Keywords
chronic subdural hematoma - recurrence - eosinophils - systemic immune inflammation
- predictors
Introduction
Chronic subdural hematoma (CSDH) is a prevalent neurosurgical condition characterized
by the accumulation of blood between the dura mater and the arachnoid membrane surrounding
the brain.[1]
[2] It mainly affects older adults, with an incidence that increases significantly with
age, peaking between 60 and 80 years of age.[3] Although the precise etiology of CSDH is still unknown, it is usually accepted to
be the consequence of bridging vein rupture in the subdural region, frequently as
a result of mild head trauma.[4] This causes blood to gradually accumulate and cause brain tissue damage underneath,
resulting in a range of neurological symptoms.[5]
The mainstay of treatment for symptomatic CSDH is surgical hematoma evacuation, with
burr hole craniotomy and drainage being the most often sought technique.[6] Up to 20% of cases experience CSDH recurrence, which poses a considerable clinical
issue even with the typically positive outcomes of surgery.[7] In addition to requiring more surgical procedures, recurrence increases the risk
of complications and worsen long-term neurological effects. Therefore, determining
credible preoperative indicators for CSDH recurrence is crucial to enhancing patient
care and achieving better outcomes. Peripheral blood indicators may play a role in
anticipating the return of CSDH, according to recent studies.[8]
[9]
[10]
[11] Promising choices among these measures include eosinophil levels and the systemic
immunological inflammation (SII) index.[12]
[13]
Eosinophils are a subset of white blood cells that are involved in inflammation reactions
as well as allergy and parasite disorders.[14]
[15] Research has shown that eosinophils are present in both the surrounding membrane
and the hematoma fluid, suggesting that they may play a role in the pathophysiology
of CSDH.[16]
[17]
[18] According to certain theories, eosinophils could be involved in the persistent inflammation
and neovascularization that are seen in CSDH, which could affect the likelihood of
recurrence.[19] Increased preoperative eosinophil levels have been linked to a higher chance of
CSDH recurrence.[20] However, the precise processes behind this correlation are yet unknown.
Apart from eosinophils, another new marker that has been utilized to predict outcomes
in a variety of medical illnesses such as cancer, cardiovascular disease, and inflammatory
disorders is the SII.[21] The SII index reflects the balance between systemic inflammation and immune response
and is dependent on the levels of neutrophils, platelets, and lymphocytes in the peripheral
blood. Blood measures, such as the absolute counts of neutrophils, lymphocytes, and
platelets, are used to compute the SII.[22] Leukocyte counts around the brain's membranes have been linked to alterations in
most investigations,[23] suggesting that they could be a valuable diagnostic sign that affects the SII index.
It offers a thorough assessment of immune function and systemic inflammation, indicating
the ratio of pro- to anti-inflammatory reactions. Therefore, the present study was
undertaken to investigate the association between preoperative eosinophil levels,
SII, and the risk of postoperative CSDH recurrence.
Materials and Methods
The sample size was calculated and resulted in a sample size of 119 patients. The
119 recruited patients had CSDHs in 123 cerebral hemispheres. The prospective study
was conducted from January 2023 to January 2024 at the Department of Neurosurgery,
Institute of Medical Sciences, Banaras Hindu University. The study received approval
from the institute's ethical board. The presumptive diagnosis of CSDH was made using
noninvasive methods, like magnetic resonance imaging (MRI) or computed tomography
(CT) scans. The inclusion and exclusion criteria were followed to recruit the patients.
Patients diagnosed with CSDH, confirmed by neuroimaging such as CT or MRI, and exhibiting
neurological symptoms attributable to CSDH, who underwent burr hole drainage or craniotomy,
and were able to attend follow-up visits, were included in the study. Patients with
a history of previous neurosurgical procedures unrelated to the current CSDH, those
with other significant intracranial pathologies such as brain tumors or arteriovenous
malformations, and patients with severe systemic diseases that might confound the
study results, such as active malignancy, were excluded from the study. Informed consent
was obtained from all participants, and thorough discussions were held regarding any
potential discomfort, disadvantages, and outcomes of the study with the participants.
