Retinal artery occlusion following intravitreal anti‐VEGF therapy

Purpose: Anti‐vascular endothelial growth factor (anti‐VEGF) therapy effectively inhibits angiogenesis and is now enjoying widespread use in the treatment of age‐related macular degeneration (AMD). It may also have a role in the treatment of macular oedema secondary to other conditions. VEGF is a signalling molecule that has a variety of roles, including vasoregulation and effects on the coagulation homeostasis. Anti‐VEGF therapy may therefore have adverse effects on ocular blood flow. Methods: Two cases of retinal artery occlusion after intravitreal injection of anti‐VEGF are presented. Both patients were given the treatment to reduce macular oedema secondary to central retinal vein occlusion. Possible mechanisms are discussed. Results: Patient 1 developed a central retinal artery occlusion within 1 month of an intravitreal injection of ranibizumab (Lucentis^®). The macular oedema was totally resolved at 1 month; final visual acuity (VA) was light perception. Patient 2 developed a branch retinal artery occlusion in the macula 2 days after an intravitreal injection of bevacizumab (Avastin^®). The macular oedema was almost resolved within 1 week and did not recur; final VA was 0.6. Conclusions: Anti‐VEGF therapy may have a role in the treatment of macular oedema caused by central retinal vein occlusions. However, our report indicates that the therapeutic principle may be associated with an increased risk of retinal arterial occlusions.     

Management of macular oedema due to retinal vein occlusion: An evidence-based systematic review and meta-analysis

Background

Central retinal vein occlusion and branch retinal vein occlusion are common causes of visual loss due to associated macular oedema. The aim of this review was to assess the effectiveness of interventions improving vision and treating macular oedema in central retinal vein occlusion and branch retinal vein occlusion.

Methods

Medical search engines and clinical trial registries were systematically searched. Randomised clinical trials with ≥90 eyes and real-world outcome studies with ≥100 eyes each with ≥6 months follow-up were included.

Results

There were 11 randomised controlled trials evaluating treatments for central retinal vein occlusion which met the inclusion criteria and 10 for branch retinal vein occlusion. There were 10 real world outcome studies of central retinal vein occlusion and 5 real world outcome studies of branch retinal vein occlusion. Meta-analysis was performed on studies that met the defined inclusion criteria. Main outcomes were change in visual acuity at 6-, 12-, 24- and 36 months by treatment.

Conclusions

Intravitreal anti-vascular endothelial derived growth factor is recommended as first line treatment over intravitreal corticosteroid due to its effectiveness and lower rate of ocular adverse events. Best outcomes are achieved when intravitreal treatment is started early. Macular laser may have an adjunctive role in branch retina vein occlusion but not central retinal vein occlusion.     

Outcomes of combination therapy with dexamethasone implant and bevacizumab in macular edema related to vascular occlusions

AimTo evaluate the anatomical and visual outcomes as well as the safety of combination therapy with dexamethasone intravitreal implant (0.7 mg) and bevacizumab in macular edema secondary to vascular occlusions.MethodsIn this interventional, prospective case series all patients received dexamethasone implant and bevacizumab in a single sitting. Patients diagnosed with retinal venous occlusion were monitored for changes in visual acuity and macular thickness. All patients underwent detailed ocular examination, best corrected visual acuity (BCVA), and optical coherence tomography examination at baseline and at Week 1, Month 1, and monthly thereafter for 6 months.ResultsTwenty four eyes of 24 treatment-naïve patients (central retinal venous occlusion, n = 9; branch retinal venous occlusion, n = 15) were identified. BCVA improved in 23 patients (95.83%) during the study period. Mean BCVA gained was 0.313 ± 0.26 (85.3% of final gain) and 0.367 ± 0.34 at Week 1 and Month 6, respectively. The percentage of patients who gained ≥2 lines were 52% at Week 1 and 68% at Month 6. The mean macular thickness reduced by 350.9 μm at Week 1 and the maximum treatment effect was seen at Month 2 (379.1 μm). Recurrence of macular edema was seen in 37.5% (9/24) of the eyes. Reinjection was needed, on average, at approximately 3.7 months from the first injection.ConclusionThis study demonstrates that the combination therapy of bevacizumab and dexamethasone implant given simultaneously is safe and synergistic resulting in significantly early and sustained visual recovery and decreased macular edema in patients having retinal vein occlusions.     

