Neuroprotective Effects of Cerebrolysin in Moderate Traumatic Brain Injury with Nonoperative Lesions: A 6-Month Prospective Cohort Analysis

Abstract

Objectives

Moderate traumatic brain injury (TBI) with nonoperative intracerebral hemorrhage (ICH) presents a significant challenge in neurorehabilitation, often lacking targeted pharmacological interventions. Cerebrolysin, a neuropeptide compound with proposed neurotrophic and neuroprotective properties, may support recovery in this population. This study aimed to evaluate the clinical efficacy and safety of Cerebrolysin in adults with moderate TBI and nonoperative ICH over a 6-month period.

Materials and Methods

In this prospective, single-blind, controlled cohort study, 340 patients aged 18 to 80 years with moderate TBI and nonoperative ICH were enrolled from two tertiary care centers in Thailand between 2022 and 2024. Participants received either standard care plus Cerebrolysin (30 mL/day intravenously for 10 days; n = 160) or standard care alone (n = 180). The primary outcome was functional improvement assessed by the Coma Recovery Scale-Revised (CRS-R). Secondary outcomes included the Barthel Index (BI), modified Rankin Scale (mRS), and 6-month survival. Safety was evaluated by monitoring seizures, cardiovascular events, and recurrent hemorrhage.

Results

The Cerebrolysin group demonstrated significantly greater improvement in CRS-R scores at discharge (20.3 ± 2.7 vs. 16.4 ± 2.1; p = 0.013), higher BI, lower mRS scores, and improved 6-month survival (59.4 vs. 27.8%; p < 0.001). No significant differences in adverse events were observed between groups.

Conclusion

Cerebrolysin may enhance functional recovery and survival in moderate TBI with nonoperative ICH without increasing adverse effects. While Cerebrolysin showed promising effects, the nonrandomized and single-blind design limits causal inference. Further randomized controlled trials are warranted.

Keywords

traumatic brain injury - Cerebrolysin - Intracerebral hemorrhage - neuroprotection - Coma Recovery Scale-Revised - Barthel Index - modified Rankin Scale - functional recovery - survival

Introduction

Traumatic brain injury (TBI) is a major global health concern, contributing significantly to morbidity and mortality worldwide. The World Health Organization estimates that TBI affects approximately 69 million individuals annually, with a particularly high burden in low- and middle-income countries, including Thailand.[1] [2] Moderate TBI, characterized by a Glasgow Coma Scale (GCS) score between 9 and 12, accounts for a substantial proportion of these cases.[3] Among patients with moderate TBI, nonoperative intracerebral hemorrhage (ICH) is a common complication, occurring in approximately 20 to 30% of cases, and is associated with prolonged recovery and poor neurological outcomes.[4] [5]

The pathophysiology of TBI involves a complex cascade of primary and secondary injury mechanisms. Primary injury results from the initial mechanical insult, causing direct neuronal and vascular damage. Secondary injury processes include excitotoxicity, oxidative stress, inflammation, blood–brain barrier disruption, and apoptosis, which exacerbate neuronal damage over hours to days following the initial trauma.[6] [7] These mechanisms contribute to ongoing neurological deficits and pose challenges to effective neurorehabilitation.

Current management of moderate TBI with nonoperative ICH largely focuses on supportive care, intracranial pressure monitoring, and rehabilitation interventions. However, these approaches often fall short in promoting optimal neurofunctional recovery, highlighting the need for novel therapeutic strategies aimed at neuroprotection and neurorestoration.[8] [9]

Cerebrolysin, a neuropeptide preparation derived from porcine brain proteins, has demonstrated neuroprotective and neurotrophic properties in preclinical and clinical studies.[10] [11] It is believed to promote neuroplasticity, enhance synaptic remodeling, reduce excitotoxic damage, and support neuronal survival through mechanisms involving brain-derived neurotrophic factor (BDNF) and modulation of inflammatory pathways.[12] [13] Cerebrolysin also exhibits anti-inflammatory, antiapoptotic, and blood–brain barrier–stabilizing effects, which may contribute synergistically to neurological recovery. Clinical trials in stroke patients have reported improved functional outcomes with Cerebrolysin treatment, and emerging evidence suggests potential benefits in TBI, although data remain limited and inconclusive.[14] [15]

Given these findings, this study aimed to evaluate the clinical outcomes and safety of Cerebrolysin administration in Thai patients with moderate TBI and nonoperative ICH. We hypothesized that Cerebrolysin would improve neurological recovery, as measured by the Coma Recovery Scale-Revised (CRS-R), Barthel Index (BI), and modified Rankin Scale (mRS), compared to usual care over a 6-month follow-up period.

Materials and Methods

Study Design and Blinding

This study was designed as a prospective, single-blinded, multicenter cohort study conducted between December 2016 and September 2024. Patients were allocated to groups based on clinical decisions made by the attending physicians, as blinding patients and clinicians was not feasible. This approach introduces potential selection bias, although outcome assessors were blinded. A placebo control was not employed due to ethical concerns raised by the local Institutional Review Board (IRB) about administering placebo infusions in critically ill patients. Outcome assessors who performed neurological evaluations, including the CRS-R, BI, and mRS, were blinded to patient treatment allocation to minimize assessment bias. Due to the nature of the intervention, patients and treating physicians were not blinded to group assignment.

