Introduction

Spontaneous intracerebral hemorrhage (ICH) constitutes 10–15% of all strokes and occurs when there is bleeding within the brain parenchyma in the absence of antecedent trauma. ICH occurs predominantly due to long-standing hypertension (HTN), cerebral amyloid angiopathy (CAA), and iatrogenic coagulopathy from antiplatelets and anticoagulants [1]. The estimated incidence of ICH is around 2 million strokes/year, a number which is rising due to an aging population, increasing use of antithrombotic therapies, and increasing diversity of the US population with minorities being disproportionately affected from hypertension [2, 3]. Less than 50% of patients survive at 1 year, and only 25% of survivors are functionally independent [4]. These statistics have not improved to any substantial extent due to the lack of proven therapies that improve long-term functional outcome.

Intracerebral hemorrhage begins with the rupture of a small artery(ies) that have been weakened by long-standing HTN or CAA. Unlike ischemic stroke, the neurological deficit from ICH progresses over several hours due to hematoma expansion, even in patients who are not on antithrombotics. The lysis of RBC’s within the hematoma releases iron and thrombin which trigger a robust inflammatory response with microglial activation and increasing glutamate levels [5]. This causes a leaky blood-brain barrier (BBB) with formation of perihematomal edema (PHE) over the next several days to weeks, which in turn aggravates mass effect and tissue compression [6]. The combined hematoma and PHE volume results in increased intracranial pressure (ICP), tissue shifts and brain herniation, lowering of cerebral perfusion pressure (CPP), and secondary neuronal death from compression and inflammation-mediated neurotoxicity. Hematoma volume has a profound negative impact not only on survival but also on functional outcome. ICH > 30 ml are statistically associated with unfavorable outcome while the combination of an ICH volume > 60 ml and Glasgow coma score (GCS) of <8 has a predicted 1-month mortality approaching 90% [7,8,9]. In closed compartments such as the posterior fossa, even ICH < 30 ml can cause profound brainstem compression, 4th ventricular obstruction with obstructive hydrocephalus, and tonsillar herniation.

There are three main targets for ICH management: (1) limiting hematoma expansion, (2) relief of mass effect created by the hematoma and PHE, and (3) attenuating secondary injury. The medical toolkit for the first two targets includes reversing coagulopathy, controlling blood pressure, and the use of ICP-lowering strategies such as hyperosmolar agents [10•]. Neuroprotective therapies such as deferoxamine mesylate were studied in a proof of concept phase II futility trial to reduce iron-triggered inflammatory edema without any functional benefit [11]. Unfortunately, medical therapies are not effective in reversing existing mass effect. Surgical hematoma evacuation is therefore an attractive therapy that not only reduces ICH volume and resulting parenchymal compression but by indirectly attenuating inflammatory cascades due to reduction in the volume of RBC’s that release inflammatory mediators. In this review, we will analyze the various surgical techniques available, identify patient populations that can potentially benefit, and provide a practical framework for clinical decision-making regarding surgery.

Treatment

The primary goal of surgery is to reduce mass effect and tissue shifts while secondarily attempting to reduce PHE formation and thereby reduce mortality but more importantly, improve functional outcome. The surgical arsenal includes open craniotomy with hematoma evacuation, decompressive craniectomy with or without hematoma evacuation, minimally invasive surgical (MIS) techniques such as instillation of thrombolytics into the ICH with aspiration/drainage or direct hematoma aspiration without thrombolytics.

Surgical management-open surgery

Spontaneous supratentorial ICH

  1. A.

    Open craniotomy with hematoma evacuation:

