Impact of brain atrophy on 90-day functional outcome after moderate-volume basal ganglia hemorrhage

This study aimed to evaluate the effect of brain atrophy on the functional outcome of patients with moderate-volume basal ganglia hemorrhage. Of 1003 patients with spontaneous intracerebral hemorrhage, 124 with moderate-volume basal ganglia hemorrhage (hematoma volume of 20–50 mL) were enrolled. The intercaudate distance (ICD) and sylvian fissure ratio (SFR) were used as linear brain atrophy parameters. The patients were divided into groups with favorable and unfavorable outcomes, according to the Glasgow Outcome Scale score, 90 days after symptom onset. Demographic and radiographic features, including the ICD and SFR, were compared between the two groups. Among the 124 patients, 74 (59.7%) exhibited a favorable outcome. The ICD and SFR values were significantly greater for the favorable group than for the unfavorable group. Multivariate analysis indicated that young age, high Glasgow Coma Scale score at admission, small hematoma volume, and increased ICD (odds ratio [OR], 1.207; 95% confidence interval [CI], 1.004–1.451) and SFR (OR, 1.046; 95% CI, 1.007–1.086, per 0.001) values had a beneficial effect on functional outcome. In conclusion, brain atrophy exhibits protective effects in patients with moderate-volume basal ganglia hemorrhage, and is an important factor for predicting functional outcome.

All the patients' medical records from hospital charts and radiographic studies were reviewed. The functional outcome was evaluated using the Glasgow Outcome Scale (GOS) at 90 days after symptom onset. A GOS score of 4-5 was considered a favorable outcome, while 1-3 was considered unfavorable. Outcome measurement was performed during outpatient visits or via telephone interviews.
This study was approved by the institutional review board of Hanyang University Medical Center. Owing to the retrospective nature, the need for informed consent was waived. Image analysis. For most patients, hematoma volume was measured from initial CT scans; follow-up CT was used when hematoma expansion was detected. To estimate hematoma volume, we used the ABC/2 formula, where A represents the largest diameter on axial CT slices, B represents the diameter perpendicular to A on the same slice, and C represents the number of slices with a visible hematoma, multiplied by the slice thickness 14 . A volume of 20-50 mL was considered moderate 15 .
We used the intercaudate distance (ICD) and sylvian fissure ratio (SFR) on CT scans as parameters of brain atrophy. The ICD, which represents central atrophy, was defined as the minimum distance between the caudate indentations on the frontal horns of the lateral ventricles 16,17 . The SFR, which represents cortical atrophy, was defined as the average maximum width of both sylvian fissures in the section where they appeared widest, divided by the transpineal inner table diameter (Fig. 1A) 16,17 . However, as hematoma on the morbid side can obscure measurements, only the unaffected hemisphere was assessed 17 . Therefore, the ICD was replaced by the hemi-ICD: the minimum distance between the caudate indentation on the unaffected side and the septum pellucidum, multiplied by 2 (Fig. 1B). The width of the sylvian fissure on the unaffected side only was used for calculating the SFR (Fig. 1C). These measurements were independently conducted by a neurosurgeon and a neuroradiologist, blinded to the clinical outcome. The mean value of each measurement was used to enhance precision. Patient treatment. All patients were hospitalized within 3 days of symptom onset, and received acute stage treatment in a neurosurgical intensive care unit. A CT scan was obtained for all patients upon admission. A second scan was obtained after 4-8 hours, unless the neurological status deteriorated. Systolic blood pressure was maintained <140 mmHg using antihypertensive agents. Osmotic diuretics (mannitol and glycerol) were administrated to control increased ICP. Prophylactic antiepileptic drugs were not used, and any anticoagulation or antiplatelet medications were discontinued for at least 5 days from the time of admission. Based on the Glasgow Coma Scale (GCS) score, hematoma volume, mass effect, and presence of herniation, surgical treatment involving stereotactic catheter insertion or hematoma evacuation with craniotomy was considered. All patients underwent a comprehensive rehabilitation program during or after hospitalization. Statistical analysis. All statistical analyses were performed using SPSS version 18.0 (SPSS, Chicago, Illinois). Student's t-test or Mann-Whitney U test was used to compare continuous variables, and chi-square or Fisher's exact test was used to compare categorical variables. Continuous variables were expressed as the mean ± standard deviation or median (interquartile ranges), while discrete variables were expressed as a count with percentage. Pearson's correlation analysis was used to investigate the correlation between two continuous variables. To identify independent predictors of the functional outcome, backward logistic regression analysis was performed. Variables were considered for multivariate analysis only if they exhibited a P-value <0.2 in univariate analysis. A P-value <0.05 was considered statistically significant.
