Magnetic resonance imaging evidence for widespread orbital dysinnervation in dominant Duane's retraction syndrome linked to the DURS2 locus

PURPOSE: High-resolution, multipositional magnetic resonance imaging (MRI) was used to demonstrate extraocular muscles (EOMs) and associated motor nerves in Duane retraction syndrome (DRS) linked to the DURS2 locus on chromosome 2. METHODS: Five male and three female affected members of two autosomal dominant DURS2 pedigrees were enrolled in the study. Coronal T(1)-weighted MRI of the orbits was obtained in multiple gaze positions, as well as with heavy T(2) weighting in the plane of the cranial nerves. MRI findings were correlated with motility. RESULTS: All subjects had unilateral or bilateral limitation of abduction, or of both abduction and adduction, with palpebral fissure narrowing and globe retraction in adduction. Orbital motor nerves were typically small, with the abducens nerve (cranial nerve [CN]6) often nondetectable. Lateral rectus (LR) muscles were structurally abnormal in seven subjects, with structural and motility evidence of oculomotor nerve (CN3) innervation from vertical rectus EOMs leading to A or V patterns of strabismus in three cases. Four cases had superior oblique, two cases superior rectus, and one case levator EOM hypoplasia. Only the medial and inferior rectus and inferior oblique EOMs were spared. Two cases had small CN3s. CONCLUSIONS: DRS linked to the DURS2 locus is associated with bilateral abnormalities of many orbital motor nerves, and structural abnormalities of all EOMs except those innervated by the inferior division of CN3. The LR may be coinnervated by CN3 branches normally destined for any other rectus EOMs. Therefore, DURS2-linked DRS is a diffuse congenital cranial dysinnervation disorder involving but not limited to CN6.     

Congenital cranial dysinnervation disorders

The European Neuromuscular Centre (ENMC) derived the term Congenital Cranial Dysinnervation Disorders in 2002 at an international workshop for a group of congenital neuromuscular diseases. CCDDs are congenital, non-progressive ophthalmoplegia with restriction of globe movement in one or more fields of gaze. This group of sporadic and familial strabismus syndromes was initially referred to as the 'congenital fibrosis syndromes' because it was assumed that the primary pathologic process starts in the muscles of eye motility. Over the last few decades, evidence has accumulated to support that the primary pathologic process of these disorders is neuropathic rather than myopathic. This is believed that for normal development of extra ocular muscles and for preservation of muscle fiber anatomy, normal intra-uterine development of the innervation to these muscles is essential. Congenital dysinnervation to these EOMs can lead to abnormal muscle structure depending upon the stage and the extent of such innervational defects. Over last few years new genes responsible for CCDD have been identified, permitting a better understanding of associated phenotypes, which can further lead to better classification of these disorders. Introduction of high-resolution MRI has led to detailed study of cranial nerves courses and muscles supplied by them. Thus, due to better understanding of pathophysiology and genetics of CCDDs, various treatment modalities can be developed to ensure good ocular alignment and better quality of life for patients suffering from the same.     

先天性脑神经异常支配眼病的分子遗传学与神经科学研究进展

先天性脑神经异常支配眼病(CCDDs)为一组先天性、非进行性一条或多条脑神经发育异常或缺失,从而导致的原发或继发脑神经异常支配眼外肌的斜视综合征,可散发或家族遗传,可伴有全身系统异常。近年来随着神经病理学、神经影像学、遗传学的研究进展,不仅明确了CCDDs的病因是神经源性的眼球运动障碍,也发现了CCDDs的致病基因,包括SALL4、HOXA1、KIF21A、PHOX2A、TUBB3及HOXB1等。针对基因突变影响大脑神经发育从而进一步导致先天性脑神经支配异常性病变发生这一问题,文章回顾了近年国内外相关文献,就已知的CCDDs的分子遗传学和神经科学研究进展作一综述,以期为CCDDs的临床和基础研究提供参考。     

