Retina Changes in Blood Flow on Optic Nerve Head After Vitrectomy for Rhegmatogenous Retinal Detachment

Takeshi Iwase, Misato Kobayashi, Kentaro Yamamoto, Kosei Yanagida, Eimei Ra, and Hiroko Terasaki

Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Correspondence: Takeshi Iwase, De- PURPOSE. To determine the preoperative characteristics and the changes in retinal blood flow partment of Ophthalmology, Nagoya following vitrectomy in eyes with a rhegmatogenous retinal detachment (RRD). University Graduate School of Medi- cine, 65 Tsurumai-cho, Showa-ku, METHODS. Twenty-five–gauge vitrectomy without scleral bucking was performed on 31 eyes of Nagoya 466-8560, Japan; 31 patients with macula-on RRD. The retinal blood flow on the optic nerve head (ONH) was [email protected]. assessed by laser speckle flowgraphy (LSFG), and the mean blur rate (MBR) and pulse Submitted: August 21, 2016 waveform parameters before and at 10 days, 1, 2, 3, and 6 months after the surgery were Accepted: October 10, 2016 examined. Eyes treated by scleral buckling, and eyes with an epiretinal membrane and cataract that underwent surgery were used as controls. Citation: Iwase T, Kobayashi M, Ya- mamoto K, Yanagida K, Ra E, Terasaki RESULTS. The mean preoperative MBR-vessel on the ONH was significantly lower in eyes with H. Changes in blood flow on optic RRD than in the fellow unaffected eyes (P < 0.001), but it was not significantly different from nerve head after vitrectomy for rheg- the operated eye and the fellow eye in the control group. A significant increase in the mean matogenous retinal detachment. In- MBR-vessel on the ONH was observed following vitrectomy in eyes affected by RRD (P < vest Ophthalmol Vis Sci. 0.001), whereas no significant difference was observed in the fellow eye, the scleral 2016;57:6223–6233. DOI:10.1167/ buckling–treated eyes, and the control eyes. Of the eight pulse waveform parameters, only iovs.16-20577 the flow acceleration index was significantly lower in eyes with a RRD than in the fellow eyes preoperatively, but then it significantly increased with time following vitrectomy. The changes in the MBR-vessel were not correlated with that of other parameters (e.g., the ocular perfusion pressure).

CONCLUSIONS. These results indicate that the retinal blood flow is reduced in eyes affected by RRD preoperatively, and can recover following successful RRD repair by vitrectomy. Keywords: retinal blood flow, rhegmatogenous retinal detachment, vitrectomy, laser speckle flowgraphy

rhegmatogenous retinal detachment (RRD) is a separation incision instruments and wide-angle viewing systems.13 Be- A of the sensory retina from the RPE caused by tears in the cause PPV without concomitant scleral buckling does not entail retina and can lead to a permanent loss of vision if untreated.1 a compressional step, it is possible to evaluate the natural Rhegmatogenous retinal detachment is usually treated by either course of ocular blood flow before and after successful RRD scleral buckling alone or by pars plana vitrectomy (PPV) with repair. However, there have been only a few studies examining or without scleral buckling. The results of a randomized the effects of PPV on the ocular blood flow in eyes with RRD. controlled trial indicated that both of these surgical procedures Kimura et al.14 reported that the ocular microcirculation is led to successful reattachment in phakic, pseudophakic, and normal 6 months after PPV for RRD. It has been reported that a 2 aphakic patients with similar final reattachment rates. gas tamponade might have subclinical adverse effects on the Although scleral buckling is a well-established surgical circulation in the region of the neuroretinal disk rim.14 treatment for RRD, it has been reported that the procedure A variety of techniques have been developed for measuring can cause problems in the ocular circulation.3–10 Diddie and the retinal blood flow including fluorescein angiography,15 Ernest7 used the microsphere technique and found that the radioactive microspheres,16 hydrogen clearance,17 laser Dopp- encircling buckling method significantly decreased the retinal ler technique,4,5 color Doppler ultrasonography,18 and the and choroidal circulation in rabbit eyes. There have also been 9 several studies reporting that scleral buckling can reduce the pulsatile technique. Time intensiveness and problems with retinal5,6,8 and choroidal blood flow.9–11 Compressional mech- reproducibility have hampered the widespread use of many of anisms have been cited as the cause of the reduced choroidal these measurement techniques. More recently, a Doppler 19 blood flow following scleral buckling.7,12 Thus, the reduced optical coherence tomographic (OCT) technique, OCT ocular blood flow has been attributed to a direct obstruction of angiography,20 and optical microangiography (OMAG)21,22 have the choroidal venous drainage by the scleral buckling, and the been developed and used to measure the blood flow on the time course of the ocular blood flow following scleral buckling optic nerve head (ONH) and retina using high-resolution depth- is always affected by the procedures. resolved imaging with high reproducibility. However, these The safety and effectiveness of PPV has improved by the techniques still have inherent limitations for clinical use improvements in the surgical instruments including micro because of the time intensiveness of the procedures.

