Department of Ophthalmology, Leiden University Medical Center, Leiden, Netherlands
2 Department of Clinical Ophthalmology, Institute of Ophthalmology and Moorfields Eye Hospital, London, and Addenbrooke’s Hospital, Cambridge, UK
Accepted for publication 29 July 2002
ABSTRACT
Aims: To investigate the association between scleritis and myositis.
Methods: Retrospective, non-comparative case series. Records and ultrasonograms were examined of 132 patients, with a diagnosis of episcleritis or scleritis, who attended the ophthalmology department at Leiden University Medical Center between 1997 and 2000. 103 were eligible for comprehensive examination. Medical records were evaluated. Ultrasonography was performed in all patients diagnosed with episcleritis or scleritis. Clinical features, precipitating factors, systemic associations, ocular complications, treatment, and outcome of each patient were assessed.
Results: Of the 103 patients, 27 (26.2%) had episcleritis and 76 (73.8%) had scleritis. Myositis was found to be present in 11 patients. It was present in 14.5% of all patients with scleritis and 30.5% of those in whom the posterior sclera was affected. The presence of the associated myositis did not worsen the visual prognosis and the presence of myositis was not associated with other systemic diseases. There were no cases of unilateral scleritis with bilateral orbital myositis. During an attack ocular complications were more common in patients with scleritis and myositis (64%) than in patients with scleritis alone (30.4%), indicating a more diffuse and potentially dangerous inflammation. There was no evidence that the inflammatory changes in the orbit had spread to involve the sclera, so it is assumed that the muscle changes are an extension of a generalised response to intense inflammation of the episclera and sclera.
Conclusion: This study found a frequent association between myositis and scleritis. Prognosis for vision was not affected by coexistence of myositis.
Keywords: scleritis; myositis; ultrasonography; systemic diseases
Inflammation of the wall of the eye and its mesodermal coverings can present in many ways from the benign simple episcleritis to the severe necrotising scleritis and is sometimes known to involve the overlying muscles. The differential diagnosis of episcleritis from scleritis and between diffuse, nodular, and necrotising disease affecting the anterior segment of the eye is well recognised.1 It is also known that the condition with which the patient first presents usually continues throughout the course of the disease.2 Scleritis is a serious, usually painful, progressive disease of the sclera itself, which if left untreated can seriously affect vision. Diffuse and nodular anterior scleritis if treated early does not normally result in any major complications but if the inflammation extends to or affects the posterior segment of the eye, it frequently results in visual loss. Recent studies using B scan ultrasonography have shown that both episcleritis and scleritis may involve the posterior segment even though there are no clinical signs. Even minor changes in the posterior segment can threaten vision.3
Primary idiopathic orbital myositis is a relatively common subtype of idiopathic orbital inflammatory disease (IOID) in which one or more of the extraocular muscles are affected. The clinical course of orbital myositis is usually characterised by an acute onset, severe pain in and around the eye, pain on movement, occasional diplopia and chemosis, a rapid response to systemic steroids and short duration, although recurrences may occur in some cases.4,5 These symptoms and signs are very similar to those encountered in patients with posterior scleritis.
This study was instituted to determine the importance of the association between myositis and scleritis, whether the extraocular muscles were involved secondary to the scleral disease, and whether it was sometimes bilateral even though only one eye was affected with the scleral disease.
MATERIALS AND METHODS
We reviewed the records of 132 patients with episcleritis or scleritis attending the department of ophthalmology at the Leiden University Medical Center between January 1997 and April 2000. Of the 132 records identified, 29 were excluded because of insufficient clinical detail to ensure a correct diagnosis or lack of insufficient follow up data for the 3 year study period. The follow up period was at least 6 months. All the patients were examined during the 3 years before the end of the study.