一个先天性眼外肌纤维化综合征家系的影像特征分析

目的:研究一个先天性眼外肌纤维化综合征（CFEOM）家系,发病者眼外肌及眼运动神经的影像学特征,初步探索该病发病机制,为其治疗提供理论基础。方法:对一个常染色体显性遗传病CFEOM1 家系,三代3 例患者进行高分辨率MRI扫描,随机抽取12 个正常人作为对照组,扫描方法:眼眶部行3mm 层厚、T1 加权MRI 扫描;颅内行1mm 层厚、3D FIESTA 扫描。比较两组眼外肌以及眼运动神经的变化。结果:发病者5 条眼外肌体积较正常对照组小,尤以上直肌明显,差异有统计学意义（P＜0.05）;眼运动神经（动眼神经、外展神经）的颅内段截面积较正常对照组小,差异有统计学意义（P＜0.05）。结论:CFEOM 病患者各条眼外肌较正常人萎缩,颅内眼运动神经有发育不良。提示该病可能为眼运动神经核发育不良引起。     

先天性眼外肌纤维化综合征MR成像分析

目的 通过观察先天性眼外肌纤维化（CFEOM）三种临床表型的眼运动神经和眼外肌及周围组织的影像学特征,为本病的病因学研究提供线索。设计 回顾性病例系列。研究对象CFEOM患者21例。方法 对21例CFEOM患者行全脑、脑干、海绵窦及眼眶的MRI扫描。全脑平扫;眼运动神经脑池段,采用头颅线圈,层厚0.8 mm,重T2加权,三维FIESTA序列扫描;眼运动神经海绵窦段,采用头颅线圈,层厚2 mm, T1加权像扫描;眼外肌和眼运动神经的眶内段,采用表面线圈,层厚2 mm,T1加权像扫描。显示脑池段的眼球运动神经、眶内各神经分支和眼外肌。主要指标 眼球运动神经分布和眼外肌的发育情况。结果 CFEOM患者的动眼神经、外展神经及滑车神经的眶内段和脑池段均表现出不同程度的发育不良。六条眼外肌均表现不同程度萎缩,以上直肌和提上睑肌最为严重,上斜肌和外直肌改变轻微。结论CFEOM患者眼运动神经和眼外肌结构均发育不良。特别是脑池段运动神经发育不良的影像学特征明确,提示CFEOM的原发病变是运动神经发育缺陷。     

Cranial nerve palsies in childhood

We review ocular motor cranial nerve palsies in childhood and highlight many of the features that differentiate these from their occurrence in adulthood. The clinical characteristics of cranial nerve palsies in childhood are affected by the child''s impressive ability to repair and regenerate after injury. Thus, aberrant regeneration is very common after congenital III palsy; Duane syndrome, the result of early repair after congenital VI palsy, is invariably associated with retraction of the globe in adduction related to the innervation of the lateral rectus by the III nerve causing co-contraction in adduction. Clinical features that may be of concern in adulthood may not be relevant in childhood; whereas the presence of mydriasis in III palsy suggests a compressive aetiology in adults, this is not the case in children. However, the frequency of associated CNS abnormalities in III palsy and the risk of tumour in VI palsy can be indications for early neuroimaging depending on presenting features elicited through a careful history and clinical examination. The latter should include the neighbouring cranial nerves. We discuss the impact of our evolving knowledge of congenital cranial dysinnervation syndromes on this field.     

High-resolution magnetic resonance imaging demonstrates abnormalities of motor nerves and extraocular muscles in patients with neuropathic strabismus.

