PRP眼周注射致失明

1、Irreversible Blindness Following Periocular Autologous Platelet-Rich Plasma Skin Rejuvenation Treatment眼周富血小板血浆注射用于皮肤年轻化治疗导致永久性失明的案例分析Krishnapriya Kalyam, M.D., Shaheen C. Kavoussi, M.D., Michael Ehrlich, M.D., Christopher C. Teng, M.D., Nisha Chadha, M.D., Sarah Khodadadeh, M.D., and Ji Liu, M.D. A

2、bstract: 摘要： A 49-year-old woman developed acute visual loss in the right eye following bilateral cosmetic platelet-rich plasma injections to rhytids in the glabellar region. External exam showed skin necrosis in the region over the right rhytids and restricted right ocular motility. Dilated fundus

3、exam was significant for ophthalmic artery occlusion. Imaging revealed right eye extraocular muscle ischemia and optic nerve infarction, along with right frontal, parietal, and occipital lobe infarction. Work-up for thromboembolic and vascular etiologies were negative. To our knowledge, this is the

4、first case reported of extensive ischemia following autologous platelet-rich plasma therapy. 一位49岁的女性在双侧眉间褶皱区域注射了富含血小板血浆后出现急性的右眼视力丧失，外部检查发现右侧褶皱区域上方出现皮肤坏死、右眼球运动受限。眼底检查显示重要的眼动脉发生栓塞。成像显示右眼眼外肌缺血和视神经梗死，右额叶、顶叶和枕叶梗死。血栓形成和血管方面的病因检查是阴性的。据我们所知，这是第一例被报道的因自体富含血小板血浆治疗而导致广泛缺血的病例。CASE REPORT 病例报告The case reported

5、here is in compliance with the Health Insurance Portability and Accountability Act (HIPAA) regulation. An otherwise healthy 49-year-old woman presented to the Yale Eye Center complaining of acute loss of vision in the right eye associated with severe nausea and eye pain. One day prior, the patient u

6、nderwent an autologous platelet-rich plasma (APRP) injection procedure by an unlicensed practitioner to reduce wrinkles in the glabellar region bilaterally. She reported that blood was taken from her antecubital region by venous puncture and centrifuged to obtain concentrated autologous plasma. Bila

7、teral forehead rhytids injections were performed. The patient was unaware the details of the plasma preparation and the size of needle that was used for injections. She tolerated the first injection on the left side well. However, during the second injection at the nasal end of right eyebrow, she fe

8、lt the needle penetrate slightly deeper, accompanied by sudden pain and fullness behind her right eye with immediate visual loss over the next few minutes. She then noted transient improvement of vision in nasal field followed by complete loss of vision. 这例案例报告受（美国）健康保险携带和责任法案(HIPAA)监管。在耶鲁大学眼科中心，一位原

9、本健康的49岁女性主诉其出现了急性的右眼视力丧失，并伴随严重的恶心和眼痛。一天前，一位无证医师向其眉间区域注射了富含血小板血浆(APRP)，以减少其双侧眉间皱纹。她声称，血液从她肘前区静脉穿刺获得，通过离心获得浓缩自体血浆，随后医生用离心所得血浆对她进行了双侧的前额褶皱部位注射。病人并不知道血浆的制备过程细节和用于注射的针头大小。首先是左侧注射，随后是右鼻侧的眉头部位注射，她觉得针头刺入略深，伴随着突如其来的疼痛，她的右眼在几分钟后出现急性视力丧失。她注意到鼻侧视力有短暂的改善，随后便出现了全盲。 On examination, vision was no light perception i

10、n the right eye and 20/20 in the left eye. A pronounced right afferent pupillary defect was present. Motility of the right eye was restricted in supraduction and adduction resulting in a right exotropia and hypotropia in primary gaze. External exam demonstrated a 1cm area of ecchymosis and induratio

