebral • cerebral infarction • tomography, x-ray computed • infarction volume

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion Appendix I Appendix II References

 
The National Institutes of Health Stroke Scale (NIHSS) is a valid, reproducible scale that measures neurological deficit^{1 2 3} and is one of the most frequently used scales in stroke intervention trials.^{4 5 6} In addition, the NIHSS is increasingly used clinically by physicians and nurses to evaluate stroke patients in emergency departments and hospital settings.

Of the 42 possible points on the NIHSS score, 7 points are directly related to measurement of language (orientation questions, 2; commands, 2; aphasia, 3) and only 2 points are related to neglect.¹ Because the left hemisphere is the language-dominant hemisphere in 99% of right-handed persons (which represents 90% to 95% of the population) and 60% of left-handed persons,^{7 8} the NIHSS may measure the severity and size of strokes in the right hemisphere differently than strokes in the left hemisphere. In a recently published report, Krieger et al⁹ reported that the minimum baseline NIHSS score for fatal brain swelling in left hemisphere strokes was 20 compared with a minimum baseline NIHSS score of 15 for right hemisphere strokes.

We examined the placebo arm of the NINDS t-PA Stroke Trial to test the hypothesis that the median size of cerebral infarction in patients with right hemisphere strokes would be greater than the median size of infarction in patients with left hemisphere strokes who have similar NIHSS scores.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion Appendix I Appendix II References

 
For the 624 patients in the NINDS rt-PA Stroke Trial, 312 were treated with tissue plasminogen activator (TPA) and 312 were treated with placebo. In this report, we used only placebo-treated patients because it was expected that TPA would have a confounding effect on lesion volume. Methods for calculation of CT lesion volumes are provided in Appendix I.

Statistical Methods
We excluded all patients with brain stem strokes. Tests of association between lesion volume, stroke hemisphere, baseline, and 24-hour NIHSS score were performed on the basis of a cube-root transformation of the lesion volume.^{10 11} This approach transforms a 3-dimensional volume into a 1-dimensional measure that stabilizes the variance. After the transformation, the variance was close to the mean and a logistic regression analysis was performed to compute the test statistics with generalized estimating equations.¹² A value of P<0.05 indicated significant associations between the lesion volume and stroke location or NIHSS score.

Because the lesion volume was significantly different between left and right hemisphere strokes after controlling for the NIHSS score at baseline, exploratory analyses were performed. Patients were stratified according to 5-point categories on the NIHSS (0 to 5, 6 to 10, 11 to 15, 16 to 20, 21 to 25, and >25) and then by hemisphere of stroke. The rationale for the use of these categories has been reported previously.³ To summarize, 45 variables constructed from 35 baseline measures were selected to test for linearity in the log odds. On the basis of this analysis, the NIHSS score was divided into 5-point categories.

The transformed lesion volumes for these smaller subgroups were then compared with the use of a logistic regression model by NIHSS score and location of stroke by hemisphere. In addition, Spearman correlation coefficients were calculated and tested for a zero correlation between NIHSS score and location of stroke by hemisphere. A Wilcoxon rank sum test was used to compare the scores for individual items of the NIHSS for right and left hemisphere strokes. Because the range of scores for each item was small, we used the mean score to describe the data.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion Appendix I Appendix II References

 
For the 290 patients with hemispheric stroke enrolled in the placebo arm of the NINDS rt-PA Stroke Trial, 216 (75%) patients had a CT scan performed at 3 months or later than 3 months. CT scans were performed after 18 hours but <3 months in 71 (24%) patients, which was then used as the extrapolated 3-month lesion volume. A total of 287 (99%) patients had a CT scan performed at >18 hours. There was a total of 151 patients with left hemisphere strokes and 139 patients with right hemisphere strokes. The baseline NIHSS was associated with stroke location (right or left hemisphere, P=0.01) and 3-month lesion volume (P0.001). After adjusting for baseline NIHSS score, the lesion volumes for patients with right hemisphere stroke were greater than the lesion volumes for patients with left hemisphere stroke (Figure, P0.001).

View larger version (28K): [in this window] [in a new window]   Figure 1. Cube-root lesion volume for right and left hemisphere strokes compared with baseline NIHSS score. Shaded areas represent 95% confidence intervals.