Scleritis was divided into anterior and posterior. Anterior scleritis incorporated diffuse, nodular, necrotising with inflammation (necrotising), and necrotising without inflammation (scleromalacia perforans). Episcleritis was not further subclassified into diffuse or nodular.1
In this department all patients diagnosed with scleritis or episcleritis have B-scan ultrasonographs in addition to the clinical and laboratory examinations. The diagnosis of myositis was made clinically and by ultrasonography using the techniques followed in the orbital clinics.6,7 Ultrasonically myositis shows diffuse thickening of both the tendon and muscle fibres with low internal reflectivity. One person (HGW), who is experienced in making both A-mode and B-mode ultrasounds of the orbit, performed all the patients’ scanning, using the Biovision-B-S with a 10 MHZ transducer and a standardised A-mode transducer and techniques of standardised ultrasonography. The transducer was placed perpendicular to the medial rectus muscle so that the muscle’s thickness could be measured accurately. Other extraocular muscles were evaluated for oedema, fibre structure, and cysts; however, the thickness could not be quantified since the echo’s transducer could not always be placed in an angle of 90° towards the measured muscle. In this clinic the normal upper diameter limit of a medial rectus is 5.4 mm measured over 45 patients. All the patients were examined by an internist, rheumatologist, otorhinolaryngologist, or neurologist. Patients diagnosed with Graves’ disease were excluded from the study. The visual acuity was measured at presentation and at the end of follow up. Visual loss was considered to be defective if there was a reduction of two Snellen lines or more. Another disease or complication which may have caused a reduction in visual acuity was recorded to determine that the visual loss could be solely attributed to the scleral inflammation. The data concerning the patients were entered into a computerised database to ensure that they were retrievable. Forward stepwise logistic regression was undertaken to determine whether any of the recorded variables had predictive value for responsiveness to treatment, outcome in terms of visual loss, and the presence of complications. The SPSS statistical software version 10 (SPSS Inc) was used for statistical analyses.
RESULTS
Of the 103 patients, 76 had scleritis and 27 had episcleritis (Table 1). Myositis was found to be present in two patients with posterior scleritis, eight patients with both anterior and posterior scleritis, and in one patient with anterior episcleritis and posterior scleritis (Table 2). The eight patients with anterior scleritis had, besides their myositis and posterior scleritis, diffuse anterior scleritis (six) and nodular anterior scleritis (two).
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Thirty patients had bilateral involvement, including two with episcleritis and 28 with scleritis. Four patients with both scleritis and myositis had scleral disease in both eyes (Table 2). One patient with bilateral episcleritis and posterior scleritis in the left eye had myositis in the left eye only. There were no patients who had scleritis in one eye and myositis in both eyes. Three patients with bilateral scleritis also had myositis in both eyes. Thus myositis only occurred in an eye with posterior scleral inflammation. Clinically, those with scleritis and myositis had periocular pain, pain on movement (90.9%), proptosis, diplopia, headache, chemosis, red eyes, and swollen eyelids (Table 2). Patients with the combination scleritis and myositis had severe pain on ocular movement (OR = 26.8: 3.3 to 220.3), whereas in the episcleritis and scleritis group without myositis only 25 patients (26.4%) had pain on movement, 44% of the patients with posterior scleritis also had pain on movement. There was only one patient in whom the B-scan abnormality did not correlate with the clinical diagnosis of myositis. The medial rectus muscle, was predominantly affected.
The visual acuity was measured at presentation and at the end of follow up in 101 patients. There were three patients with both scleritis and myositis who had loss in visual acuity both at presentation and after treatment (Table 2). One patient had a serous retinal detachment in the affected eye with scleritis and developed a cataract in the same eye. Another patient with unilateral disease had a concurrent iridocyclitis and developing cataract. The last patient with bilateral scleritis and myositis had bilateral concomitant secondary glaucoma. In the scleritis group without myositis, 21 patients had visual loss at presentation of whom 15 still had a decrease in visual acuity after treatment. Vision was especially affected in patients with exclusively posterior scleritis both at presentation (44%) and after treatment (36%). Patients with both scleritis and myositis did not have any greater risk of developing deficient vision at presentation and after treatment compared to patients with scleritis alone. Ocular complications were more common in those patients with scleritis and myositis (64%), consisting of cataract, keratitis, high intraocular pressure, glaucoma, and uveitis compared to those who had scleritis (30.4%) alone (OR = 4.0: 1.1 to 14.8). Patients were treated both for their scleritis and additional ocular complication. The additional eye disease responded completely after treatment.