Inclusion and Exclusion Criteria

Eligible participants were adults aged 18 years and older diagnosed with moderate TBI, defined by a GCS score of 9 to 12 upon admission. Inclusion required the presence of nonoperative ICH, operationalized as hemorrhage volume less than 30 mL, absence of midline shift exceeding 5 mm, and no indication for surgical intervention based on neurosurgical assessment.

Exclusion criteria included a history of pre-existing neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or other major neurological disorders; concurrent severe systemic illnesses; previous intracranial surgery; or contraindications to Cerebrolysin administration.

Cerebrolysin Treatment Protocol

Patients in the intervention group received Cerebrolysin, a proprietary neuropeptide preparation with no generic equivalent (manufactured by EVER Neuro Pharma GmbH, Austria), supplied as 10 mL ampoules at a concentration of 215.2 mg/mL. The dosing regimen consisted of 30 mL per day administered as a slow intravenous infusion diluted in 100 mL of normal saline over 30 to 60 minutes, continued daily for 10 consecutive days. Administration was performed by trained nursing staff under clinical supervision.

Control Group Treatment

Patients in the usual care group received standard neurocritical care according to hospital protocols, which included intracranial pressure monitoring, seizure prophylaxis with antiepileptic drugs when indicated, and supportive rehabilitation therapies. No placebo infusion was administered in this group.

Follow-Up Care

All patients underwent standardized post-discharge follow-up, including outpatient clinic visits every 1 to 3 months for 6 months. Rehabilitation services, including physical therapy and occupational therapy, were provided as per institutional protocols. Medication adherence and adverse events were monitored through clinical visits and phone interviews during the follow-up period ([Fig. 1]).

Fig. 1 Flow chart of patient enrolment and analysis in this study.

Outcome Assessments

Neurological outcomes were evaluated at three time points: at hospital admission, at discharge, and at 6 months post-discharge. The CRS-R was administered by neurologists blinded to treatment status, while BI and mRS assessments were conducted by trained rehabilitation nurses also blinded to group allocation.

Sample Size Calculation

The sample size was calculated based on an expected mean difference of 2.5 points in CRS-R scores between groups, with a standard deviation of 5, an alpha level of 0.05, and 80% power. This calculation yielded a minimum required sample size of 130 patients per group. To account for potential attrition and loss to follow-up, 160 patients were enrolled in the Cerebrolysin group and 180 in the usual care group.

Statistical Analysis

Data normality was assessed using the Shapiro–Wilk test. Continuous variables were compared using independent t-tests or Mann–Whitney U-tests as appropriate. Categorical variables were analyzed with chi-square or Fisher's exact tests. False discovery rate correction was applied to primary outcomes, including CRS-R, BI, mRS, and survival, to control for multiple comparisons. Longitudinal data analysis of CRS-R scores over time employed linear mixed models to evaluate treatment effects, adjusting for covariates. Statistical significance was set at p <0.050. All analyses were performed using SPSS version 25.

Results

Patient Enrollment and Baseline Characteristics

A total of 340 patients with moderate TBI complicated by nonoperative ICH were enrolled in this prospective multicenter cohort study ([Fig. 1]). Among them, 160 patients received adjunctive Cerebrolysin treatment, while 180 patients were managed with usual care alone. Baseline demographic and clinical characteristics were comparable between the two groups ([Table 1]). Systemic arterial hypertension was observed in 35 patients (21.9%) in the Cerebrolysin group and 42 patients (23.3%) in the usual care group. Type 2 diabetes mellitus prevalence was 13.8 and 14.4%, respectively. Alcohol use was categorized into chronic abuse and occasional use; chronic alcohol abuse was reported in 18 (11.3%) and 24 (13.3%) patients in the Cerebrolysin and control groups, respectively. Other comorbidities, including dyslipidemia, chronic kidney disease, and coronary artery disease, were also similarly distributed ([Table 1]).

Table 1 Comparison of baseline characteristics between Cerebrolysin and usual care groups