Baseline clinical and demographic characteristics of the patients were recorded. Clinical
characteristics were defined as follows. A diastolic blood pressure of 90 mm Hg or
higher, a systolic blood pressure of 140 mm Hg or higher, or the use of antihypertensive
medication were the markers of hypertension. The usage of hypoglycemic medications
or a hemoglobin A1c value greater than 6.5% were used to characterize diabetes mellitus.
A platelet counts of less than 100 × 103/µL was defined as thrombocytopenia. At presentation, patients were classified as
either H1 blocker, steroid, oral antiplatelet, or anticoagulant users.
Ten days before surgery, the preoperative differential leukocyte count (DLC) was measured
using peripheral blood. The SII was calculated using the following formula: SII =
neutrophil count × platelet count/lymphocyte count.[24] The standard surgical protocol was followed for doing the burr hole surgery. The
surgical procedure was outlined as follows: burr hole craniotomy was performed under
local anesthesia, followed by evacuation and irrigation of the hematoma. Only in the
cases where the initial burr hole proved challenging for irrigation and evacuation
of hematoma was a second burr hole created. For irrigation, normal saline was utilized.[25] A closed drainage system was usually left in the hematoma cavity for 12 to 48 hours
after surgery. Following surgery, the patients were monitored for a minimum of 3 months
or until the CSDH disappeared, indicating resolution. Any future recurrence of postoperative
CSDH was documented. A symptomatic ipsilateral growth of the CSDH on postoperative
day 7 or later, indicating the necessity for repeat surgery, was considered a recurrence
of CSDH. Severe headaches, dementia, decreased consciousness, and neurological deficits,
including limb weakness or aberrant gait, were considered indicative of CSDH recurrence.
Early subdural hemorrhage after surgery that happened before postoperative day 6 was
regarded as a surgical complication rather than a recurrence.
Data Analysis
The data were anonymously coded and recorded in Microsoft Excel 2021 (Microsoft.,
Inc). Statistical analysis was conducted using SPSS software version 29 (SPSS Inc.,
Chicago, IL). Descriptive statistical analysis was employed to present the data in
percentages and frequencies. Logistic regression analysis was carried to investigate
the risk factors for CSDH recurrence. A p-value less than 0.05 was considered statistically significant. The data were presented
with the mean ± standard deviation. Missing data were addressed using several imputation
strategies. This method involved creating several complete datasets by filling in
missing values with plausible estimates based on observable data patterns. Each imputed
dataset was then analyzed independently. The results from these analyses were pooled
to produce the final estimates, thus accounting for the uncertainty associated with
the missing data.
To control confounders, we ran multivariate regression analyses, which allowed us
to analyze the independent relationship between the variables of interest and the
result while correcting for any confounding factors.
Results
Initially, we identified 119 patients who underwent 123 surgeries for CSDH. Among
these, 12 patients were excluded from the study due to insufficient data regarding
their medical history, and 2 patients with four CSDH surgeries did not attend the
follow-up. Finally, 105 patients participated in the study ([Fig. 1]). Out of the 105 patients, CSDH recurrence was observed in 11 patients, accounting
for approximately 10.5% of the recruited patients. The demographic variables, along
with the presence of certain comorbidities and medications involved, are shown in
[Table 1].