The median volume of stroke in placebo-treated patients by 5-point strata of baseline and 24-hour NIHSS scores is presented in Table 1. The median volume of right hemisphere stroke was greater than the median volume of left hemisphere stroke for all NIHSS categories at baseline and at 24 hours. For each 5-point category of the NIHSS score <20, the median volume of right hemisphere strokes was more than double the median volume of left hemisphere strokes. The difference in volume for these small subgroups reached statistical significance for baseline NIHSS scores of 16 to 20 and 26 and for 24-hour NIHSS scores of 11 to 15 and 16 to 20. There was a trend toward a larger volume in right hemisphere strokes for 24-hour NIHSS scores of 0 to 5 (P=0.06) and 6 to 10 (P=0.06). The difference in significance values reflects the smaller power of the subgroup analysis compared with that in the Figure, which used data from the entire placebo arm of the NINDS rt-PA Stroke Trial.

View this table: [in this window] [in a new window]   Table 1. Median 3-Month Lesion Volume by Location and NIHSS Strata

The median volume of right hemisphere strokes was approximately equal to the median volume of left hemisphere strokes in the next highest 5-point category (Table 1). For example, the median volume of infarction for a 24-hour NIHSS score of 16 to 20 in patients with a right hemisphere stroke was 133 mL (interquartile range 81 to 209 mL) as compared with a median volume of infarction of 102 mL (interquartile range 28 to 158 mL) for patients with a left hemisphere stroke with a 24-hour NIHSS score of 21 to 25.

At the baseline NIHSS examinations, 36% of left hemisphere strokes had an NIHSS score >20 compared with 13% of right hemisphere strokes (P0.001). At 24 hours, 28% of left hemisphere strokes had an NIHSS score >20 compared with only 13% of right hemisphere strokes (P<0.01).

The Spearman correlation coefficient (r) of the NIHSS scores with 3-month lesion volume by stroke hemisphere is shown in Table 2. The correlation between the NIHSS score at 24 hours and CT lesion volume was very good regardless of location (right hemisphere r=0.72, P0.0001; left hemisphere r=0.71, P0.0001; and all strokes including brain stem r=0.68).

View this table: [in this window] [in a new window]   Table 2. Correlation of Lesion Volume With Baseline and 24-Hour NIHSS Scores

The mean score of each NIHSS item for patients with left and right hemisphere strokes is shown in Table 3. The only items that did not show hemispheric preference were level of consciousness (item 1a), visual fields (item 3), and limb ataxia (item 7). Level of consciousness questions (item 1b) and commands (item 1c), right arm motor (item 5b), right leg motor (item 6b), and dysarthria (item 9) were significantly greater in patients with left hemisphere stroke than patients with right hemisphere stroke. Best gaze (item 2), facial palsy (item 4), left arm motor (item 5a), left leg motor (item 6a), and sensory change (item 8) were found to be statistically significantly greater in right hemisphere strokes compared with left hemisphere strokes. Because of the large number of items compared, the probability value should be considered descriptive.

View this table: [in this window] [in a new window]   Table 3. Mean Item Score for Right vs Left Hemisphere

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion Appendix I Appendix II References

 
Our study demonstrates that for a given NIHSS score, the total lesion volume for patients with right (usually nondominant for language) hemisphere strokes is statistically larger than the lesion volume for patients with left (usually dominant for language) hemisphere strokes. This difference reflects the weighting of the NIHSS with regard to language function, which is localized to the dominant and usually the left hemisphere as compared with hemineglect, which is more prominently related with nondominant hemisphere strokes. Measurement of language accounts for 7 of 42 possible points in the NIHSS as compared with only 2 points associated with neglect.

Our findings may have implications for clinical trials as well as clinical practice. The baseline NIHSS score has been associated with the volume of infarct at 3 months, the clinical severity of stroke at 3 months, the risk of intracerebral hemorrhage in the setting of thrombolytic therapy,^{13 14} and the likelihood of arterial clot on conventional cerebral angiogram (written communication from Thomas J. Tomsick, University of Cincinnati, 1999). The NIHSS is frequently used as an exclusion criteria for acute stroke trials,^{4 5 6} both for patients with very mild strokes and low NIHSS scores and patients with very severe strokes and high NIHSS scores.⁶ Persons with nondominant or right hemisphere strokes with a mild deficit as measured by the NIHSS may be less likely to be enrolled in clinical trials or be treated with TPA in clinical practice than patients with mild dominant left hemisphere strokes. In the placebo group of the NINDS t-PA Stroke Trial, 151 patients had a left hemisphere stroke and 139 patients had a right hemisphere stroke. Similarly, among TPA-treated patients in the NINDS t-PA Stroke Trial, 160 patients had a left hemisphere stroke and 135 patients had a right hemisphere stroke.