Standard procedure

Open craniotomy involves lifting a reasonable size of bone overlying the ICH to gain access to the hematoma, evacuating the hematoma under direct visualization, after which the bone is replaced. The Surgical Trial in Intracerebral Hemorrhage (STICH 1) was a pragmatic international multicenter randomized trial (1995–2003) that compared early open craniotomy with hematoma evacuation versus initial conservative medical treatment on 6-month functional outcome measured by a prognosis-adjusted extended Glasgow outcome score (GOSE) [12••]. Patients were eligible if the treating neurosurgeon had equipoise and uncertainty about the benefits of either treatment. Included patients had a spontaneous supratentorial ICH ≥ 2 cm in diameter, GCS of ≥5, and no underlying structural etiology or intraventricular hemorrhage (IVH). One thousand thirty-three patients were enrolled—503 were assigned to the surgical arm. In the intent to treat (ITT) analysis, early surgical treatment was not superior with an odds ratio (OR) of 0.89 (95% CI 0.66–1.19, p = 0.414), an absolute benefit of only 2.3% (95% CI −3.2–7.7), and a relative benefit of 10% (−13 to 33). However, in a pre-specified subgroup analysis, patients with lobar ICH < 1 cm from the cortical surface had a trend toward improved outcome.

STICH 2 investigated open craniotomy with hematoma evacuation within 48 h of ictus and within 12 h of randomization in 305 patients with a lobar ICH < 1 cm from the cortical surface, ICH volume between 10 and 100 ml, and GCS > 7 [13••]. The underlying rationale was that normal brain tissue would be less exposed to surgical injury in a lobar ICH close to the surface as compared to that sustained while evacuating a deep ICH where there is presumably injury to eloquent areas and white matter tracts along the surgical path. At 6 months, superiority of surgery was not established with 59% unfavorable outcome in the surgical group versus 62% in the conservative group with an OR 0.86 (95% CI 0.62–1.2, p = 0.367). The only subgroup of patients who benefited from open evacuation (OR 0.49 (95% CI 0.26–0.92)) were those who had a priori poor prognosis (determined based on characteristics such as age, admission GCS, and ICH volume) with admission GCS of 9–12. Although it appears from the STICH trials that open craniotomy is not beneficial, an individual patient data meta-analyses from 15 surgical trials actually showed both mortality and morbidity benefit with surgery with OR 0.74 (95% CI 0.64–0.86, p < 0.0001), but the validity of these results is limited due to significant heterogeneity in the included patients and types of surgical procedures performed [13, 14].

Indications and contraindications

What can be pragmatically concluded is that open craniotomies maybe most beneficial in the select group of patients presenting with intermediate levels of depressed consciousness, i.e., GCS of 9–12 [13••]. For these patients, the American Heart Association guidelines acknowledge a potential role for open craniotomy for mortality benefit in patients who are deteriorating and otherwise considered salvageable (Class 2b, LOE C) [15••]. Open craniotomy with clot evacuation does not benefit patients who have deep ICH, patients who are moribund (GCS < 9), or who have relatively normal consciousness (GCS > 12) (Table 1).

Table 1 Surgical management in supratentorial intracerebral hemorrhage without significant intraventricular hemorrhage
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Special points

The STICH trials did not include patients where the neurosurgeon believed that surgery was better than a wait and watch approach nor did it include patients with cerebellar ICH (discussed below).

  1. B.

    Decompressive craniectomy:

Standard procedure

Decompressive craniectomy (DC) is done with a minimum A-P diameter of 12 cm with underlying expansile durotomy. In malignant ischemic stroke and traumatic brain injury, this procedure has been shown to relieve refractory ICP by allowing edematous brain to undergo extracranial herniation and thereby avoid compression and secondary ischemia of normal brain tissue [16, 17]. This procedure is not only life saving and at least in malignant ischemic stroke, leads to better functional outcomes in patients <60 years of age [16].