Table 1
Demographic variables of the patients (n = 105)
|
Variable
|
n
[a]
|
|
Age
|
61.8 ± 8.4
|
|
Gender
|
|
Male
|
94 (89.5)
|
|
Female
|
11 (10.5)
|
|
Days of admission
|
5.45 ± 1.6
|
|
Comorbidity
|
|
Hypertension
|
30 (28.6)
|
|
Asthma
|
9 (8.6)
|
|
Thrombocytopenia
|
5 (4.8)
|
|
Diabetes Mellitus
|
32 (30.5)
|
|
Medication
|
|
Antiplatelets
|
16 (15.2)
|
|
Anticoagulants
|
4 (3.8)
|
|
Steroids
|
10 (9.5)
|
|
Histamine H1-receptor antagonist
|
15 (14.3)
|
|
Bilateral Operation
|
4 (3.8)
|
|
Hematoma (vol, mL)
|
87.3 ± 15.5
|
|
Recurrence of CSDH
|
11 (10.5)
|
Abbreviation: CSDH, chronic subdural hematoma.
a The values are represented as frequency and in round brackets as a percentage. Age,
days of admission, hematoma volume, and recurrence of CSDH are presented as mean ± standard
deviation.
Fig. 1 Flowchart showing the selection of patients. CSDH, chronic subdural hematoma.
Preoperative DLC was evaluated to explore any association with CSDH recurrence. The
distribution revealed that eosinophil count was significantly higher in patients who
experienced a recurrence of CSDH (p < 0.001; [Fig. 2]), while other white blood cell indices, except neutrophils (p = 0.038), did not show any significant relation with CSDH recurrence ([Table 2]). However, the SII index was significantly higher in patients who experienced recurrence
of CSDH compared with nonrecurrent patients (p = 0.003; [Fig. 3]).
Fig. 2 Distribution of eosinophil count in chronic subdural hematoma (CSDH) patients.
Fig. 3 Systemic immunological inflammation (SII) index in chronic subdural hematoma (CSDH)
recurrent and nonrecurrent patients.*** signifies that P-Value of data is significant.
Table 2
Preoperative differential leukocyte count in CSDH patients (n = 105)
|
Differential leukocyte count (/µL)
|
CSDH recurrence
|
p-Value
|
|
No (n = 94)
|
Yes (n = 11)
|
|
Neutrophils
|
7,053 ± 489
|
8,822 ± 149
|
0.038
|
|
Lymphocytes
|
3,031 ± 447
|
1,143 ± 93
|
0.317
|
|
Monocytes
|
333 ± 186
|
210 ± 106
|
0.106
|
|
Eosinophils
|
40 ± 29
|
340 ± 136
|
< 0.001
|
|
Basophils
|
5 ± 6
|
3 ± 2
|
> 1.0
|
|
Platelets
|
225,834 ± 131,286
|
264,000 ± 17,395
|
0.981
|
|
SII
|
535,926 ± 310,318
|
2,046,900 ± 197,283
|
0.003
|
Abbreviation: SII, systemic immunological inflammation.
We found a direct correlation between the recurrence rate of CSDH and preoperative
eosinophil count. To determine if a patient is eosinophil rich or eosinophil poor
and to correlate eosinophil-rich/eosinophil-poor status with other independent variables,
we calculated a cutoff value for eosinophils. A receiver operating characteristic
(ROC) curve with an area under the curve (AUC) of 0.902 (95% confidence interval [CI]:
0.73–2.53; p = 0.041) was obtained ([Supplementary Fig. S1], available in the online version). We identified 100/µL as the cutoff value. Thus,
eosinophil count ≥100/µL was considered rich, and lower than these counts were considered
eosinophil poor. Among the 105 patients, 11 were found to be eosinophil rich and 94
were eosinophil poor. Certain demographic variables such as male gender, diabetes
mellitus, and hematoma volume showed significant associations with eosinophil-rich
and eosinophil-poor status ([Table 3]). The relationship between anticoagulant medication use was found significantly
associated with the eosinophil status (p = 0.05); however, comorbidities like asthma, hypertension, thrombocytopenia, and
other medication were found insignificant with the eosinophil status ([Table 3]).
