What does the CT angiography “spot sign” of intracerebral hemorrhage mean in modern neurosurgical settings with minimally invasive endoscopic techniques?
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- Nagasaka, T., Inao, S. & Wakabayashi, T. Neurosurg Rev (2013) 36: 341. doi:10.1007/s10143-012-0437-7
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Hematoma expansion is correlated with morbidity and mortality for patients with intracerebral hemorrhage (ICH). Recent studies demonstrated that contrast extravasation on contrast-enhanced CT and small-enhancing foci, so-called spot signs, on CT angiography are associated with subsequent hematoma enlargement. Such radiological markers of ICH may have significant implications not only as a surrogate marker for hematoma expansion in medical hemostatic therapy but also as indication for surgery. In this article, a brief description of contrast extravasation and “spot sign” will be provided first. The findings of some of the important trials that shaped the current landscape of therapeutic interventions for ICH will then be reviewed. Many neurosurgeons have faced a significant dilemma since the Surgical Trial in Intracerebral Haemorrhage (STICH) trial was published. Under adverse circumstances, many neurosurgeons assume that minimally invasive surgical interventions are still likely to benefit some patients and will be more effective. Among future candidate strategies for ICH, the most promising is neuroendoscopic surgery with direct hemostatic devices, which attains direct local hemostasis at the sites of vascular rupture. It is plausible that ultra-early direct hemostatic surgery given in the emergency setting might reduce hematoma volume and rebleeding and improve outcome. Finally, a description of future avenues of minimally invasive surgery for ICH treatment and suggestions for the design of further studies using reliable predictor of hematoma expansion spot sign will be provided. Neuroendoscopic interventions are minimally invasive and are likely of benefit in hemostasis and hematoma removal. On the basis of these observations, the spot sign of ICH has sub-emergency surgical implications.
KeywordsIntracerebral hemorrhageMinimally invasive surgeryNeuroendoscopySpot sign
Spontaneous intracerebral hemorrhage (ICH) is one of the most devastating forms of cerebrovascular disease. ICH accounts for 15 % of all strokes in the USA and Europe and 20 to 30 % of strokes in Asian populations . First, a brief description of the neurosurgical implications of “spot signs” will be provided. In this article, some of the important trials that shaped the current landscape of therapeutic interventions for ICH will also be reviewed. To that end, the growing clinical evidence indicating that the use of neuroendoscopy is effective will be reviewed.
“Contrast extravasation” and “spot signs” as a surrogate marker in hematoma expansion
Hematoma expansion occurs early after onset and has been shown to be an independent marker for poor outcome [3, 4, 10, 24–26, 29]. Focal contrast accumulation on contrast-enhanced CT (CE-CT) has been assumed to represent the active extravasation and pooling of contrast media within a hematoma and can predict future hematoma expansion and poor outcome [3, 17, 26, 36, 37, 52].
Although spot signs are also suggested as a predictive factor for in-hospital mortality in secondary ICH in patients with vascular abnormalities , this article principally focuses on spot signs in primary ICH.
In recent years, the “spot sign,” a bright spot on computerized tomography angiography (CTA) source images, has entered into the spotlight [11, 12, 17, 52]. While “contrast extravasation” is observed on non-enhanced CT completed several minutes after CTA as a pooling of contrast in the hematoma area, the definitions used differ with respect to radiologic findings.
In the original description of the spot sign by Wada et al., contrast extravasation had a much lower sensitivity and positive predictive value than the spot sign . By contrast, a recent study demonstrated a higher sensitivity for predicting hematoma expansion when using a combination of the spot sign and contrast extravasation [15, 19]. Therefore, although the two signs considerably overlap, both the spot sign and contrast extravasation are predictive of hematoma expansion, which is closely related to clinical deterioration and poor clinical outcome.