11、n above the right medial brow. The eyelids were soft and there was no proptosis or resistance to retropulsion. Anterior segment exam was unremarkable in both eyes except moderate conjunctival hyperemia in the right eye. Intraocular pressure was within normal limits bilaterally. Fundus exam of the ri

12、ght eye revealed profound optic disc pallor, diffuse retinal whitening including fovea, marked attenuation of arterioles with abrupt ending of the vessels in midperiphery, and central macular edema. Absence of a cherry red spot suggested diffuse choroidal ischemia. No Hollenhorst plaque was seen. Th

13、e left fundus exam was unremarkable. 通过检查发现，病人右眼无光感，左眼光感为20/20，右眼相对性瞳孔传入障碍（RAPD 的基本原理:当光线从健侧移向患侧时,一方面是患侧受光照刺激的传入冲动少,同时患眼还受到健眼撤除光照后的瞳孔开大反应的间接影响,故削弱了患眼的缩瞳运动。而当光线自患眼移向健眼时,由于患侧受光线刺激后的神经传入冲动明显减少,其对健眼的这一效应明显减低,健眼瞳孔明显收小,故出现双眼对光照的反应不对称。 最终的效应就是，交替照射后造成了不同步效应累积，经时间差累积，就出现了健侧瞳孔缩小、患侧散大。）由于右眼球上转和内转运动功能受限，因此患者在凝

14、视时出现外斜视和下斜视。外部检查发现在右眉中点上方有一直径约1cm大小的皮下血肿和硬结，眼睑皮肤柔软，没有眼球突出或后退现象。除了右眼结膜有中度充血之外，眼球前段检查并无发现两眼的显著差别，双侧眼内压也均在正常范围值内。眼底检查发现右眼广泛的视神经盘苍白、包括中央凹在内的弥漫性视网膜白化、视网膜赤道部血管终末支小动脉的显著衰减和中央黄斑水肿。樱桃红点的缺失提示弥散的脉络膜缺血，没有发现Hollenhorst斑块。左眼底检查无明显异常。Head and neck CT showed right subacute frontal lobe ischemia without identifiable

15、 compromised vessels. MRI/MRA of brain and orbit demonstrated restricted diffusion along the course of the right optic nerve and multiple subacute infarcts involving right frontal, parietal, and occipital lobes (Fig. 1). Asymmetric abnormal FLAIR/T2 signal of the right medial rectus muscle was sugge

16、stive of ischemia (Fig. 2). Bone marrow edema within the right frontal bone with irregular enhancement involving the overlying skin was also shown. MRA of the brain and neck was negative for cavernous sinus pathology, or vertebral or carotid artery dissection. CTA of the head and neck and transthora

17、cic echocardiogram identified no embolic origin. Echocardiogram and carotid dopplers were negative. 头颈部CT显示：右额叶在无明显血管损伤情况下出现亚急性缺血。脑部和眼眶部MRI/MRA显示缺血部位沿视神经限制性扩散，并发现涉及右额叶、顶叶、枕叶在内的多发性亚急性梗死灶(图1)。不对称的FLAIR/T2异常信号提示右侧内直肌缺血(图2)。右额骨内骨髓水肿和其覆盖的皮肤水肿导致前额组织不规则增大。头部和颈部CT提示无海绵窦病变，无脊椎和颈动脉损伤。头颈部CTA和经胸超声心动图没有发现栓子来源，超声

18、心动图和颈动脉多普勒检查阴性。FIG. 1. MRI brain: FLAIR image and DWI demonstrate ischemia of right frontal and parietal lobes (arrows). DWI, diffusion weighted image. 图1 脑MRI示：右额叶和顶叶水肿（箭头所示）。FIG. 2. MRI head and orbit: FLAIR and DWI images demonstrate right medial rectus ischemia. DWI, diffusion weighted image. 图1