When the NIHSS was initially developed and reported, it was found to have a high interrater reliability (=0.69) and correlated with both lesion volume and outcome.¹ Brott et al¹ reported that the Spearman correlation of the NIHSS score at 1 week to lesion volume at 1 week was 0.74 (1.0 representing perfect correlation and zero representing no correlation) and that this was true for both left hemisphere (0.72) and right hemisphere (0.74) strokes. It was also found that the correlation between baseline NIHSS score and 7- to 10-day CT lesion volume had a strong correlation (r=0.74, P0.0001) that occurred regardless of which cerebral hemisphere was involved (r=0.72 for left hemisphere, r=0.74 for right hemisphere).² Our results are consistent with the original analysis of Brott et al.

The high degree of correlation between the NIHSS score and lesion volume for both hemispheres may seem counterintuitive to the idea that the NIHSS is "more sensitive" to the size of left hemisphere strokes. Yet, a high correlation simply refers to the amount of change in the score compared with a change in lesion volume. In the Figure, the total lesion volume correlated well with the baseline NIHSS score for both right and left hemisphere strokes. It is clear that the slope of the regression line is the same for both right and left hemisphere lesions but that the intercepts are different. Thus the NIHSS accurately reflects underlying lesion volume over a range of volumes, with an offset between the 2 hemispheres reflecting the overrepresentation of the left hemisphere in the NIHSS items.

A limitation of this study is that it represents the findings of a single database within a highly selected patient population. Our findings need to be verified in other data sets¹¹ in which the volume of cerebral infarction is carefully measured. Patients in the NINDS t-PA Stroke Trial were examined serially by investigators certified to use the NIHSS and who underwent rigorous retraining every 6 months.³ Therefore it is likely that our results would be replicated in a future study.

The NIHSS reliably and accurately predicts the volume of infarction but does so differently, depending on stroke location. A multivariate model of outcome that includes location of stroke as well as other relevant items such as the NIHSS score may be required to more accurately predict clinical outcomes. Such a model may provide clinicians and investigators with better estimates of hemorrhage risk, long-term outcome, and the likelihood of intra-arterial clot in patients with stroke. The clinical implications of these findings need further investigation.

	Acknowledgments

 
This study was supported by contracts from the National Institutes of Neurological Disorders and Stroke (N-01-NS-02382, N01-NS-02374, N01-NS-02377, N01-NS-02381, N01-NS-02379, N01-NS-02373, N01-NS-02378, N01-NS-02376, and N01-NS-02380).

	Appendix I

Top Abstract Introduction Subjects and Methods Results Discussion Appendix I Appendix II References

 
Calculation of CT Lesion Volume
CT images were obtained and processed at baseline, 24 hours, 7 to 10 days, and 3 months after stroke onset. All of the CT scans were performed on third- or fourth-generation CT scanners. Technical factors included 120 kV, 170 mA, matrix size of 512x512, and scanning time of 3 seconds per slice for posterior cranial fossa and 2 seconds per slice for the supratentorial compartment. All slices were contiguous without interruption with a display field of view of 20 cm. All the CT scans were to be performed from the level of the foramen magnum to high vertex region.

All of the CT scan images were sent to the Coordinating Center for central review. CT scan data were archived on either magnetic tape or optical disk for a lesion volume calculation in 75% of Part 1 patients and optical disk archiving in multiple formats thereafter. For CT scans that did not have available magnetic tape or optical disk, the lesion volume was calculated on the basis of the CT film.

Two different methods were used for evaluating the size of the lesion volume. To measure CT lesion volume, a CT technologist trained by the Central Coordinating Neuroradiologist manually traced the lesion on the digitized image on a computer screen for each slice of the CT scan. The volume of the lesion size was calculated from the number of slices in which the lesion was visible on the CT scan. The Central Coordinating Neuroradiologist then analyzed the entire CT scan and inspected the lesion outlined by the CT technologist and manually made appropriate corrections. The final corrected lesion volume outlined by the Central Coordinating Neuroradiologist was entered into the CT scan database.

