How Dexamethasone Affects Necessity for Surgical Intervention for Chronic Subdural Hematoma: Systematic Review and Meta-Analysis

Abstract The effectiveness of dexamethasone in managing chronic subdural hematoma (cSDH) patients remains uncertain although the drug is widely used in this condition. The present systematic review aims to understand the role of dexamethasone in reducing the need for surgery in cSDH patients. This study was conducted as per the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the electronic databases of PubMed, SCOPUS, Cochrane Central Register of Controlled Trials (the Cochrane Library), and ScienceDirect with a predefined search strategy. The population consisted of cSDH patients older than 18 years and treated primarily with dexamethasone. The primary outcome was the need for surgery after dexamethasone therapy in cSDH patients. The meta-analysis of a group of patients was done with the invariance method to estimate the pooled odds of the requirement for surgery after dexamethasone therapy. In the studies with a one-to-one comparison of dexamethasone with placebo/observation, the Mantel–Haenszel statistics were used to determine the odds of surgery. The quality of the studies was assessed with the Newcastle–Ottawa scale (NOS) and the Cochrane risk of bias tool was used to assess the risk of bias in randomized studies. In total, 598 studies were obtained from the database search and after applying the inclusion and exclusion criteria, 10 studies were finally selected for the qualitative and quantitative synthesis. One of the 10 studies was a randomized controlled trial (RCT), while the rest were observational studies. There were 653 patients who received the primary dexamethasone therapy. Of these, 388 patients did not require surgery, while 256 needed surgeries after the therapy. The pooled estimate of requirement for surgery after dexamethasone therapy was 0.41, with a 95% confidence interval of 0.37 to 0.45. A meta-analysis of the one-to-one comparison from three included studies showed a higher need of surgery in the (comparator) placebo/observation group than in the dexamethasone group with odds ratio of 7.16 (95% confidence interval: 2.21–23.13, with p  = 0.0001). In addition, we identified the gaps in literature, and the complications and mortality reported in the studies. Dexamethasone is effective in reducing the requirement for surgery in some selected cSDH cases, although many patients still require surgical intervention.


Introduction
Chronic subdural hematoma (cSDH) is a commonly managed clinical entity in neurosurgical practice.2][3] The management options for cSDH include surgical intervention (trepanation or burr hole craniostomy) in symptomatic cases and conservative management in asymptomatic patients.cSDH is diagnosed in individuals older than 70 years and individuals with coagulation disorders and alcohol abuse. 4Despite this increase in the incidence of cSDH, there is no consensus on the treatment options, and they vary on a regional, national, and international level. 2 Asymptomatic cSDH is often treated conservatively.In contrast, symptomatic cSDH is recognized worldwide by neurosurgeons as a surgical emergency requiring prompt treatment to prevent brain herniation.Despite the large number of studies, the decision to administer different treatment modalities depends on the treating physician's expert opinion, and no consensus exists.There are a lot of variations in the medical and surgical practice and the duration of surgery in cases of failed medical management.Therefore, research question about the role of dexamethasone as a stand-alone treatment option in cSDH and identification of the variables that might be associated with the failed medical therapy is relevant.This was the primary objective of the present study.The secondary objective was to determine the types of evidence available and gaps in the literature related to the question.

Objectives
The present systematic review aims to study the need for surgery in dexamethasone as a stand-alone treatment in cSDH and to identify factors associated with the failed medical management requiring additional surgery.The secondary objective was to map the key concepts and types of evidence available in gaps in the literature related to the question.

Methods
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 5 and the Cochrane Manual of Systematic Reviews and Meta-analyses. 6igibility Criteria

Inclusion Criteria
• Studies with at least one arm with the dexamethasone alone group.• Age 18 years or older.
• Study design: randomized controlled trials (RCTs), quasirandomized controlled studies, and prospective and retrospective observational studies.

Exclusion Criteria
• Studies that did not include at least one dexamethasone group.• Study design: case series, case reports, letters, editorials, comments, animal studies, and studies published in languages other than English.

Outcome Measure
Patients on dexamethasone alone requiring surgical intervention.

Search Strategy
We searched the PubMed, SCOPUS, Cochrane Central Register of Controlled Trials (the Cochrane Library), and ScienceDirect databases with predefined search terms (►Table 1).The reference lists of the included studies were evaluated for potentially eligible studies.We included studies including RCTs, quasi-randomized controlled studies, and prospective and retrospective observational studies.Case series, case reports, letters, editorials, comments, animal studies, and studies published in languages other than English were excluded.No restrictions were placed on the time, setting, and source of publication.
included studies showed a higher need of surgery in the (comparator) placebo/observation group than in the dexamethasone group with odds ratio of 7.16 (95% confidence interval: 2.21-23.13,with p ¼ 0.0001).In addition, we identified the gaps in literature, and the complications and mortality reported in the studies.Dexamethasone is effective in reducing the requirement for surgery in some selected cSDH cases, although many patients still require surgical intervention.

