Malignant cerebral infarction within the territory supplied by the middle cerebral artery (MCA) is characterized by extensive ischemia involving 50% or more of its vascular territory [8]. This extensive ischemic injury to the cerebral hemisphere precipitates substantial edema, ultimately leading to brain herniation syndrome [25,30]. Malignant MCA infarction is associated with a high mortality rate under conservative management, reaching up to 80% [3,8], which is reduced to 55% following surgical intervention [4,12,23,32]. The severity of malignant MCA infarction arises from both the extensive ischemic area and the occurrence of cerebral and extracerebral complications. Among these cerebral complications, hemorrhagic transformation (HT) holds particular clinical significance. According to ECASS I [5], HT is classified into two main types: hemorrhagic infarction (HI) and parenchymal hemorrhage (PH), each with subtypes: HI 1 (petechial hemorrhages at the infarct margins), HI 2 (petechial hemorrhages throughout the infarct, no mass effect attributable to the hemorrhages). PH 1 (hematoma ≤30% of infarcted area, minor mass effect attributable to the hematoma), and PH 2 (hematoma >30% of infarct zone, substantial mass effect attributable to the hematoma). Clinically, HT is classified as symptomatic or asymptomatic. A large volume of ischemic damage, as seen in malignant MCA infarction, is a significant risk factor for both HT and mortality [25,30]. Some authors regard HT as a natural process in the evolution of ischemic stroke due to blood-brain barrier disruption [2], while most agree that HT arises as a complication of ischemic stroke and reperfusion therapy following successful recanalization of ischemic brain tissue [28,29]. A large infarction volume is regarded as a contraindication for systemic intravenous thrombolysis (IVT). Despite this, certain patients with malignant MCA infarction may still be administered systemic IVT if early computed tomography (CT) scans do not demonstrate ischemic changes in the MCA territory at admission within the therapeutic window [2,17,20,33]. According to published literature, up to 21.4% of patients with malignant MCA infarction undergo IVT [6]. The occurrence of HT further deteriorates clinical outcomes and prognoses [9,11], comprising 28.5% of all fatalities associated with malignant MCA infarction [18]. Therefore, ascertaining the frequency of HT and assessing its impact on the clinical course and outcome of malignant MCA infarction is of essential clinical significance.

We retrospectively analyzed 74 patients with malignant MCA infarction admitted to a single center in Rostov-on-Don, Russia, between September 2017 and March 2025. The patients’ ages ranged from 44 to 92 years (mean age 71.5±2.0 years), and 54.0% were female. Ethics approval was obtained prior to study initiation to ensure compliance with ethical standards and patient confidentiality. Conservative therapy was administered to 57 patients (77.0%), while 17 patients (22.9%) underwent decompressive hemicraniectomy (DHC). In 41.1% of these surgical cases, DHC was supplemented with infarctectomy and tentoriotomy, according to the method previously described and published by the authors [19]. Non-contrast multi-slice computed tomography (MSCT) of the brain was performed upon admission, at 24 hours, and during follow-up to confirm ischemic lesions and exclude other causes of neurological deterioration. The lateral shift of midline structures was measured as the displacement of the septum pellucidum from the midline to the contralateral side, at the level of the head of the caudate nucleus, on horizontal MSCT slices. Hemorrhagic transformation (HT) was assessed according to the ECASS I (European Cooperative Acute Stroke Study) classification. The pathogenetic subtype of ischemic stroke was determined using the International Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria [1]. Daily assessment of consciousness level was performed using the Glasgow Coma Scale (GCS), and the severity of neurological deficit was assessed using the National Institutes of Health Stroke Scale (NIHSS) [24]. The volume of ischemia in the affected cerebral hemisphere was calculated as AxBxC/2 based on brain MSCT imaging [14,22]. Intravenous thrombolysis was performed within the therapeutic window upon admission, before radiological confirmation of the ischemic lesion on brain MSCT. Cerebral angiography was conducted in patients eligible for endovascular thrombectomy.