Early and complete removal of hematoma to prevent secondary injury
Surgical evacuation of the intracerebral hematoma is primarily based on the idea of reducing the mass effect and thereby decreasing intracerebral pressure, improving regional blood flow, and restricting the release of toxic breakdown products released by the clot . Secondary brain injury after ICH is a possible therapeutic target if a “perihemorrhagic penumbra” exists [5, 21, 45, 47]. Orakcioglu et al. found that, in a rat ICH model, clot evacuation is associated with the normalization of perfusion . Reversible perfusion reduction in this model indicates that early evacuation may help to reduce secondary neuronal changes . Therefore, the early and complete removal of ICH via a minimally invasive method can reduce the secondary injury associated with ICH .
Using the spot sign and contrast extravasation to identify patients whose hematoma is expected to grow is an attractive way of triaging patients into therapeutic interventions that target early neurological deterioration. However, the (STICH) trial has significantly affected the clinical management of ICH [27, 32]. Many questions surround the efficacy of surgical intervention for ICH [27, 32, 50], and many neurosurgeons face a dilemma. How should we make a decision about whether to evacuate an intracerebral hematoma in the hyperacute stage? If we turned the evaluation efforts over to the radiologists, how long and how frequently should the spot sign or the size of the hematoma be followed up?
Although the surgical interventions are likely of benefit in hemostasis and hematoma removal, the findings of some of the important trials that shaped the current landscape of therapeutic interventions for ICH will be reviewed.
Medical hemostatic therapy with recombinant factor VIIa
A multicenter, randomized, double-blind, placebo-controlled trial was conducted from August 2002 through March 2004 . This study was a dose-ranging, proof-of-concept trial, in which the doses of recombinant factor VIIa (rFVIIa) ranged from approximately half to twice the currently labeled dose of 90 μg per kilogram for hemophilia. This approach resulted in a reduction of mortality and an improvement of the functional outcome at 90 days. There was a small increase in the frequency of thromboembolic adverse events in the rFVIIa group (7 %) compared to the placebo group (2 %) .
A subsequent multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2005 and February 2007, the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, showed the reduction of hematoma expansion but no improvement in survival or functional outcomes . On the basis of these results, the routine use of rFVIIa as a hemostatic therapy for all patients with ICH within a 4-h time window cannot be recommended .
Hemostatic therapy is likely of minimal benefit in cases where hematoma expansion is not expected due to the dynamic property of ICH [10, 14, 29]. It would be desirable to avoid treating patients in whom hematoma expansion is unlikely.
A spot sign has important clinical implications and has been used as a surrogate marker in hemostatic intracerebral hemorrhage trials . Therefore, two phase II clinical trials will test the use of the spot sign in stratifying patients for treatment with rFVIIa. In these “Spot Sign” Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy (SPOTLIGHT) and the Sport Sign for Predicting and Treating ICH Growth Study (STOP-IT) trials, patients presenting with a spot sign will be randomized to receive rFVIIa versus a placebo. The primary outcomes will include hematoma expansion at 24 h and life-threatening thromboembolic complications .
In medical treatment settings, repeated CE-CT may provide useful information. Chakraborty et al. report a case of a warfarin-associated ICH demonstrating the time-dependent appearance of a spot sign. Repeat imaging was also presented and verified cessation of the spot sign after INR correction . In our opinion, if the early disappearance of the spot sign is detected, medical intervention may also achieve treatment success for primary ICH.
Minimally invasive surgery: hematoma puncture and drainage therapy
This more effective and minimally invasive surgery is one of the most promising therapeutic approaches for ICH. Hematoma puncture and drainage therapy with or without infusion of urokinase or recombinant tissue plasminogen activator (rtPA) are well-documented surgical interventions [2, 49, 51, 53]. To date, the largest study of hematoma puncture and drainage therapy is that of “minimally invasive craniopuncture therapy”  by Wang et al. Although aspiration and drainage using catheter placement might improve independent survival following ICH, the higher rebleeding rate in the craniopuncture group (9.7 %) compared to the conservative group (5 %) is still an area of concern .
In the Minimally Invasive Surgery plus Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) trial, stereotactic catheter placement and hematoma aspiration with injections of rtPA were initiated in 2006 and are expected to reach completion in 2013 . The results of this landmark trial are eagerly anticipated.