Statistical Analysis
The statistical analysis for meta-analysis of the included studies was performed for one group in R and for one comparison between dexamethasone and placebo/ observation group in RevMan.For meta-analysis of one group, the inverse variance method was used with Logit transformation, DerSimonian-Laird estimator for tausquared and Clopper-Pearson confidence interval.The overall effect was calculated as odds ratio (OR) with its 95% confidence interval (95% CI).Random effects model was used, and heterogeneity was assessed by Cochrane Q test and I 2 test, with a threshold of p-value less than 0.10 or I 2 more than 50% indicating substantial heterogeneity.Publication bias was displayed by a funnel plot if the number of included studies were more than 10.

Study Site and Design
The study by Sun et al 43 was a single-center prospective cohort study conducted between 1998 and 1999.

Population
The patients were older than 18 years with symptomatic cSDH.

Intervention
A dose of 4 mg dexamethasone four times a day for 3 weeks was prescribed.Surgical management included burr hole and evacuation within 2 days of starting dexamethasone therapy and dexamethasone was continued for 2 weeks

Outcome
Glasgow Outcome Scale (GOS) at 6 months.Failure of treatment was defined as neurological deterioration with radiological evidence of re-accumulation of cSDH.

Results
A total of 112 patients were included in the study, of which 26 patients were treated with dexamethasone alone, 69 with surgery and 2 weeks of dexamethasone, 13 with surgical drainage alone, and 4 patients received only observation.One out of 26 patients with dexamethasone therapy required surgeryafter 1 month.Two patients in the observation group required surgery.In all, 84% of patients treated with dexamethasone only had good GOS at 6 months, while 91% patients who had a surgery and with dexamethasone had good GOS at 6 months.In the surgery alone group, 77% had good outcome and 50% had good outcome in the observation alone group at 6 months of followup.The main complication observed was hyperglycemia.

Study Site and Design
This was a single-center study comprising 122 cSDH patients reviewed retrospectively. 36

Population
In the study, patients with MGS scores of 1 to 2, that is, alert, oriented, tired, or disoriented with possible variable neurological deficits were given dexamethasone, while patients with MGS scores of 3 to 5 who are stuporous or comatose were assigned to the surgery group.

Intervention
The authors used dexamethasone 4 mg three times a day and reassessed the patients after 48 to 72 hours; patients who did not show any improvement were then reassigned to the surgery group.Other responders were ambulated and discharged with a tapering dose of steroids.Follow-ups were done after 6 weeks and at complete cure or clinical and radiological stabilization.The surgical protocol consisted of twist drill mini-craniostomy and subdural drainage.In the case of nonimprovement of patients, dexamethasone was used after the drainage.

Outcome
MGS at discharge.Length of hospital stay.

Results
The median age of the patients was 78 years (range: 25-97 years).Forty-seven patients were older than 80 years, while 98 patients were older than 70 years.In all, 101 patients were given dexamethasone, 19 had surgery, and 2 were untreated.Of the patients who were given dexamethasone, 76 were given dexamethasone alone, while 25 had dexamethasone in combination with surgery.Twenty-two patients initially assigned dexamethasone required surgery, and 3 more needed a second drain and posterior craniotomy.Ninetyseven of 101 patients with dexamethasone treatment achieved favorable outcomes as defined by MGS scores of 0, 1, or 2. Seventy-four of 76 patients who were given dexamethasone alone had good results.Thirty-four patients developed complications, mainly comprising hyperglycemia and nosocomial infection.However, the complications were not reported individually for the groups.The median length of hospital stay was almost similar in the dexamethasone and surgery groups.

Study Site and Design
This is a prospective single-center study conducted from April 2013 to May 2015. 44pulation cSDH patients with Glasgow coma scale (GCS) score 15/15.

Intervention
Dexamethasone 4 mg three times a day for 3 days was prescribed.Neurological evaluation was done at 72 hours and the patients who did not show improvement were subjected to surgery.Patients who showed improvement were discharged on tapering dose of steroids for 4 weeks as tab prednisolone 10 mg three times a day for 1 week, tab prednisolone 10 mg twice a day for 1 week, tab prednisolone 5 mg twice a day for 1 week, tab prednisolone 5 mg once a day for 1 week, and then stopped.Surgery consisted of single parietal burr hole and evacuation of the cSDH with subdural drain placement.

Outcome
Radiological and neurological cure assessed at 6 weeks was defined as success of the steroid treatment.Dexamethasone in cSDH Agrawal et al.

Results
In all, 26 patients were included in the study with similar underlying demographic, neurological, and radiological characteristics.Ten of 26 patients required surgery after 72 hours.Five more were subjected to surgery at 3 to 6 weeks of follow-up due to recurrence of symptoms and nonresolution of cSDH radiologically.Finally, 11 of 26 patients got complete resolution of the symptoms and radiological cure at 6 weeks of follow-up.Two patients developed complications of hyperglycemia and gastritis related to steroids.