Table 3
Eosinophil rich/poor status in CSDH patients
|
Factor
|
Total
|
Eosinophil status
|
p-Value
|
|
Rich
|
Poor
|
|
No. of CSDH
|
105
|
11 (10.5)
|
94 (89.5)
|
|
|
Mean age
|
105
|
74 ± 3
|
60 ± 7
|
0.081
|
|
Male
|
94
|
11 (12)
|
33 (88)
|
0.031
|
|
Medical history
|
|
Hypertension
|
30
|
10 (34)
|
20 (66)
|
0.791
|
|
Diabetes mellitus
|
32
|
9 (29)
|
23 (71)
|
0.051
|
|
Thrombocytopenia
|
5
|
0
|
5 (100)
|
–
|
|
Asthma
|
9
|
0
|
9 (100)
|
–
|
|
Drugs used
|
|
Antiplatelets
|
16
|
11 (68)
|
5 (32)
|
0.052
|
|
Anticoagulants
|
4
|
3 (75)
|
1 (25)
|
0.050
|
|
Steroids
|
10
|
3 (30)
|
7 (70)
|
0.059
|
|
Histamine h1-receptor antagonist
|
15
|
2 (13)
|
13 (87)
|
0.503
|
|
Bilateral Operation
|
4
|
0
|
4 (100)
|
–
|
|
Hematoma (vol, mL)
|
105
|
122.5 ± 8
|
83.2 ± 10
|
0.048
|
Abbreviation: CSDH, chronic subdural hematoma.
Multivariate and univariate regression analyses were conducted to check the association
of various risk factors with CSDH recurrences ([Table 4]). In the univariate analysis, age (adjusted odds ratio [AOR] 0.23; 95% CI: 0.11–0.37;
p < 0.001), hypertension (AOR: 0.31; 95% CI: 0.22–0.53; p = 0.05), diabetes mellitus (AOR: 0.37; 95% CI: 0.17–0.51; p = 0.005), SII (AOR: 1.94; 95% CI: 1.51–2.39; p = 0.005), and hematoma volume (AOR: 2.14; 95% CI: 1.17–3.15; p < 0.001) were found to be independent predictors of CSDH recurrence, along with thrombocytopenia
(AOR: 0.58; 95% CI: 0.41–0.67; p < 0.001) and the use of anticoagulant and antiplatelet drugs, with an AOR of 0.76
(95% CI: 0.17–1.86; p = 0.002) and an AOR of 1.17 (95% CI: 0.87–2.01; p < 0.001), respectively ([Table 4]). The multivariate analysis showed hematoma volume AOR of 3.10 (95% CI: 2.47–5.62;
p < 0.001), thrombocytopenia (AOR: 3.67; 95% CI: 2.26–7.81; p = 0.019), and antiplatelet regimen as significant predictors of CSDH recurrence (AOR:
1.73; 95% CI: 0.94–5.91; p = 0.047; [Table 4]).
Table 4
Univariable and multivariable logistic regression analysis of predictors of CSDH recurrence
|
Variable
|
Univariate
|
Multivariate
|
|
AOR (95% CI)
|
p-Value
|
AOR (95% CI)
|
p-Value
|
|
Age
|
0.23 (0.11–0.37)
|
<0.001
|
–
|
–
|
|
Gender
|
0.13 (0.08–5.17)
|
0.394
|
–
|
–
|
|
Medical condition
|
|
Hypertension
|
0.31 (0.22–0.53)
|
0.050
|
0.48 (0.44–4.69)
|
0.327
|
|
Asthma
|
0.13 (0.10–1.99)
|
0.364
|
Ref
|
|
Diabetes mellitus
|
0.37 (0.17–0.51)
|
0.005
|
0.43 (0.23–5.30)
|
0.052
|
|
Thrombocytopenia
|
0.58 (0.41–0.67)
|
<0.001
|
3.67 (2.26–7.81)
|
0.019
|
|
Drugs used
|
|
Histamine
|
0.18 (0.09–0.61)
|
0.301
|
Ref
|
|
Steroids
|
1.24 (0.03–3.71)
|
0.104
|
0.48 (0.21–3.86)
|
0.061
|
|
Anticoagulants
|
0.76 (0.17–1.86)
|
0.002
|
1.84 (0.38–8.25)
|
0.138
|
|
Antiplatelets
|
1.17 (0.87–2.01)
|
<0.001
|
1.73 (0.94–5.91)
|
0.047
|
|
Bilateral Operation
|
–0.12 (–0.6 to 0.35)
|
>0.999
|
0
|
|
Hematoma (vol, mL)
|
2.14 (1.17–3.15)
|
<0.001
|
3.10 (2.47–5.62)
|
<0.001
|
|
SII
|
1.94 (1.51–2.39)
|
0.005
|
–
|
–
|
Abbreviations: AOR, adjusted odds ratio; CI, confidence interval; CSDH, chronic subdural
hematoma; SII, systemic immune inflammation.