The inclusion criterion for the study was a volume of ischemic damage to the cerebral hemisphere ≥145 cm³ based on brain MSCT scan. Exclusion criteria included infarct volume in the brain hemisphere <145 cm³, concomitant malignancy, low consciousness level (coma) on admission, bilateral involvement, traumatic hemorrhage, brainstem ischemia, or underlying blood pathology, including coagulopathy. Criteria for surgical intervention included hemispheric ischemia volume ≥145 cm³, GCS score ≥9 on admission, and absence of decompensated aggravated somatic concomitant pathologies. To prevent thromboembolic complications, all patients received anticoagulant therapy at appropriate doses.

Most patients were admitted with impaired consciousness, scoring between 9 and 15 points on the Glasgow Coma Scale (mean GCS 12.9±0.2, Me=13 points), which resulted from massive edema of the cerebral hemisphere. The demographic and clinical characteristics of the cohort are summarized in Table 1.

The severity of neurological deficit according to the NIHSS at admission ranged from 9 to 30 points (mean score 19.2±0.5, median=20 points), while the maximum score during follow-up reached 38 points. Midline shift at the septum pellucidum level was detected in 14.8% of patients on admission, ranging from 1.38 to 6.18 mm (mean 3.4±0.4 mm); during follow-up, it increased to 1.1-28 mm (mean 7.8±0.6 mm; median=5.67 mm). Additional ischemic involvement of the anterior and/or posterior cerebral arteries occurred in 32.4% of cases (79.1% anterior, 38.0% posterior, 9.5% contralateral anterior, and 19.0% combined anterior/posterior involvement). To prevent thromboembolic complications, all patients received anticoagulant therapy. Hemorrhagic transformation occurred in 53 patients (71.6%): The frequency of occurrence of various types of hemorrhagic transformation within the general cohort is detailed in Table 2. Intravenous thrombolysis was administered for 11 patients with malignant MCA infarction (15% of the total group). Following unsuccessful IVT, one patient underwent DHC, one - endovascular thrombectomy. Intravenous thrombolysis in all malignant MCA infarction patients (100%) was complicated by the development of HT. HT of HI type occurred in 81.8% of them (Fig. 1), HI 1 - in 7 (63.6%), and HI 2 - in 2 (18.1%) patients. HI of HT type was asymptomatic and did not lead to worsening of the condition or aggravate neurological deficits. Symptomatic HT of the PH type developed in 18.2% (n=2) of patients (Fig. 1), one with PH 1 and one with PH 2. The development of HT of PH type has a negative effect on the course and outcome of the disease - it leads to the impairment of consciousness down to coma, the development of transtentorial herniation and, ultimately, to a fatal outcome. In our cohort study of patients, administration of IVT to malignant MCA infarction patients did not lead to regression (complete or partial) of neurological deficit. According to the data gathered by the authors, a systematic review and meta-analysis of 120 studies evaluating IVT outcomes in large vessel occlusion strokes found limited efficacy in patients with large infarct volumes, such as malignant MCA infarctions, demonstrating minimal evidence of neurological deficit regression [26]. Conversely, in the subgroup of malignant MCA infarction patients who did not receive IVT, HT was less frequent, occurring in 66.6% of cases (42 patients). The comparative analysis of the frequency of occurrence of different types of hemorrhagic transformation based on whether intravenous thrombolytic therapy was received or not is summarized in Table 3. Moving beyond treatment type, hemorrhagic transformation in our cohort study also varied among patients with different pathogenetic subtypes of ischemic stroke, occurring more frequently in the cardioembolic subtype (79.3%). The frequency of HT according to the TOAST pathogenetic subtype is summarized in Table 4. Furthermore, when considering treatment, despite the greater effectiveness of surgical treatment compared to conservative therapy, the occurrence of hemorrhagic transformation differs. The frequency of hemorrhagic transformation is lower in patients receiving only conservative treatment (71.4%) compared to those undergoing surgical treatment (76.4%). Additionally, in patients who receive decompressive hemicraniectomy (DHC) without infarctectomy, the incidence of hemorrhagic transformation is 60%, whereas it is 100% in patients who undergo DHC with infarctectomy. The comparative analysis of the frequency of hemorrhagic transformation according to the treatment type is summarized in Table 5. HT significantly depends on the volume of ischemic damage to the cerebral hemisphere (with an increase in the volume of ischemia, the probability of its occurrence increases) (t-test=2.3; df=72; P=0.0251) (Fig. 2).

Midline shift significantly depends on the development of HT (t-test=8.8; df=71; P=0.0403); with the HT occurrence, the midline shift of the brain increases (Fig. 3).