Supratentorial ICH > 60 cc has a dismal outcome with a 30-day mortality rate of >90% [18]. Open craniotomy with clot evacuation may not sufficiently relieve ICP, particularly in deep ICH. In such patients, DC can be a lifesaving procedure. Three small randomized studies have explored DC ± clot evacuation. In one prospective open label randomized study of 40 patients with hypertensive ICH (mean volumes of 75 cc), those who were < 70 years and GCS 6–12 with lobar ICH had a favorable prognosis in the adjusted 6-month Glasgow outcome scale (GOS) with DC (70 vs. 20%, p = 0.0015) [19]. However, in another randomized study of 89 patients (mean ICH volume of 50 cc), those who underwent DC with clot evacuation had longer operative times and increased intraoperative blood loss without a difference in postoperative ICP and with worse outcomes at 3 months [20]. A third randomized study included 30 patients with basal ganglia ICH with mean volumes of 48 cc and mean GCS ~ 7. Twelve were assigned to wide fronto-temporo-parietal DC of at least 150 mm2 with hematoma evacuation [21]. At 6 months, the DC group had favorable outcome with GOS > 3 (31 vs. 35%). Finally, in a meta-analysis of 8 studies (1 RCT, 7 retrospective), DC significantly (n = 227) reduced mortality compared with the control group (n = 286), (RR 0.67, 95% CI 0.53–0.85, p = 0.0008) but did not improve functional outcome [22•]. A large retrospective cohort study utilizing the National Inpatient Sample of 1144 patients who underwent DC for spontaneous ICH surprisingly found that older age > 70 years was not an adverse prognostic factor for short-term outcomes, nor did it predict in-patient mortality; however, older patients were more likely to end up in long-term care facilities (OR 1.2, 95% CI 1.04–1.38, p = 0.01) [23•].

Indications and contraindications

In a practical sense, DC ± clot evacuation is a lifesaving option for younger patients who have a large ICH (~ 50 cc and above) with midline shift and who are not deeply comatose (i.e., GCS not <6) at the time of surgery [15]. This can also be offered in select older patients who do not have concomitant significant comorbidities with the explicit understanding that DC is a lifesaving treatment but there is no data currently that it improves functional outcome.

Special points

The optimal timing of DC is unclear, although a < 72 h from ictus is reasonable. There is an ongoing randomized trial (SWITCH - NCT 02258919, www.clinicaltrials.gov) which is evaluating prophylactic DC for ICH of intermediate severity in 300 participants.

Cerebellar intracerebral hemorrhage

Cerebellar hemorrhage accounts for only 10% of all ICH, but these can behave as a “malignant” ICH when the ICH ± PHE attains >3–4 cm in size due to the tight confines of the posterior fossa which does not allow much wiggle room for expansion and is associated with a high likelihood of rapid neurological deterioration from obstructive hydrocephalus, brainstem compression, and/or tonsillar herniation [24, 25]. There are no randomized trials comparing surgical to conservative management in cerebellar ICH, and it is unlikely these will ever be done as withholding surgical evacuation from patients with large compressive cerebellar ICH or conversely, performing surgery on patients with small cerebellar ICH who are fully conscious can be considered unethical.

Standard procedure

Suboccipital craniectomy with hematoma evacuation with or without removal of the arch of C1 is the procedure of choice. Placement of an external ventricular drain (EVD) alone to relieve obstructive hydrocephalus is not recommended as it is insufficient to address the brainstem compression that caused the hydrocephalus in the first place and therefore, does not/is not expected to fully reverse clinical decline. There is also a theoretical but small risk of upward supratentorial cerebellar herniation due to CSF drainage alone.

Data from non-randomized studies suggest that outcomes are better with surgery, particularly in patients who have cerebellar ICH > 3 cm or who are deteriorating due to mass effect [26, 27]. However, a recent meta-analysis of 578 patients with cerebellar ICH, drawn from 4 observational cohorts, surprisingly showed that surgical decompression was not associated with better functional outcomes on the modified Rankin Scale (mRS) when compared with a conservative approach (30.9 vs. 35.5%, adjusted OR 0.94, 95% CI 0.81–1.09, p = 0.43) [28••]. In exploratory subgroup analyses, cerebellar ICH < 12 cc had a twofold worse functional outcome with surgery (35 vs. 61%, p = 0.01). Survival at 3 and 12 months was significantly increased among surgical patients (78.3, 71.7 vs. 61.2%, 57.2%, p = 0.001, 0.008) respectively and this was mostly driven by the mortality benefit of surgery in those with cerebellar ICH ≥ 15 cc (which is roughly equivalent to >3 cm in size (74.5 vs. 45.1%, p < 0.001).