Study Site and Design
This was a single-center placebo controlled double blind RCT conducted between January 2007 and May 2009. 42pulation cSDH patients aged more than 18 years with MGS scores of 0 to 2.

Intervention
A dose of 12 mg dexamethasone per day for 3 weeks and then tapered over next 1 week.Total dose of dexamethasone administered was 267 mg.

Control
Placebo.

Outcome
Succes of medical management in avoiding surgery during 6 months following enrolment or interruption of medical management due to serious adverse effect.

Results
The study included 20 participants, 10 in the dexamethasone group and 10 in the placebo group.One patient in the dexamethasone group needed surgery between 3 and 18 days after enrolment, while 3 patients had serious adverse effects.In the placebo group, three patients needed surgery.Six of 10 patients in the dexamethasone group had treatment success at 6 months, while 7 in the placebo group had treatment success.

Study Site and Design
This retrospective single-center study was conducted between January 2012 and December 2016. 37

Population
In total, 171 adult symptomatic cSDH patients with a followup period greater than 3 months were included.

Intervention
Patients were divided into three groups: dexamethasone alone, dexamethasone as adjunct to burr hole, and burr hole alone.Dexamethasone was given 8 mg thrice daily for 1 week and then tapered over the next week.

Outcome
Recurrence occurred in 1, 10, and 3 patients in the dexamethasone as an adjunct to burr hole, burr hole alone, and dexamethasone alone groups, respectively.Mortality was one, eight and zero in the dexamethasone as an adjunct to burr hole, burr hole alone, and dexamethasone alone groups, respectively.

Results
One hundred seventy-one patients were included in the study, with a mean age of 76.4 AE 9.3 years.Ten patients were treated with dexamethasone alone, 136 with burr hole alone, and 25 with dexamethasone as an adjunct to the burr hole treatment.The mean length of hospital stay was 7.7 AE 3.2, 7.1 AE 4.9, and 3.5 AE 2.0 days for the Edlmann et al 16 Protocol Huang et al 20 Case series Jong 22 Protocol Kolias 23 Protocol Fan, 2020 17 In vitro study Hutchinson, 2020 21 No dexamethasone alone group Mebberson, 2020 24 No dexamethasone alone group Wang, 2020 33 No dexamethasone groups Diener, 2021 14 Non-English Fan et al 18 In vitro study Holl et al 19 Conference abstract Simon 28 Non-English Tariq and Bhatti 30 Dexamethasone was used after surgery Vetter 31 Non-English Wang et al 32 Animal model Yuan et al 34 Case series Edlmann et al 15 Subgroup from Dex-CSDH trial 21 Saul et al 27 Practice article AbdelFatah 10 Case series David et al 12

Comment
Sioutas et al 29 Dexamethasone and statin given together Dexamethasone in cSDH Agrawal et al.Dexamethasone in cSDH Agrawal et al.
dexamethasone as an adjunct to burr hole, burr hole alone, and dexamethasone alone groups, respectively.

Study Site and Design
This single-center retrospective study conducted between January 2016 and December 2017. 41pulation cSDH patients aged more than 18 years with modified Rankin scale (mRS) score of 1 to 3 were divided into two groups: those who received dexamethasone and those who did not receive dexamethasone.

Intervention
A dose of 8 mg dexamethasone per day for 1 week followed by 4 mg per day for the second week followed by 4 mg once every 2 days in the third week.

Outcome
Need for surgical intervention at 3 weeks after the dexamethasone therapy.

Results
Thirty-eight participants in the study were divided into two groups: 22 in the group who received dexamethasone and 16 in the group who did not receive dexamethasone.Nine out of 22 patients who received dexamethasone underwent surgery between days 3 and 12, while 13 of 16 who did not receive dexamethasone underwent surgery between days 3 and 8.The complications and morbidity rates were similar in the two groups.

Study Site and Design
This retrospective multicenter study was conducted between January 2014 and December 2016. 40

Population
Symptomatic cSDH patients aged more than 18 years with MGS scores of 1 to 2. Asymptomatic patients with MGS score of 0 and MGS scores of 3 to 4 requiring emergency surgery were excluded.

Intervention
A dose of 3 to 4 mg dexamethasone twice daily with or without bolus was prescribed.The expert opinion was bolus administration of dexamethasone.Surgery consisted of burr hole evacuation with the placement of a subdural drain.Surgery was done in patients not responding or deteriorating with dexamethasone and by the expert opinion.

Outcome
The primary outcome was an mRS and MGS at 3 months.Secondary outcomes were mRS and MGS at discharge and follow-up, additional surgeries, and crossover of medically managed patients to surgery.