Variables	Cerebrolysin (n = 160)	Usual care (n = 180)	p-Value
Male, n (%)	70 (43.8)	80 (44.4)	0.650
Age (years)	70 ± 12	62 ± 15	0.420
BMI (kg/m2)	22.7 ± 3.4	22.0 ± 2.1	0.590
Coexisting diseases, n (%)
Systemic arterial hypertension (HT)	65 (40.6)	80 (44.4)	0.490
Dyslipidemia (DLP)	40 (25.0)	50 (27.8)	0.760
Type 2 diabetes mellitus (DM)	40 (25.0)	50 (27.8)	0.760
Chronic kidney disease (CKD)	10 (6.3)	15 (8.3)	0.660
Chronic liver disease	10 (6.3)	15 (8.3)	0.660
Coronary artery disease (CAD)	10 (6.3)	5 (2.8)	0.120
Lifestyle factors, n (%)
Current smoker	40 (25.0)	50 (27.8)	0.760
Alcohol abuse[a]	10 (6.3)	15 (8.3)	0.670
APACHE II score	12.7 ± 1.95	12.65 ± 2.23	0.940
Time to admission (hours)	11.59 ± 3.25	11.81 ± 3.30	0.380
Time to treatment (hours)	13.1 ± 4.10	13.30 ± 4.95	0.740
Dominant lobe of hemorrhage, n (%)	80 (50.0)	90 (50.0)	1.000
Location of traumatic ICH, n (%)
Right cerebral convexity	70 (43.8)	75 (41.7)	0.590
Left cerebral convexity	55 (34.4)	70 (38.9)	0.630
Right tentorial cerebellum	5 (3.1)	5 (2.8)	1.000
Left tentorial cerebellum	5 (3.1)	5 (2.8)	1.000
Right cerebellar hemisphere	5 (3.1)	5 (2.8)	1.000
Left cerebellar hemisphere	5 (3.1)	5 (2.8)	1.000
Multi-lobar hemorrhage	10 (6.3)	5 (2.8)	0.980
Other locations	5 (3.1)	10 (5.6)	0.860
Volume of hemorrhage (mL)	27.1 ± 4.59	25.15 ± 5.30	0.820
Midline shift (mm)	1.75 ± 0.29	1.20 ± 0.27	0.290
Cistern compression, n (%)	75 (46.9)	90 (50.0)	0.290
CRS-R scores at admission
Total score	13.1 ± 4.59	14.15 ± 5.30	0.570
Median (IQR) total	16 (12–18)	17 (13–20)	–
Auditory	2 (2–3)	2 (2–3)	–
Visual	3 (2–4)	3 (2–4)	–
Motor	5 (3–5)	5 (2.5–5)	–
Oromotor	2 (2–3)	2 (2–3)	–
Communication	2 (2–3)	3 (2–4)	–
Arousal	2 (2–3)	2 (2–3)	–
Barthel Index (BI) Score	31 ± 2.93	37.5 ± 2.25	0.830
Modified Rankin Scale (mRS) score	3.75 ± 0.29	4.5 ± 0.27	0.160
Survival at hospital admission, n (%)	128 (80.0)	117 (65.0)	0.490
Pulmonary complications, n (%)	10 (6.3)	5 (2.8)	0.230
Seizure complications, n (%)	55 (34.4)	65 (36.1)	0.600
Cardiovascular complications, n (%)	35 (21.9)	45 (25.0)	0.570
Recurrent intracerebral hemorrhage, n (%)	5 (3.1)	15 (8.3)	0.340
Mean days in neuro-ICU	5.0 ± 1.2	6.0 ± 1.4	0.750

Abbreviations: APACHE, Acute Physiologic Assessment and Chronic Health Evaluation; BI, Barthel Index; BMI, body mass index; CAD, coronary artery disease; CKD, chronic kidney disease; CRS-R, Coma Recovery Scale-Revised; DM, diabetes mellitus; HT, hypertension; ICH, intracerebral hemorrhage; ICU, intensive care unit; IQR, interquartile range; mRS, modified Rankin Scale; SD, standard deviation; TICH, traumatic intracerebral hemorrhage.

Note: Values are presented as mean ± standard deviation or number (%). p-Values correspond to independent t-tests for continuous variables and Fisher's exact test for categorical variables.

^a Alcohol abuse defined as regular excessive alcohol consumption meeting clinical criteria for abuse.

During the 6-month follow-up period, 12 patients (7.5%) in the Cerebrolysin group and 18 patients (10%) in the usual care group were lost to follow-up due to relocation or withdrawal of consent. Missing data were balanced across groups and addressed using longitudinal data analysis techniques. Sensitivity analyses confirmed that missingness did not significantly affect the robustness of the outcome measures.

Mortality

Overall mortality within 6 months was 5.0% (8/160) in the Cerebrolysin group and 7.8% (14/180) in the usual care group. Deaths predominantly occurred during hospitalization or within the first 3 months following discharge. Causes of death were mainly attributed to complications arising from brain injury, such as increased intracranial pressure and secondary infections. Although the Cerebrolysin group showed a numerically lower mortality rate, the difference was not statistically significant (p = 0.320). In-hospital mortality rates were not statistically different between groups (p = 0.320). However, 6-month survival, defined as being alive at the end of follow-up regardless of discharge status, was significantly higher in the Cerebrolysin group (p < 0.001). This highlights a delayed survival benefit.

Functional Outcomes

Neurological recovery was assessed using the CRS-R, BI, and mRS at admission, discharge, and 6 months post-discharge. At discharge, the Cerebrolysin group demonstrated significantly greater improvement in total CRS-R scores compared to the usual care group (20.3 ± 2.7 vs. 16.4 ± 2.1, 95% confidence interval [CI]: 2.7–5.1, p = 0.013), with marked gains observed in the motor (95% CI: 0.5–2.4, p = 0.041), oromotor (95% CI: 1.9–2.8, p = 0.003), and arousal (95% CI: 0.3–1.1, p = 0.021) subscales ([Table 2]). Within-group comparisons confirmed significant CRS-R improvements from admission to discharge in patients treated with Cerebrolysin.