The second method of lesion volume calculation was CT scan review by the physicist trained by the Central Coordinating Neuroradiologist. Proprietary software developed at Henry Ford Hospital¹⁵ was used to automatically segment normal and abnormal tissue. Preset threshold CT units were used to segment lesion volume. Segmented lesion volumes were calculated by computer. Segmentation was done from the histogram of the CT image. In addition, a nonlinear edge-preserving filter was used to suppress noise.^{16 17} After automated segmentation, manual correction to the lesion segmentation was performed by the physicist. Finally, the Central Coordinating Neuroradiologist reviewed the entire CT scan, and appropriate corrections were carried out manually on each slice of the CT scan before final data entry. The hard copies of films that did not have a copy on magnetic tape or optical disk were sent to the University of Virginia for lesion measurements. The hard copies were digitized with the use of a Lumisys model 150 digital scanner set at 100-µm spot size or a Vidar scanner at 8 bits per pixel and 150 dots per inch. These images were transferred to a Hewlett-Packard Apollo 9000 series computer for linear and volume measurements. Lesion volume was calculated with segmentation performed on each slice. The operator manually outlined the lesion on each slice multiplied by the slice thickness. The lesion was identified on all the slices, which were then added for the calculation of the final volume of the lesion. Quality control checks were performed to ensure that all images were properly scanned and available for lesion measurements. Slice thickness and the measurement scale were taken into account for calculations of each lesion volume.

For our analyses, we included only those patients who had a measured lesion volume on a CT performed after 18 hours of symptom onset. The volume of any hemorrhagic component (symptomatic or asymptomatic) was included in the lesion volume. CT lesion volume at 3 months or later was used when available. For patients without a 3-month or later lesion volume, we used the lesion volume of the latest CT scan performed after 18 hours of symptom onset.

	Appendix II

Top Abstract Introduction Subjects and Methods Results Discussion Appendix I Appendix II References