Results
Sixty patients received primary surgery without dexamethasone, and 60 patients received prior dexamethasone therapy.At 3 months, 70% in the immediate surgery group and 76% in the primary dexamethasone group had a favorable outcome (mRS score of 0-3).Twenty-two percent in the prior surgery group and 12% in the primary dexamethasone group had recurrence at 6 months.Eighty-three percent of patients (50/60) received primary dexamethasone therapy crossover to surgery after a mean duration of 6 days, and therefore, 17% of patients were able to evade the surgery, of which 8 had an improved MGS score at discharge, and 2 had unchanged scores.The rate of complications was lower in the primary surgery group (35%) versus the primary dexamethasone group (55%).The mortality was similar among both groups, and the length of hospital stay in the primary dexamethasone group was twice that in the surgery group.

Study Site and Design
This was a retrospective multicentric study conducted between January 2008 and December 2018. 38

Population
The patients were adults with cSDH.The patients with hyperdense components with more than one-third of the hematoma volume were excluded.

Intervention
Dexamethasone in tapering doses in symptomatic cSDH patients is defined as MGS scores of 1 to 3. The amount of dexamethasone was 8 mg twice daily for 1 week, then tapering with the end of treatment on day 23.

Outcome
Need for additional surgery.

Results
Two hundred eighty-three patients were included in the study, of which 146 received one course of dexamethasone, 30 received more than one course of dexamethasone, and 107 received additional surgery after dexamethasone.The mean age of the participants was 70 years, with a standard deviation (SD) of 10.The need for further surgery was more in patients with MGS score of 2, using statins, more significant midline shift, larger hematoma thickness, bilateral hematoma, and separated type of hematoma.Additional surgery was less common in patients with a trabecular pattern on cSDH and using antithrombotic.The mean duration of dexamethasone therapy in the study was 30 days, and the time from the dexamethasone therapy to surgery was 12 days.The main complications were infection, hyperglycemia, pulmonary embolism, thrombotic events, and seizures.

Study Site and Design
This single-center retrospective study was conducted between March 2020 and February 2022. 1

Population
Newly diagnosed adult patients with symptomatic cSDH with MGS scores of 1 to 2.

Intervention
A dose of dexamethasone 8 mg twice a day for 4 days and tapering over till the 20th day.Surgical procedure consisted of single burr hoe craniostomy at the maximum site of hematoma thickness.

Results
A total of 30 patients were included in the study.Nine patients required surgical intervention.Out of these nine patients, three required surgery at 3 days or less, 4 to 7, and greater than 7 days each.The mean length of hospital stay was 11.67 days.

Study Site and Design
This multicentric study was a part of the dexamethasone therapy versus surgery for chronic subdural haematoma (DECSA) trial conducted from September 2016 to February 2021. 39

Population
Adult patients with MGS scores of 1 to 3 cSDH, baseline computed tomography (CT), scan and on dexamethasone primary treatment.

Intervention
Dexamethasone was given twice daily, amounting to the daily dosage of 16 mg on days 1 to 4, 8 mg on days 5 to 7, 4 mg on days 8 to 10, 2 mg on days 11 to 13, 1 mg on days 14 to 16, 0.5 mg on days 17 to 19, and stopped at day 20, resulting in a total amount of 110.5 mg dexamethasone.The surgical group consisted of burr hole craniostomy.Surgery was done, if necessary, based on the CT scan and neurological examination at 2 weeks of follow-ups or when the dexamethasone treatment was discontinued early due to clinical severity or comorbidities affecting the recovery.

Outcome
The primary outcome was identifying the cSDH subtype most responsive to the dexamethasone therapy.The secondary outcome was neurological outcome assessed by MGS and classified as unchanged, worsened, improved, need of additional surgery, and complications.

Results
Eighty-five participants with a mean age of 76 years were included in the study (SD: 11).The included patients had 114 cSDH, of which 56 were homogeneous, 8 laminar, 20 separated, and 30 trabecular.Fifty patients completed the 19-day duration of dexamethasone therapy, and in 35 patients, dexamethasone had to be terminated early because of the worsening clinical situation.After 2 weeks of dexamethasone treatment, hematoma thickness decreased by a mean of 3 mm, midline shift reversed by the standard of 2 mm, and hematoma volume was reduced by a mean of 14 mL.Hematoma thickness was reduced by a maximum of up to 5 mm in cSDH without hyperdense component, while reduction in the hematoma volume was maximally seen in the separated type of cSDH.Patients with hematoma without hyperdense components showed higher improvement rates than those with hyperdense components.Patients with separated hematoma had the lowest improvement rates.Complications were reported in 57% of patients, with falls, hyperglycemia, and delirium occurring the most.Additional surgery was required in 48 (57%) patients with the 16-day mean duration to surgery and was highest in the separated cSDH type.Three studies had presented results from a one-to-one comparison of dexamethasone and placebo/observation. [41][42][43] One of the studies was an RCT, 41 while one study composed of participants who were a subgroup of an RCT. 39The duration, dose of dexamethasone, and duration of surgery after enrolment are described in ►Tables 4 and 5.