Comparison Between Intravitreal Bevacizumab and Triamcinolone for Macular Edema Secondary to Branch Retinal Vein Occlusion

Purpose

To compare the effects of intravitreal bevacizumab to those of triamcinolone acetonide injection for the treatment of macular edema secondary to branch retinal vein occlusion.

Methods

This retrospective study included 50 eyes of 50 patients who received a single injection of intravitreal bevacizumab (1.25 mg/0.05 mL, 22 eyes) or triamcinolone acetonide (4 mg/0.1 mL, 28 eyes) as the only treatment for macular edema secondary to branch retinal vein occlusion; all patients had a post-injection follow-up duration of >24 weeks. Best corrected visual acuity (BCVA), intraocular pressure (IOP), and central macular thickness (CMT) by optical coherence tomography were measured for up to 24 weeks after injection.

Results

BCVA was improved at 1, 4, 8,12 weeks post-injection in the bevacizumab group, and at 1, 4, 8 weeks post-injection in the triamcinolone group. No significant difference was found between the two groups except at 12 weeks. CMT decreased significantly within each group, and no significant difference between groups was found. In the bevacizumab group, no elevated IOP was observed, whereas IOP was significantly increased at 4, 8, and 12 weeks after triamcinolone injection; IOP was therefore significantly different between the two groups.

Conclusions

Intravitreal bevacizumab is a comparatively simple treatment method that can effectively improve BCVA and reduce CMT without ocular and systemic complications. Consequently, intravitreal bevacizumab injections may be useful as both an alternative and primary treatment for macular edema secondary to branch retinal vein occlusion.     

Central nervous system tuberculosis presenting as branch retinal vein occlusion

Branch retinal vein occlusion (BRVO) associated with ocular tuberculosis (TB) is a rare presentation of retinal vasculitis but it can also present in the absence of active uveitis. We present a 39‐year‐old patient with BRVO who slowly developed bilateral papilloedema due to TB in the central nervous system. To our knowledge, this is the first case of systemic central nervous system TB confirmed by biopsy presenting as a branch retinal vein occlusion and shows the importance of extensive causative investigation of BRVO, especially for young patients.     

Sheathotomy in complicated cases of branch retinal vein occlusion

Purpose: To report the clinical experience and results of using a microsurgical technique to decompress the arteriovenous connection in complicated branch retinal vein occlusion (BRVO) combined with haemorrhage, oedema and ischaemia. Methods: We carried out a retrospective, non‐randomized, interventional case study of the surgical sheathotomy decompression procedure. We enrolled 12 patients (seven women, five men; median age 64 years) with BRVO and decreased visual acuity (VA) caused by haemorrhage, oedema and ischaemia. The mean duration of thrombosis was 7 months (2–15 months). The patients were examined for pre‐ and postoperative best corrected VA (BCVA), intraocular pressure (IOP) and fundus photography. Ten patients were examined with fluorescein angiography and eight with ocular coherence tomography (OCT). Postoperative progression of cataract was recorded, as were other complications. The mean follow‐up time was 20 months (8–39 months). Results: Best corrected VA had improved in nine patients, was unchanged in one patient and had deteriorated in two patients at the last follow‐up. Noted complications were venous haemorrhage at surgery in five patients, retinal detachment in one patient and progression of cataract in four patients. Conclusions: Microsurgical treatment with sheathotomy of BRVO is a technically feasible procedure with few complications. Postoperative increased reperfusion could explain the resolution of macular haemorrhage, oedema and ischaemia, and may improve visual function in patients with this common vascular eye disease.     

并发视网膜中央动静脉阻塞的特殊PORN1例

目的:报道1例艾滋病患者特殊的进行性外层视网膜坏死(PORN),同时合并视网膜中央动脉及静脉阻塞。方法:病例报告。结果:患者表现为进行性外层视网膜坏死,视神经亦受累,合并视网膜中央动静脉阻塞,与带状疱疹性视网膜病变的最初表现一样。积极的治疗包括玻璃体腔和特异性系统抗带状疱疹病毒治疗,以及强化的抗逆转录病毒治疗(HAART)。视网膜坏死静止,对侧眼未受累,而患眼的视力极差。结论:首次报道了1例并发视网膜中央动静脉阻塞的特殊PORN,积极的局部联合系统治疗使得局部病情控制,并预防了对侧眼发病。     