 
The following persons and institutions participated in the NINDS rt-PA Stroke Trial: Clinical Centers: University of Cincinnati (150 patients), Principal Investigator: T. Brott; Co-investigators: J. Broderick, R. Kothari; M. O'Donoghue, W. Barsan, T. Tomsick; Study Coordinators: J. Spilker, R. Miller, L. Sauerbeck; Affiliated Sites: St. Elizabeth (South), J. Farrell, J. Kelly, T. Perkins, R. Miller; University Hospital, T. McDonald, Bethesda North Hospital, M. Rorick, C. Hickey; St. Luke (East), J. Armitage, C. Perry, Providence, K. Thalinger, R. Rhude, The Christ Hospital, J. Armitage, J. Schill, St. Luke (West), P.S. Becker, R.S. Heath, D. Adams; Good Samaritan Hospital, R. Reed, M. Klei; St. Francis/St. George, A. Hughes, R. Rhude, Bethesda Oak, J. Anthony, D. Baudendistel, St. Elizabeth (North), C. Zadicoff, R. Miller; St. Luke-Kansas City, M. Rymer, I. Bettinger, P. Laubinger; Jewish Hospital, M. Schmerler, G. Meiros; University of California, San Diego (146), Principal Investigator: P. Lyden; Co-investigators: J. Dunford, J. Zivin; Study Coordinators: K. Rapp, T. Babcock, P. Daum, D. Persona; Affiliated Sites: UCSD, M. Brody, C. Jackson, S. Lewis, J. Liss, Z. Mahdavi, J. Rothrock, T. Tom, R. Zweifler; Sharp Memorial, R. Kobayashi, J. Kunin, J. Licht, R. Rowen, D. Stein; Mercy Hospital, J. Grisolia, F. Martin; Scripps Memorial, E. Chaplin, N. Kaplitz, J. Nelson, A. Neuren, D. Silver; Tri-City Medical Center, T. Chippendale, E. Diamond, M. Lobatz, D. Murphy, D. Rosenberg, T. Ruel, M. Sadoff, J. Schim, J. Schleimer; Mercy General, Sacramento, R. Atkinson, D. Wentworth, R. Cummings, R. Frink, P. Heublein; University of Texas Medical School, Houston (104). Principal Investigator: J.C. Grotta, Co-investigators: T. DeGraba, M. Fisher, A. Ramirez, S. Hanson, L. Morgenstern, C. Sills, W. Pasteur, F. Yatsu, K. Andrews, C. Villar-Cordova, P. Pepe; Study Coordinators: P. Bratina, L. Greenberg, S. Rozek, K. Simmons; Affiliated Sites: Hermann Hospital, St. Lukes Episcopal Hospital, Lyndon Baines Johnson General Hospital, Memorial Northwest Hospital, Memorial Southwest Hospital, Heights Hospital, Park Plaza Hospital, Twelve Oaks Hospital; Long Island Jewish Medical Center (72), Principal Investigators: T.G. Kwiatkowski (6/92-), S.H. Horowitz (12/90–5/92); Co-investigators: R. Libman, R. Kanner, R. Silverman, J. LaMantia, C. Mealie, R. Duarte; Study Coordinators: R. Donnarumma, M. Okola, V. Cullin, E. Mitchell; Henry Ford Hospital (62), Principal Investigator: S.R. Levine; Co-investigators: C.A. Lewandowski, G. Tokarski, N.M. Ramadan, P. Mitsias, M. Gorman, B. Zarowitz, J. Kokkinos, J. Dayno, P. Verro, C. Gymnopoulos, R. Dafer, L. D'Olhaberriague; Study Coordinators: K. Sawaya, S. Daley, M. Mitchell; Emory University School of Medicine (39), Principal Investigator: M. Frankel (7/92–10/95), B. Mackay (11/90–6/92); Co-investigators: J. Weissman, J. Washington, B. Nguyen, A. Cook, H. Karp, M. Williams, T. Williamson; Study Coordinators: C. Barch, J. Braimah, B. Faherty, J. MacDonald, S. Sailor; Affiliated sites: Grady Memorial Hospital, Crawford Long Hospital, Emory University Hospital, South Fulton Hospital: M. Kozinn, L. Hellwick; University of Virginia Health Sciences Center (37), Principal Investigator: E.C. Haley, Jr; Co-investigators: T.P. Bleck, W.S. Cail, G.H. Lindbeck, M.A. Granner, S.S. Wolf, M.W. Gwynn, R.W. Mettetal, Jr, C.W.J. Chang, N.J. Solenski, D.G. Brock, G.F. Ford; Study Coordinators: G.L. Kongable, K.N. Parks, S.S. Wilkinson, M.K. Davis; Affiliated Sites: Winchester Medical Center, G.L. Sheppard, D.W. Zontine, K.H. Gustin, N.M. Crowe, S.L. Massey; University of Tennessee (14), Principal Investigator: M. Meyer (2/93-), K. Gaines (11/90–1/93); Study Coordinators: A. Payne, C. Bales, J. Malcolm, R. Barlow, M. Wilson; Affiliated Sites: Baptist Memorial Hospital, C. Cape; Methodist Hospital Central, T. Bertorini; Jackson Madison County General Hospital, K. Misulis; University of Tennessee Medical Center, W. Paulsen, D. Shepard; Coordinating Center: Henry Ford Health Sciences Center, Principal Investigator: B.C. Tilley; Co-investigators: K.M.A. Welch, S.C. Fagan, M. Lu, S. Patel, E. Masha, J. Verter; Study Coordinators: J. Boura, J. Main, L. Gordon; Programmers: N. Maddy, T. Chociemski; CT Reading Centers: Part A, Henry Ford Health Sciences Center, J. Windham, H. Soltanian Zadeh; Part B, University of Virginia Medical Center, W. Alves, M.F. Keller, J.R. Wenzel; Central Laboratory: Henry Ford Hospital; N. Raman, L. Cantwell; Drug Distribution Center: A. Warren, K. Smith, E. Bailey; National Institute of Neurological Disorders and Stroke, Project Officer: J.R. Marler. Data and Safety Monitoring Committee: J.D. Easton, J. F. Hallenbeck, G. Lan, J. D. Marsh, MD Walker; Genentech Participants: Juergen Froelich, MD, Judy Breed, Fong Wang-Chow.

Received August 18, 1999; revision received August 18, 1999; accepted August 18, 1999.

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