19、 头部和眶部MRI示：右内直肌缺血（箭头所示）。 Laboratory tests revealed mildly elevated erythrocyte sedimentation rate (26mm/h, normal 020), and C-reactive protein (3.8mg/L, normal 0.13.0) with a normal complete blood count test. Further work-up for thrombotic and arteritic processes were all negative, including PT/PTT,

20、 INR, Beta2glycoprotein, homocysteine, protein-C and S, D-dimer, antithrombin III, cardiolipin, jak2, C3, C4, Anti-DNA ab, Lupus anticoagulant, rheumatoid factors, antineutrophil cytoplasmic antibody, and hemoglobin screen. 实验室检查：全血细胞计数显示红细胞沉降率(26毫米/小时,正常0-20)和c反应蛋白(3.8 mg / L,正常0.1 - -3.0)轻度升高。进一步的

21、血栓形成以及动脉检查都是阴性的，包括PT / PTT、INR、Beta2糖蛋白、同型半胱氨酸、c蛋白和S蛋白、D-二聚体、抗凝血酶III、心磷脂、jak2、C3、C4、Anti-DNA ab、狼疮抗凝物、类风湿因子抗中性粒细胞胞浆抗体和血红蛋白。The patient was diagnosed with acute right ophthalmic artery occlusion and brain infarction as a complication of periorbital APRP injection. Having arrived outside the window of

22、 intra-arterial tPA, she was treated with ocular massage, topical timolol 0.5% and brimonidine 0.2%, and oral steroids. The patient declined anterior chamber paracentesis. She was given intravenous antibiotics for possible infectious cause of periorbital swelling and erythema. External and fundus ph

23、otography 1 week after presentation demonstrated ecchymosis and ischemia of the right glabellar region (Fig. 3) and diffuse retinal whitening and ischemia (Fig. 4). Ocular motility returned to normal by week 2. One year after presentation, the patients vision remained no light perception in the righ

24、t eye with residual scarring and hard nodules of the right glabellar region. Patient subsequently underwent scar revision surgery of the right glabella a year later. The pathology of scar tissue showed lipid-based foreign body with giant cell reaction that was consistent with prior injection of fore

25、ign material within deep tissues (Fig. 5). 病人被诊断为急性右眼动脉栓塞和脑梗死，是由眶周自体富血小板血浆注射导致的并发症。除了动脉内tPA溶栓治疗，给予眼球按摩，0.5%的噻吗心安和0.2%溴莫尼定滴眼，口服类固醇类药物。病人拒绝了前房穿刺。为了避免眶周组织肿胀和红斑引起感染，予静脉给予抗生素。1周后的外部和眼底摄影展示了眉间区域的瘀斑和局部缺血状况(图3)，以及弥漫性视网膜白化和缺血(图4)。第2周眼球活动恢复正常。1年后，病人的右眼视力仍然没有光感，右眉间区域仍有残留的瘢痕和硬结节。病人在随后的1年进行了右眉间区域的瘢痕修复手术。瘢痕组织的病理显

26、示类脂质异物引起的巨细胞反应与之前注射入肌肉深层的异物引起的反应是一致的(图5)。FIG. 3. Ecchymosis and ischemia of right glabellar region 1 week after injection of APRP to rhytids. APRP, autologous platelet-rich plasma. 图3示注射1周后右眉间区域的瘀斑和缺血。FIG. 4. Color fundus photo of right eye taken 1 week after vision loss following PRP, demonstrating

27、 diffuse retinal whitening and ischemia. PRP, platelet-rich plasma. 图4 右眼失明后1周后彩色眼底照片示弥漫性视网膜白化和缺血。FIG. 5. H&E stain of the right glabella scar tissue (×400). The bold arrow shows the giant cell reaction for foreign bodies (thin arrow) within deep muscle layers. 图5右眉间瘢痕组织HE染色(×400)。箭头指示

