New Frontiers in Hemorrhagic Stroke: The Role of Minimally Invasive Surgery and Endoport Systems

The global prevalence of individuals with intracerebral hemorrhage (ICH) has grown from 11.2 million in 1990 to 16.6 million in 2021, with a meta-analysis reporting a steady incidence rate of 29.9 per 100,000 over the past 40 years.^1,2 Case fatality has been historically high in this population; 1-month case fatality rates have ranged between 24.5% and 55.8%.³ Given the high mortality and morbidity burden, there has been much attention on innovating treatment options to improve these outcomes. Open surgical interventions (eg, decompressive craniectomies) have shown little functional benefit and are reserved for individuals with large hematomas contributing to substantial clinical deterioration.^4,5

There has been growing interest in minimally invasive surgical (MIS) approaches for treating ICH. These techniques aim to reduce clot burden along with the additional parenchymal injury associated with conventional craniotomy and corticectomy. Multiple MIS approaches for the treatment of individuals with ICH (eg, catheter-based aspiration, minimally invasive parafascicular surgery [MIPS], endoscopic surgery) have been introduced. This review synthesizes current evidence on MIS approaches for ICH evacuation, summarizes pivotal clinical trials, outlines procedural strategies and selection criteria, and discusses emerging studies that may reshape the management of spontaneous ICH.

Evidence and Key Trials
Minimally Invasive Surgery plus rt-PA for ICH Evacuation (MISTIE III, NCT01827046)⁶ and Early Minimally Invasive Removal of ICH (ENRICH, NCT02880878)⁷ are landmark trials exploring the use of MIS approaches for treating individuals with ICH. MISTIE III evaluated the use of image-guided catheter-based aspiration with alteplase (Activase; Genentech, South San Francisco, CA) flushes in participants with spontaneous, nontraumatic, supratentorial ICHs ≥30 mL in volume. The procedure aimed to decrease the clot burden to <15 mL after catheter placement, with up to 9 doses of alteplase administered every 8 hours. A majority of MISTIE III trial participants’ hemorrhages were “deep,” with 34.8% of cases being lobar hemorrhages. Despite achieving significant reductions in hematoma size when compared with the medically managed group, the primary end point (modified Rankin Scale [mRS] score 0–3 at 1 year) was not achieved (45% in the MIS group vs 41% with standard medical management [adjusted risk difference, 4% (95% CI, –4 to 12); P=.33]). However, secondary and exploratory analyses suggested potential mortality benefit and improved outcomes in individuals who achieved the target clot reduction. 

In the ENRICH trial, hematomas were directly evacuated using a Myriad device (NICO; Indianapolis, IN) via MIPS. Participants with spontaneous, supratentorial ICH (30–80 mL) within 24 hours of last known well (ie, last time person was known to be free of stroke symptoms) were enrolled and randomized to either MIPS plus guideline-based care or guideline-based care alone. The trial met its primary outcome of a difference in utility-weighted mRS score at 180 days (mean utility-weighted mRS .458 in the MIPS group and .374 in the control group, with a posterior probability of superiority of .981, surpassing the predefined threshold of .975). Subgroup and interim analyses revealed that participants with lobar hemorrhages largely drove the benefit, whereas no significant advantage was observed for participants with anterior basal ganglia bleeds.

Catheter-based evacuation in the MISTIE III trial achieved close to 70% hematoma volume reduction, with a median initial hematoma volume of ~42 mL.⁶ The median initial hematoma volume was larger in the ENRICH trial (54 mL), and a comparable ~70% reduction in volume was achieved.⁷ MISTIE III and ENRICH included similar percentages of individuals with symptomatic hemorrhage after final treatment (2.4% and 3.3%, respectively).