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Laser speckle flowgraphy (LSFG) is a noninvasive, real-time All patients underwent a comprehensive ophthalmic method that has been used to measure the relative blood flow examination as standard examination in our hospital including on the ONH. The measurement duration is only 4 seconds and the measurements of the IOP and axial length, slit-lamp can be performed without the intravenous injection of any biomicroscopy, fundus photography with the Optomap camera contrast agents.23–25 A recent update of the software embed- (Optos plc., Dunfermline, Scotland), spectral-domain OCT (SD- ded in the most recent LSFG device (LSFG Analyzer, v. 3.1.62; OCT; Spectralis OCT, Heidelberg Engineering, Heidelberg, Softcare Co., Ltd., Fukutsu, Japan) enables the recording of Germany), and LSFG before, and 10 days, and 4, 8, 12, and images synchronized with each cardiac cycle, and can then 24 weeks after the surgery. determine the various blood flow parameters at each All patients were asked to abstain from alcoholic and heartbeat. Laser speckle flowgraphy can detect the speckle caffeinated beverages on the morning of the day of the contrast pattern produced by the interference of the illumi- examination because the intake of alcohol and caffeine can nating laser light that is scattered by the movement of influence the IOP28,29 and blood pressure.30,31 Thirty minutes erythrocytes in the blood vessels. This enables the device to before the LSFG examinations, 0.4% tropicamide/phenyleph- calculate the relative blood flow in the vessels of the ONH and rine (Mydrin P; Santen Pharmaceutical Co., Ltd., Osaka, Japan) retina, which is expressed as the mean blur rate (MBR).23–25 was used to dilate the pupil. The subjects rested for 10 to 15 The ‘‘vessel extraction’’ function of the software then identifies minutes in a quiet, dark room before the examination, and all the vessel and tissue areas on the ONH so that the MBR of each examinations were performed in the sitting position. The area can be assessed separately. The vessel area can be used to refractive error (spherical equivalent) was measured with an evaluate the blood flow in the retinal vessels excluding the autorefractometer (KR8900; Topcon, Tokyo, Japan), and the choroidal blood vessels.26 Aizawa et al.27 reported that the axial lengths were measured by partial optical coherence coefficient of variation (COV) for determining the MBR was 3.4 interferometry (IOLMaster; Carl Zeiss Meditec, La Jolla, CA, for the ONH. Therefore, LSFG is considered to be suitable for USA). The IOP was measured with a handheld tonometer measuring the blood flow rates on the ONH. (Icare; Tiolat Oy, Helsinki, Finland). The systolic and diastolic However, there have been only a few reports describing the blood pressures (SBP and DBP) were measured at the left ocular blood flow in eyes affected by RRD before surgery and brachial artery at the height of the heart in a sitting position that following PPV. It is not easy to estimate the preoperative with an automatic sphygmomanometer (CH-483C; Citizen, retinal blood flow in eyes affected by RRD because the retinal Tokyo, Japan). The mean arterial blood pressure (MAP), and vessels are tortuous and ascend vertically to the surface to the mean ocular perfusion pressure (MOPP) were calculated as RPE in the areas where the retina is detached. follows: MAP ¼ DBP þ 1/3 (SBP DBP), MOPP ¼ 2/3MAP 32 Thus, the aim of this study was to evaluate the blood flow IOP. on the ONH in the PPV-treated eyes with RRD by comparing The size of the retinal tear and the extent of the retinal the values with that of the fellow eyes and the scleral buckling– detachment were calculated as the ratio of retinal tear or treated eyes. Laser speckle flowgraphy was used to determine extent of detachment area to the area of the entire fundus the changes in the ONH blood flow before and after surgery. photograph taken with the Optomap camera. Laser Speckle Flowgraphy (LSFG) ETHODS M The LSFG-NAVI (Softcare Co., Ltd.) instrument was used to Ethics Statement determine the ONH blood flow. The principles of LSFG have been described in detail.33–36 Briefly, this instrument consists This was a retrospective, cross-sectional, single-center study, of a fundus camera equipped with an 830-nm diode laser as the and the procedures used were approved by the Ethics light source and a standard charge-coupled device sensor (750 Committee of the Nagoya University Hospital (Nagoya, Japan). width 3 360 height pixels) as the detector. After switching on The study was performed at the Nagoya University Hospital, the laser, a speckle pattern appears due to the interference of and the study conformed to the tenets of the Declaration of the light scattered by the movements of the erythrocytes. The Helsinki. MBR is a measure of the relative blood flow velocity, and it is determined by examining the pattern of the speckle contrast Subjects produced by the erythrocytes in the ocular blood vessels. The MBR images are acquired at a rate of 30 frames/seconds over a We reviewed the medical records of all patients who had 4-second period. The same site can be measured by using the undergone 25-G PPV for RRD at the Nagoya University Hospital auto-tracking system. To evaluate the circulation on the ONH, a from July 2013 to March 2015. The unaffected fellow eyes, circular marker was set surrounding the ONH (Fig. 1A). The patients who had undergone scleral buckling for a RRD and ‘‘vessel extraction’’ function of the software then identified the PPV for an epiretinal membrane (ERM) with phacoemulsifica- vessel and tissue areas on the ONH so that the MBR of each tion and aspiration for cataract were studied as controls. All of could be assessed separately (Fig. 1B). The MBR of the vessel the patients signed an informed consent form before the (MBR-vessel) and tissue areas (MBR-tissue) on the ONH were surgery. determined. The software in the instrument was able to track and compensate for the eye movements during the measure- Exclusion Criteria ment period. The LSFG was measured three times at each time- point in all eyes. The average of the variables derived from the The exclusion criteria included the presence of any optic disc LSFG device was calculated. The ratio of the MBR of the abnormalities such as those related to glaucoma, optic disc affected eye to the fellow eye was used to evaluate the atrophy, history of intraocular surgery, presence of vitreous relationship between the retinal blood flow rate and the other hemorrhage, severe cataract, and absence of a posterior variables. vitreous detachment (PVD) in eyes treated by PPV. Subjects The laser speckle flowgraphy analyzer software allows the were also screened for any medical condition that could recording of images synchronized to each cardiac cycle and influence the hemodynamic of the eye such as diabetes, derives various heartbeat waveform parameters (Figs. 1C, 1D). hypertension, arrhythmia, and vascular diseases. The mean blur rate for the overall area of the ONH was used