28、了肌肉深层的异物（小箭头）引起的巨细胞反应（大箭头）。DISCUSSION 讨论Autologous platelet-rich plasma is obtained by centrifuging autologous blood until the plasma platelet level exceeds that of normal blood. Autologous platelet-rich plasma is commonly used in the setting of ulcers, burns, wounds, hair loss, and facial rejuvenat

29、ion by way of angiogenesis and collagen synthesis through upregulation of growth factors and cytokines contained in platelet alpha granules.Recently, physicians and cosmetologists across the country have been exploring its use as cosmetic filler for skin augmentation. 自体富含血小板血浆通过自体血液离心获得，血浆血小板水平超过正常

30、的血液。自体富血小板血浆常用于溃疡、烧伤、创面和脱发的治疗；由于血小板颗粒中包含多种生长因子和细胞因子，可以通过这些细胞因子和生长因子的上调促进血管再生和胶原合成，因此富血小板血浆也常被用于面部年轻化治疗。近年来，医师和美容师常将它作为美容填充剂用于面部皮肤扩张。There are varieties of APRP based on their preparation process and resultant components. For instance, Leukocyte-rich PRP contains more white blood cells than tradition

31、al PRP isolated by dual speed centrifugation. Platelet-rich fibrin matrix has a lower concentration of platelets than traditional PRP by including plasma and proteins in a larger volume. These variables can make difference in the ingredients of oxygen-free radicals and lysosomal enzymes, as well as

32、growth factor concentrations, release, and binding abilities. Some practitioners deliberately modify these products before injection, including mixing the PRP with fillers.The patient declined to disclose the contact information of the practitioner who performed the injection. Therefore, it was uncl

33、ear if this APRP product was made properly or altered before the injection. 由于制备过程和合成成份不同，得到的自体富血小板血浆也不尽相同，例如，双速离心获得的PRP较传统PRP相比，其白细胞含量更高。富血小板纤维蛋白与传统PRP相比，血小板含量降低，但是血浆和蛋白含量增高。这些变量使氧自由基和溶酶体酶的成分产生差异，生长因子的凝集、释放、粘附能力也不同。也有一些从业者先将PRP与其他填充剂混合，再进行注射。由于患者拒绝透露注射医师的联系方式，因此，目前还不清楚用于注射的APRP产品是否正确制备或是在注射之前已被改变。A

34、utologous platelet-rich plasma therapy is relatively contraindicated in patients who is under chronic antiaggregant therapy. Cautions should be taken if the patient has nonsteroidal anti-inflammatory drug usage 7 to 10 days before the procedure, an active infection, systemic use of corticosteroids w

35、ithin 2 weeks before injection, and conditions putting the patient in a hypercoagulative state, such as smoking and oral contraceptive use. Past medical history and medication reconciliation should be carefully obtained before APRP treatment. This patient was a nonsmoker and was not taking any medic

36、ations before the injection. 自体富血小板血浆治疗的相对禁忌证是患者正接受慢性抗血小板聚集治疗。需要注意的情况有：患者注射之前已使用7-10天非甾体类抗炎药；活动性感染；患者注射之前已系统使用皮质类固醇2周；患者处于高凝状态：如吸烟或使用口服避孕药。注射之前应仔细核对既往史和协同用药情况。这个患者是不抽烟的，而且注射前并没有服用任何药物。Visual complications from various periocular synthetic cosmetic fillers have been previously reported. Recently, US

37、Food and Drug Administration issued a safety alert on the risks of visual loss and stroke secondary to the unintentional soft tissue filler injection into facial blood vessels. Autologous platelet-rich plasma is not often used as a physical filler. The effects are usually the result of growth factor

38、s and other material contained or secreted by platelets rather than the physical filling effects. To our knowledge, there have been no reports of vision loss associated with APRP when used as a filler. Carle et al.6 described 3 patients who presented with sudden loss of vision after injection of 3 d