Discussion
Preoperative eosinophil count and CSDH recurrence have a strong correlation (p < 0.001), suggesting that eosinophils may play a role in the pathophysiology of recurrence.
Eosinophils are well known for their roles in inflammatory processes such as tissue
healing, allergic reactions, and parasite infections.[12]
[14]
[15] Numerous mechanisms could account for their contribution to recurrence in the setting
of CSDH. For instance, eosinophils release proinflammatory mediators like cytokines,
chemokines, and growth factors that have the ability to intensify the inflammatory
cascade, increasing vascular permeability and drawing additional immune cells to the
site of damage in the subdural region, encouraging hematoma growth and recurrence.[26]
[27] Furthermore, eosinophils produce proteins and enzymes, such as major basic protein
and eosinophil peroxidase, which causes fibrosis and tissue damage.[28] Fibrosis and chronic inflammation are the defining characteristics of chronic systemic
inflammatory diseases like CSDH. The presence of prolonged eosinophil has also been
linked to the creation of a fibrous, thick capsule around the hematoma, which may
facilitate recurrence.[29]
[30] Likewise, vascular endothelial growth factor, which is formed by eosinophils, has
the ability to induce angiogenesis, which may facilitate the growth and recurrence
of hematomas.[31]
Previous investigations support the fact that patients with recurrent CSDH have increased
eosinophil levels. For instance, Matsubara et al showed that preoperative eosinophils
have a rich predictive power in predicting the recurrence of CSDH.[20] This implies eosinophils penetrate the hematoma membrane and release inflammatory
cytokines that aid in the genesis of the immune response. Likewise, Davidson et al
observed a correlation between increased eosinophil-to-lymphocyte ratio and recurrence
of CSDH,[12] implying a possible function of eosinophils in the advancement or recurrence of
the disease.
Neutrophils (p = 0.047) were the only white blood cell index that showed a significant correlation
with CSDH recurrence, indicating a distinct function for neutrophils in the pathophysiology
of recurrence. As the first immune system cells to respond to tissue damage and infection,
neutrophils are essential to the acute inflammatory response.[32] Patients with recurrent CSDH may have high levels of these substances, which could
indicate persistent inflammation and tissue damage in the subdural region. The lack
of association between other leukocyte cell types and CSDH recurrence suggests that
chronic inflammation and immune dysregulation, rather than an acute immune response,
may drive disease progression.[33]
Conflicting reports exist regarding the association of various DLCs in identifying
CSDH recurrence. For instance, Zhang et al suggested higher numbers of neutrophils
and platelets in recurrent CSDH patients compared with control groups.[10] Similarly, another study found that lymphocytes play a nonsignificant role in predicting
CSDH recurrence.[34] Additionally, a study identified the neutrophil-to-lymphocyte ratio as an independent
predictor associated with CSDH, although it could not conclusively determine if this
ratio is a significant predictive factor for CSDH recurrence.[35]
Individuals with a recurrence of CSDH were shown to have a considerably higher SII
index than individuals without a recurrence. The SII is a composite indicator of the
immunological state and systemic inflammation that takes platelet, lymphocyte, and
neutrophil numbers into account.[24]
[36] A proinflammatory condition is evident by elevated SII levels, which show an imbalance
in the immune response with more neutrophils and fewer lymphocytes. Patients with
recurrent CSDH may have a more prominent inflammatory response, as indicated by their
increased SII. Reduced lymphocytes and elevated neutrophil counts could indicate persistent
subdural space inflammation that encourages hematoma recurrence. Studies investigating
the SII index are more prevalent in the context of traumatic brain injury, with only
a few studies evaluating its use in predicting brain hemorrhage.[37]
[38]
[39] Our results are consistent with these findings, indicating that the SII index, derived
from a ratio of two fitted parameters, is likely more reliable than other parameters.
