Gradual Lesion Expansion and Brain Shrinkage Years After Stroke
Background and Purpose—Lesioned brains of patients with stroke may change through the course of recovery; however, little is known about their evolution in the chronic phase. Here, we aimed to quantify the extent of lesion volume change and brain atrophy in the chronic poststroke brain using magnetic resonance imaging.
Methods—Optimized T1-weighted scans were collected more than once (time between visits=2 months to 6 years) in 56 patients (age=36–90 years; time poststroke=3 months to 20 years). Volumetric changes attributable to lesion growth and atrophy were quantified with automated procedures. We looked at how volumetric changes related to time between visits, using nonparametric statistics, after controlling for age, time poststroke, and brain and lesion size at the earlier time.
Results—Lesions expanded more in patients who had longer time-intervals between their imaging sessions (partial rank correlation ρ=0.56; P<0.001). The median rate of lesion growth was 1.59 cm3 per year. Across patients, the whole-brain atrophy rate was 0.95% per year, with accelerated atrophy in the ipsilesional hemisphere.
Conclusions—We show gradual lesion expansion many years after stroke, beyond that expected by normal aging and after controlling for other variables. Future studies need to understand how structural reorganization enables long-term recovery even when the brain is shrinking.
It is well established that patients with stroke improve their skills with time. Paradoxically, such improvement typically happens when the brain is shrinking because of, for example, Wallerian degeneration that causes lesion expansion1 and shrinkage of remote regions directly or indirectly connected to the lesion site.2,3 However, accurate estimates of the rate and extent of such changes through the chronic phase are scarce in the neuroimaging literature.1,2 Here, we report a retrospective study of 56 first-time patients with stroke that aims to (1) quantify longitudinal changes in lesion size and brain atrophy during many years after stroke; and (2) test how the amount of change depended on age, lesion size, time poststroke, and time between repeated scans.
Materials and Methods
Patients were selected from our Predicting Language Outcome and Recovery After Stroke (PLORAS) database4 using the following criteria: (1) scanned more than once, (2) all data collected 3 months after stroke with the same magnetic resonance protocol, (3) lesions visible on T1 images, (4) no evidence of other neurological conditions, and (5) tested with the Comprehensive Aphasia Test (CAT).5 A total of 56 patients (14 females) were selected (Figure I in the online-only Data Supplement) with the following features: (1) an age between 36 and 90 years (median=61 years), (2) time poststroke between 3 months and 20 years (median=38 months), (3) time between repeated visits from 2 months to 6 years, (4) 2 repeated scans (n=43), 3 repeated scans (n=10), or 4 repeated scans (n=3), and (5) left hemisphere damage (n=48), right hemisphere damage (n=5), or bilateral damage (n=3).
We used an optimized automated procedure on high-resolution T1-weighted scans to look at volume changes with time in both lesions and brain atrophy (ie, shrinkage outside the frank lesion), in the chronic poststroke brain; see illustration in Figures III and IV in the online-only Data Supplement. Briefly, we ensured an accurate estimation of the amount of change in the following multistep procedure: (1) matching, voxel-by-voxel, the signal across longitudinal anatomic scans, (2) quantifying longitudinal volumetric changes for each patient by generating a standardized difference image between the scan at the first versus the later time point, and (3) looking at associations between volumetric changes and time between first visit and last visit using nonparametric statistical analyses. Specifically, we were able to (1) investigate how volumetric changes depended on a range of factors by varying age, lesion size, years poststroke, and time between repeated scans; and (2) test whether the rate of brain shrinkage was similar in the lesioned and intact hemisphere. See Methods in the online-only Data Supplement for additional methodological details.
First, lesion growth was significant for all patients, irrespective of whether they were tested in the first year or many years after their stroke, and increased with time between visits (Figure). Specifically, lesions expanded more in patients who had longer time-intervals between their visits (Spearman partial rank correlation ρ=0.56; P<0.001) after controlling for age, lesion volume, years poststroke, and total intracranial volume. This effect was not dependent on sex (Results in the online-only Data Supplement).
