Intraoperative Optical Coherence Tomography

Recently, surgical instruments and imaging technology in ophthalmology have shown a great improvement. However, advances in the field of the operating microscope technology still remained unchanged with the various limitations for the surgeons. Invention of optical coherence tomography (OCT) led to a revolution in the diagnosis and monitoring of numerous anterior and posterior segment pathologies. Recently, OCT has been introduced into the operating room with an impact on the surgeons. In this chapter, we review the evolution of OCT for intraoperative use with its feasibility, surgical impacts, and limitations.


Introduction
Optical coherence tomography (OCT) is a rapid, noninvasive, noncontact, and cross-sectional imaging method that produces images of ocular tissues. OCT uses reflected light to obtain the images from the different layers on the ocular tissues that produce different backscattered lights [1]. After using of spectral-domain OCT (SD-OCT) instead of time-domain OCT (TD-OCT), the images produced by OCT have become with higher resolution; thus, OCT has begun to provide more detailed information on ophthalmologic diagnoses [2]. Recent developments in ocular imaging technology have made the OCT a vital diagnostic tool in patient care. More recently, the availability of OCT during surgery has begun to be discussed. The introduction of OCT into the operating room (OR) called as intraoperative OCT (iOCT) has provided new insights into the surgical management during ophthalmic surgeries.

Intraoperative OCT
A number of researchers have examined the potential role of iOCT in various conditions and procedures, such as macular hole (MH), epiretinal membrane (ERM), retinal detachment surgery, and lamellar keratoplasty [3][4][5][6]. However, conventional clinical OCT devices are large and not portable; therefore, it would be difficult and impractical to transfer the conventional OCTs into OR. In addition, the supine position of the patient during a surgery and changes to surgical flow are other potential obstacles for image acquisition with good quality. All these hurdles forced researchers to produce a portable OCT device. Initial attempts with intraoperative OCT indicated successful results in imaging of excised tumors, postmortem specimens, structural changes after laser surgery, and in vitro human arteries and nerves [7][8][9][10]. Early investigations with iOCT were based on timedomain technology. Nevertheless, these investigations resulted in suboptimal image quality due to lower sensitivity and speed than novel technologies of SD-OCT and swept-source OCT (SS-OCT). In recent years, to overcome suboptimal imaging during surgeries, researchers have discovered the microscope-integrated OCT devices (MIOCTs). So far, a short overview about the evolution of iOCT devices was introduced. The following section will discuss various iOCT systems and devices and their technologies.

Intraoperative OCT systems and devices
iOCT devices can be classified into two main categories: portable OCT during surgical pauses and microscope-integrated OCT (MIOCT). Subsequently, portable OCTs have three subgroups: handheld, external-mounted, and microscopemounted. On the other hand, MIOCTs have two subgroups: live two-dimensional (2D) OCT imaging and live four-dimensional (4D) OCT imaging (Tables 1 and 2).

Portable OCT devices
Portable OCT devices were the beginning step for iOCT. There are two basic portable systems in the literature: the Bioptigen EnVisu (Bioptigen, Research Triangle Park, NC/Leica, Wetzlar, Germany) and the Optovue iVue (Optovue, Fremont, CA, USA) [6, 11-13]. These devices can be used with the systems, including handheld, external-mounted, and microscope-mounted for image acquisition.
Handheld imaging was the first examples of the portable OCTs [11,14]. This system has a compact handheld imaging probe connected over flexible optical fiber to a portable device. In spite of restrictions on image reproducibility and optimal aiming with the device, handheld imaging can present a good image quality. Moreover, unlike clinic tabletop OCT devices, handheld OCT has no requirement upright and cooperative patient situation. Nevertheless, the need to protect the sterile surgical field and the occurrence of motion artifacts due to instability are examples of several handicaps of handheld OCT. More importantly, the main disadvantage of handheld OCT is that it is limited to surgical pauses because of the need to remove the microscope from the patient during imaging. Unfortunately, it is impossible to obtain images of the structural changes that ensued from live tissue-instrument interactions during surgery. Mounting systems for the portable OCT systems were developed to address most of the handheld imaging. These external mounts contribute more stability, yet these systems require a supplementary footprint and place in the operating room [4, 6]. The microscope holders allow the surgeon to attach the portable probe directly to the microscope body, thus providing more stability than handheld imaging. Microscope foot pedal controls make it possible to control the probe position with X-Y-Z foot pedals. This foot pedal control makes easier imaging with improved image repeatability [4].
Unfortunately, the main disadvantage of portable OCTs is that it is limited to surgical pauses because of the need to remove the microscope from the patient during imaging. In other words, it is impossible to obtain images of the structural changes that ensued from live tissue-instrument interactions during surgery.