Male gender, thrombocytopenia, and hematoma volume strongly correlated with the eosinophil-rich
and eosinophil-poor status.[40]
[41] The eosinophil-rich status was found to be significantly correlated with male gender,
which is in line with other studies showing a higher prevalence of CSDH in men.[42] This suggests that there may be a gender-specific susceptibility to CSDH recurrence,
which could be brought on by differences in hormonal profiles or inherited tendencies.
Furthermore, a strong association was found between thrombocytopenia and the presence
of eosinophils. Although we did not assess these characteristics in our study, low
platelet counts in thrombocytopenia may indicate underlying systemic disorders or
hematologic issues that could impact the inflammatory response and cause a recurrence
of CSDH. The strong association between hematoma volume and eosinophil-rich status
suggests that larger hematomas are associated with eosinophil-rich inflammatory responses.[43]
Our findings have significant clinical implications that could influence patient management
and clinical practice in treating CSDH. The identification of preoperative eosinophil
counts and the SII index as predictive markers for CSDH recurrence can provide clinicians
with valuable tools for risk stratification. Patients identified as high risk based
on these biomarkers could benefit from more aggressive management strategies, such
as enhanced surgical precision, extended postoperative observation, and early intervention
protocols for recurrence. Additionally, routine preoperative screening for these markers
could become a standard part of the clinical workflow, thereby enabling personalized
treatment plans that improve patient outcomes and reduce the likelihood of recurrence.
By incorporating these predictive markers into clinical protocols, we can enhance
the overall quality of care for patients with CSDH, leading to better prognostic assessments
and optimized therapeutic interventions.
Limitations
Although our study provided insightful information, there is a certain limitation
associated with this study. The limited number of 105 patients in the sample may not
accurately reflect the heterogeneous group of people with CSDH, which could impact
how broadly applicable our results are. Second, selection bias may have been introduced
and impacted the accuracy of our results due to the exclusion of some patients and
the loss of others to follow-up. Third, our research did not fully account for other
potential confounding factors, such as underlying systemic disorders, surgical procedures,
and postoperative treatment, even though we did find significant relationships between
these variables and CSDH recurrence. Finally, only preoperative characteristics were
examined in this investigation; postoperative variables and long-term outcomes may
offer a more complete knowledge of CSDH recurrence.
Conclusion
This study confirms the relationship between preoperative variables and chronic subdural
CSDH recurrence. We observed that eosinophil count is a strong predictor of recurrence
of CSDH, along with a few demographic and clinical factors. The significant relationship
between eosinophil count and recurrence raises the possibility that eosinophils have
a role in the pathogenesis of CSDH and its recurrence, presumably via promoting tissue
damage and fibrosis and inducing proinflammatory responses. Furthermore, a more marked
systemic inflammatory response is shown by a higher SII index in patients with recurrent
CSDH, which may be a factor in the recurrence of hematomas. The incorporation of eosinophil
count and SII index as biomarkers into clinical protocols can greatly enhance the
management of CSDH by enabling precise risk stratification and personalized patient
care strategies. Future clinical protocols that include routine assessment of these
markers may lead to more effective prevention of CSDH recurrence. Although our study
was limited by a small sample size, further research is warranted to confirm and validate
our findings.
