Cerebrovascular diseases, including ischemic and hemorrhagic strokes, affect more
than 6 million US adults annually. Strokes cause high rates of morbidity and mortality
due to the central nervous system's sensitivity to disruptions in blood flow, and
are refractory to traditional surgical interventions. A variety of minimally invasive
surgical and endovascular approaches have recently been developed to improve patient
outcomes following stroke.
Hemorrhagic strokes, also referred to as intracranial hemorrhages (ICH), have clinical
outcomes largely dependent on hemorrhage location, size, and secondary peri-hematomal
edema (Rennert et al., 2015). In theory, clot evacuation addresses local mass effect
and enhances survival of edematous penumbral tissue (Rennert et al., 2015), however,
multiple clinical trials have failed to show a definitive benefit for surgical hematoma
evacuation following ICH (Rennert et al., 2015). The largest of these is the 2005
International Surgical Trial in Intracerebral Haemorrhage (STICH) trial (Mendelow
et al., 2005), wherein 1,033 patients with spontaneous lobar and/or basal ganglia
ICH were randomly selected for surgical evacuation within 24 hours of presentation,
or initial conservative treatment. In this study there was no significant difference
in favorable outcomes across groups (26% vs. 24%, P = 0.4), yet subgroup analysis
revealed that patients with superficial hematomas (≤ 1 cm from the cortical surface)
may benefit from surgery, supporting the hypothesis that decreasing secondary neurologic
injury from manipulation of injured penumbral tissue during clot removal critically
affects outcomes. Current guidelines thus recommend consideration of open surgical
evacuation only in specific clinical scenarios, such as lobar clots > 30 mL and within
1 cm of the cortical surface. In this setting, there has been a recent push to develop
minimally invasive approaches for ICH removal.
One such minimally invasive approach is stereotactic surgery (i.e., using an imaging
based three dimensional roadmap for surgical localization) combined with intra-clot
injection of thrombolytic agents, such as tissue plasminogen activator (tPA). The
Minimally Invasive (Stereotactic) Surgery plus rTPA for ICH Evaluation (MISTIE) randomized
clinical trials have demonstrated the safety and effectiveness of this approach for
reducing clot and perihematomal edema (Rennert et al., 2015), with a larger phase
III clinical efficacy trial currently ongoing. Stereotactic endoscopic evacuation
of intraventricular hemorrhages (IVH) in ICH is also being explored, as is targeted
infusion of intraventricular thrombolytics based on pre-clinical and clinical safety
data (Gaberel et al., 2014; Rennert et al., 2015).
Endoscopic techniques (i.e., burr hole craniotomy with direct hematoma visualization/removal
through a sheath) are similarly appealing due to minimization of secondary neurologic
injury from surgical manipulation. Direct hematoma visualization with this approach
also allows for identification and real-time treatment of the original bleeding source,
and is associated with improved evacuation rates compared to stereotactic aspiration
(Cho et al., 2006). Moreover, this technique may be particularly well suited for deeper
hemorrhages, with preliminary data showing improved clot evacuation rates and post-operative
neurologic status compared to open surgery in patients with hemorrhage in deeper brain
structures such as the putamen and thalamus (Nagasaka et al., 2011).
New technology combining real-time neuronavigation with neuroendoscopy has also been
developed and trialed for ICH evacuation (Rennert et al., 2015). The initial multi-center
clinical experience with one such system was recently reported, with twenty-nine patients
with lobar, basal ganglia, and brainstem hemorrhages (including six with the poor
prognostic finding of intraventricular extension) treated with a nearly 92% technical
success rate and low morbidity and mortality (Spiotta et al., 2015). While general
clinical guidelines for endoscopic ICH evacuation are currently supratentorial hemorrhages
≥ 30 mL, with a goal of <15 mL post-operative residual, combined neuronavigation/neuroendoscopy
has already been integrated into the senior author's clinical practice (
Figure 1
), and has the potential to expand these indications and gain widespread adaptation
for the treatment of ICH as additional clinical data is obtained.
Figure 1
Endoscopic hematoma evacuation.
Representative pre-operative non-contrast computed tomography (CT) axial (A) and sagittal
(B) images of a 63-year-old female with a left basal ganglia hemorrhagic conversion
of an ischemic stroke. The patient was treated via navigated neuroendoscopic hematoma
evacuation (C) using a frontal craniotomy (trajectory indicated by the red arrow in
[B]). Post-operative imaging (D) confirmed a 94% reduction in clot size.