Microscope-integrated OCT devices
A step-by-step initiative in the iOCT has been the integration of OCT into microscope optics called MIOCT. Leica (Leica, Wetzlar, Germany) and Zeiss (Carl Zeiss Meditec, Oberkochen, Germany) were the first examples of these systems. In the Zeiss adaptation, a modified Cirrus (Carl Zeiss Meditec) and a modified Visante (Carl Zeiss Meditec) OCT system integrated into Zeiss microscope optical path for the posterior and anterior segment imaging, respectively, were used [3, 15, 16]. These two systems allow surgeons for real-time imaging by visualizing the instrument-tissue interaction. On the other hand, these two systems bring with it new software requirements, the need for heads-up image acquisition, and the compatibility of OCT with the surgical instrument used during imaging. Additionally, surgical maneuvers during the surgery also require Z-axis stabilization and automated tracking system to improve image quality. After the investigation of first MIOCT systems, three commercial systems were identified. Zeiss Rescan 700 was defined as the first FDA-approved MIOCT system. This system is integrated into the Zeiss Lumera 700  microscope platform. Zeiss Rescan 700 was also integrated into the microscope foot pedal system to provide surgeon targeting, orientation control. More importantly, Zeiss Rescan 700 has the first MIOCT having Z-tracking system [17,18]. The second FDA-approved MIOCT system was the Haag-Streit MIOCT system (Haag-Streit, Koeniz, Switzerland). This system consists of a side port using OPMedT (OPMedT, Lübeck, Germany) OCT system. This system has not only a microscope-mounted viewing but also a heads-up screen too [19]. Unlike Zeiss Rescan, the Haag-Streit Surgical iOCT has no control system with Z-tracking; differently, this system has an optical zoom. The third commercially available and FDA-approved MIOCT system was Bioptigen EnFocus iOCT system. This system can be adapted to both Leica and Zeiss microscopes. The system has a 4-μm resolution and a different static en face on external monitor as a visualization mode. Dissimilarly, Bioptigen EnFocus system has an essential long-fiber that provides more flexibility to insert the OCT device and its computer inside the operating room (Figure 1) [20].
With regard to limitations of the MIOCT devices, while a volumetric data could be obtained, acquisition of the volume is slow, and volume analysis as well as visualization has necessitated comprehensive postprocessing. Another important limitation of MIOCT devices is an inefficient display of continuous instrument movement due to intraoperative real-time visualization limited by B-scans. In other words, intraocular instruments used during live surgery generally give rise to shadows on the underlying tissue in B-scan mode. This issue requires alignment of the surgical maneuvers with the B-scan to eliminate instrumental ghosting during surgery. Ehlers et al. [21] described and characterized this shadowing effect with ex vivo porcine eye surgeries. Regarding surgical instrument shading, some authors have suggested the idea of an automated instrument tracking system using a stereo camera pair [22].  All real-time MIOCTs described above were limited to B-scan due to involvement of SD-OCT system having slower A-scan rate. Carrasco-Zevallos et al. [23] were the first authors who described the volumetric iOCT imaging of live model eye surgery. They presented a custom ultrafast SS-OCT system operating at 100 kHz of A-scan rate. This speed was three to five times faster than previous MIOCT devices. A software called a special graphics-processing unit was simultaneously used to get, process, and render volumes. Later, the same authors developed a custom microscope-integrated heads-up display (HUD) unit for stereoscopic imaging of MIOCT volumes [24,25]. SS-MIOCT and stereoscopic HUD together were called as 4D MIOCT. In 2015, 4D MIOCT was first demonstrated by Carrasco-Zevallos et al. [23] for imaging of human retinal surgery. The volumetric frame rate varied 3.3-10 volumes per second during the surgery. Through a special mode "stream saving," OCT volumes were saved, and thus continuous volumetric recording could be acquired in the surgery. Visualization of the stereoscopic volumes by the HUD was enabled, and the surgeon could control the volume rendering via a foot pedal joystick.
Although 4D MIOCT devices have faster scan rate than 2D MIOCT due to faster A-scan rate, it requires faster A-scan rate as well as human flicker fusion rate (16 Hz) to attain optimal lateral resolution. In addition to that, instrumental shading effect is still one of the major limitations in 4D MIOCT as well in 2D MIOCT devices.