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FIGURE 1. Representative composite color maps of the MBR as measured by LSFG. (A) Red color indicates a high MBR and the blue color indicates a low MBR. To measure the MBR of the blood flow on the ONH a circle was set around the ONH. (B) A binary formatted image for segmentation between the vessel (white area) and tissue (black area) areas. (C) Changes in the MBR on the ONH during one heartbeat. White arrow indicates one beat. (D) Pulse waves showing changes in the MBR, which are synchronized with the cardiac cycle for 4 seconds. The total number of frames in one scan is 118.

for the pulse waveform analyses. All eight parameters of the vitrectomy. Next, air was injected into the vitreous cavity to pulse waveform analysis of LSFG were studied.37 close the scleral port if needed. In cataract surgery, a 2.4-mm wide self-sealing superior Surgical Technique sclerocorneal tunnel was created at 12 o’clock, and a continuous curvilinear capsulorhexis was performed. The lens Standard three-port PPV was performed with 25-G instruments nucleus was removed and the residual cortex was aspirated after retrobulbar anesthesia with 2.5 mL of 2% lidocaine and with an irrigation/aspiration (I/A) tip. Next, a foldable acrylic 2.5 mL of 0.5% bupivacaine. None of the patients had IOL was implanted into the capsular bag. concurrent scleral buckling surgery. Cataract surgery was In segmental scleral buckling procedure, retinal breaks performed in eyes with a cataract. To begin the PPV procedure, were identified in all patients and were treated by transscleral a trocar was inserted at an approximate angle of 308 parallel to cryotherapy. Mattress sutures were placed 7.0 to 7.5 mm apart with 4-0 supramid (Kono, Chiba, Japan) for the segmental the limbus. Once the trocar was past the trocar sleeve, the buckle and a silicone sponge (Mira No. 506; Mira, Inc., angle was changed to be perpendicular to the retinal surface. Waltham, MA, USA) was sutured as an explant in all cases. After creating the three ports, PPV was performed using the Neither the scleral dissection, extraocular muscle disinsertion, Constellation system (Alcon Laboratories, Inc., Fort Worth, TX, nor the concomitant encircling was required for any patients. USA). Subretinal fluid drainage was performed if necessary. In eyes with a RRD, the vitreous was removed as completely as possible, then fluid-air exchange and subretinal fluid Statistical Analyses drainage from the causative retinal tear(s) or iatrogenic hole were performed. Endophotocoagulation was applied to the We evaluated the changes in MBR-vessel by a mixed-model causative retinal tear(s) or any iatrogenic holes. Then 20% method to incorporate appropriate covariates between repeat- sulfur hexafluoride (SF6) was injected into the vitreous upon ed measured values over time. Specifically, we assumed the completion of the PPV. After the IOP was adjusted to normal following model: levels, the cannulas were withdrawn. The sclera was pressed yij ¼ ai þ f ðtj; Gi : bÞþeij ð1Þ and massaged with an indenter or sutured with 8-0 vicryl to close the wound. i(subject) ¼ 1,. . .,31, j(time) ¼ 0, 10 (days), 1, 2, 3, 6 (months) In eyes with an ERM, the ERM and ILM were peeled from where yij is the MBR at time j of subject i. ai is a subject- the retina using ILM-peeling forceps (25þ Grieshaber Revolu- specific random effect, Gi ¼ 1 represents the affected eye and 0 tion DSP ILM forceps; Alcon Laboratories, Inc.) after core the unaffected eye. The function f(tj:b), which represents a