Although the minimally invasive drainage approaches unquestionably represent useful methods, these approaches have a number of shortcomings. All of these drainage treatments require bleeding cessation before the evacuation of a stable hematoma . The indication for drainage therapy in spot sign-positive ICH is less obvious because drainage therapy has many difficulties in hemostasis after the occurrence of rebleeding or hematoma expansion. It therefore may be reasonable to follow these patients closely or to perform hemostasis with direct surgical intervention. As such, any results of the drainage therapy studies implying changes in our current surgical indications for ICH should be interpreted with extreme caution [2, 33, 49, 51, 53]. The possibility of using the spot sign status of hematoma is more relevant to guide the selection of a particular strategy for surgical intervention.
Minimally invasive surgery with hemostatic techniques: neuroendoscopic surgery
In the last decade, significant advances have been made in neuroendoscopic surgical instruments and techniques [38, 39, 43]. Endoscopic evacuation of ICH is proving to be effective and to have advantages [20, 38, 39, 41–44, 54, 55]. Recent reports showed that the hematoma evacuation rate of endoscopic surgery was 83.4–99 % [7, 20, 22, 28, 38, 39, 41, 44, 55] and support the idea that neuroendoscopic surgery can play a crucial role in the treatment of spontaneous ICH at a hyperacute stage.
Prevention of rebleedings by direct surgical hemostasis
Although hematoma growth is traditionally considered to occur mainly during the first few hours following onset [4, 16, 24, 25], Kim et al. reported that contrast extravasation on CT was observed up to 48 h following symptom onset, suggesting that hematoma growth may continue to occur later in the ICH course . These observations may carry implications for designing the treatment window to be used in further direct surgical hemostasis trials to target the prevention of rebleeding.
Although minimally invasive hematoma evacuation using a neuroendoscope may theoretically be attractive and can be advocated as the primary treatment of choice, the superiority of neuroendoscopic surgery has so far not been proven in large trials. Therefore, the technique is still considered to be investigational [32, 35, 41].
Some authors suggest that early surgery with a standard craniotomy might not be recommended based on the currently available data because of a high rebleeding rate and poor outcome . However, recent reports showed that neuroendoscopic surgeries performed in the early stage were associated with a minimal rebleeding rate (0–3.3 %) compared with the traditional craniotomy method (5–10 %) [9, 28, 41]. In our experience, if almost complete removal has been attained after endoscopic surgery, there is a low likelihood of rebleeding during the postoperative period and neurological deterioration can be avoided [38, 39, 41]. In addition to the therapeutic clues offered by these studies, an additional trial should investigate whether complete hematoma removal definitely reduces rebleeding and improves survival and functional outcome.
Prevention of rebleeding; endoscopic direct hemostasis vs. hematoma puncture and drainage therapy
Although relatively higher, but variable, rebleeding rates ranging from 0 and 9.7 % to approximately 20 % were reported in hematoma puncture and drainage therapies [49, 51, 53], we simply cannot conclude from these data that hematoma puncture and drainage therapy would have been equivalent to or worse than surgical interventions. Furthermore, it was possible that there could be a selection bias and variability in the dose and types of hematoma lysis agent used.
In addition, hematoma lysis may be associated with a Janus head-like phenomenon; a favorable influence on the hematoma lysis rate may have an unfavorable impact on the post-surgical rebleeding rate. This might explain why significant hematoma volume reduction did not result in outcome improvement in the SICHPA (stereotactic treatment of ICH by means of a plasminogen activator) trial .
As described above, minimally invasive craniopuncture therapy performed by Wang et al. improved independent survival and might be one of the most promising strategies available. However, the rebleeding rate (9.7 %)  was higher than that of neuroendoscopic direct hemostatic surgery. The benefits of hematoma removal might be offset by the rise of the rebleeding rate in patients at risk. The MISTIE study  will indicate whether these strategies not only have safe and effective profiles but also have sufficiently low rebleeding rates.
Prevention of rebleeding; endoscopic direct hemostasis vs. medical hemostasis with rFVIIa
Specific detailed features relative to hematoma expansion are not provided in medical hemostatic trials [30, 31]; hence, the frequency of rebleeding cannot be gauged against those reported in neuroendoscopic direct hemostatic studies. A rational future strategy for improving the outcome of ICH may still include early hematoma evacuation. Hematoma evacuation might be coupled with medical therapy including pretreatment or postoperative add-on therapy with rFVIIa.