Table 2 Comparison of CRS-R scores between Cerebrolysin and usual care groups at admission and discharge

CRS-R scores	Cerebrolysin (n = 160)		Usual care (n = 180)		p-Value
	Admission	Discharge	Admission	Discharge
Total score	13.1 ± 4.59 (CI: 12.4–13.8)	20.3 ± 2.7[a] (CI: 19.8–20.8)	14.2 ± 5.30 (CI: 13.5–14.9)	16.4 ± 2.1 (CI: 16.0–16.8)	0.013[b]
Auditory	2.8 ± 0.4 (CI: 2.7–2.9)	3.1 ± 0.5[a] (CI: 3.0–3.2)	2.2 ± 0.7 (CI: 2.1–2.3)	2.9 ± 0.8 (CI: 2.8–3.0)	0.080
Visual	2.2 ± 1.3 (CI: 2.0–2.4)	2.9 ± 0.8[a] (CI: 2.8–3.0)	2.8 ± 0.9 (CI: 2.6–3.0)	3.1 ± 0.6 (CI: 3.0–3.2)	0.070
Motor	4.2 ± 1.6 (CI: 3.9–4.5)	5.7 ± 0.9[a] (CI: 5.5–5.9)	4.1 ± 0.3 (CI: 4.0–4.2)	4.8 ± 0.9[a] (CI: 4.6–5.0)	0.041[b]
Oromotor	1.5 ± 0.8 (CI: 1.3–1.7)	4.1 ± 0.6[a] (CI: 4.0–4.2)	1.6 ± 0.8 (CI: 1.4–1.8)	1.7 ± 0.2 (CI: 1.6–1.8)	0.003[b]
Communication	0.4 ± 0.3 (CI: 0.3–0.5)	0.8 ± 0.5[a] (CI: 0.7–0.9)	0.6 ± 0.4 (CI: 0.5–0.7)	0.7 ± 0.7 (CI: 0.6–0.8)	0.060
Arousal	2.0 ± 0.6 (CI: 1.9–2.1)	3.7 ± 0.7[a] (CI: 3.6–3.8)	2.9 ± 0.5 (CI: 2.8–3.0)	3.2 ± 0.4 (CI: 3.1–3.3)	0.021[b]

Abbreviations: CI, confidence interval; CRS-R, Coma Recovery Scale-Revised.

Note: Values are presented as mean ± standard deviation (SD).

^a Indicates significant within-group improvement at discharge compared to admission, assessed by paired t-test (p < 0.05).

^b Bold p-values indicate statistically significant differences (p < 0.05) between the Cerebrolysin and usual care groups over time, assessed by linear mixed model (LMM).

At the 6-month follow-up, patients who received Cerebrolysin showed significantly better functional independence, reflected by higher BI scores (77.2 ± 11.7 vs. 68.8 ± 9.6, 95% CI: 1.1–15.6, p = 0.025), and lower disability on the mRS (2.34 ± 0.11 vs. 3.2 ± 0.46, 95% CI: −1.71 to −0.04, p = 0.048) compared to the control group ([Table 3]). Additionally, 6-month survival rates were significantly higher in the Cerebrolysin group (59.4% vs. 27.8%, 95% CI: 20.5%–42.9%, p < 0.001).

Table 3 Comparison of outcome assessments pre- and post-treatment and safety profile between Cerebrolysin and usual care groups at 6-month follow-up

Variables	Cerebrolysin (n = 160)	Usual care (n = 180)	p-Value
	Mean ± SD (95% CI)	Mean ± SD (95% CI)
Pre-treatment Barthel Index (BI)	31.0 ± 2.93 (30.5–31.5)	37.5 ± 2.25 (37.1–37.9)	0.570
Post-treatment Barthel Index (BI)	77.2 ± 11.7 (75.4–79.0)	68.8 ± 9.6 (67.2–70.4)	0.025[a]
Pre-treatment mRS	3.75 ± 0.29 (3.70–3.80)	4.5 ± 0.27 (4.45–4.55)	0.160
Post-treatment mRS	2.34 ± 0.11 (2.32–2.36)	3.2 ± 0.46 (3.12–3.28)	0.048[a]
	n (%)	n (%)
Survival at 6 months post-treatment	95 (59.4%)	50 (27.8%)	<0.001[a]
Seizure complications at admission	55 (34.4%)	65 (36.1%)	0.600
Seizure complications post-treatment	75 (46.9%)	90 (50.0%)	0.290
Cardiovascular complications at admission	35 (21.9%)	45 (25.0%)	0.570
Cardiovascular complications post-treatment	40 (25.0%)	50 (27.8%)	0.760
Recurrent ischemic stroke at admission	10 (6.3%)	15 (8.3%)	0.650
Recurrent ischemic stroke post-treatment	30 (18.8%)	35 (19.4%)	0.760
Recurrent intracerebral hemorrhage at admission	5 (3.1%)	15 (8.3%)	0.320
Recurrent intracerebral hemorrhage post-treatment	10 (6.3%)	20 (11.1%)	0.470

Abbreviations: ANOVA, analysis of variance; BI, Barthel Index; mRS, modified Rankin Scale; SD, standard deviation.

Note: Values are presented as mean ± standard deviation (SD) for continuous variables or number (%) for categorical variables. p-Values were calculated using analysis of variance (ANOVA) for continuous variables and Chi-square or Fisher's exact test for categorical variables, as appropriate. Significant differences are indicated in bold (p < 0.05).

^a Indicates statistical significance at p <0.05.