Prospective comparisons of intravitreal injections of triamcinolone acetonide and bevacizumab for macular oedema due to branch retinal vein occlusion

Purpose: To compare the efficacy of intravitreal injections of triamcinolone acetonide (TA) and that of bevacizumab for macular oedema because of branch retinal vein occlusion (BRVO). Design: Prospective, comparative, randomized, interventional clinical trial. Methods: Forty‐three eyes of 43 patients with macular oedema because of BRVO were randomly assigned to 4‐mg intravitreal injections of TA (IVTA)(21 patients, IVTA group) or 1.25‐mg intravitreal injections of bevacizumab (IVB) (22 patients, IVB group) and followed for 12 months. No additional treatments were administered for 3 months after the initial injection; additional injections were administered when macular oedema recurred between 3 and 12 months after the initial injection. The best‐corrected visual acuity (BCVA) and the central retinal thickness (CRT) were measured at baseline and monthly. The main outcome measures were changes in the logarithm of the minimal angle of resolution BCVA and CRT from baseline to 12 months. Results: Eighteen eyes of 18 patients in the IVTA group and 18 eyes of 18 patients in the IVB group completed follow‐up at 12 months. The mean improvements in BCVA from baseline to 12 months were 0.12 in the IVTA group and 0.33 in the IVB group, which was significantly (p = 0.032) higher than in the IVTA group. There was no significant difference between the two groups in the mean reduction in CRT from baseline to 12 months after the initial injection. Two eyes in the IVTA group required intraocular pressure–lowering medications. Conclusion: Intravitreal injection of bevacizumab may be of greater benefit than that of TA for macular oedema because of BRVO.     

Combined occlusion of branch retinal artery and vein secondary to prepapillary arterial loops

A middle-aged diabetic and hypertensive man presented with diminished vision in the left eye. Fundus examination revealed prepapillary arterial loops, but with features of venous rather than arterial occlusion. Fluorescein angiography and optical coherence tomography confirmed the presence of a branch retinal vein occlusion along with two branch retinal artery occlusions. The resultant macular edema responded well to intravitreal triamcinolone and laser photocoagulation though the visual improvement was moderate.     

Combined retinal vascular occlusion: Demography,clinical features,visual outcome,systemic co-morbidities,and literature review

Purpose:To document the clinical features, systemic association, and treatment outcome of patients with a combined retinal vein and artery occlusion (CRVAO) and review of literature.Methods:A retrospective chart review of patients diagnosed with CRVAO at a tertiary eye care center. Patient''s demographic details and associated ocular and systemic factors were recorded. Treatment included laser photocoagulation, anti-vascular endothelial growth factor (VEGF) intravitreal injection or transscleral cyclophotocoagulation (TSCPC), alone or in combination. At last, follow- up treatment response was measured in visual acuity status, regression of neovascularization, and control of intraocular pressure (IOP). All cases reported in the current decade were analyzed and compared with this study.Results:Seventeen eyes with CRVAO accounted for 0.3% of total vascular occlusion (total 5151 patients were seen in this period). The mean age was 48.12 ± 17.5 years (range: 12-87 years) and there were 9 females. Nine eyes had CRVO + CRAO; 6 eyes had BRVO + BRAO, and one patient each had CRVO + BRAO and CRAO + BRVO. Fluorescein angiography (FA) showed delayed ''arm to retina'' time (>20 seconds) in all 10 eyes and delayed arteriovenous transit time in 9 out of 10 eyes. Optical coherence tomography (OCT) showed hypereflective inner retinal layers (16 eyes) and neurosensory detachment (7 eyes). The most common systemic associations were hypertension and dyslipidemia (n = 7 people; 41.18%) each. Four patients (23.5%) had a plaque in carotid arteries with normal 2D echocardiography. Ten (59%) eyes were treated with intravitreal bevacizumab + laser; four (23.5%) eyes were treated with laser only, and three (17.6%) eyes were treated with laser + anti-VEGF + TSCPC. At last follow up, vision improved in 9 (52.9%) eyes; stable in 3 (17.7%) eyes, and reduced to perception of light in 5 (29.4%) eyes.Conclusion:Combined CRVAO is a rare emergency leading to acute vision loss. Early diagnosis and treatment for ocular complications and systemic evaluation for cardiovascular risk factors are needed.     