Next-generation neuroendoscopic surgery with a multipurpose cannula and/or bipolar cautery
A pilot feasibility study using a multipurpose cannula indicated that endoscopic surgery may have a safe and effective profile as an early surgical intervention for spontaneous ICH . The use of monoshaft bipolar cautery and its application in a bimanual hemostatic device system is another promising approach .
Possible earlier endoscopic intervention under the guidance of a spot sign
Further studies and careful analysis are needed to identify the subgroups of patients in whom direct hemostasis with endoscopic techniques improves surgical outcomes. In cases with continuous oozing, exposure of the bleeding vessel and direct hemostasis are the suggested courses of action .
If CTA and CE-CT are proven to predict hematoma expansion accurately, patients with a spot sign and contrast extravasation might be considered for appropriate surgical hemostasis or more aggressive exposure of the bleeding points and direct coagulation. However, cases without a spot sign that are unlikely to have hematoma expansion might be treated by using less aggressive therapy, such as puncture and drainage therapies because in these settings hematoma reduction alone may be enough.
Pathophysiology behind the spot sign and the future integration of radiological and surgical findings
The possible pathophysiologies behind the spot sign may relate to underlying Charcot–Bouchard aneurysms, amyloid-related microaneurysms, pseudoaneurysms, or active extravasation, but this is not well-established . If certain identifications of continuous extravasations and sufficient predictions for hematoma expansion are facilitated by the information-rich new radiographic technology, such as multisection CTA and/or CE-CT, we expect that more relevant stratification factors, which indicate early surgical hemostasis, will emerge.
Neuroendoscopic surgery has a significant competitive advantage in identifying bleeding points and performing direct hemostasis. These advantages also warrant a future trial that integrates the intraoperative findings of bleeding points for comparison to radiologic findings.
Future avenues in neuroendoscopic surgery for ICH
The observation that a spot sign is a reliable predictor of hematoma expansion may carry implications for designing the treatment window to be used in further neuroendoscopic surgery trials. For the best design of such a trial, we need better clinical and radiological characterizations that help select patients who are the most likely to benefit from hyperacute surgical interventions.
We suggest that endoscopy may play a crucial role in modern neurosurgical therapy for ICH. The direct identification of the bleeding point and coagulation of the responsible vessels under endoscopic visual control facilitate effective hematoma evacuation and can also simplify postoperative management. For the patient, as the beneficiary of an effective and minimally invasive strategy, neuroendoscopic surgery has several advantages. It is of the utmost importance that neurosurgeons take maximum advantage of the available neuroendoscopic techniques.
As a suggestion for further studies, it is necessary to establish evidence for the following: (1) appropriate candidates for neuroendoscopic surgery; (2) appropriate methods, timing, hematoma volume and location, and predictive factors to maximize the effect and minimize complications for each manifestation; (3) sensitive indicators of monitoring and assessment methods for rebleeding or hematoma expansion; and (4) long-term efficacy and safety, as well as the contribution to prognosis.
The assessment of the possibility of future hematoma expansion using a spot sign on CT angiography may serve as a very efficient and straightforward method of risk stratifying patients in surgical settings. The findings from previous medical hemostatic ICH trials set the stage for future works in which surgical interventions that target continuous bleeding can be assessed to more clearly delineate the advantages of direct surgical hemostasis suggested by previous studies. However, because the risk of rebleeding may increase in spot sign-positive patients, it is important that neurosurgeons consider both direct surgical hemostasis and medical hemostatic therapy including combination with rFVIIa in such high-risk emergency surgery settings. Further studies and careful analyses are needed to explore whether modern neuroendoscopic and medical hemostatic approaches improve outcomes.
Drs Yoichi Uozumi, Kyozo Kato, and Berk Orakcioglu provided important advice and support regarding this article. This article was supported by a JFE (The Japanese Foundation for Research and Promotion of Endoscopy) Grant.