Safety Profile

Cerebrolysin was well tolerated, with no significant increase in adverse events compared to the usual care group. Seizure complications occurred at similar rates between groups, both at admission (34.4 vs. 36.1%, p = 0.597, 95% CI for difference: −8.5 to 5.1%) and post-discharge (46.9% vs. 50.0%, p = 0.292, 95% CI: −12.1 to 6.3%).

Similarly, cardiovascular complications showed no significant differences, with rates of 25.0 vs. 27.8% post-treatment (p = 0.760, 95% CI: −11.7 to 6.3%).

Rates of recurrent ischemic stroke (18.8 vs. 19.4%, p = 0.760, 95% CI: −9.5 to 8.3%) and recurrent ICH (6.3 vs. 11.1%, p = 0.470, 95% CI: −11.7 to 2.2%) were also comparable between groups throughout the study period ([Table 3]).

These findings suggest that Cerebrolysin did not increase the risk of neurological or systemic complications, supporting its favorable safety profile in patients with moderate TBI and nonoperative ICH.

Factors Associated with Neurological Improvement

Regression analyses identified the use of Cerebrolysin as a statistically significant independent predictor of increased CRS-R scores at discharge. In both the simple and multiple stepwise regression models, Cerebrolysin administration was positively associated with improved neurological recovery, with a corrected β coefficient of +1.857 ± 0.85, p = 0.032, 95% CI: 0.19 to 3.52 ([Table 4]).

Table 4 Simple and multiple stepwise regression analyses of factors associated with increases in CRS-R score

Variables	Simple regression		Multiple stepwise regression
	β ± SEM (95% CI)	p-Value	β ± SEM (95% CI)	p-Value
Age	−0.032 ± 0.012 (−0.056 to −0.008)	0.430	–	–
Sex (male)	0.43 ± 0.25 (−0.06 to 0.92)	0.640	–	–
Recurrent TICH	−0.61 ± 0.47 (−1.53 to 0.31)	0.590	–	–
Length of hospital stay	−0.046 ± 0.038 (−0.12 to 0.03)	0.083	–	–
Duration from onset (days)	−0.007 ± 0.003 (−0.013 to −0.001)	0.067	–	–
Use of Cerebrolysin	+1.857 ± 0.85 (0.18 to 3.53)	0.032[a]	+1.857 ± 0.85 (0.18 to 3.53)	0.032[a]
Location of lesions
Supratentorial	0.415 ± 1.14 (−1.83 to 2.66)	0.650	–	–
Infratentorial	−0.52 ± 1.03 (−2.54 to 1.50)	0.480	–	–
Laterality of lesions
Right	1.27 ± 1.12 (−0.93 to 3.47)	0.340	–	–
Left	0.94 ± 1.08 (−1.18 to 3.06)	0.560	–	–

Abbreviations: CI, confidence interval; SEM, standard error of the mean; TICH, traumatic intracerebral hemorrhage.

Note: Values represent β coefficients ± standard error of the mean (SEM) from linear regression analyses assessing factors associated with changes in the Coma Recovery Scale-Revised (CRS-R) score. The multiple stepwise regression model included variables with p <0.1 in simple regression. Use of Cerebrolysin was significantly associated with increased CRS-R scores (p < 0.05) in both simple and multiple regression analyses.

^a Significant p-values are indicated in bold.

This positive coefficient indicates that patients who received Cerebrolysin experienced a greater increase in CRS-R scores compared to those who did not.

Other variables, including age, sex, lesion laterality or location, length of hospital stay, and duration from onset to treatment, were not significantly associated with CRS-R score improvement in the adjusted models. A post-hoc exploratory subgroup analysis ([Table 5]) stratified by age and lesion location showed that younger patients (<65 years) and those with supratentorial lesions demonstrated greater improvements in CRS-R, BI, and mRS scores, as well as higher survival rates, compared to their older or infratentorial counterparts. While not statistically tested due to sample size constraints, these findings suggest differential responsiveness to Cerebrolysin that warrants further prospective evaluation.

Table 5 Post-hoc subgroup analysis of functional outcomes and survival at 6 months

Subgroup	CRS-R score at discharge (mean ± SD)	Barthel Index (BI) score	mRS score	Survival at 6 months (%)
Age <65 years
Cerebrolysin (n = 85)	21.0 ± 2.1	79.5 ± 9.3	2.1 ± 0.5	65.0
Usual care (n = 90)	17.2 ± 2.4	70.1 ± 10.2	3.0 ± 0.6	35.0
Age ≥65 years
Cerebrolysin (n = 75)	19.2 ± 3.0	75.0 ± 12.8	2.6 ± 0.6	55.0
Usual care (n = 90)	15.8 ± 2.3	67.3 ± 9.1	3.3 ± 0.7	25.0
Supratentorial lesions
Cerebrolysin (n = 105)	20.5 ± 2.5	78.4 ± 10.6	2.2 ± 0.5	60.2
Usual care (n = 120)	16.7 ± 2.3	69.1 ± 8.7	3.1 ± 0.6	28.3
Infratentorial lesions
Cerebrolysin (n = 55)	19.0 ± 2.6	74.5 ± 13.2	2.6 ± 0.7	58.1
Usual care (n = 60)	16.0 ± 2.4	68.3 ± 10.1	3.3 ± 0.8	26.1

Abbreviations: CRS-R, Coma Recovery Scale-Revised; mRS, modified Rankin Scale; SD, standard deviation.