Unilateral branch retinal arterial occlusion following administration of bevacizumab for branch retinal vein occlusion

Intravitreal bevacizumab has been adopted as a well-established treatment modality for the treatment of macular edema associated with branch retinal vein occlusion. It is considered a safe and efficacious option for improving visual acuity. We present an interesting case of unilateral superotemporal branch retinal vein occlusion in a 55-year-old man who received two doses of intravitreal bevacizumab one month apart. Laboratory tests including complete hypercoagulability and thrombotic work-up were completed but the patient successively developed branch retinal artery occlusion. We reviewed cases in literature and combined possible etiologies. We report a previously unpublished case of retinal artery occlusion following the use of intravitreal bevacizumab. Several studies have shown evidence of systemic thromboembolic events after the use of intravenous and systemic bevacizumab; however, to the best of our knowledge, no case has been reported of retinal artery occlusion immediately after administration of intravitreal bevacizumab.     

Intravitreal Bevacizumab for the Treatment of Neovascular Glaucoma Associated With Central Retinal Artery Occlusion

We report three cases of neovascular glaucoma secondary to central retinal artery occlusion (CRAO) which were effectively managed with intravitreal bevacizumab (IVB) followed by panretinal photocoagulation (PRP). Neovascular glaucoma without peripheral anterior synechiae developed between one and five weeks following CRAO onset. All patients received 0.75 mg (0.03 ml) IVB. In all patients, complete regression of the iris and anterior chamber angle neovascularization was confirmed within one week. PRP was applied two weeks after the injection. The follow-up period was four to seven months (average, five months). Intraocular pressure was controlled in all patients using topical antiglaucoma medications alone. However, one patient experienced a recurrence of neovascularization three months after the initial combination treatment. This patient received another IVB injection and additional PRP, and the recurrent neovascularization resolved. There were no local or systemic adverse events in any patients. Therefore, intravitreal bevacizumab may be an effective adjunct in the treatment of neovascular glaucoma associated with CRAO.     

视网膜静脉阻塞的危险因素分析

目的 分析视网膜中央静脉阻塞(central retinal vein occlusion,CRVO)和视网膜分支静脉阻塞(branch retinal vein occlusion,BRVO)的危险因素;并对CRVO和BRVO危险因素进行直接比较.方法 对46例CRVO(CRVO组)、33例BRVO(BRVO组)与79例老年性白内障或屈光不正患者(对照组)行危险因素和血脂谱分析,并对比观察.结果 多元线性回归分析结果显示:高同型半胱氨酸血症(P＜0.000 1)、高总胆固醇(P=0.003 0)、高脂蛋白a(P =0.027 0)、高血压(P =0.022 0)、短眼轴(P ＜0.000 1)与CRVO显著相关;而高同型半胱氨酸血症(P＜0.0001)、高总胆固醇(P =0.008 0)、高血压(P=0.002 0)、高体质量指数(P=0.004 0)、短眼轴(P=0.001 0)与BRVO相关.一元线性回归分析示CRVO和BRVO上述危险因素比较没有明显差别.结论 CRVO、BRVO危险因素包括系统(高血脂、高血压、高同型半胱氨酸)和眼部(短眼轴)的多种因素,但是这些危险因素在CRVO和BRVO之间没有显著差异.     

Full colour reproduction of figures originally submitted in colour

Case reports on three patients who underwent vitrectomy assisted t-PA injection for the management of branch retinal vein occlusion. Three-port, 20-gauge vitrectomy was performed under local anesthesia. After posterior vitreous detachment and fluid-air exchange, 50 μ g t-PA/0.5 ml were injected in the eye. All patients were instructed for strict supine position for 6 hours. Main outcome measure was visual acuity. Three patients with branch vein occlusion (BVO) were studied, with duration of symptoms less than 25 days, and mean follow-up period of 18.8 months. Although no intraoperative complications were noticed, no one showed any significant improvement of vision. One patient required a second operation for the management of intravitreal hemorrhage, and another developed an epiretinal membrane. Vitrectomy assisted t-PA injection does not seem to improve the course of branch retinal vein occlusion in this small case series. Future research on intravitreal thrombolysis needs to be focused on additional mechanical approaches and modalities that can facilitate the access of the drug into the vascular lumen.     