39、ifferent dermal fillers (hyaluronic acid, autologous fat, and bovine collagen mixed with polymethylmethacrylate microspheres) into the forehead area.They hypothesized that retrograde flow of fillers through arteries resulted in ocular ischemia. Studies have demonstrated retrograde embolic travel thr

40、ough the retinal, ophthalmic, and often internal carotid arterial systems. The authors believe that a similar mechanism was responsible for vision loss in the patient. In a series of 44 patients, concurrent ocular and brain infarctions occurred in 27% and final visual acuity was NLP in 61% of subjec

41、ts. Visual prognosis was worst with autologous fat.7 In a 2012 systematic review of 29 articles describing 32 patients with visual loss following cosmetic injections, the nasolabial (n = 7) and scalp (n = 3) areas were the most common injection sites, followed by the forehead, glabella, cheek, and t

42、emples. All patients but 3 (18%) remained NLP.8 眼周注射各类合成的美容填充剂而导致视觉并发症的案例曾被报导过。如今，美国食品药品监督管理局提出了一则安全警示：如果无意间将软组织填充剂注入面部血管内，会有引起失明和中风的风险。自体富血小板血浆不经常作为物理填充剂，其作用通常依赖于血小板中包含的生长因子或分泌的其他物质，而不是物理填充效果。据我们所知，并没有使用自体富血小板血浆作为填充剂导致失明的案例报道。Carle等描述了3位患者由于在前额区域被注入三种不同的真皮填充物(透明质酸、自体脂肪、牛胶原蛋白和有机玻璃微球的混合物)而导致急性视力丧失，他们

43、推测，填充物通过动脉逆行导致眼部缺血。研究表明栓子逆行进入视网膜动脉、眼动脉或是颈内动脉系统。作者认为该患者的失明应该是相同机制。在一系列的44名患者中，并发眼和脑梗死的发生率为27%，有61%的患者最终视敏度为无光感，自体脂肪填充的患者视觉预后最差。在一篇2012年（有关29篇文章）的系统回顾中描述了32位患者在美容注射后出现视力丧失，其中鼻唇沟(n = 7)和头皮(n = 3)区域是最常见的注射部位，其次是前额、眉间、脸颊和双鬓处。除了3位患者(18%)外，其他患者视力仍然无光感。These reports highlight the importance of intimate unde

44、rstanding of facial vascular anatomy during cosmetic injections. The patients case of ophthalmic artery occlusion following APRP exemplifies the visual loss that can inadvertently occur with both traditional and novel cosmetic materials. Full awareness of injection plane to be intradermally rather t

45、han subdermally may help reduce or eliminate vascular compromise. Aspirating before injection, applying topical vasoconstrictors, and using smaller needles (30 to 32 G) with slow technique and judicious use of pressure are recommended precautionary measures.8,11,1315 Early recognition is important a

46、nd immediate and aggressive treatment is mandate should vascular complications occur.14,15这些报告强调了面部血管解剖知识在美容注射中的重要性，自体富血小板血浆注射导致眼动脉栓塞的案例告诉我们：无论是传统的还是新型的美容材料，都可能在不经意间造成失明并发症。注意注射平面，皮内注射而不是皮下注射可以减少或消除血管并发症。注射前回抽、应用局部血管收缩剂、用小针头(30 - 32 G)缓慢注射、掌握注射压力都是预防措施。如果出现了血管并发症，早期的快速诊断和积极的对症治疗都是十分重要的。The authors h

47、ypothesize that the technique used in administering the APRP may have contributed to the visual complications. The site of injection was close to superior orbital artery and superior trochlear artery, presumably causing inadvertent injection of APRP into the artery. Pressure from the syringe likely

48、resulted in retrograde flow of the platelet clot, from the superior orbital or trochlear artery to proximal branches, resulting in occlusion of the ophthalmic artery and other regions of the right middle cerebral artery, which caused diffuse ischemia. Ischemic area of the glabella in this patient se