Risk of Bias
The risk of bias in the RCT assessed by Cochrane risk of bias tool suggested low risk of bias in the domains of random sequence generation and allocation concealment (selection bias), blinding of participants and personnel (performance bias), and selective reporting (selection bias), while the risk of bias was unclear in the domain of detection, attrition, and other biases. 42Quality assessment for the other included observation studies by Newcastle-Ottawa scale showed a median of 7/9, suggesting good quality in most of the studies.The quality assessment is as shown in ►Table 6.

Statistical Analysis (or Meta-Analysis)
In included studies, a total 653 patients received dexamethasone alone at the time of presentation.Of these, 388 patients did not require surgery and 265 patients required additional surgery at follow-up with a pooled proportion of 0.41 and 95% CI of 0.37 to 0.45 as shown in ►Fig.2. In the meta-analysis of one-to-one comparison from three included studies (►Fig.3), there was more need for surgery in the placebo/observation group than in the dexamethasone group with an OR of 7.16 and 95% CI of 2.21 to 23.13, with a p-value of 0.0001.We performed the sensitivity analysis to remove the RCT from these groups and found similar results (►Fig.3).The heterogeneity computed was low.

Discussion
][7][8][9][10][11][12] Due to the high chances of recurrence after surgery, the role of dexamethasone has been explored as either monotherapy or perioperative adjuvant therapy in cases of cSDH. 13To justify the role of dexamethasone, the rationale is based on the property of dexamethasone to reduce inflammation and angiogenesis, thus reducing the chances of recurrence. 14Although there are reports in which the role of dexamethasone is explored in the management of cSDH patients, the effectiveness of dexamethasone is still controversial. 15As mentioned, there were evidence synthesis studies on dexamethasone as an adjunctive treatment to prevent recurrence following surgery.However, although individual primary research studies have found conflicting results supporting dexamethasone as a safe and efficacious treatment option, systematic reviews often have not found consistent results favoring dexamethasone.The vast heterogeneity in the studies, including the dose, duration, type of cSDH, population heterogeneity, and adjunctive treatment, is possibly the reason.Since the dose and duration of dexamethasone widely varied among the studies and population variation, we adopted the scoping review approach to address our research question.
4][45] In addition, studies have found that dexamethasone is adjuvant to surgical therapy, and a more extended dexamethasone therapy reduces the risk of recurrence. 11,25,37,46The survey by Miah et al suggested that although several patients could evade the need for surgery with primary dexamethasone therapy, they required more extended hospital stays and a higher risk of complications. 40However, further studies did not support the findings. 38The emerging results could not be established as high-grade evidence in multiple systematic reviews due to high selection bias and significant heterogeneity in the individual primary research studies.
The use of corticosteroids in cSDH was initiated and extensively studied by Dr. Bender in 1974. 47Over time, dexamethasone became a standard treatment for cSDH in Rotterdam.In 2011, it was included in regional guidelines as a primary option.Surgery is recommended if there is clinical deterioration or no improvement within 72 hours.However, no agreement exists on using dexamethasone nationally or internationally.9][50][51] In addition to the clinical outcome, radiological improvement has been studied using dexamethasone in cSDH.One study reported that the resolution of hematoma took a longer time with steroid treatment.However, patients remained clinically stable, and some patients on dexamethasone treatment needed a follow-up of up to 6 months for a radiological cure. 360][51][52] Further studies have Miah et al 39 The Netherlands 37 48 Dexamethasone in cSDH Agrawal et al. found that the neomembrane of the cSDH has plasma cells and macrophages that produce vascular endothelial growth factor (VEGF) and beta fibroblast growth factor (bFGF) that promote angiogenesis, suggesting that cSDH is an angiogenic disease due to a subacute inflammatory response. 48The potential role of inflammation in the causation of cSDH is the rationale for using steroids to treat cSDH.Glucocorticoids potentially limit the formation of neomembrane by their inhibitory effect on lymphokines and prostaglandins and stimulation of inflammatory inhibitors like lipocortin. 4,49lucocorticoids also stimulate plasminogen secretion and inhibit VEGF, interrupting the bleeding-reabsorptionrebleeding cycle in cSDH. 4examethasone was used in the current study to assess its efficacy as a stand-alone therapy for the treatment of cSDH and its effect on the requirement for further surgery. 38In total, 594 individuals who got dexamethasone alone as the primary therapy for cSDH were included in the study's systematic review and meta-analysis of 35 trials. 38More than one-third of the patients receiving dexamethasone needed further surgery, according to the findings.Larger hematomas and higher MGS ratings showed that these individuals had more severe injuries.Compared to individuals who did not undergo surgery, the OR for needing subsequent surgery was 2.91, indicating a noticeably greater chance. 38These results imply that a significant fraction of patients still need surgery, even if dexamethasone may help minimize the need for surgery in some people.
A study Qian et al 25 evaluated the risk variables for recurrence of cSDH and discovered that advanced age, midline displacement more significant than 10 mm, and separated hematoma were all related to a higher risk of recurrence.However, they found that postoperative dexamethasone medication lowered the recurrence rate considerably. 25This shows that dexamethasone may protect against the repetition of cSDH and should be included in the therapeutic strategy.
Numerous traits were also shown in the research 38 associated with a greater likelihood of requiring further surgery.Statin use, a more remarkable midline shift, a larger hematoma thickness, a bilateral hematoma, a separated hematoma, an MGS score of 2, and a bilateral hematoma were among these.Contrarily, the usage of antithrombotic and the existence of trabecular hematoma reduced the likelihood of further surgery. 38These results provide meaningful data on patient characteristics that could guide treatment decisions and help identify patients who might benefit from early surgical intervention.
Researchers investigated several cSDH treatment approaches in 2005, 43 including dexamethasone alone, surgical drainage with or without dexamethasone, and observation without any kind of therapy.Most patients who were treated with dexamethasone alone had favorable outcomes, with just a tiny minority requiring retreatment.Whether dexamethasone was used during surgery or not, the results were comparable.On the other hand, observation alone had a lower success rate, with only Table 6 Quality assessment of the included studies according to the Newcastle-Ottawa scale Sl.
no. Dexamethasone in cSDH Agrawal et al.