Data availability. All data generated or analysed during this study are included in this published article (and its Supplementary Information files).

Results
Overall clinical outcome and group comparisons. Of the 124 patients (36 women; 55.7 ± 11.8 years) with moderate-volume basal ganglia hemorrhage, 74 (59.7%) showed favorable functional outcomes based on the GOS score at 90 days. Table 1 shows the baseline characteristics of the patients according to functional outcome. Brain atrophy parameters were significantly greater for the favorable group than for the unfavorable group. However, due to severe brain edema affecting the contralateral hemisphere, ICD and SFR measurements were not obtained for 7 and 3 patients, respectively.
Prognostic factors for favorable outcome. The results of the logistic regression analysis are summarized in group, with an ICD <13.22 mm). Clinical and radiographic features were compared between the two groups ( Fig. 2 and Supplementary Table S1). The mean age was significantly different between the atrophy and non-atrophy groups (60.5 ± 12.1 vs. 50.7 ± 10.1 years; P < 0.001), and the ICD increased with advancing age ( Fig. 2A, correlation coefficient = 0.432; P < 0.001). Figure 2B presents the relationship between hematoma volume and midline shift. The mean midline shift was significantly smaller in the atrophy group than in the non-atrophy group (3.3 ± 2.2 vs. 6.1 ± 3.1 mm; P < 0.001). Additionally, there was no apparent correlation between the increase in midline shift and the hematoma volume in the atrophy group (correlation coefficient = 0.190; P = 0.150), whereas the midline shift was  significantly augmented by the hematoma volume in the non-atrophy group (correlation coefficient = 0.631; P < 0.001). Figure 2C and D show the distribution of initial GCS scores and the treatment modalities used for the two groups. The admission GCS score was higher in the atrophy group than in the non-atrophy group (median, 14, interquartile range [IQR], 13-14 vs. 11.5, 9-13; P < 0.001). Moreover, the proportion of patients with a GCS score ≥13 was higher in the atrophy group than in the non-atrophy group (78.0 vs. 34.5%; P < 0.001), and patients in the former group exhibited a greater tendency of receiving nonsurgical treatment compared with those in the latter (44.1 vs. 13.8%; P < 0.001).

Discussion
This study was performed to assess the contribution of advanced brain atrophy to favorable functional outcome in patients with moderate-volume basal ganglia hemorrhage. Several studies have found that brain atrophy prevents malignant outcomes by reducing the mass effect in patients with large cerebral infarctions 9-12 . Furthering these findings, the protective effect of brain atrophy against space-occupying lesions has been demonstrated in this study. Both the ICD and SFR were significantly correlated with a favorable outcome. This indicates that the relative increase in the intracranial volume reserve, caused by brain atrophy, may prevent an increase in ICP and subsequent brain herniation, thereby protecting against cerebral edema. Conversely, Herweh et al. suggested cerebral atrophy as an independent risk factor for poor outcome following spontaneous ICH and reported that preexisting neurodegenerative changes may result in an unfavorable outcome in such cases 13 . This apparent discrepancy in results can be attributed to the difference in study design, in terms of patient inclusion. Herweh et al. included hemorrhages in any supratentorial region that exhibited a wider volumetric range and smaller mean volume (mean, 12.8; range, 0.3-153.4 mL) compared with those included in this study 13 . Since local mass effects have different impacts depending on their locations, swelling in the basal ganglia is more strongly associated with a poor outcome compared with swelling at other locations 9 . Consequently, superficially located smaller hematomas are considered to result in a less prominent mass effect compared with the lesions included in this study.