Visual improvement in central retinal vein occlusion (CRVO) following intravitreal injections of bevacizumab (Avastin®)

Acta Ophthalmol. 2010: 88: 836–841

Abstract.

Purpose: To perform a prospective study on central retinal vein occlusion (CRVO) to evaluate whether visual acuity can be improved and macular oedema reduced in response to intravitreal injections of bevacizumab. Methods: The case material comprised 13 patients (aged 34–79 years), duration of CRVO was 2 weeks to 6 months, baseline ETDRS visual acuity 0.06–0.4 (mean Snellen 0.13, derived from logMAR value) and intraocular pressure (IOP) 12–20 (mean 15.2) mmHg. Clinical examination, including optical coherence tomography (OCT), was carried out at baseline and every 6 weeks, digital fluorescein angiography at baseline, at 3 months and 6 months. Intravitreal injections of bevacizumab (1.25 mg) were given under microscopic control at baseline and every 6 weeks during the 6‐month follow‐up. Results: Following one intravitreal injection of bevacizumab, average visual acuity improved by 13 ETDRS letters at 1 month (p < 0.05) and in response to 4 injections by 24 letters (logMAR 0.48) at 6 months (p < 0.05). Foveal thickness as measured by OCT decreased from 596 μm at baseline to 288 μm at 6 months (p < 0.05) concomitant with resorption of intra‐ and subretinal fluid. IOP ranged from 10 to 24 (17.3) mmHg at 6‐month follow‐up. No adverse events occurred. Conclusions: In response to four intravitreal injections of bevacizumab during 6 months, a substantial improvement in visual acuity and reduction in central retinal thickness were achieved. A randomized clinical trial is warranted to further evaluate the efficacy and safety of this treatment modality.     

Genetic thrombophilia in patients with retinal vascular occlusion

Background: This study was carried out to determine the prevalence of genetic thrombophilia in patients with retinal vascular occlusion.Methods: We investigated 116 consecutive patients with central retinal vein occlusion (CRVO, n = 48), branch retinal vein occlusion (BRVO, n = 33), central retinal artery occlusion (CRAO, n = 21), branch retinal artery occlusion (BRAO, n = 14). All patients underwent comprehensive tests for coagulation disorders including determinations of protein C, protein S, lupus anticoagulants, prothrombin gene mutation (G20210A), resistance to activated protein C (APCR), and were screened for vascular disease risk factors. APC resistance was confirmed by a PCR method to detect the factor V R506Q mutation. A PCR method was also used to detect the G20210A mutation. For comparative purposes, we screened 209 consecutive patients with deep vein thrombosis (DVT) and 581 patients with coronary heart disease (control group) for APC resistance.Results: 13 (27%) of 48 patients with CRVO had the factor V R506Q mutation. The factor V R506Q mutation was detected in six (18%) of 33 patients with BRVO, but in only one patient with CRAO and in two patients with BRAO. Other thrombophilic defects were not detected. The APCR prevalence within the CRVO group was significantly increased when compared to the control group (8%). There was no significant difference in the factor V R506Q mutation prevalence between the CRVO group and the DVT group (19%).Conclusion: The factor V R506Q mutation is the most commoncause of genetic thrombophilia in patients with CRVO and has a similar prevalence as in DVT patients.     

Changes in aqueous cytokines after intravitreal triamcinolone versus bevacizumab for macular oedema in branch retinal vein occlusion