Groups
50% of patients needing surgical drainage. 43These findings point to dexamethasone's effectiveness as a cSDH treatment option, alone or in combination with surgical drainage.Delgado-López et al 36 investigated the effectiveness of several treatment modalities in 122 individuals with cSDH.They discovered that dexamethasone alone, subdural drain insertion, and craniotomy all resulted in favorable outcomes in most patients.However, patients with a midline displacement of more than 10 mm and a separated hematoma had a higher risk of recurrence and required reoperation. 36These findings emphasize the need to consider unique radiological features and patient considerations when determining the best treatment plan for cSDH.
A study by Miah et al 39 looked at dexamethasone as a standalone treatment for cSDH in another trial.They included 283 patients, of whom 38% had surgery after receiving one or more rounds of dexamethasone.At 6 months, the research found that 83.9% of patients in the dexamethasone group had a favorable result (mRS score of 0-3) compared to 90.3% in the placebo group, with a statistically significant betweengroup difference in favor of the placebo group. 39The findings above underscore the necessity for further investigation and raise skepticism regarding the efficacy of dexamethasone as a sole intervention for cSDH.
Additionally, an RCT was conducted, involving 748 patients, to assess dexamethasone's effectiveness as a treatment for cSDH. 21The research findings indicated a decreased incidence of positive results (as measured by the mRS score of 0-3) in the cohort receiving dexamethasone in comparison to the cohort receiving placebo after a period of 6 months (83.9 vs. 90.3%).After adjusting for confounders, dexamethasone had an OR of 0.55 for a good result.This shows a considerable placebo advantage. 21These data suggest that dexamethasone alone may not be as beneficial as thought.
Dexamethasone-treated patients had 84.8% positive outcomes in a prospective cohort trial. 24Dexamethasone prevented recurrence, whereas placebo caused 20.83%.Period of stay and mRS scores showed no significant differences. 24These findings indicate dexamethasone's potential efficacy in avoiding recurrence, although its influence on overall clinical results is unknown.Dexamethasone in cSDH Agrawal et al.
In addition, the effects of various cSDH treatment modalities, such as conservative therapy, burr hole surgery alone, and burr hole surgery in conjunction with dexamethasone, were also studied. 37The outcome after surgical versus nonsurgical treatment of chronic subdural 37 ; group to the other two groups reported that the conservative management group's length of hospital stay was much shorter.However, there were no appreciable variations in the death or recurrence rates across the therapy groups. 37These findings highlight the necessity of individualized treatment strategies based on the traits and preferences of the patient.
A recent study by Miah et al 40 compared primary surgery without dexamethasone to dexamethasone therapy as an initial treatment for cSDH.According to the researchers, the two therapy groups had no significant difference in functional results or death.Dexamethasone increased cSDH recurrence and reoperation.Dexamethasone patients had comparable hospital stays to open surgery patients. 40This research found that dexamethasone may improve functional results in the short term but may increase long-term recurrence and surgical intervention.
Papacocea et al 41 compared dexamethasone therapy to observation in cSDH patients.Dexamethasone recipients avoided surgery at 59.1%,compared to 18.7% in the observation group.Dexamethasone field treatment caused hyperglycemia in a small minority of research subjects. 41owever, dexamethasone may reduce surgery.These findings highlight the necessity to monitor and address harmful consequences.
Overall, this study's and other research's findings provide information on the efficacy of dexamethasone as a potential cSDH treatment.Even though dexamethasone may help some patients avoid surgery, a sizable fraction still needs it.Patients who could benefit from early surgical intervention can be identified using traits such as MGS, hematoma features, and comorbidities.However, inconsistent findings from several trials point to the necessity for more investigation to define the function of dexamethasone in individualized treatment plans for cSDH.To enable individualized treatment options for cSDH, future prospective studies should concentrate on identifying individuals who would benefit most from immediate surgery versus those in whom dexamethasone could be an adequate field. 38he findings indicate that even while dexamethasone can improve functional outcomes in a sizable fraction of cSDH patients, a significant portion may still need further surgery.There is a greater chance of surgery being necessary if there is an enormous hematoma, a higher midline shift, or statin usage.However, the possibility of subsequent surgery is decreased using antithrombotic and the existence of trabecular hematoma.Remembering that dexamethasone therapy might cause side effects, including hyperglycemia, is crucial.Therefore, based on the patient's clinical features and reaction to the first treatment, treatment recommendations should be tailored to them specifically.Further investigation is necessary to validate these findings and ascertain the optimal treatment approach, specifically by implementing prospective trials involving larger sample sizes.Consequently, treatment recommendations should be customized to suit the patient's clinical characteristics and response to the initial treatment.Further investigation is necessary to corroborate these findings and ascertain the optimal treatment approach for cSDH.8][39][40][41]43 Considering the numerous research on the efficacy of dexamethasone for cSDH, while dexamethasone may provide favorable results for a major proportion of patients, a significant number of people still require different surgical surgery.Larger hematoma size, higher midline shift, and statin usage have been linked to an increased risk of surgery.Still, antithrombotic use and the existence of trabecular hematoma have been linked to a decreased likelihood of subsequent surgery.
Given the disparities in the studies' findings, evaluating individual patient features and reactions to the first treatment is critical when deciding the best cSDH method.8][39][40][41] Finally, a personalized therapy strategy that considers patient-specific characteristics will be critical for improving outcomes in cSDH patients.