INTRODUCTION: Although the ocular motility examination has been used traditionally in the diagnosis of strabismus that is a result of cranial nerve (CN) abnormalities, magnetic resonance imaging (MRI) now permits the direct imaging of lesions in CN palsies. METHODS: Prospectively, nerves to extraocular muscles (EOMs) were imaged with T1 weighting in orbits of 83 orthotropic volunteers and 96 strabismic patients in quasicoronal planes using surface coils. Intraorbital resolution was 234-312 microns within 1.5- to 2.0-mm thick planes. CNs were imaged at the brainstem using head coils and T2 weighting, yielding 195 micron resolution in planes 1.0-mm thick in 6 normal volunteers and 22 patients who had oculomotor (CN3), trochlear (CN4), or abducens (CN6) palsies and Duane syndrome. RESULTS: Oculomotor (CN3) and abducens (CN6) but not trochlear (CN4) nerves were demonstrable in the orbit and skull base in all normal subjects. Patients with congenital CN3 palsies had hypoplastic CN3s both in orbit and skull base, with hypoplasia of involved EOMs. Patients with chronic CN6 and CN4 palsies exhibited atrophy of involved EOMs. Patients with Duane syndrome exhibited absence or hypoplasia of CN6 in both orbit and brainstem regions, often with mild hypoplasia and apparent misdirection of CN3 to the lateral rectus muscle. Unlike CN6 palsy, patients with Duane syndrome exhibited no EOM hypoplasia. Patients with congenital fibrosis exhibited severe hypoplasia of CN3, moderate hypoplasia of CN6, and EOM hypoplasia, particularly severe for the superior rectus and levator muscles. CONCLUSION: High-resolution MRI can directly demonstrate pathology of CN3 and CN6 and affected EOM atrophy in strabismus caused by CN palsies. Direct imaging of CNs and EOMs by MRI is feasible and useful in differential diagnosis of complex strabismus.     

Congenital fibrosis syndrome associated with central nervous system abnormalities

Background Congenital fibrosis of extraocular muscles (CFEOM) is a complex strabismus syndrome that typically occurs in isolation and results from dysfunction of all or part of cranial nerves III (CNIII) and IV (CNIV) and/or the muscles that these nerves innervate. Only a few patients with CFEOM and additional central nervous system malformations have been reported. We describe four additional patients with CFEOM associated with central nervous system (CNS) abnormalities.Methods Four patients who presented with congenital restriction of eye movements in association with neurological abnormalities underwent complete ophthalmological examination including electroretinography (ERG) and eye movement recordings. Neurological examinations, neuroradiological studies, muscle histology, chromosomal and genetic linkage analysis were performed.Results Clinical examination and forced duction testing confirmed that all four patients met criteria for CFEOM; all had congenital restrictive ophthalmoplegia primarily affecting extraocular muscles innervated by the oculomotor nerve. Two brothers had CFEOM and Marcus Gunn jaw winking. In each of the four cases, CFEOM occurred in association with one or several neuroradiological findings, including agenesis of the corpus callosum, colpocephaly, hypoplasia of the cerebellar vermis, expansion of the ventricular system, pachygyria, encephalocele and/or hydrancephaly.Conclusions We present four cases of CFEOM in association with CNS malformations that confirm that CFEOM can be part of a more complex neurological dysfunction and provide further support to a neurogenic aetiology for this disorder. We also describe for the first time the coexistence of CFEOM and Marcus Gunn jaw winking in two siblings. This suggests a genetic mechanism. Aberrant innervation supports primary developmental abnormality of cranial nerves in CFEOM.     

正常人眼球运动神经的MRI影像解剖

目的 采用MRI成像技术显示正常人眼球运动神经的颅内段、海绵窦段和眶内段的影像特征.方法 正常受试者20名,年龄24～38岁,平均(28.25±4.07)岁.眼球运动神经脑池段采用头线圈,层厚0.8 mm,3D-RESTA序列扫描;海绵窦段采用头线圈,冠状而FSE,T1WI扫描,层厚2.0 mm,层间距0.3 mm;眼眶段采用表面线圈,冠状面FSE,T1WI扫描,层厚2.0 mm,层间距0.3 mm.对照火棉胶包埋0.1mm层厚,HE染色的完整眼眶冠状切片,在连续冠状MRI影像上追踪和分辨动眼神经、滑车神经和外展神经,直至分支进入相应的眼外肌.结果脑池段动眼神经和外展神经显示率为100%,滑车神经显示率为95%;海绵窦段动眼神经显示率100%,外展神经和滑车神经部分显示;在连续冠状的眼眶组织切片指引下,眶内段外展神经和动眼神经下支的分支完全显示,动眼神经上支显示60%,滑车神经显示40%.结论连续的薄层三维FIESTA序列扫描结合多平面重组技术,MRI能清晰地显示眼运动神经脑池段及其毗邻关系.MRI能清晰显示眶内动眼神经下支和外展神经.由于动眼神经上支和滑车神经结构精细,毗邻关系复杂,部分显示.对眼球运动神经路径上复杂的解剖结构的知识背景,影响分析MRI呈现的影像学信息.(中华眼科杂志,2009,45:219-224)     