One third of the patients with scleritis and one in 10 of those with episcleritis had an associated systemic disease (Table 3) but only two of the 11 patients with both scleritis and myositis had an associated systemic disease. Patients with an associated systemic disease had a greater risk of developing the ocular complications of scleritis after their remission (OR = 3.7: 1.4 to 9.7).
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DISCUSSION
Scleritis has been known to be associated with swelling of the adjacent muscles and their fascial sheaths for many years.8–10 However, the significance and the frequency of this association has not yet been fully explored.
The inflammation of the muscles and their sheaths is poorly defined and has been termed orbital myositis, extraocular muscle fasciitis, and/or tenonitis. The muscles and sheaths have been found to be infiltrated by inflammatory cells and the inflammation may be accompanied by orbital granulomas similar histologically to that found in scleral disease and in some instances contiguous with it. Both orbital myositis and scleritis can be extremely painful and both tissues can be involved in systemic diseases particularly those which have a systemic vasculitis. Idiopathic orbital myositis is currently included within idiopathic orbital inflammatory syndromes.4,11 It is rarely associated with any other condition and differs from dysthyroid eye disease (Graves’ orbitopathy).4,11 As a consequence any patient with Graves’ disease was excluded from this study, except one patient with anterior episcleritis who had thyrotoxicosis without muscular involvement.
In this series all patients who presented with any form of episcleral or scleral inflammation had a B-scan ultrasonography, which was performed by the same individual. This B-scan ultrasound included an orbital scan of the ocular muscles and their sheaths.6,7,12 We consider that scleritis should be added to the list of conditions normally associated with myositis because orbital myositis was found frequently enough in both patients with posterior scleritis alone (30.5%) or in those who had both anterior and posterior segments (25%) involved (Figs 1 and 2).11 In this study all patients with myositis had posterior scleritis. Of these nine had involvement of the anterior sclera as well. They all had the clinical symptoms of orbital myositis and had at least one thickened medial rectus on B-mode ultrasound. The pain was often unbearable. All patients consulted a general doctor or ophthalmologist within 2–5 days after the first symptoms because of the severity of the disease. Pain on movement occurred in patients with scleritis alone (26.4%), although not as frequently and severe as in patients with both scleritis and myositis (90.9%). Therefore, this symptom is very indicative of the combination of scleritis and myositis. Patients with both scleritis and myositis had more additional ocular problems than patients with scleritis alone, indicating a more widespread and potentially more damaging inflammatory response (OR = 4.0: 1.1 to 14.8). There were only two patients with scleritis and myositis who had an associated disease. There is no suggestion that orbital vasculitis, pseudotumour, rheumatic arthritis, or other connective tissue diseases are related to this combined condition.
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Other studies into orbital myositis show frequent involvement of the horizontal recti, although every muscle may be engorged in this condition.16,17 In a large series of patients it was shown that the frequency of muscle involvement, in decreasing order, was medial rectus (43%), superior rectus (19%), lateral rectus (17%), superior oblique (9%), inferior rectus (7%), and inferior oblique (5%).17 Although unilateral, single muscle inflammation with tendon association is most common, orbital myositis may be bilateral, in which case one or more extraocular muscles with or without their tendons may be involved.17–19 It has not been possible to determine in this series whether the swelling of the muscles seen ultrasonographically was a myositis or just swelling of the fascia. It is probable that the swelling of the muscle and its sheath is secondary to the scleral inflammation rather than the inflammatory response extending into the scleral coats from a primary myositis, because there was no evidence of other orbital disease in these patients. The age group of the patients is that of scleritis rather than myositis and, in addition, myositis alone was never present in the opposite orbit to the eye which had scleritis or the scleritis-myositis combination.