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TABLE 1. Clinical Characteristics of Subjects

RRD

Characteristic Vitrectomy Scleral Buckling ERM Cataract P Value

n,eyes31461515– Age, y 55.8 6 10.6 44.6 6 17.4 72.0 6 9.1 72.5 6 11.9 <0.001 Male/Female 21/10 28/18 9/6 7/8 0.596 Preoperative IOP, mm Hg 12.4 6 3.0 13.1 6 3.3 12.9 6 3.2 13.1 6 3.2 0.732 Axial length, mm 25.91 6 1.69 25.89 6 1.71 24.36 6 1.56 23.42 6 1.34 <0.001 Systolic blood pressure, mm Hg 133.0 6 18.3 127.3 6 16.3 127.6 6 21.7 129.7 6 18.3 0.933 Diastolic blood pressure, mm Hg 80.3 6 10.9 78.6 6 11.6 72.7 6 12.4 79.5 6 12.8 0.483 Mean arterial pressure, mm Hg 97.9 6 12.7 94.8 6 12.5 91.0 6 13.6 96.3 6 14.3 0.639 Ocular perfusion pressure, mm Hg 53.1 6 9.4 50.3 6 9.1 47.6 6 9.8 51.7 6 8.8 0.784 Heart rate, bpm 75.4 6 15.9 71.6 6 12.1 69.9 6 8.3 75.4 6 8.7 0.557 PPV/PPVþPEAþIOL/PEAþIOL 20/11/0 – 0/15/0 0/0/15 <0.001 PEA, phacoemulsification and aspiration.

fixed effect of time on the refraction, was specified as a MOP, and pulse waveform parameters. We used paired t-tests to polynomial function: compare normally distributed data between the affected eyes

2 2 and the fellow eyes at specific time-points. Pearson correlation f ðtj; Gi : bÞ¼b0 þ b1Gi þ b11tj þ b12tjGi þ b21tj þ b22tj Gi coefficient analysis was used to determine the correlations k k þþbk1tj þ bk2tj Gi: between the ratio of preoperative MBR-vessel in the affected ð2Þ eyes to those in the fellow eyes and the independent variables such as the size of retinal tear, extent of RD, preoperative MOPP, The b parameters represent the fixed-time effects and heart rate, IOP, age, visual acuity, and axial length. All statistical interaction between the time and group effects, respectively. analyses were performed with SAS9.4 (SAS, Inc., Cary, NC, USA). A P less than 0.05 was considered statistically significant. The order of polynomials in f(tj,Gi:b) was selected on the basis of the Akaike information criteria (AIC). For the residual term eij of the refraction value, we assumed a heterogeneous compound symmetrical structure within patients. RESULTS Chi-square tests were used to compare categorical data, and Patient Demographics and Surgical Characteristics independent t-tests were used to compare normally distributed data. Repeated 1-way ANOVA with post hoc Bonferroni One hundred thirty-six eyes of 136 patients underwent PPV in corrections was used to evaluate changes in the MBR, IOP, our department for the repair of a RRD between July 2013 and

FIGURE 2. Color map of MBR obtained by LSFG. (A) Composite color before vitrectomy (left), 10 days (middle), and 24 weeks (right) after the vitrectomy. The MBR of the vessel areas of the ONH increases after surgery, whereas the MBR of the tissue areas does not change significantly. (B) The change in the MBR on the ONH in one heart beat in a patient with a RRD before (left), 10 days (middle), and 24 weeks (right) after vitrectomy. MV, mean blur rate of vessel areas; MT, mean blur rate of tissue areas.

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FIGURE 3. Changes in the MBR of the vessel areas of the ONH of eyes with RRD. (A) The mean MBR of the vessel areas of the ONH is significantly lower in eyes with a RRD than in the fellow unaffected eye preoperatively and until 10 days postoperatively. The mean MBR of the vessel areas of the ONH at 3 and 6 months after vitrectomy is significantly increased relative to that before the surgery in an eye with a RRD. No significant difference is observed in the fellow eye. (B) No significant difference in the mean MBR of the tissue area in eyes affected by RRD and the fellow eye before and after the surgery. There is no significant difference in the MBR of the tissue area over time in both the RRD and fellow eyes.