Clinical applications of intraoperative OCT
In this part of the chapter, we will provide information on the clinical use of iOCT. In terms of both anterior and posterior segments, there are numerous of clinical studies related to feasibility and real-time assessment of the surgical feedback during the anterior and posterior surgeries [4-6, 11, 13, 14, 16-18, 20]. The two most important prospective clinical studies are the PIONNER study and the DISCOVER study [4,20]. In these studies, the portable microscope-mounted iOCT in the PIONNER study (n = 531) and the microscope-integrated iOCT in the DISCOVER study (n = 227) were evaluated. There are not only large-scale prospective but also numerous smaller clinical studies in the literature. In the section that follows, feasibility and efficacy of iOCT for the anterior segment applications will be argued.
iOCT has been used for full-thickness and lamellar keratoplasty surgeries for decision-making. Particularly, iOCT can be very useful to evaluate in cases with extensive synechiae or iridocorneal scars. It may help to protect iris tissue from traumas during initial trephination [26]. Furthermore, the graft-host position can be estimated during surgery; thereby, it can help to construct proper graft-host relationship. In anterior lamellar keratoplasty, the presence of residual corneal opacities following microkeratome-assisted removal of anterior stromal layers can be detected, and their extensions may be easily confirmed by iOCT. Again, the thickness of residual stromal bed can be assessed, thus increasing the safety of operation [27]. As is known, it is very important to maintain an intact descemet membrane (DM) during deep anterior lamellar keratoplasty (DALK), and large bubble technique is widely used for this purpose. The iOCT helps to confirm the presence of large bubbles, detect subclinical large bubbles, and conduct additional dissections. In addition to these, the presence of any interface fluid can be determined with the help of the iOCT, thus helping to determine the extra maneuvers that need to be done to ensure proper position of tissues to the end of the surgery. However, the instrumental shadowing effect may hinder the visualization of the underlying structures, thereby limiting the effective use of iOCT during intrastromal insertion of the needle. Therefore, surgical pause is necessary to evaluate the underlying tissues [17, 28,29]. iOCT is a helpful intraoperative imaging method not only in full-thickness and lamellar but also in endothelial keratoplasty applications, e.g., descemet stripping automated endothelial keratoplasty (DSAEK) and descemet membrane endothelial keratoplasty (DMEK). Especially, in double-pass technique in DSAEK, the residual donor thickness following the first microkeratome passing can be easily determined with guiding iOCT to select of ideal blade size for the next microkeratome passing. This will minimize the chance of perforation of donor tissue by obtaining very thin donor lenticules [30]. Additionally, iOCT provides an advantage to identify and remove the descemet membrane in case of extreme edematous corneas. Furthermore, iOCT allows a continuous monitoring during the graft insertion and unfolding process. In DMEK, iOCT is a very convenient tool to provide faster graft orientation and position, especially in cases with edematous cornea [31]. In the DISCOVER study, it was reported that the surgeons required additional surgical maneuvers in 41% of the cases having DSAEK [18]. Similarly, in the PIONNER study, results showed that 19% of the cases in which surgeons believed the graft was completely apposed had still persistent fluid detected in the iOCT; hence, it would require more maneuvers and vice versa; in 47% of cases where the surgeon believed the graft to be partially apposed, there was complete apposition in iOCT imaging [4]. These two studies have also revealed that iOCT aids changes in dissection depth in 38-56% of cases [4,20]. Briefly, it can be concluded that iOCT in keratoplasty procedures can minimize unnecessary manipulations and surgical time.
Recently, iOCT has been used in various stages of a cataract surgery. The wound structure, status of posterior capsule, and position of intraocular lens (IOL) can be easily assessed via iOCT during a cataract surgery [32]. In a case report, it was reported that MIOCT was a very feasible tool to evaluate the wound architecture, integrity of the posterior capsule, IOL position, and efficacy of stromal hydration. The authors suggested that iOCT could be helpful in real-time early detection of various complications of cataract surgery, thus allowing the surgeon to manage the complication immediately [33].
More recently, in taking biopsy and excisional procedures, such as retrocorneal fibrosis and pterygium excision, and evaluating intraoperative changes in corneal structure during excimer laser phototherapeutic keratectomy, feasibility of iOCT was assessed, and the results were promising [34,35].