Scleritis, whether anterior or posterior, is accompanied by oedema of the overlying episclera but high quality ultrasonography shows that the posterior episclera and the muscle sheaths can be involved in an inflammatory process without the sclera apparently being involved. If episcleral inflammation affects the extension of the episclera onto the optic nerve, then vision can be affected and, if it tracks forward on and around the muscle, it can present as an episcleritis as occurred in one patient in this series.
No complications directly related to the myositis could be identified but the source of the very severe pain and pain on movement experienced by patients with the combination of scleritis and myositis was almost certainly due to inflammation of the muscles rather than derived predominantly from the sclera. The treatment of myositis and scleritis is identical and both responded to non-steroidal anti-inflammatory agents or systemic steroids. Additional immunosuppression therapy was never required. As anticipated the myositis recovered rapidly but there was a delay in the final resolution of the scleral inflammation. B-scan ultrasound of the orbit should be included in the investigation of scleral disease as the presence of a myositis indicates a more extensive disease and, as a consequence, more aggressive therapy may be indicated.
Financial support: There was no particular funding involved for this study.
Commercial interest: None.
REFERENCES
1 历史回顾
包涵体肌炎(inclusion body myositis, IBM)是一种慢性炎症性肌病。其主要病理特点是肌浆或肌核内有管状细丝包涵体。Yunis［1］首先提出IBM这一疾病名称。在此之前Adams［2］等报告了1例肌细胞内包涵体肌病，这种包涵体在光镜下与Yunis描述的包涵体很相似。后来Chou［3］在1例慢性多发性肌炎患者的肌肉中发现了这种包涵体，当时称之为粘病毒样结构。直至1978年Carpenter［4］对14例IBM的临床病理特点进行了总结，并正式确立了IBM为一独立疾病。此后有大量IBM的临床病理报告，并在免疫病理、细胞化学和分子生物学方面进行了深入研究。最近，Griggs［5］等发表了专题文章，提出了IBM的临床和实验室诊断标准，进一步确立了IBM的临床病理概念。