Previously identified prognostic factors (age, hematoma volume, and admission GCS score) are also well-reflected in our study [5][6][7][8]18,19 . Interestingly, age did not exhibit significant effect in univariate analysis, although it was strongly associated with clinical outcome 19 . This may be due to age-related differences in brain atrophy. As brain atrophy is mostly influenced by age 20,21 , it seems to counteract the worsening effect of advanced age on clinical outcome. Another study investigated the prognostic factors for spontaneous ICH using inclusion criteria similar to those used in this study, and likewise showed a weak correlation between age and clinical outcome in univariate analysis (P = 0.282) 15 .
The admission GCS scores and midline shift showed significant differences between the atrophy and non-atrophy groups. The initial GCS score is a powerful and independent prognostic factor for clinical outcome 22 . The GCS scores and proportion of patients with a GCS score ≥13 were significantly higher in the atrophy group than in the non-atrophy group. Midline shift resulting from brain edema is a major determinant of cerebral herniation and a malignant outcome 23,24 . In this study, the midline shift was smaller in the atrophy group than in the non-atrophy group. Moreover, the increase in midline shift, in proportion to the hemorrhage volume, was smaller in the atrophy group. Therefore, preexisting brain atrophy may provide protection against an unfavorable outcome by decreasing ICP and preventing midline shift in the acute phase, despite possible neurodegeneration unrelated to injury. In the atrophy group, however, involvement of the dominant hemisphere was less frequent (33.9% vs. 55.2%; P = 0.003) and hematoma volumes were relatively small (median, 29.5, IQR, 23.4-36.8 vs. 35.9, 24.9-44.4 mL; P = 0.141) compared with those in the non-atrophy group. This may have influenced the disparity in other variables between the two groups.
In the present study, only patients with a hematoma volume of 20-50 mL were included. While the treatment and prognosis of moderate-volume hemorrhage have the greatest uncertainty 4 , a hematoma volume <20 mL manifests in little mass effect, and bleeding >50 mL correlates with high mortality, even with adequate treatment 18 . Hence, the compensatory effect of brain atrophy would not be obvious in either of these groups. Additionally, patients with hemorrhage extending to the ventricles were excluded because this may influence the outflow of cerebrospinal fluid (CSF) and measurement of the ICD.
We used the ICD and SFR as linear brain atrophy parameters. However, in some patients, hematoma obscured measurements in the contralateral hemisphere. Although 7 patients were excluded from atrophy measurement because the contralateral ventricle and/or sylvian fissure were already collapsed, mild deformation was seen in a small number. This subtle change may have caused inaccuracy in measurements. Several studies have used a semiautomatic method to perform volumetric analysis of the intracranial and CSF spaces 11,13 . While this process improves measurement accuracy, it requires a specialized assessment technique and is not easily applicable in clinical practice. Therefore, we used linear measurements that allow simple and reliable assessment of brain atrophy, with considerable interobserver agreement 16,17 .
This study has the following limitations: firstly, since the study was retrospective, selection bias cannot be excluded, and some data were unobtainable; secondly, the number of enrolled patients was relatively small, which can lower the statistical power, because inclusion was limited to patients with a precise hemorrhage size and location; thirdly, treatment modalities were varied; this heterogeneity may have affected the results; finally, as mentioned earlier, the measurement of brain atrophy may not be precise in some patients due to severe brain edema affecting the contralateral hemisphere.
In conclusion, preexisting brain atrophy exhibits a protective effect in patients with basal ganglia hemorrhage. This suggests that brain atrophy, along with age, hematoma volume, and initial neurological state, may provide prognostic information regarding the functional outcome following moderate-volume basal ganglia hemorrhage.