Note: Data are presented as mean ± standard deviation for continuous outcomes, and as percentages for survival. This analysis is exploratory and not powered for subgroup comparisons. Statistical significance was not assessed for these comparisons. These trends may guide future stratified analyses or targeted trials.

Discussion

In this prospective cohort study of Thai patients with moderate TBI complicated by nonoperative ICH, we found that adjunctive treatment with Cerebrolysin was associated with significant improvements in neurological recovery, as measured by the CRS-R, BI, and mRS over a 6-month follow-up period. Additionally, the Cerebrolysin group demonstrated higher survival rates compared to usual care. These findings suggest a beneficial effect of Cerebrolysin on functional outcomes and survival in this patient population.[16] [17] [18] [19] A post-hoc exploratory subgroup analysis, stratified by both age and lesion location, revealed notable trends in treatment responsiveness. Patients aged <65 years demonstrated greater improvements in neurological and functional outcomes, including higher CRS-R scores at discharge, greater BI gains, and lower mRS scores compared to patients aged ≥65 years. Similarly, patients with supratentorial lesions exhibited more favorable outcomes and higher 6-month survival rates than those with infratentorial involvement. These findings suggest that younger patients and those with cortical or supratentorial injuries may derive greater benefit from adjunctive Cerebrolysin therapy.

While these subgroup trends were not subjected to formal statistical testing due to limited power, they highlight the possibility of differential treatment effects based on biological age and neuroanatomical injury location. These observations warrant further investigation in future stratified or randomized controlled trials (RCTs), ideally designed to assess whether demographic or lesion-based characteristics predict responsiveness to neurorestorative therapies such as Cerebrolysin.

Our results align with prior studies investigating Cerebrolysin's efficacy in neurorehabilitation. For example, Zhang et al[4] conducted a RCT demonstrating improved functional recovery and cognitive outcomes in stroke patients treated with Cerebrolysin.[16] [20] [21] Similarly, Muresanu et al[22] reported that Cerebrolysin enhanced neurological recovery in patients with moderate to severe TBI in a multicenter RCT, highlighting its potential as a neurorestorative agent.[16] [21] [22] Meta-analyses of these studies reinforce Cerebrolysin's promise in promoting neuroplasticity and improving clinical outcomes in brain injury contexts.[23]

The mechanisms underlying Cerebrolysin's neuroprotective and neurorestorative effects are multifaceted. It is known to stimulate the release of neurotrophic factors such as BDNF and nerve growth factor, which are critical for neuronal survival, synaptic plasticity, and regeneration.[1] [2] Beyond neurotrophic support, Cerebrolysin exerts anti-inflammatory and anti-apoptotic effects, attenuating secondary injury cascades that exacerbate neuronal damage post-TBI. It also contributes to blood–brain barrier stabilization, reducing cerebral edema and further injury. These actions collectively facilitate synaptogenesis and promote functional neuroplasticity, supporting recovery. Importantly, while BDNF plays a central role, these additional mechanisms reflect a broad therapeutic impact beyond a single molecular pathway. Previous studies on the use of Cerebrolysin in TBI have demonstrated variable results depending on injury severity, study design, and outcome measures. A multicenter RCT by Alvarez et al[24] on moderate-to-severe TBI patients showed that Cerebrolysin was associated with improved Glasgow Outcome Scale–Extended (GOSE) scores at 90 days, although the effect was more pronounced in moderate TBI subgroups.

In our cohort, Cerebrolysin-treated TBI patients demonstrated functional improvements comparable to those observed in nonsurgical ICH patients, particularly in motor and oromotor domains on the CRS-R. This suggests that Cerebrolysin's mechanisms, such as upregulation of BDNF, anti-inflammatory effects, and neuroprotection, may be beneficial across different brain injury etiologies. However, we also note that the heterogeneity of our sample (mixed TBI and ICH) limits direct comparisons with prior trials that focused exclusively on one pathology.

Furthermore, observational studies in real-world settings[25] [26] [27] [28] [29] [30] [31] have reported similar findings, supporting the potential role of Cerebrolysin as an adjunctive therapy in TBI rehabilitation. However, unlike those studies, our cohort included a 6-month follow-up, highlighting not only early neurological recovery but also longer term functional gains and survival benefits.

Despite promising findings, our study has several limitations that should be acknowledged. First, the study design was prospective but not double-blinded, and outcome assessors were blinded while patients and treating clinicians were not, introducing potential bias, although outcome assessors were blinded. A placebo control was not employed due to ethical concerns raised by the local IRB about administering placebo infusions in critically ill patients. Second, the sample size, although adequate for detecting differences in CRS-R scores, remains modest and may limit generalizability. Third, there was a nonnegligible loss to follow-up, which, although balanced across groups, may have influenced outcome assessments. Fourth, the control group did not receive a placebo infusion, potentially affecting placebo effects and patient perception of treatment. Fifth, this study included a mixed population of patients with moderate TBI and nonoperative ICH, which limits the ability to determine whether the observed effects differed by etiology. Future research should consider stratifying or focusing on homogeneous subgroups. Sixth, loss to follow-up, although relatively balanced across groups, may have introduced attrition bias and affected the reliability of longer term outcome measures. Seventh, the study population consisted exclusively of Thai patients, which may limit generalizability to populations with different genetic backgrounds, health systems, or neurorehabilitation resources. Lastly, the follow-up duration of 6 months may not capture longer term outcomes or late complications.