2 临床表现
2.1 发病率和发病年龄［6～8］ IBM临床并不少见，约占炎症性肌病的15%～28%。男性好发，男女比例为3∶1。多在50岁以后但可以早至20岁起病。Lotz报告的平均发病年龄为56.1岁。Chou［9］和Eisen［10］报告20～30岁和60～70岁是其发病的两个高峰年龄段。我国目前尚未见经电镜证实的IBM病例报告，这并不一定说明我国IBM少见，很可能与电镜观察不够普及以及观察方法不当有关。
IBM多为散发，但自1988年Coll报告了1个家族性IBM之后，又有一些家族性病例报告［11，12］。IBM是否与遗传有关，目前尚不能肯定。
2.2 肌无力特点［6～8］ IBM起病隐匿，缓慢进展，首发症状约70%为下肢近端无力，也可为下肢远端、上肢或四肢均匀无力起病。肌无力可对称或不对称，随着病情进展，远端肌无力可达50%，但仅有35%其远端无力的程度达到或超过近端无力。最易受累的肌肉是肱二头肌、肱三头肌、髂腰肌、股四头肌和胫前肌，而三角肌、胸大肌、骨间肌、颈屈肌、腓肠肌及足趾屈肌受累较轻。
2.3 其它症状及体征［6～8］ 腱反射常减低，尤以膝反射减退最为常见。少数患者可有感觉异常。吞咽困难较常见，约50%患者就诊时已发现了吞咽困难。后者多由食管上段和环咽部肌肉功能障碍所致。
2.4 合并症［6］ IBM常合并其它疾病，按其发生率依次为心血管病、周围神经病、糖尿病、自身免疫性疾病，包括间质性肺炎、银屑病、红斑性狼疮和皮肌炎。这些合并症与IBM之间有无病因方面的联系目前尚不能肯定。
3 实验室检查
3.1 肌电图(EMG)［6～8］ IBM的EMG特点与PM/DM相似，表现为异常自发性活动增多，短时程运动单位电位和多相波增多。所不同的是IBM长时程和短时程运动单位电位可在同一块肌肉同时出现，后者被称为混合电位(mixed potentials)。混合电位常见于失神经支配，但Lotz认为IBM的混合电位与神经源性损害无关。
3.2 肌酶谱［5，6］ IBM的血清CK水平可正常或轻度增加，一般不超过正常值的10～12倍。
3.3 肌活检病理［4～8］ 光镜下IBM的肌肉病理改变为：(1) 镶边空泡(rimmed vacuoles)或衬里空泡(lined vacuoles)。这种空泡常位于肌膜下或肌纤维中央，呈圆形、多角形或不规则形态，直径为2～25 μm。HE染色可见空泡边缘有颗粒状嗜碱性物质沉积，镶边或衬里空泡即由此而得名。(2) 肌内膜炎细胞浸润或单核细胞侵入非坏死纤维。(3) 成群的萎缩纤维，平均每低倍视野下可见2群。(4) 嗜酸性包涵体，为一圆形包涵体，HE染色着红色，常位于镶边空泡的周围，每张切片一般不超过3个。以上4种病理改变的出现频率依次为100%、96%、92%和58%，前3种的出现率为88%，4种同时出现仅为46%。其它病理改变包括单个肌纤维坏死，肌核大而疏松，肌膜下肌浆内嗜碱性颗粒聚积以及刚果红染色，荧光显微镜下观察可发现染成桔黄色的淀粉样物质。
电镜下IBM特征性的病理改变为肌浆或肌核内有管状细丝包涵体(tubulofilament containing inclusions)，这种包涵体由盘绕的管状细丝组成，细丝外径10～20 nm，内径3.6～8 nm，长为1～5 μm。有时其上可见5 nm宽的横纹，高分辨率电镜下可见细丝由3～4.5 nm宽的亚单位紧密接连而成。肌浆内的包涵体可能来自于肌核，细丝可以呈相互平行或向心性排列，也可以杂乱无序。其周边常包绕糖原颗粒、不规则的髓样结构、膜碎片及胞浆的分解产物。在胞浆内还可以见到一种直径6～10 nm的淀粉样纤维和絮状无结构物质聚集。电镜下寻找包涵体并不容易，应先做半薄切片在光镜下定位，至少需选3个空泡纤维，经仔细观察才能发现包涵体。
IBM在电镜下可见细胞核崩解，其内容物释放到胞浆内，有学者认为镶边空泡就是细胞核分解的结果。线粒体的改变包括数量增多及嵴内晶体样包涵体形成。毛细血管内皮细胞变得明显，泡饮现象活跃。Arahata和Engel［13，14］应用免疫电镜研究发现，IBM中单核细胞对非坏死纤维的侵入现象常见，被侵入的非坏死纤维胞浆和肌原纤维常常受挤压而被部分取代，严重时可导致整个肌纤维破坏。
4 诊断标准