Although results of the MISTIE III and ENRICH trials suggest potential benefits of MIS approaches for improving functional outcomes of people with ICH, the findings highlight additional areas of exploration. The Minimally Invasive Endoscopic Surgical Treatment with Apollo vs Medical Management for Supratentorial ICH Trial (INVEST, NCT02654015), Dutch Intracerebral Hemorrhage Surgery Trial (DIST, NCT05460793), and Artemis in the Removal of Intracerebral Hemorrhage (MIND, NCT03342664) are 3 recently completed (but unpublished) trials highlighting the use of newer catheter/aspiration systems: Apollo (Medtronic; Minneapolis, MN) and Artemis (Penumbra; Alameda, CA).^8–11 Ultra-Early, Minimally Invasive Intracerebral Hemorrhage Evacuation (EVACUATE, NCT04434807) and Minimally Invasive Intracerebral Hemorrhage Evacuation (MIRROR, NCT04494295) are ongoing trials using the Aurora Surgiscope System (Aurora; Pittsburgh, PA), with the former also aiming to clarify how early evacuation (within 8 hours of ICH) may improve mRS score at 6 months after onset.^8,12,13 A summary of early trial results can be found in the Table.

Patient Selection
When determining which individuals may benefit from ICH evacuation, along with hematoma size and location, the individual’s comorbidities must be considered. As evidenced by the exclusion criteria within the ENRICH trial, certain disease states, such as end-stage renal or liver disease, can make successful surgical evacuation challenging due to intrinsic coagulopathy.⁷ Furthermore, regardless of whether a clinician chooses to pursue endoscopic or port-based hematoma evacuation, normal parenchyma is often traversed and may induce new deficits. Thus, there is little room to improve functionality in individuals who present with a Glasgow Coma Scale score of 15 or with minimal symptoms (ie, National Institutes of Health Stroke Scale score <5). In contrast, individuals in extremis with Glasgow Coma Scale score <5 may be better served by maximal surgical decompression via hemicraniectomy, as a burr-hole would be insufficient to address residual edema and intracranial pressure in such cases.

The timing of surgical intervention is also key, as it affects both technical and logistical considerations. In contrast to the ENRICH trial, in which participants received interventions within 24 hours of symptom onset, a substantial portion of MISTIE III trial participants received intervention beyond 60 hours from ictus. As the hematoma evolves and organizes, blood products become increasingly adherent to surrounding brain tissue. Intraoperatively, this can result in increased manipulation of surrounding parenchyma to evacuate the clot, increased operative time, and potentially higher amounts of residual clot burden. Further studies, such as MIRROR and EVACUATE, are needed to elucidate whether there is a benefit of surgery in an even more acute timeline.

MIS Techniques and Pearls
The term “minimally invasive” is broad. Catheter-based, endoscopic, and port-based methods are all classified as minimally invasive, but differ greatly in evacuation technique. 

As noted in the MISTIE III trial, once the catheter is placed, serial doses of recombinant tissue plasminogen activator are required for adequate hematoma evacuation, resulting in a slow, stepwise evacuation.⁶ Median time from ictus to end of treatment was 123 hours in MISTIE III. A 6-hour stability CT scan is also required in the MISTIE III protocol, to avoid the potentially disastrous effects of injecting tissue plasminogen activator into an actively expanding hemorrhage. In addition, surgeons are unable to directly address active hemorrhage with the catheter, which would necessitate an open surgical technique. Overall, despite being minimally invasive, catheter-based evacuation raises concerns for delay in treatment, prolonged time for treatment, and an inability to address active hemorrhage. 

The endoscopic Artemis device necessitates a 14-mm burr hole. A peel-away sheath is inserted into the deep aspect of the hematoma under neuronavigation, through which the endoscopic aspirator can be inserted. This allows for a more direct visualization of the hematoma, and the endoscope-aspirator system is slowly withdrawn in a deep-to-superficial fashion as aspiration occurs. Endoscopic evacuation only allows for visualization at the tip of the endoscope; direct visualization is offered, but the view is limited, and tissue located radially from the endoscope cannot be seen. Modifications to this technique exist, as demonstrated by the Stereotactic Intracerebral Hemorrhage Underwater Blood Aspiration (SCUBA) technique described by Kellner et al.¹⁴ In this technique, after a deep-to-superficial evacuation is performed in similar fashion, sterile saline at a pressure of 25 cm H2O is passively irrigated within the surgical cavity, allowing it to gently reexpand. Active sites of bleeding can then be visualized and addressed with continued irrigation or electrocautery. 