Indications and contraindications

Patients with cerebellar ICH > 3–4 cm (i.e., ~ ≥ 15 cc) appear to have clear mortality benefit from DC with hematoma evacuation and EVD placement as soon as possible (American Heart Association guidelines Class I; Level of Evidence B), but the functional improvement is yet to be proven [15]. Although there is no consensus about the optimal strategy for surgical management of cerebellar ICH < 3 cm, the following characteristics may be considered for decision-making. (Table 2) If the patient is conscious, close monitoring in an intensive care unit (ICU) is appropriate, because deterioration is unpredictable but usually happens within the first 72 h from ictus. At the first sign of decline in the level of consciousness, stat CT imaging is done to determine if the primary cause is brain stem compression/tonsillar herniation or obstructive hydrocephalus from extension of the cerebellar ICH into the 4th ventricle. If it is the former, then posterior fossa DC with EVD is favored. Neurological deterioration due to only IVH-related obstructive hydrocephalus responds well to an initial approach of CSF drainage followed by suboccipital decompression if there is progressive brainstem compression.

Table 2 Surgical management in posterior fossa intracerebral hemorrhage
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Special points

The role of admission GCS in determining outcomes from surgery is less clear in cerebellar ICH as compared to supratentorial ICH because some patients who are comatose can still have good outcomes after surgery [29]. Therefore, in the absence of overwhelming comorbidities or advanced age, surgery should not be withheld in patients with a poor preoperative neurological status.

Minimally invasive surgery

The goal of any surgical procedure is to evacuate a majority of the hematoma as quickly as possible while minimizing the risks of intervention, such as surgical injury, rebleeding, prolonged anesthesia exposure, and post-surgical infections. In addition, ideally, the procedure should be easy enough to be done with little specialized training. Such a surgical procedure does not exist as of yet, but minimally invasive surgery (MIS) checks off several of the above requirements.

The lack of benefit seen in open craniotomy is presumed to be from surgical disruption of white matter fibers, injury to eloquent areas, and venous injury—all of which prohibit optimal motor recovery. MIS procedures aim to minimize secondary surgical injury by utilizing a small operative footprint (e.g., preoperatively mapping a precise surgical tract to reach deep hematomas). In some MIS procedures, the hematoma evacuation is under direct visualization with the ability to seal off bleeding vessels in the walls of the cavity and therefore minimize rebleeding. Animal studies also demonstrate that instillation of thrombolytic into the hematoma with subsequent aspiration reduced perihematomal glutamate content, improved BBB permeability, and reduced PHE [30].

  1. A.

    Endoscopic aspiration:

Standard procedure

Endoscopic aspiration is an active evacuation technique whereby the hematoma is aspirated under direct microscopic visualization without the use of thrombolytics. It involves a small craniotomy (usually 2–3 cm in length) with advancement of an endoscopic system with a camera at the distal tip. There are several different techniques (discussed below), and these differ in their use of intraoperative CT guidance, sheath placement with stereotactic guidance, or an “underwater” aspiration technique.

  1. a.

    Intraoperative ct guided technique:

Standard procedure

This technique involves placement of an endoscopic sheath into the hematoma under real-time CT guidance and was adopted in the ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) arm of the MISTIE (MIS plus recombinant tissue plasminogen activator (r-tPA)) trial [31]. In the 20 enrolled patients, the procedure time was short (mean of 1.9 h) and led to a ICH volume reduction of 71.2% with an associated 12% increase in good outcome (modified Rankin Score (mRS) of 0–3 at 1 year) when compared with medical control from MISTIE trial.

  1. b.

    SCUBA technique:

Standard procedure

The Stereotactic Intracerebral Hemorrhage Underwater Blood Aspiration (SCUBA) technique has shown good early results [32•]. A low-profile endoscopic sheath (Penumbra/Apollo vibration/suction systems) is stereotactically placed into the hematoma and clot is aspirated via the endoscope containing a 2.6-mm aspiration wand with a vibrational wire, irrigation system, and a vacuum pump. Aspiration is done progressively at each 1.5-cm interval increments along the insertional axis. Subsequently, the cavity is irrigated with normal saline to allow for direct visualization of residual clot and for signs of active bleeding which are then cauterized or sealed off. In a study of 47 patients, the average reduction of ICH volume was 88% from a mean of 42.6 cc to a postoperative ICH volume of 4.2 mL. The ongoing MIND trial (NCT 03342664, www.clinicaltrials.gov) is a prospective multicenter randomized trial of 500 patients that is evaluating a similar minimally invasive neuro evacuation/aspiration device (Artemis, Penumbra Inc). INVEST Feasibility (NCT02654015, www.clinicaltrials.gov) is also an ongoing multicenter single-arm feasibility study evaluating both the Apollo and Artemis systems in about 50 patients.