March 2015. Of these, 105 eyes were excluded for macula-off Changes in MBR in Eyes With RRD, ERM, and RRD (n ¼ 76), presence of proliferative vitreoretinopathy grade Cataract C or worse (n ¼ 2), vitreous hemorrhage (n ¼ 8), glaucoma (n ¼ 4), diabetic retinopathy (n ¼ 2), or an inability to attend regular The findings in a representative case of RRD treated by PPV are follow-up visits (n ¼ 13). In the end, 31 eyes with macula-on shown in Figure 2. This was a 48-year-old woman who had RRD (mean age, 55.8 6 10.6 years) were studied. macula-on RRD in the right eye which was successful repaired. The demographics and surgical procedures to treat the RRD The MBR-vessel before surgery was 25.4 arbitrary units (AU), and the control patients are shown in Table 1. Forty-six eyes of which increased to 41.6 AU at week 24 after the surgery (Fig. 46 patients with macula-on RRD that underwent scleral 2A). Although the peak time of the MBR was similar within one buckling (mean age, 44.6 6 17.4 years), 15 eyes of 15 patients cycle before and after the surgery, a higher maximum MBR and with an ERM (mean age, 72.0 6 9.1 years), and 15 eyes of 15 a greater increase of the MBR to the peak was observed with patients that underwent cataract surgery (mean age, 72.5 6 increasing time after the PPV (Fig. 2B). 11.9 years) were studied as controls. There were significant Preoperatively, the mean MBR-vessel on the ONH was differences in the age (P < 0.001), axial length (P < 0.001), significantly lower in eyes affected by RRD than in the fellow and surgical procedures (P < 0.001) among the groups. unaffected eye and this held until 10 days postoperatively in In the RRD treated by PPV group, PPV alone was performed the RRD treated by PPV group (Fig. 3A; Table 2). A significant on 20 eyes (PPV alone) and PPV combined with phacoemul- increase was observed in the mean MBR-vessel of the ONH sification and IOL implantation was performed on 11 eyes from 33.7 6 6.7 AU before surgery to 39.2 6 6.1 AU at week (combined surgery). 24 (P < 0.001) in the RRD eyes. There was no significant

TABLE 2. Change in MBR, IOP, and Circulating Parameters in Eyes With RRD Treated by PPV

Parameter Before Surgery Day 10 Month 1 Month 2 Month 3 Month 6 P Value

RRD eye MBR vessel 33.7 6 6.7*† 32.2 6 8.5*† 36.2 6 8.6 35.6 6 8.4 39.9 6 5.7 39.2 6 6.1 0.001‡ MBR tissue 10.5 6 2.6 10.2 6 2.5 10.1 6 2.8 9.5 6 2.4 10.7 6 2.6 10.4 6 2.7 0.188 IOP 12.3 6 2.7*† 14.4 6 4.3 14.7 6 2.5 14.0 6 2.4 15.4 6 4.0 14.6 6 3.1 0.005 MOPP 53.0 6 9.5 48.1 6 9.2 49.5 6 9.8 47.7 6 8.6 48.3 6 7.8 49.2 6 12.2 0.146 Fellow eye MBR vessel 40.1 6 6.7*† 37.6 6 7.3*† 39.2 6 8.9 38.7 6 6.8 41.2 6 6.0 41.5 6 5.0 0.780 MBR tissue 10.7 6 2.3 10.3 6 2.4 10.8 6 2.4 10.8 6 1.8 10.9 6 1.7 10.7 6 1.4 0.675 IOP 14.1 6 2.9*† 13.6 6 3.1 14.1 6 3.1 13.4 6 2.7 14.4 6 3.8 14.4 6 2.9 0.315 MOPP 51.8 6 8.6 48.9 6 9.8 49.3 6 10.9 47.3 6 7.7 48.9 6 11.5 49.4 6 10.9 0.466 * P < 0.001. † Statistically significant difference is observed using unpaired t-test between in eyes with RRD group and the fellow eye group at the each period. ‡ Statistically significant difference is observed using 1-way ANOVA to evaluate the change of each parameter with time.

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TABLE 3. Comparison of Vitrectomy Alone and Combined Surgery Regarding the MBR Before and After Surgery in Eyes With RRD Treated by PPV

Surgical Procedure Location Before Surgery Day 10 Month 1 Month 2 Month 3 Month 6 P Value

PPV, n ¼ 20 Vessel 33.9 6 8.8 31.4 6 9.5 35.3 6 9.1 35.4 6 2.2 39.6 6 3.2 39.3 6 4.5 0.030 Tissue 10.8 6 2.0 10.4 6 1.9 10.3 6 2.5 9.9 6 2.0 10.6 6 2.1 10.2 6 0.9 0.122 PPVþPEAþIOL, n ¼ 11 Vessel 33.3 6 7.0 33.7 6 8.0 37.5 6 8.3 36.1 6 10.1 40.3 6 6.7 39.2 6 7.8 0.007 Tissue 10.0 6 2.9 10.2 6 2.9 9.9 6 3.3 8.6 6 2.7 10.7 6 3.0 10.6 6 3.2 0.620