49、emed rather superficial for an arterial embolization, indicating possible concurrent vein occlusion. The limited ocular motility can be explained by the acute ischemic injury to the extraocular muscles, which was confirmed by imaging. The authors infer that the syringe was not drawn back upon before

50、 injection to assess for intravascular needle placement and this may have led to inadvertent intra-arterial injection. The presumed etiology is further supported by negative systemic work-up and normal echocardiogram, MRA, and CTA imaging. 作者认为自体富血小板血浆的操作技术可能导致了视觉并发症的发生，注射部位如果靠近眶上动脉和滑车上动脉，可能会无意间将APR

51、P注入到动脉。注射器的压力可能导致血小板凝块从眶上或滑车上动脉逆流入临近的动脉分支，从而导致眼动脉和右侧大脑中动脉的其他分支阻塞，造成弥漫性缺血。这位患者眉间的缺血区域较为表浅，表明可能并发静脉阻塞。眼球运动受限有可能是因为眼外肌的急性缺血损伤。作者推断操作者注射前并没有回抽注射器以确定针头位置，这可能无意间造成动脉内注射，系统性检查、超声心动图、MRA和CTA成像检查结果阴性支持此病因推断。Skin nodularity at the site of injection is sometimes more problematic with improper use of physical f

52、illers. It is not a usually seen effect after APRP injection. However, poor centrifugation technique of APRP or improper mixing of fillers can form delayed onset inflammatory or noninflammatory nodules of the tissues.15 The pathological exam of the glabella scar in this patient confirmed the presenc

53、e of foreign bodies within the deep tissues. 注射部位的皮肤结节主要是由于物理填充剂的不当使用产生的，常规APRP注射后看不到这一现象。然而，APRP制备过程中不合适的离心技术或是不恰当地添加了其他填充剂，都有可能使组织产生迟发型炎症反应或非炎性结节。患者眉间部位瘢痕组织的病理学检查证实了深层组织中异物的存在。The findings in this case emphasize the importance of adequate training in new procedures. The authors recommend that caut

54、ion be taken when injecting fillers in the glabellar region due to the rich vascular supply in this region and to prevent skin necrosis or devastating visual complications. Furthermore, the authors suggest that periocular injections be performed by licensed practitioners who are familiar with orbita

55、l anatomy and the rich anastomosis of facial arteries. Qualified practitioners are highly trained and are more capable to deal with complications that may arise. While extraocular in nature, filler injections can cause devastating visual consequences and awareness and proper counseling of patients i

56、s important. 本案例强调了新技术实施前充分的培训是非常必要的；作者建议在眉间等血液丰富的区域进行注射填充应当非常谨慎，以防止皮肤坏死或严重的视觉并发症。此外，作者建议，眼周的注射一定要由熟悉眼眶解剖以及面部复杂的动脉吻合结构的职业医师进行操作。合格的从业人员都是训练有素，更能够合理处理可能出现的并发症。即使是在眼外，注射填充剂也有可能造成严重的视觉并发症，这应该被重视；另外，与患者的合理沟通也非常重要。REFERENCES参考文献1. Sommeling CE, Heyneman A, Hoeksema H, et al. The use of platelet-rich plas

57、ma in plastic surgery: a systematic review. J Plast Reconstr Aesthet Surg 2013;66:30111. 2. Sclafani AP, McCormick SA. Induction of dermal collagenesis, angiogenesis, and adipogenesis in human skin by injection of platelet-rich fibrin matrix. Arch Facial Plast Surg 2012;14:1326. 3. Andia I, Abate M.

58、 Platelet-rich plasma: underlying biology and clinical correlates. Regen Med 2013;8:64558. 4. Sclafani AP, Azzi J. Platelet preparations for use in facial rejuvenation and wound healing: a critical review of current literature. Aesthetic Plast Surg 2015;39:495505. 5. Di Matteo B, Filardo G, Lo Presti M, et al. Chronic anti-platelet therapy: a contraindication for pl