Analysis revealed no significant relationship between the development of HT subtypes HI 1 (Kruskal-Wallis test: H (2, N=74)=2.66; P=0.2646), HI 2 (Kruskal-Wallis test: H (2, N=74)=1.83; P=0.4003), PH 1 (Kruskal-Wallis test: H (2, N=74)=0.67; P=0.7142), PH 2 (Kruskal-Wallis test: H (2, N=74)=2.08; P=0.3529), the course (the severity of the disease assessed by the GCS and NIHSS), and the outcome of the disease.

The overall mortality rate was 44.5%, with 45.2% in the HT subgroup (n=53) and 42.8% in non-HT patients (t-test: P=0.8514). The frequency of mortality varies within the cohort according to the type of hemorrhagic transformation, occurring more frequently in patients with the PH type. The comparative analysis of the mortality rate of patients according to the type of HT is summarized in Table 6.

Hemorrhagic transformation (HT) is a common cerebral complication of malignant MCA infarction, occurring in 67.2% of cases. It is associated with extensive ischemic damage to the cerebral hemisphere and the development of profound edema. Published evidence indicates that a large ischemic volume constitutes a major risk factor for HT [13]. In line with this, a significant correlation was identified in the present study between ischemic volume and the incidence of HT, demonstrating a clear increase in HT frequency with greater ischemic volume. Accordingly, malignant MCA infarction may be regarded as a predictor of HT development. Data collected by the authors revealed that prophylactic anticoagulation therapy did not exert a significant influence on HT risk, likely owing to the severe disability of the patient population. Similarly, a study conducted on 186 consecutive patients in Osaka, Japan, reported that thrombolytic and/or anticoagulant therapy did not significantly affect the incidence of hemorrhagic infarction (40.0% with therapy versus 40.7% without therapy) [16]. In our cohort study, we found that the frequency of hemorrhagic transformation (HT) was lower in patients who received only conservative therapy without IVT (66.6%) compared to those who underwent surgical treatment (76.4%). Additionally, the incidence of HT was 100% in patients who received decompressive hemicraniectomy (DHC) with infarctectomy, compared to 60% in those who received DHC alone without infarctectomy. We hypothesize that this difference may be explained by the ability of DHC to reduce intracranial pressure and increase cerebral blood perfusion. The administration of intravenous thrombolysis (IVT) in patients with malignant MCA infarction may be complicated by symptomatic hemorrhagic transformation (HT), which can result in a fatal outcome, consistent with the findings of several authors [28,31]. Specifically, HT of the parenchymal hemorrhage type 2 (PH 2) occurred exclusively in patients who underwent IVT and was associated with mortality, representing an indirect complication of successful recanalization. The occurrence of HT in malignant MCA infarction patients receiving intravenous thrombolytic therapy underscores the necessity for identifying early biochemical markers capable of predicting the malignant nature of ischemic damage prior to verification by computed tomography. Asymptomatic hemorrhagic infarction types HI 1 and HI 2 were the most frequently observed forms of HT. The high prevalence of asymptomatic HT (81%) in malignant MCA infarction patients who did not receive IVT confirms its natural development in the ischemic area, resulting from disruption of the blood-brain barrier. These findings align with the conclusions of other authors [7,15,27]. The mortality rate among patients with HT-complicated malignant MCA infarction (45.2%) was slightly higher than that observed in non-HT patients (42.8%), which accounts for the absence of a statistically significant difference between HT occurrence and the clinical course or outcomes in this patient population. This phenomenon is likely attributable to the presence of additional significant factors influencing both the progression of malignant MCA infarction and patient outcomes [21]. Furthermore, malignant MCA infarction in the absence of HT is itself associated with a severe clinical course and unfavorable prognosis, primarily due to the extensive ischemic volume and the development of critical, massive cerebral edema.

This study provides robust quantitative evidence of the high frequency (up to 71.4%) of HT in malignant MCA infarction patients, regardless of IVT use. The findings underscore the limited benefits and risks of IVT in large infarcts and reframe asymptomatic HT as a natural disease progression rather than solely a treatment complication. Overall, this study fills a critical gap by highlighting the need for early diagnostic markers and improved management strategies, advancing understanding and care of HT in malignant MCA infarction.