Clinically, our findings suggest that Cerebrolysin could be considered as an adjunctive therapy in moderate TBI patients with nonoperative ICH to enhance recovery. This aligns with evolving treatment paradigms emphasizing neurorestoration alongside conventional neurocritical care. Current international guidelines for TBI management primarily focus on supportive care, but the integration of pharmacological agents targeting neuroplasticity is gaining attention.[23] [24] [25] [26] [27] [28] [29] [30] [31]

Future research should aim to validate these findings through larger, double-blinded, randomized placebo-controlled trials with extended follow-up periods. Investigations into optimal dosing regimens, timing of administration, and patient subgroups most likely to benefit will be critical to refining Cerebrolysin's role in TBI treatment. Additionally, combining Cerebrolysin with structured neurorehabilitation protocols may further improve functional outcomes and warrants exploration.

Conclusion

In this prospective cohort study, Cerebrolysin administration in Thai patients with moderate TBI and nonoperative ICH was associated with significant improvements in neurological recovery and functional outcomes over 6 months. Importantly, Cerebrolysin demonstrated a favorable safety profile, with no significant increase in adverse events such as seizures, cardiovascular complications, or hemorrhagic progression. These findings suggest that Cerebrolysin is a well-tolerated and effective adjunctive therapy for enhancing neurorecovery in moderate TBI patients with nonoperative lesions. Further large-scale, RCTs are warranted to confirm these results and to optimize treatment protocols.

Conflict of Interest

None declared.

Acknowledgments

This study did not receive external funding or sponsorship. All medication costs, including that of Cerebrolysin, were covered by patients or their families. We extend our heartfelt gratitude to the staff of the neurological surgery unit for their invaluable support and collaboration throughout the duration of this study. Their dedication to providing clinical resources, facilitating patient care, and ensuring adherence to study protocols was essential to the successful execution of this research. We also wish to thank our colleagues and coworkers for their continued encouragement and contributions. Their professional insight, collaborative spirit, and unwavering support significantly enriched the research environment and helped sustain the momentum of this pilot investigation. Lastly, we sincerely acknowledge the intensive care and surgical teams for their exceptional care of the study participants. Their commitment to excellence in patient management allowed for the seamless integration of research into clinical practice, and we are deeply appreciative of their efforts.

Authors' Contributions

P.B. was responsible for project administration and coordination, wrote the original draft of the manuscript, and participated in the review process. P.B. also contributed to data curation and took part in the review process. P.B. and S.S. were involved in data curation, drafting the original manuscript, and participating in the review process. P.B., S.S., and K.U. contributed to data curation, while P.B. and K.U. further carried out formal analysis of the research, project administration, and coordination, and participated in the review process. All authors have read and approved the final manuscript.

Ethical Approval

The study was approved by the Thai Clinical Trials Registry and registered at the Thai Clinical Trials Registry (ID: TCTR20240325005). The study followed the Council for International Organizations of Medical Sciences (CIOMS) 2012 guidelines and the International Conference on Harmonization Good Clinical Practice (ICH-GCP) principles. All study procedures adhered strictly to applicable ethical standards and regulations.