change over time in the unaffected fellow eyes. No significant 5A and 5B. The mean MBR-vessel and MBR-tissue on the ONH difference was found in the mean MBR-issues on the ONH did not change significantly with time in eyes with an ERM and between the RRD and unaffected eyes before and after the with a cataract (Figs. 5C, 5D). In addition, no significant surgery (Fig. 3A; Table 2). There was no significant difference differences were detected between eyes with an ERM or with a in the MBR-tissue over time in both the RRD and the unaffected cataract and the fellow eye at any time-point. eyes (Fig. 3B; Table 2). The MBR-vessel on the ONH of eyes that underwent PPV alone was compared with that in eyes that had had combined Changes in Pulse Waveform Parameters in Eyes surgery. There were no significant differences in the MBR- With RRD, ERM, and Cataract vessel or the tissues on the ONH between these two groups Of the eight pulse waveform parameters, only the mean flow before and after surgery. However, a significant increase was acceleration index (FAI) was significantly lower in eyes with a observed in the MBR-vessel with increasing time in both unilateral RRD than in the fellow eyes preoperatively in eyes groups (Table 3). Composite color maps of the MBR in a representative eye with RRD treated by PPV (P ¼ 0.001; Fig. 6, Table 4). A treated by scleral buckling are shown in Figure 4A. While the significant increase was observed in the FAI following surgery mean MBR-vessel and MBR-tissue on the ONH did not change in eyes with a RRD (P < 0.001), but no significant change was significantly with time in eyes treated by scleral buckling (Figs. observed in the fellow eye over time (Fig. 6B). 4B, 4C), the mean MBR-vessel on the ONH was significantly There were no significant changes in the other seven lower in eyes affected by RRD than in the fellow unaffected waveform parameters in eyes with a RRD. In addition, no eye before and after surgery, even in the final observation time significant changes were observed in all of the waveform point 24 weeks after surgery (Fig. 4B). parameters in the unaffected fellow eye of the patients with Composite color maps of the MBR in a representative eye unilateral RRD treated by PPV, eyes with RRD treated by scleral with an ERM and an eye with a cataract are shown in Figures buckling and eyes with an ERM or a cataract.

FIGURE 4. Composite color map and the changes in the MBR on the ONH in the eye with RRD treated by scleral buckling. The composite color map before scleral buckling (left), 10 day (middle), and 24 weeks (right) after the scleral buckling (A). (B) The mean MBR of the vessel areas of the ONH is significantly lower in eyes with a RRD than in the fellow unaffected eye preoperatively and postoperatively. There is no significant change in the MBR of the vessel area in the operated and the fellow eyes during the follow-up period. (C) There is no significant change in the MBR of the tissue area of the ONH in the operated and the fellow eyes during the follow-up period.

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FIGURE 5. Composite color map and the changes in the MBR on the ONH in an eye with an ERM and eye with a cataract. The composite color maps before vitrectomy (left), 10 day (middle), and 24 weeks (right) after the vitrectomy in eye with an ERM (A) and with a cataract (B). (C) There is no significant change in the MBR of the vessel area in eyes with an ERM and with a cataract during the follow-up period. (D) There is no significant change in the MBR of the tissue area of the ONH in eyes with an ERM and with a cataract.

Correlation Between MBR and Other Parameters in on the ONH over time was not correlated with the IOP or the Eyes With RRD Treated by PPV MOPP. In addition, only the FAI of the eight pulse waveform parameters in RRD eyes was significantly lower than that of the The preoperative parameters in eyes with a RRD are shown in fellow eyes preoperatively, and then it increased significantly Table 5. The MBR ratio of the affected eye to the fellow eye was with increasing time after the PPV. On the other hand, while 82.2 6 15.8%. The relative size of the retinal tear was 0.74 6 the mean preoperative MBR-vessel on the ONH in the scleral 0.65%, and the extent of the retinal detachment was 25.6 6 buckling-treated RRD eyes was lower than that of the fellow 11.6% of the entire photographed retina. The flare intensity unaffected eyes, it did not change with time after scleral was 12.3 6 20.2 photon count/ms in eyes with a RRD. buckling. Pearson correlation coefficient analyses showed that there It was not easy to measure the preoperative retinal blood was no significant correlation between the preoperative MBR flow at the detached retinal area because the retinal vessels are ratio and other parameters (Table 6). tortuous and ascend vertically on the surface of the RPE in a The trend of the changes in the MBR on the ONH was not bullous detached retina and each retinal vessel has a different correlated with the BCVA, IOP, MOPP, and flare (Table 7). diameter and blood flow velocity. Thus, these alterations in the retinal morphology make it difficult to determine whether the preoperative retinal blood flow is reduced in the detached area DISCUSSION compared with that in the normal attached retina. Accordingly, we evaluated the preoperative retinal blood flow for the Our results showed that the mean preoperative MBR-vessel on vascular areas of the ONH in eyes with a RRD and compared it the ONH in RRD eyes was lower than that of the fellow with that in the fellow unaffected eyes. MBR-vessel on the unaffected eyes, and it increased significantly with increasing ONH is separated from MBR using the ‘‘vessel extraction’’ time after the PPV. The trend of the changes in the MBR-vessel function of the software (i.e., which can be dominantly

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FIGURE 6. Flow acceleration index in eyes with a RRD and normal fellow eye. (A) Flow acceleration index was calculated from the maximum change among all frames (1/30 seconds) in a rising curve. (B) The mean FAI is significantly lower in eyes with a RRD than in the fellow eyes preoperatively. A significant increase is observed in the FAI following surgery in eyes with a RRD (P < 0.001), whereas no significant difference is observed over time in the fellow eye.