Purpose: To investigate the changes in the aqueous levels of various cytokines after intravitreal triamcinolone or bevacizumab for branch retinal vein occlusion (BRVO). Methods: Twenty‐four eyes with macular oedema associated with BRVO and six eyes of six patients undergoing cataract surgery participated in this study. Each patient with BRVO randomly received an intravitreal injection of either 4 mg triamcinolone or 1.25 mg bevacizumab. Aqueous samples were obtained before and 4 weeks after the intravitreal injection in the BRVO group and before surgery in the control group. Aqueous concentrations of 16 cytokines were measured via multiplex bead assay. Results: Prior to the administration of the drugs, aqueous levels of interleukin (IL)‐6, IL‐8, IL‐17 and vascular endothelial growth factor (VEGF) were significantly higher in the BRVO group than in the control group (p = 0.044, p = 0.013, p < 0.001, and p = 0.008, respectively). Between the control group and the BRVO group, no significant differences were noted between pre‐ and postinjection best‐corrected visual acuity (p = 0.60, p = 0.54) and central foveal thickness (p = 0.47, p = 0.82). In the triamcinolone group, levels of IL‐6, IL‐17, IP‐10, platelet‐derived growth factor (PDGF)‐AA and VEGF were reduced significantly (p = 0.012, p < 0.001, p < 0.001, p = 0.015, and p < 0.001, respectively). But in bevacizumab group, only VEGF was significantly reduced (p < 0.001). Between the IVTA group and the IVBe group, no significant differences in the changes in VEGF levels were noted (p = 0.06). Conclusion: Triamcinolone injection reduces plural inflammatory cytokines in BRVO, while bevacizumab has no influence on other cytokines as selective anti‐VEGF therapy. No differences in the therapeutic effect were noted between an inhibition of plural inflammatory cytokines and an inhibition of VEGF only.     

Bilateral retinal venous occlusion in pigmentary glaucoma

Background The association of central retinal vein occlusion with primary open angle glaucoma is well known. This communication reports the occurrence of branch retinal vein occlusion and central retinal vein occlusion in a case of pigmentary glaucoma.Methods A 32-year-old man presented with old branch retinal vein occlusion in one eye and resolving central retinal vein occlusion in the other eye. Examination revealed bilateral Krukenbergs spindle and hyperpigmented trabecular meshwork. Intraocular pressure was 30 mmHg OU. Topical antiglaucoma medication was prescribed.Results Intraocular pressure was controlled with topical antiglaucoma medication.Conclusion The present report suggests that intraocular pressure monitoring is important in eyes even with branch retinal vein occlusion. Pigment dispersion may be the underlying cause for bilateral retinal vein occlusion, especially in young patients.     

Intravitreal injection of bevacizumab alone or with triamcinolone acetonide for treatment of macular edema caused by central retinal vein occlusion

AIM: To compare the efficacy and safety of intravitreal bevacizumab alone versus bevacizumab combined with triamcinolone acetonide in eyes with macular edema caused by central retinal vein occlusion (CRVO) in Chinese patients. METHODS: Seventy-five eyes of 75 patients were enrolled in this prospective, randomized, consecutive study. Thirty-six patients in group 1 were treated with an intravitreal injection of bevacizumab (1.25mg/0.05mL), and 39 patients in group 2 were treated with intravitreal bevacizumab (1.25mg/0.05mL) combined with triamcinolone acetonide (2mg/0.05mL). The main outcomes of the mean best corrected visual acuity (BCVA), central retinal thickness (CRT), and intraocular pressure (IOP) were measured. RESULTS: In group 1, the mean BCVA improved from 37.78±6.14 (baseline) to 48.06±3.86, 46.48±4.77 and 44.18±5.78 at four, six and twelve weeks post-injection, respectively (P<0.01, P=0.03, P=0.04). In group 2, the mean BCVA improved from 35.92±6.20 (baseline) to 50.69±4.22, 48.76±5.59 and 45.70±6.56 at the same time points (P<0.01 each). However, there was no significant differences in the mean BCVA (F=0.043, P=0.836) and CRT (F=0.374, P=0.544) between these two groups. During the follow-up, five patients in group 1 and six patients in group 2 with high IOP were controlled with anti-glaucoma drugs. CONCLUSION: Intravitreal injection of bevacizumab alone or combined with triamcinolone acetonide has a short beneficial effect in Chinese patients with macular edema caused by CRVO, but there is no significant difference between the two groups.     

视网膜血管阻塞性疾病的治疗新挑战

视网膜动脉阻塞和视网膜静脉阻塞是临床上最常见的致盲眼病。近年来,随着眼科医疗设备和诊疗技术的提高,视网膜血管阻塞性疾病有了一些新疗法（如高压氧治疗、视乳头放射状切开术、视乳头穿刺术、视网膜血管外膜切开术、激光诱导脉络膜视网膜静脉吻合术、选择性动脉内溶栓、经玻璃体视网膜中央动脉插管术、经玻璃体微穿刺术、玻璃体腔注射贝伐单抗、激光光凝治疗等）,给此类疾病的治疗带来新的希望,但对每种新疗法均需进一步科学、谨慎地探讨和观察随访。