In the ENRICH trial, the Myriad system was used in conjunction with the BrainPath (NICO Coropration, Indianapolis, IN) access port to perform MIPS. This system offered solutions to some of the challenges seen in endoscopic evacuation. The BrainPath access port uses a cone-shaped trocar with a blunted tip within a 13.5-mm frosted cannula to access the deepest portion of the hematoma, in similar fashion to endoscopic surgery. In principle, the blunted cone tip allows white matter fibers to be displaced rather than transected as the hematoma is accessed. Upon removal of the trocar, surgeons can directly visualize the hematoma both at the tip of the port and through the frosted sides. The Myriad device can then be inserted, offering both aspiration for liquid portions of the hematoma as well as a cutting tip to remove more organized, solid clot that may not be as easily aspirated. The frosted sides allow surgeons to visualize hematoma located radially that can be accessed. Active sites of bleeding, such as those that may be suspected based off a “spot sign” on preoperative imaging, may be addressed directly through the port. 

As mentioned previously, ENRICH trial results demonstrated a significant benefit in functional outcomes for lobar but not basal ganglia hemorrhages. The finding that a tubular port system was more effective for hemorrhages closer to the brain surface, which would seem readily accessible without the need for such a device, may appear paradoxical. Indeed, some surgeons may use a minicraniotomy followed by corticectomy and hematoma evacuation through bipolar cautery and handheld suction for lobar hemorrhages. However, this technique represents a superficial-to-deep approach. As the surgeon removes the superficial portion of the clot, the surrounding parenchyma will collapse as the surgeon aspirates more deeply, necessitating repeated dynamic and increased retraction under poor visualization, thereby adding risk for aspiration of normal parenchyma and incomplete evacuation. 

Ultimately, all 3 techniques use neuronavigation for initial sheath or cannula placement, allowing for precise creation of a long axis along the hematoma for evacuation, rather than blind exploration. For MIPS in particular, neuronavigation allows surgeons to create this axis in a parafascicular fashion. Although not standard practice, intraoperative CT scans may allow surgeons to determine whether a second pass is needed to better complete their evacuation.¹⁴

Future Directions
In addition to the considerable emphasis on functional outcomes after MIS ICH evacuation, other secondary benefits deserve consideration. ENRICH trial results demonstrated reductions in intensive care unit length of stay and decompressive hemicraniectomy rates.⁷ These life-saving hemicraniectomies often entail wound-healing complications, may lead to ex vacuo hydrocephalus, and necessitate a subsequent surgery for cranioplasty. Avoidance of hemicraniectomy can be considered a benefit of MIS evacuation and is a point of discussion when speaking to families before surgical intervention.

From the hospital perspective, the use of MIPS resulted in a cost savings of $2,782 per patient compared to standard medical management ($74,252 vs. $77,034). This reduction was attributed to shorter ICU stays, fewer non-MIPS neurosurgical procedures, lower mortality rates, and decreased rehospitalizations. When considering the broader healthcare perspective—which includes both hospital and non-hospital expenses—MIPS in patients with lobar ICH was associated with a cost savings of $8,850 per patient and a gain of 0.068 quality-adjusted life years compared to medical management.¹⁵

The ENRICH trial ultimately adapted its enrollment to select for lobar hemorrhages. The question remains whether specific anterior basal ganglia hemorrhage characteristics may predict good response to surgical intervention. Early work suggests that the specific location of initial foci of hemorrhage and pattern of extension may predict response to evacuation.¹⁶ Rapid Evacuation and Access of Cerebral Hemorrhage (REACH, NCT06870812), a new trial studying individual with anterior basal ganglia hemorrhages between 20 and 80 mL, may provide further insight into which volumes of deep hemorrhages are more likely to have good functional outcomes after surgical intervention. 

Whether endoscopic or port-based, as ICH evacuation becomes increasingly feasible, surgical intervention for hemorrhagic stroke is aimed to improve survival and yield functional benefits for people with stroke.