Minimally invasive surgical techniques are also being increasingly utilized in ischemic
strokes, where the rapid restoration of normal blood flow via thrombolytics or mechanical
thrombectomy is critical. In fact, for large vessel occlusive strokes, multiple large,
randomized trials were recently stopped for dramatic outcome improvement with thrombectomy
for acute large vessel stroke (Berkhemer et al., 2015; Campbell et al., 2015; Goyal
et al., 2015), making this intervention the new standard of care (Powers et al., 2015).
The initial data with mechanical thrombectomy nonetheless demonstrated a decoupling
of clinical outcomes with the technical success of angiographic reperfusion (Teng
et al., 2015). These findings, combined with the known detrimental effects of disruptions
in physiologic blood flow on endothelial cell maintenance, remodeling, and cytokine
signaling, support the hypothesis that vascular endothelial cell damage resulting
from altered flow dynamics, reperfusion injury, and/or iatrogenic trauma may potentiate
secondary neuronal injury in post-thrombectomy stroke patients (
Figure 2
) (Teng et al., 2015).
Figure 2
Schematic illustration of the hypothesis that thrombectomy-associated iatrogenic endothelial
cell injury can influence stroke outcomes.
To better assess the effect of thrombectomy devices on the endothelium, we recently
developed a novel in vitro live cell platform capable of characterizing endothelial
injury patterns and mechanisms across thrombectomy devices (
Figure 3
) (Teng et al., 2015). This technology allowed for the tubular growth of endothelial
cells under peristaltic flow, with post-thrombectomy injuries easily visualized and
quantified with a novel rotational-scanning image system and three-dimensional reconstruction.
Specifically, six thrombectomy devices were tested across three vessel diameters in
vitro: (1) 5MAX ACE (Penumbra, Inc., Alameda, CA) with A Direct Aspiration first Pass
Technique (ADAPT), (2) MERCI (3.0 firm) (Concentric Medical Inc/Stryker Corp., Kalamazoo,
MI), (3) 5MAX with Separator (Penumbra, Inc.), (4) 5MAX with Separator 3D (Penumbra,
Inc.), (5) Solitaire FR (4 × 20 mm) (Covidien, Ltd, Mansfield, OH) and (6) TREVO (Stryker
Corp.). Characteristic injuries were seen across devices, ranging from a nearly complete
degloving injury with the Merci retriever, to a focused circumferential or linear
denudation with the 5MAX ACE with the ADAPT technique and the Separator 3D. These
findings were surprising by ours (Teng et al., 2015) and others (Gory et al., 2013)
data from in vivo experiments, and validate the in vitro live cell model as an important
tool for thrombectomy device assessment and future design evaluations.
Figure 3
In vitro live cell model demonstrating the heterogeneous effects of thrombectomy devices
on the endothelium.
(A) Representative 3D reconstructions of full vessel scans post-thrombectomy demonstrating
endothelial injury patterns. (B) Correlation between fluorescent whole vessel scans
and endothelial cell density, confirming the fidelity of the model. (C) Cumulative
in vitro post-thrombectomy cell area comparisons across devices, providing data for
future device design. Figure reproduced with permission from Stroke (Teng et al.,
2015).
As research in other surgical fields has demonstrated multiple advantages of minimally
invasive techniques, including avoidance of large incisions requiring less sedation,
less trauma to the patient, and potentially lower treatment costs resulting from shorter
hospital courses and a reduced need for post-operative intensive medical care, it
is not surprising that minimally invasive surgical approaches to stroke have recently
gained traction. As highlighted herein, the successful development and integration
of such technology requires a strong pre-clinical foundation and well designed clinical
trials. The promising results in the aforementioned and ongoing clinical trials suggest
the future utilization of minimally invasive techniques for the treatment of hemorrhagic
and ischemic stroke will continue to increase.
RCR, JSP and AAK contributed to idea generation, paper preparation, and revisions.
The authors are grateful to Victor W. Wong for his original figure artwork. AAK has
previously received competitive grants from Covidien Ltd. and Penumbra Inc, and holds
consulting arrangements for physician training with Stryker Neurovascular, Covidien
Ltd., and Penumbra Inc. AAK has no direct financial interests related to this work.
RCR and JSP have no disclosures concerning the materials or methods used in this study
or the findings specified in this paper.