Limitations and Considerations for Future Research
The inconsistency in the results, as seen from the metaanalysis, is possible because of the differences in the underlying population characteristics, dose, and duration of dexamethasone, for example, in the study by Miah et al. 40 The authors found that the number of patients requiring additional surgery was relatively high (50 of 60).In their research, dexamethasone was given for 12 days.In the study by Holl et al, 38 the number of patients requiring additional surgery was less than that in the survey by Miah et al. 40 In this study, the authors used dexamethasone for a longer duration, a mean of 30 days, and had the protocol of additional dexamethasone in nonresponders.
Holl et al 38 found that patients who had a higher degree of neurological involvement assessed by MGS, bilateral cSDH, larger thickness of the hematoma, use of statins, separated type of cSDH, and more extensive extent of midline shift tend to require additional surgery after therapy with dexamethasone.Minimal knowledge exists on the natural history of cSDH due to the lack of literature.It is understood that cSDH might follow a self-limiting course; however, the pathophysiological process becomes a vicious cycle, demanding some form of mandatory intervention.cSDH, after formation, expands in its thickness and reaches the laminar stage.Following the laminar stage, the neovascular membrane formation accelerated and turned cSDH into a separate pattern and then into the trabecular pattern, after which absorption of cSDH begins.This could explain why more patients with separate cSDH types require surgical intervention.
One crucial issue identified from the present review was that there was no consistency in the dose and duration of dexamethasone therapy.Some studies used a shorter time, smaller quantity, and a single course of dexamethasone.In contrast, others used a more extended period, more significant amount, and multiple methods of dexamethasone therapy.Although most studies reported on the functional outcome, even that differs by the tool used to measure the outcome.Some studies used mRS and MGS at discharge or follow-up, while others used clinical response and the need for additional surgery to measure optimal outcomes.Only a few studies have focused on the radiological development and clinical outcome.The mortality and length of hospital stay were also assessed in these study reports; however, there was heterogeneity in the population.For example, some studies have evaluated the mortality in medical management overall without subdividing the groups into those who did not need surgery after failed medical management.At the same time, some have taken patients with surgery as the primary mode of administration.The recurrence was not uniformly defined in all the studies.Some studies used nonimprovement or worsening radiological profile as recurrence, while some studies defined recurrence as patients who initially improved and then had a recurrence of symptoms.As it is understood that cSDH has heterogeneity in its pathophysiology, considerable heterogeneity has been observed in the studies on managing this enigmatic disease.This restricts achieving evidence of high quality and certainty.
In the study by Papacocea et al, 41 the authors performed a one-to-one comparison of cSDH receiving dexamethasone and not and determining the need for surgery in both the cohorts.The authors found that 40.9% patients who had received dexamethasone needed additional surgery, while 81.3% cSDH patients who did not received dexamethasone required additional surgery.They also found that not only dexamethasone decreased the requirement for surgery in cSDH but it also increased the duration after which surgery was required.Although the findings seem promising and supportive for the use of dexamethasone alternative to surgery, it should be borne in mind that the sample size of the study by Papacocea et al was very small and consisted of only 38 patients.Although the authors ensured that both the groups in their study was homogenous with respect to underlying characteristics and demographics, the decision for surgery could still be biased by the surgeon's decision and other underlying characteristics of cSDH.The low rate of complications and morbidity was attributed by the authors to a lower dose of dexamethasone in their protocol.
Prud'homme et al 42 reported an interesting finding that the hematoma thickness reduced at a faster rate in patients receiving dexamethasone; however, the radiological results at 6 months of follow-up were similar in the dexamethasone group and the placebo group.However, the sample size was very small limiting the generalizability of the results.
2][43] In the study by Sun et al, 43 the sample in the group of observation comprised only four patients.Further there was selection bias in the classification of patients into different groups as the elderly patients with comorbidities were treated with dexamethasone only although the hematoma thickness and cSDH characteristics did not differ significantly among the groups.
In an RCT by Hutchinson et al, 21 the authors found that dexamethasone therapy had worse functional outcome at 6 months than placebo in cSDH.As most patients underwent surgery at the index admission, the trial was not designed to find if dexamethasone therapy could reduce the need for surgery.However, in the trial, there was a group of 38 patients that underwent observation.Of these, 22 received dexamethasone.At 6 months, a favorable outcome was seen in 84% of patients receiving dexamethasone and 100% in patients receiving placebo.This finding and other findings in the literature suggest a possibility that although dexamethasone reduces the need for surgery, it may potentially worsen the long-term functional outcome in cSDH patients.The exact association and underlying mechanisms need larger studies focused on the role of dexamethasone in reducing the need for surgical procedure.