In a single small-center retrospective case series, endoscopic aspiration of cerebellar hemorrhages >3 cm was compared to standard posterior fossa craniectomy [33]. In 22 of 37 patients undergoing endoscopy, there was 95% reduction of ICH volume, decrease in procedural time (141 ± 42.5 min vs. 241± 64 min), minimal blood loss, and no overt signs of resultant CSF leak. However, this study did not show any functional benefit.

  1. iii.

    Stereotactic aspiration with thrombolysis:

Standard procedure

This involves stereotactically placing a catheter into the hematoma followed by instillation of thrombolytics to lyse the hematoma and promote liquefaction of the clot, which is then directly aspirated during the same session or left to drain via a catheter over several days [34,35,36,37,38,39,40,41,42].

The Stereotactic Treatment of Intracerebral Hematoma by Means of Plasminogen Activator Trial (SICHPA) used a stereotactically placed catheter to instill urokinase in 6-h intervals for 48 h into a hematoma [37]. When compared to medical management, this led to a relative reduction in hematoma volume of 34% without a difference in mortality or morbidity at 180 days. In a subsequent trial, a YL-1 puncture needle was stereotactically inserted into the center of the hematoma to directly aspirate the clot followed by injection of lytic fluid (containing urokinase) through the needle to dissolve residual blood [38]. In a Chinese multicenter trial, 367 patients with basal ganglia ICH 25–40 mL in size, presenting within 72 h, were randomized to MIS or medical management. Both groups had similar mortality; however, the 90-day rate of functional dependence (mRS > 2) was significantly reduced (40 vs. 63%) within the MIS group. In a meta-analyses of 2996 patients from 4 trials of stereotactic thrombolysis compared to standard craniotomy, this MIS technique demonstrated significantly lower rates of death or dependence with OR 0.80 (95% CI 0.69–0.93, p = 0.004) [39].

These early studies paved the way for the NIH funded phase 2 and 3 trials of MISTIE [40, 41]. In the open-label phase 2 MISTIE trial, 96 patients with ICH of ≥20 ml who had stable hematoma on consecutive CT’s 6 h apart were randomized to medical management or the MISTIE procedure with the aim of testing feasibility and safety [40]. The procedure involved using imaging guidance to advance an introducer cannula through a burr hole into the middle of the hematoma using one of three pre-defined trajectories selected based on ICH location and shape. Clot aspiration was completed through a rigid cannula with a 10-mL syringe and then replaced with a flexible drainage catheter. The intent was to maximally engage the hematoma with this catheter and thereby maximize the surface area of the hematoma in contact with r-tPA. One milligram of r-tPA was flushed through the catheter every 8 h for up to 9 doses or until residual hematoma was <15 ml. (Fig. 1). In 54 surgical patients, the MISTIE protocol reduced hematoma size by 57% from an initial mean volume of 35 ml, with a nonsignificant trend toward improved functional outcome (mRS score of ≤3) at 180 days (33 vs. 21%) without any significant increase in symptomatic bleeding, infection, or 30-day mortality. In addition, MISTIE 2 also reported significantly decreased PHE (22 ± 35%) versus an increase in PHE of 47 ± 46%, (p < 0.001) in the medical management arm.

Fig. 1
figure 1

Sixty-two year old male with 65-cc left lobar ICH (shown in 3 axes, A–C, 3D reconstruction in G), enrolled in the MISTIE III trial. A drainage catheter was placed stereotactically via a posterior approach and is in good engagement with the long axis of the ICH, as best shown in F. Thrombolytic (r-tPA) 1 mg was instilled via the catheter at 8-h intervals for six doses with drainage of the liquefied ICH via the catheter. Final clot volume at the end of dosing is 4 cc (E, F, H).