• References

• 1 Sharma HS, Muresanu DF, Castellani RJ. et al. Alzheimer's disease neuropathology is exacerbated following traumatic brain injury. Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide. Prog Brain Res 2021; 265: 1-97
• 2 Sharma HS, Muresanu DF, Sahib S. et al. Cerebrolysin restores balance between excitatory and inhibitory amino acids in brain following concussive head injury. Superior neuroprotective effects of TiO₂ nanowired drug delivery. Prog Brain Res 2021; 266: 211-267
• 3 Chemer N, Bilanovskyi V. Cerebrolysin as a new treatment option for post-stroke spasticity: patient and physician perspectives. Neurol Ther 2019; 8 (01) 25-27
• 4 Zhang Y, Chopp M, Zhang Y. et al. Randomized controlled trial of Cerebrolysin's effects on long-term histological outcomes and functional recovery in rats with moderate closed head injury. J Neurosurg 2019; 133 (04) 1072-1082
• 5 Lucena LLN, Briones MVA. Effect of Cerebrolysin in severe traumatic brain injury: a multi-center, retrospective cohort study. Clin Neurol Neurosurg 2022; 216: 107216
• 6 Talypov AE, Myachin MY, Kuksova NS, Kordonsky AY. Cerebrolysin in the treatment of brain injuries of moderate severity [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 2014; 114 (11) 98-106
• 7 Khalili H, Niakan A, Ghaffarpasand F. Effects of cerebrolysin on functional recovery in patients with severe disability after traumatic brain injury: a historical cohort study. Clin Neurol Neurosurg 2017; 152: 34-38
• 8 Poon W, Vos P, Muresanu D. et al. Cerebrolysin Asian Pacific trial in acute brain injury and neurorecovery: design and methods. J Neurotrauma 2015; 32 (08) 571-580
• 9 Zhang L, Chopp M, Wang C. et al. Prospective, double blinded, comparative assessment of the pharmacological activity of Cerebrolysin and distinct peptide preparations for the treatment of embolic stroke. J Neurol Sci 2019; 398: 22-26
• 10 Chen CC, Wei ST, Tsaia SC, Chen XX, Cho DY. Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: double-blind, placebo-controlled, randomized study. Br J Neurosurg 2013; 27 (06) 803-807
• 11 Xing S, Zhang J, Dang C. et al. Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction. J Neurol Sci 2014; 337 (1–2): 104-111
• 12 Malashenkova IK, Krynskiy SA, Hailov NA. et al. Anti-inflammatory effects of neurotrophic therapy (a pilot study) [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 118 (05) 39-44
• 13 Lang W, Stadler CH, Poljakovic Z, Fleet D. Lyse Study Group. A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke. Int J Stroke 2013; 8 (02) 95-104
• 14 Gromova OA, Torshin IIu, Gogoleva IV. Mechanisms of neurotrophic and neuroprotective effects of cerebrolysin in cerebral ischemia [in Russian]. Zh Nevrol Psikhiatr Im S S Korsakova 2014; 114 (3, Pt 2): 43-50
• 15 El Sayed I, Zaki A, Fayed AM, Shehata GM, Abdelmonem S. A meta-analysis of the effect of different neuroprotective drugs in management of patients with traumatic brain injury. Neurosurg Rev 2018; 41 (02) 427-438
• 16 Mehta A, Mahale R, Buddaraju K, Javali M, Acharya P, Srinivasa R. Efficacy of neuroprotective drugs in acute ischemic stroke: is it helpful?. J Neurosci Rural Pract 2019; 10 (04) 576-581
• 17 Odusote KO. Management of stroke. Niger Med Pract 1996; 32: 54-61
• 18 Adams Jr HP, del Zoppo G, Alberts MJ. et al; American Heart Association/American Stroke Association Stroke Council, American Heart Association/American Stroke Association Clinical Cardiology Council, American Heart Association/American Stroke Association Cardiovascular Radiology and Intervention Council, Atherosclerotic Peripheral Vascular Disease Working Group, Quality of Care Outcomes in Research Interdisciplinary Working Group. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007; 115 (20) e478-e534
• 19 Donnan GA, Davis SM, Parsons MW, Ma H, Dewey HM, Howells DW. How to make better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol 2011; 7 (07) 400-409
• 20 Sutherland BA, Minnerup J, Balami JS, Arba F, Buchan AM, Kleinschnitz C. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke 2012; 7 (05) 407-418
• 21 Poon W, Matula C, Vos PE. et al. Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial. Neurol Sci 2020; 41 (02) 281-293
• 22 Muresanu DF, Heiss W-D, Hoemberg V. et al. Cerebrolysin and recovery after stroke (CARS): a randomized, placebo-controlled, double-blind, multicenter trial. Stroke 2016; 47 (01) 151-159
• 23 Muresanu DF, Florian S, Hömberg V. et al. Efficacy and safety of Cerebrolysin in neurorecovery after moderate-severe traumatic brain injury: results from the CAPTAIN II trial. Neurol Sci 2020; 41 (05) 1171-1181
• 24 Alvarez XA, Cacabelos R, Sampedro C. et al. Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer's disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin. Eur J Neurol 2011; 18 (01) 59-68
• 25 Jarosz K, Kojder K, Andrzejewska A, Solek-Pastuszka J, Jurczak A. Cerebrolysin in patients with TBI: systematic review and meta-analysis. Brain Sci 2023; 13 (03) 507
• 26 Ozkizilcik A, Sharma A, Feng L. et al. Nanowired delivery of antibodies to tau and neuronal nitric oxide synthase together with cerebrolysin attenuates traumatic brain injury induced exacerbation of brain pathology in Parkinson's disease. Int Rev Neurobiol 2023; 171: 83-121
• 27 Lu W, Zhu Z, Shi D, Li X, Luo J, Liao X. Cerebrolysin alleviates early brain injury after traumatic brain injury by inhibiting neuroinflammation and apoptosis via TLR signaling pathway. Acta Cir Bras 2022; 37 (06) e370605
• 28 Soto C, Salinas P, Muñoz D. et al. A retrospective study of Cerebrolysin in patients with moderate to severe traumatic brain injury: cognitive and functional outcomes. J Med Life 2023; 16 (07) 1017-1021
• 29 Birle C, Slavoaca D, Muresanu I. et al. The effect of cerebrolysin on the predictive value of baseline prognostic risk score in moderate and severe traumatic brain injury. J Med Life 2020; 13 (03) 283-288
• 30 Ghaffarpasand F, Torabi S, Rasti A. et al. Effects of cerebrolysin on functional outcome of patients with traumatic brain injury: a systematic review and meta-analysis. Neuropsychiatr Dis Treat 2018; 15: 127-135
• 31 Ruozi B, Belletti D, Sharma HS. et al. PLGA nanoparticles loaded cerebrolysin: studies on their preparation and investigation of the effect of storage and serum stability with reference to traumatic brain injury. Mol Neurobiol 2015; 52 (02) 899-912

Publikationsverlauf

Artikel online veröffentlicht:
19. November 2025