Posterior segment
Similar to the use of iOCT for anterior segment surgery, iOCT has a wide range of potentials for posterior segment surgery. Numerous vitreoretinal pathologies were described with iOCT, such as retinopathy of premature (ROP), proliferative diabetic retinopathy, macular hole, epiretinal membrane (ERM), retinal detachment, and myopic foveoschisis [4,5,20,[36][37][38][39]. The iOCT has provided new insights into the underlying pathophysiology for some of these conditions. PIONEER and DISCOVER studies provided valuable information about iOCT for posterior segment surgeons [4,20]. We will discuss the results of these studies at the end of this section.
Chavala et al. [11] reported that they identified preretinal structures and retinoschisis with iOCT in case of ROP. They suggested that these new findings might markedly affect the surgeons to make a decision resulting in various alterations during the operation. It is thought that iOCT may allow the surgeons to assess the extents of both horizontal and anteroposterior tractional structures in ROP cases; thus, the surgeons could carefully dissect or peel while sparing the other retinal structures. Additionally, iOCT is very useful detecting the flat neovascular fronds in ROP cases as well as other vascular retinopathies; thereby, this could prevent iatrogenic hemorrhages by determining the extent and location of the neovascular fronds during the surgery.
The iOCT helps the surgeon to determine the firmness of vitreomacular tractions; therefore, in case of foveal cyst, de-roofing risk would diminish, and inadvertent macular hole could be eliminated. Similarly, during an ERM and internal limiting membrane (ILM) peeling, the iOCT decreases the risk of inadvertent grasping of the retina while completing ERM/ILM peeling (Figure 2). In a recent study, it was reported that a membrane peeling with the guidance of iOCT was enabled without the use of adjuvant dyes to identify of membrane edges [36]. Especially in a macular hole surgery, this advantage of iOCT allows visualization of the alterations in the macular hole architecture as well as in the outer retina [37,40]. In addition, during a macular hole surgery, the surgeon may worry about inadvertent touching or tearing on nerve fiber layer. In such situation, the iOCT with real-time feedback can prevent inadvertent damage on nerve fiber layer.
One of the retinopathies in which the iOCT is used is myopic foveoschisis. As known, there are multiple layers of schisis in this retinopathy, and this involves vital dye staining to make certain that the whole cortical vitreous has been removed. However, the cases with myopic foveoschisis have a longer axial length, thus giving rise to poor dying. The iOCT can allow not only to better evaluate the ILM but also to prevent iatrogenic breaks by improving visualization in a myopic retina.
iOCT enables to provide more information in retinal detachment cases. In recent various studies, the iOCT revealed the presence of subclinical persistent subretinal fluid under perfluorocarbon tamponade in most of the cases undergoing retinal  [23]. detachment operation [4,5,20]. Furthermore, iOCT can help to detect proliferative vitreoretinopathy changes and border architecture of retinal tears.
In proliferative diabetic retinopathy, iOCT provides an enhanced imaging during delamination of membranes. For this reason, the iOCT facilitates the identification of the surgical plane, which permits membrane peeling in a safe manner. In addition to that, in the cases of dense vitreous hemorrhage, iOCT can help to assess intraoperatively the underlying macular pathology, such as intraretinal fluid, macular edema, or presence of a membrane, which may impact the surgeon in changing operation plan [38,39].
Recently, in the 3-year outcome reports of the DISCOVER study, the use of iOCT for image-guided retinal biopsy and placement of Argus II implant was reported. It was demonstrated that iOCT facilitates insertion of the biopsy site and enabled confirming placement of the implant in optimal location [41,42]. More recently, a few studies reported the use of iOCT verifying subretinal location of gene therapy and stem cells during the operation [43,44].
Finally, the outcomes in posterior segment surgery in the PIONNER and DISCOVER studies showed that iOCT identified residual membranes in 13-22% of the cases whom the surgeon believed that membrane peeling was completed; conversely, in 15-40% of the cases, the surgeon still thought the presence of residual membrane, yet iOCT indicated that complete removal of the membrane had been performed [4,20]. Additionally, iOCT provided addition of useful data concerning surgical anatomic features in 59.4% of the cases, and the information obtaining with iOCT impacted the surgery in 29.2% of the cases [20].

Conclusion
As known, in a very short time, conventional tabletop OCT has acquired its place in practice; subsequently, real-time intraoperative feedback with the iOCT appears to be a revolution in the OCT technology. Up to now, overall study reports related to iOCT, especially the PIONNER and DISCOVER study, have enhanced our understanding of iOCT technology and its unique advantages in surgical efficiency. iOCT may lead to refine and replace conventional surgical procedures with novel procedures, so that, with this technology, improved individual surgical management and patient care can be achieved. However, this technology has still a few limitations. The overall outcomes related to feasibility of iOCT need to be validated with additional prospective randomized trials.

Conflict of interest
There are no conflicts of interest.
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.