expressed as retinal blood flow). Our results showed that mean characteristics of the eyes studied, measurement methods, and preoperative MBR-vessel on the ONH in RRD eyes was lower measured areas. than that of the fellow eyes preoperatively. Earlier studies showed that PPV resulted in an increase in The normality of the preoperative ocular blood flow in eyes the retinal oxygen concentration,40 which led to vasoconstric- with a RRD is still controversial. There have been several tion by the autoregulation of the retinal blood flow. These studies that reported that the blood flow in the central retinal changes resulted in a decrease in the retinal blood flow.41 On artery and the ophthalmic artery in eyes affected by RRD was the other hand, a recent study reported that these changes are normal before surgery.38,39 On the other hand, Eshita et al.8 transient, and the blood flow returns to the previtrectomy state 42 reported that the retinal microcirculation in the macular area after 150 minutes. Our results demonstrated that there were was altered in RRD eyes, and the degree of alteration was no significant differences in the MBR-vessel on the ONH in eyes correlated with the extent of the RRD. Our results are in with an ERM or a cataract following the surgery. In fact, eyes general agreement with their results in terms of the retinal with an ERM underwent PPV combined with cataract surgery, and eyes with a cataract had no significant change in the MBR- circulation in eyes affected by RRD before both of PPV and vessel on the ONH. These findings indicated that it is not likely scleral buckling. However, there was no significant correlation that the PPV affected the blood flow on the ONH following between the reduction in the retinal blood flow and the extent surgery. of the RRD in our patients. All of the PPV-treated RRD eyes had Interestingly, the lower preoperative MBR-vessel on the a PVD, which resulted in the bullous and tortuous retinal ONH significantly increased following PPV in eyes with a RRD. detachment, and the height and flection of the detachment The change of the MBR-vessel on the ONH over time was varied among the patients. The discrepancy between our similar in spite of the differences in the surgical procedures for findings and their results is unclear, but might be caused by the PPV alone and for the combined surgery. These results are consistent with finding that the MBR-vessel on the ONH in eyes TABLE 4. Preoperative Value of MBR and Pulse Waveforms in Eyes with a cataract did not change following surgery as was also With RRD Treated by PPV observed in the control eyes. Although the MOPP can affect the ocular blood flow, there Parameter RRD Eye Fellow Eye P Value was no significant correlation between the MBR-vessel on the MBR ONH and the MOPP.In addition, no other parameters (e.g., IOP and flare) were significantly correlated with the MBR-vessel on ONH vessel 33.7 6 7.6 40.1 6 6.7 <0.001 Tissue 10.5 6 2.6 10.7 6 2.3 0.296 the ONH with increasing postoperative times. The FAI in the RRD eyes was lower than that of the fellow Pulse waveform eye but it increased following PPV along with the increase of Skew 10.7 6 2.1 11.2 6 1.8 0.156 BOS 79.1 6 5.1 78.4 6 5.1 0.248 TABLE 5. Preoperative Characteristic in Eyes With RRD Treated by PPV BOT 54.0 6 5.2 51.7 6 4.9 0.100 Rising rate 12.9 6 1.1 12.3 6 1.1 0.247 Parameter Mean 6 SD Falling rate 12.7 6 1.1 12.7 6 1.1 0.722 FAI 3.5 6 1.2 4.3 6 1.2 0.001 Preoperative MBR vessel, a/f ratio, % 82.2 6 15.8 ATI 32.0 6 3.0 21.0 6 4.4 0.387 Size of retinal tear, % 0.74 6 0.65 Resistivity index 0.32 6 0.07 0.33 6 0.05 0.135 Extent of RD, % 25.6 6 11.6 Flare, photon count/ms 12.3 6 20.2 BOS, blowout score; BOT, blowout time; ATI, acceleration time index. a, affected eye; f, fellow eye