Conclusion
To summarize, the utility of dexamethasone in patients with persistent subdural hematoma is still being determined, and more study is needed.While it may reduce the need for surgery in some cases, many patients still require surgical intervention.The study heterogeneity, small number of RCTs, and absence of standardized methods for dexamethasone administration and dose underline the need for care in interpreting the findings.Future prospective studies with a larger sample size, extended follow-up periods, and standardized treatment regimens are required to improve the discipline.These studies should try to identify the patient subgroups that might benefit the most from various treatment modalities, develop appropriate dose regimes, and assess long-term results.By addressing these research gaps, evidence-based guidelines for clinical practice and improving outcomes in patients with persistent subdural hematoma can be produced.

Fig. 1
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
indicates that it meets the criteria in the Newcastle-Ottawa Scale.Indian Journal of Neurotrauma © 2024.The Author(s).

Fig. 2
Fig.2Forest plot of meta-analysis of proportions for need of surgery in patients with primary dexamethasone therapy.CI, confidence interval.

Fig. 3
Fig. 3 Forest plot of one-to-one comparison of dexamethasone with placebo/observation.CI, confidence interval.

Table 1
7etails of search strategyTwo investigators (A.A. and O.A.) independently evaluated the studies and extracted data in a predesigned proforma as per the inclusion criteria.The details included were study ID, authors, year, country, inclusion criteria, sample size in each group, age, gender, dose of dexamethasone, treatment groups, reported outcomes, need for surgery in patients who received dexamethasone group, any complications, details of the Markwalder Grading Scale (MGS)7at admission, the Glasgow Outcome Scale, or any other scale used to categorize cSDH.The Cochrane Collaboration's tool 8 was used for assessing the risk of bias in randomized studies.The Newcastle-Ottawa Quality Assessment Scale 9 was used to assess the quality of the research included; studies with a score of 9 were regarded to have good methodological quality (7-9 points).For observational studies, ratings in the range of 6 were considered of moderate quality, whereas scores of 5 or less were considered of low quality.The authors were contacted for missing data.Consultation by consensus helped clear up any confusion.
Indian Journal of Neurotrauma © 2024.The Author(s).Dexamethasone in cSDH Agrawal et al.

Table 2
Excluded studies with reasons

Table 3
Characteristics of included studies 1Indian Journal of Neurotrauma © 2024.The Author(s).
The complication rate of infection was 24.4% in all the patients, 15.8% in the single course of dexamethasone only group, 40% in the group with additional course of dexamethasone, and 31.8% in dexamethasone with surgery group.Mortality was 17 patients in the single course of dexamethasone, 5 patients in dexamethasone and an additional course of dexamethasone group, and 12 patients in the group requiring further surgery.

Table 4
Details of various treatment options used in included studies

Table 5
Dose, duration of dexamethasone therapy, and duration of surgery after enrolment Indian Journal of Neurotrauma © 2024.The Author(s).