Second, lesion growth was gradual, with intermediate values observed between those obtained at earlier and later visits in all 13 patients with 3 or 4 repeated scans (Figure). Across patients, the rate of lesion growth varied from 0 to 7.6 cm3/year, with a median rate of 1.59 cm3/year. This rate of lesion growth depended on initial lesion volume (Spearman rank correlation coefficient ρ=0.70; P=0.01). Thus, after adjusting for lesion volume, the median percentage rate of lesion growth was 6.8% per year, with this rate decreasing with years poststroke (ρ=−0.72; P=0.008).
Third, the median whole-brain atrophy rate outside the frank lesion was 0.95% per year across all patients. In the 53 patients with unilateral damage, atrophy in both hemispheres was highly correlated (ρ=0.73; P<0.001), but with an accelerated atrophy (Wilcoxon signed-rank test: P=0.01) in lesioned compared with nonlesioned hemisphere (ie, median hemispheric atrophy rate of 0.99% and 0.85% per year, respectively).
Our findings show that brain lesions continue to expand for many years in the chronic stroke period. We were able to provide more accurate volumetric estimates of lesion growth and atrophy rates than previous studies because our estimates were derived from optimized automated procedures with high spatial resolution (1 mm)3 for longitudinal changes in the same cohort of patients. Those volumetric estimates were shown to increase gradually with the time between repeated visits and depended on other factors that were not fully considered in previous reports, including age, time poststroke, time between repeated visits, and brain size and lesion size. As expected, there was little impact of the conspicuous brain shrinkage on long-term recovery of language functions (Figure V and Results in the online-only Data Supplement for additional details).
Across our 56 patients, lesions grew at a rate of 1.59 cm3/year (equivalent to 6.8% per year when adjusted for initial lesion volume). This is to some extent larger than a previous estimate from Naeser et al1 (range=0% to 7% for 12 patients), perhaps because of differences in scanning techniques (here magnetic resonance imaging instead of computerized tomography), methodology (automated instead of manual segmentations), sample size (56 versus 12), and the interval between repeat tests that was shorter here (2 months to 6 years) than in the study of Naeser et al (4.7 years to 12 years). However, our estimates are at similar rates to those reported for other lesions including for instance MS (eg, a median change rate6 of 8% and a growth7 of 0.8–2.9 cm3/year).
Outside the lesion, our patients with stroke also showed a significant atrophy at a rate of 0.95% per year, which is higher than the typical age-related atrophy of ≈0.5% but lower than the 1.5% to 2.5% rates commonly seen in patients with Alzheimer disease.8,9 Moreover, we note an accelerated atrophy in the lesioned hemisphere compared with the contralesional hemisphere, suggesting a dominant contribution of stroke-related factors on atrophy rate during the recovery course. Whether this could explain why patients with stroke are prone to developing dementia10 and depression11 needs further investigation.
In summary, we have shown that the brain continues to shrink for many years, after stroke onset at a rate that is higher than in normal aging brains but significantly less than in dementing brains. A shrinking brain after stroke is not necessarily a deteriorating brain in the sense that lesion growth and atrophy result from the multiple degenerative and restorative processes by which our plastic brains reorganize themselves to consolidate recovery. Indeed, we found little impact of brain shrinkage on long-term recovery of language functions. Future work needs to examine whether this finding generalizes to other, nonlanguage, abilities and how lesion growth and atrophy rates interact with intervention with time. For instance, longitudinal studies can examine whether specific pharmacological or behavioral therapies in the acute phase may have a long-lasting impact on brain reorganization that may change brain shrinkage rates in the chronic phase.
We are grateful to the patients for their participation.
Sources of Funding
This work was funded by the Wellcome Trust and the James S. MacDonnell Foundation.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.003587/-/DC1.
- Received September 18, 2013.
- Accepted December 4, 2013.
- © 2014 American Heart Association, Inc.
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