Full size image

MISTIE III was an open label phase 3 trial that randomized 506 patients with ICH of ≥30 mL to the MISTIE procedure versus standard medical care [41••]. The MISTIE protocol resulted in a 69% reduction in hematoma size from a median ICH volume of 45 cc to 16 mL compared to 47 mL in the standard group. Despite this, there was no significant difference for good functional outcome (mRS 0–3, 46 vs. 41% at 365 days). This was likely driven by the fact that only 58% of patients actually reached the prespecified surgical goal of 15 mL or less [42]. A secondary analysis showed that if patients reached a final hematoma volume of 15 ml or < 70% of baseline, then that was associated with good functional outcomes, with each additional milliliter of hematoma volume removed beyond 15 mL increasing good outcome increased by 10%. There was also variability in the performance of the surgical task with surgeons who had performed ≥4 or more procedures achieving more comprehensive clot evacuation.

  1. B.

    Endoport evacuation:

Standard procedure

Endoport evacuation procedures are adapted from techniques used in resection of deep seated/subcortical tumor with the intent of providing a safe “corridor” with minimal disruption of white matter tracts. One such is the BrainPath endoport system where the sheath plus obturator is advanced along a parafascicular and transsulcal approach whereby the obturator, with an atraumatic tip, separates and displaces the brain parenchyma without cutting into it. Once the hematoma is reached, the obturator is removed and the hematoma is removed by aspiration and suction via the sheath. The downside of this approach is longer anesthesia times. The safety and feasibility of the BrainPath system was shown in a single-center retrospective series of 11 patient where the mean reduction in hematoma volume was 87% [43]. A subsequent multicenter study of 39 patients using diffusion tensor imaging (DTI) showed that 72% of the patients had a > 90% reduction in ICH volume with 52% of patients achieving a 90 day mRS of <3 [44••]. ENRICH (Early MiNimally-invasive Removal of IntraCerebral Hemorrhage (ICH) (NCT 02880878, www.clinicaltrials.gov) is an ongoing multicenter randomized adaptive clinical trial evaluating this technique within 24 h of ictus versus standard medical management in 300 participants.

Comparison among MIS techniques

A metanalysis of MIS techniques evaluated 15 randomized MIS trials against open craniotomy or medical treatment and found overwhelming evidence of achieving a combined outcome of reduced mortality and functional independence with mRS < 3 (OR 0.44, 95% CI 0.29–0.67, p = 0.0002). This benefit was similar for both stereotactic thrombolysis and endoscopic surgery when the MIS was done within 72 h after ictus [45].

Indications and contraindications

It is indeed an exciting time for surgical ICH removal with a plethora of MIS techniques utilizing minimally disruptive techniques and keyhole craniotomies, but caution is to be exercised before a particular MIS technique or for that matter MIS in general can be routinely recommended in clinical care. All of the MIS techniques have been studied only in a limited number of carefully selected participants, with requirements for specialized training among the operators. There is significant variability in the inclusion criteria for the trials limiting generalizability of the results. For example, MISTIE had only a 2.5% inclusion rate of screened patients. There is variability in the timing of surgery ranging all the way from <24 to <72 h after ICH onset and also in outcomes assessment ranging all the way from outcomes at hospital discharge, 3, 6, or 12 months making comparison among MIS techniques difficult. We recognize that there are strong preferences among individual neurosurgeons to offer one of the above procedures in select patients but at the time of writing this manuscript, we cannot recommend one technique over the other, or even recommend an MIS approach outside of clinical trials or registries due to the above limitations [15••].

Conclusions

ICH still remains a devastating disease but there is hope on the horizon with the rapid emergence of a plethora of MIS techniques combined with advances in pre- and intraoperative stereotactic imaging and navigational mapping. These techniques have already demonstrated safety and feasibility. We await the results on the ongoing RCTs to determine the efficacy of an individual MIS technique and the patient population which stands to derive the most benefit from surgery.