Carpenter［4］、Ringel［15］和Lotz［6］均曾提出了IBM的临床病理诊断标准，但一直未被普遍接受。最近，Mendel等［5］对近来的研究成果进行了归纳总结，提出了更为详细的诊断标准。
4.1 特征性的表现 (1) 临床特征：1) 病程＞6个月；2) 起病年龄＞30岁；3) 肌无力：必须累及上肢和下肢的近端和远端，患者至少有下述表现之一：① 屈指无力； ② 屈腕无力较伸腕无力明显； ③ 股四头肌无力(等于或小于4级)。(2) 实验室特征：1) 血清CK不超过正常值的12倍； 2) 肌活检：① 炎症性肌病伴单核细胞对非坏死纤维的侵入； ② 空泡纤维； ③ 下述二者之一：(a) 肌细胞内淀粉样物质沉积(需用刚果红染色荧光显微镜下观察)； (b) 电镜下发现15～18 nm的管状细丝包涵体；(c) EMG符合炎症性肌病的特点(但常见长时限电位)。(3) 家族史：少数患者可有家族史。
4.2 相关疾病 IBM可与其它疾病同时发生，尤其是自身免疫性疾病。
4.3 IBM的诊断标准 (1) 确诊的IBM：患者表现所有肌活检病理特征。IBM一经肌活检病理确诊，任何临床表现和其它实验室检查均不能将其否定。(2) 疑似IBM：如果患者仅具备了IBM炎症性病理改变的诊断标准，即有单核细胞对非坏死纤维的侵入，加之临床符合(1)中1)、2)、3)，实验室检查符合(2)中1)、3)则为疑似IBM。
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5 发病机制
IBM确切的发病机制至今未明。Chou［3，9］曾怀疑包涵体为一粘病毒产物，且后来发现麻疹病毒抗体能与IBM的包涵体结合，但有关IBM与病毒感染间的关系至今未得到肯定。Arahata［13，14］采用免疫电镜方法对IBM的免疫机制进行研究结果发现，IBM中单核细胞对非坏死纤维的侵入以及肌内膜的单核细胞浸润均较PM、DM和DMD多见。但对产生这一现象的确切机制并不清楚。Oldfors［10］对IBM线粒体DNA(mtDNA)的分析研究中发现，约有47%的IBM有多发性mtDNA缺失。mtDNA的这种改变不能用年龄或继发于炎症等因素来解释。DiMauro［5］认为IBM出现多发性mtDNA缺失可能由核DNA与mtDNA间的联系中断所致，并认为线粒体的这一改变在肌肉变性和无力的病因方面起着重要作用。
在IBM的发病机制研究中，肌核的改变尤其是核基质的改变越来越受到重视。超微结构观察发现的核内管状细丝包涵体、核崩解以及由此形成的镶边空泡等IBM的特征性病理改变均与肌核有关。采用金免疫定位的方法在空泡纤维内发现多种类似于Alzheimer病患者脑内出现的异常蛋白质。这些蛋白质包括β淀粉样物质、β淀粉样物质前体蛋白、泛蛋白(ubiquitin)、朊蛋白(prion)、Tau蛋白及载脂蛋白E(ApoE)［16，17］。这些异常蛋白的产生也提示肌核DNA有异常表达。总之，一旦肌核改变做为IBM的起动病因得到证实，那么IBM的炎症性改变就可能是一种继发反应。
家族性IBM与散发性IBM在发病机制方面是否存在不同，目前尚不能肯定。值得注意的是有一些家族性镶边空泡肌病在临床表现和病理特征上很象IBM，只是前者没有炎细胞浸润。Mendell［5］将这些患者称之为遗传性包涵体肌病(hereditary inclusion body myopathy)以便与IBM区别。
6 治疗及预后
对类固醇激素治疗无效是IBM区别于PM/DM的重要临床特征［17，18］。尽管类固醇治疗能减少IBM患者肌肉内炎细胞的浸润，降低血清CK水平，但镶边空泡纤维和嗜刚果红物质均增加，临床肌无力加重或仅有轻微改善［19］。这进一步表明IBM炎症浸润可能只是继发性。静脉注射免疫球蛋白(IVIg)可使部分IBM患者肌无力和吞咽功能改善，生活能力提高，但改善的程度有限［20～24］。究竟IVIg治疗IBM是否有效，尚需对大宗病例采用严格的研究设计进行证实。
IBM预后不佳，Lotz［6，23］对28例患者平均随访72个月，结果表明IBM呈缓慢进行性发展，有6例患者起病15年后生活已不能自理，1例10年后卧床不起，12年后死于呼吸、心脏衰竭。
参考文献
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