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TABLE 6. Results of Pearson Correlation Coefficient Between the Ratio TABLE 7. Correlation Between MBR Vessel and Other Factors With of Eyes Affected by RRD to Fellow Eye in Preoperative MBR Vessel and Time in Eyes With RRD Treated by PPV Other Variables in Eyes With RRD Treated by PPV Factor Coefficient 95% Confidence Interval P Value Preoperative MBR Vessel (a/f) BCVA 1.312 3.388 to 7.676 0.671 Variable rPValue IOP 0.1620 0.3551 to 0.2382 0.427 MOPP 0.0642 0.2654 to 0.1301 0.518 Extent of RD 0.203 0.390 Flare 0.0826 0.0864 to 0.1253 0.662 Axial length 0.200 0.427 Preoperative MOPP 0.207 0.442 Size of retinal tear 0.176 0.457 of retinal blood flow with the same concentration oxygen Preoperative IOP 0.197 0.464 passes into the detached retina, the retina is fed with a BCVA 0.120 0.613 relatively higher oxygen concentration than the normal Heart rate 0.098 0.717 attached condition. The situation would then be similar to Age 0.063 0.791 hyperoxia, which should lead to arterial vasoconstriction by Flare 0.050 0.855 autoregulation of the retinal blood flow resulting in a decrease BCVA, best corrected visual acuity. of retinal blood flow. After successful RRD repair, the photoreceptor layer thickness and the foveal area thickness 52 the MBR-vessel in eyes with successful RRD repair. The FAI is increase in parallel with an improvement of vision. These calculated from the maximum change of all frames (1/30 changes should cause the photoreceptors to return to normal seconds) in a rising curve expressing the speed which the oxygen consummation. blood flow is elevated. These results suggest that the normal Second, the normal blood flow is disturbed by the tortuous blood flow was disturbed in the tortuous vessels running vessels running vertically in eyes with a bullous retinal vertically in eyes with bullous retinal detachment before detachment before surgery which results in a lower MBR- surgery, and the blood flow became normal postoperatively vessel on and FAI in the ONH. After the PPV, the retina is because the retina was attached and flattened. flattened and the blood flow rate recovers to the normal state There have been only a few studies that reported an resulting in an increase in the MBR-vessel on the ONH. There increase in the retinal blood flow after successful reattachment should also be an increase in the FAI. of a RRD. In most of these reports, the RRD was reattached by In the tissue areas of the ONH, the MBRs was not scleral buckling. Scleral buckling causes compressive forces on significantly different between the RRD eyes and the fellow the peripheral vasculature by the indentation, which result in a eyes at all experimental times, and no significant differences decrease of ocular blood flow. In addition, the procedures of were observed with time in all of the groups. These results scleral buckling reported are not consistent (e.g., use of an confirm that PPV itself does not affect the MBR on the ONH. exoplant8,10 or implant,5,11 and concomitant use of these with This study has several limitations. First, the diameters of the the encircling procedures5,8,10,11). Thus, a decrease in the rate retinal vessels were not measured. Ogasawara et al.5 reported of ocular blood flow and the time course of blood flow varies that the retinal arteries become slightly narrower following among the different studies.5,8,10,11 Our results showed that scleral buckling but no significant change was observed as the mean MBR-vessel on the ONH did not change with time in opposed to the changes in the blood flow velocity. These eyes with RRD treated by segmental scleral buckling without results suggest that the changes of the retinal vessel diameter encircling, while the preoperative MBR-vessel in RRD eyes was before and after surgery might be small. A second limitation is lower than that of the fellow unaffected eyes. The preoperative the effect of PPV for retinal blood flow should be determined situation was the same but the postoperative progress was in eyes that have undergone PPV alone. However, there was no different between the PPV-treated and the scleral buckling eyes significant difference in the MBR-vessel on the ONH in eyes with a RRD. with cataract and ERM, which underwent combined surgery. Taken together, our findings indicate that the blood flow of These findings indicate that the MBR-vessel on the ONH in the vascular areas of the ONH, representing retinal blood flow, RRD eyes would not be affected by PPV. Third, we did not decreases in eyes affected by RRD and returns to the level evaluate the height or volume of the retinal detachment. The before the onset of RRD following PPV. In addition, the scleral functional recovery after macula-off RRD is correlated with the buckling procedures might mask the real time course of ocular height of the macular detachment,53 which would suggest that blood flow following successful RRD repair. these parameters might affect retinal blood flow. And fourth, There are several reasons why the retinal blood flow is the size of the sample was not large enough to make strong reduced in eyes with a RRD. First, the detached sensory retina conclusions. Further studies with a larger number of patients should not require as much oxygen as the attached retina are needed to confirm our findings. because the photoreceptors are the main consumers of oxygen In conclusion, our results showed a significant reduction of and they do not function well in the situation of a retinal MBR-vessel on the ONH in eyes affected by RRD preoperative- detachment. Experimental studies have demonstrated a loss of ly, and the MBR-vessel increased following successful RRD the outer segments of the photoreceptors due to a RD, thereby repair by PPV. There was no significant correlation between disrupting the normal outer segment renewal and leading to the increase in the MBR-vessel on the ONH and other factors. outer segment shortening and eventual degeneration of the These findings indicate that the retinal blood flow is reduced in inner segments.43–46 eyes affected by RRD preoperatively and can recover following A detachment of the neural retina from the RPE induces a successful RRD repair by PPV. variety of changes in several cell types (e.g., photoreceptors, Muller¨ cells, and other retinal neurons).47 Recent OCT studies have shown disruptions of the photoreceptor microstructures Acknowledgments and the integrity of the outer retinal zones in cases of macula- Supported by a Grant-in-Aid for Scientific Research (C) (TI; Tokyo, off RRD.48–51 These changes are accompanied by a thinning of Japan) and a Grant-in-Aid for Scientific Research (B) (HT; Tokyo, several retinal layers in eyes with a RRD.52 If the same volume Japan).

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