Proprioception in the extraocular muscles of mammals and man

This article summarizes the authors' previous studies on proprioceptors in extraocular muscles (EOMs) of mammals and man. They report on muscle spindles in the EOMs of man, Golgi tendon organs in the EOMs of even-toed ungulates, and palisade endings in the EOMs of the cat. Muscle spindles: Muscle spindles are present in the EOMs of some mammals and in the EOMs of man. Compared with muscle spindles in other skeletal muscles, those in human EOMs exhibit structural differences. These structural differences may indicate a special function. Golgi tendon organs: Golgi tendon organs are absent in human EOMs. Golgi tendon organs exhibiting a specific morphology are present in the EOMs of even-toed ungulates. Their high number and rich innervation indicate functional importance. Palisade endings: Palisade endings are nervous end organs confined to the EOMs of mammals and man. It is assumed that these organs have a proprioceptive function. The authors show that palisade endings are immunoreactive for antibodies against choline acetyltransferase. Neuromuscular contacts, if present in palisade endings, are alpha -bungarotoxin positive as well. Taken together, these results show that palisade endings exhibit molecular characteristics of effector organs.     

Absence of the fourth cranial nerve in congenital Brown syndrome

Purpose: To elucidate the aetiology of congenital Brown syndrome. Methods: Four consecutive patients diagnosed with unilateral congenital Brown syndrome had a comprehensive standardized ocular motility examination. Any compensatory head posture was measured. Brain magnetic resonance imaging (MRI) with regard for the IV cranial nerve (CN) was performed in all patients. Orbital MRI was performed in 2/4 patients, with images acquired in eight directions of gaze and superior oblique (SO) muscle areas compared. Results: CN IV could not be identified bilaterally in two patients, but was absent only on the side of the Brown syndrome in the two other patients. On the normal side, orbital MRI revealed a smaller SO muscle area in upgaze than in downgaze, demonstrating normal actions of this muscle. On the side of the Brown syndrome, the SO area remained the same in upgaze and in downgaze and approximately symmetric to the area of SO in downgaze on the normal side. Conclusions: These cases add further anatomical support to the theory of paradoxical innervation in congenital Brown syndrome. CN IV was absent in two patients on the side of the Brown syndrome, but without muscle hypoplasia. SO muscle size did not vary in up‐ and downgaze, which we interpreted as a sign of constant innervation through branches of CN III.     

MRI多颅神经异常与斜视诊断

目的 运用MRI评价多条颅神经的形态学异常改变,分析其对斜视病因诊断的价值。设计 回顾性病例系列。研究对象 55例斜视患者。方法 患者行MRI检查,采用3D FIESTA序列,分析脑池段颅神经的MRI表现。主要指标 脑池段颅神经的发育情况。 结果 观察所有55例患者多对颅神经脑池段,发生颅神经异常的MRI表现包括：21例眼外肌纤维化综合征者中,脑池段动眼神经2条未显示,38条动眼神经纤细;16例双侧眼球后退综合征、15例眼外肌纤维化综合征和3例眼-面麻痹综合征中,脑池段外展神经41条未显示,19条纤细,2条脑池段外展神经走行区纤细索条影,1条起始位于脑干中部,1条走行区只见不规则形索条影。3例眼-面麻痹综合征和6例眼球后退综合征患者中,6条面神经、6条听神经、3条舌下神经脑池段未显示。结论 MRI能够清晰显示颅神经脑池段的异常改变,为神经源性斜视的诊断提供客观依据。（眼科,2013, 22： 299-303）     

Strabismus surgery in children with M?bius syndrome.

M?bius syndrome is a congenital disorder of facial diplegia associated with lateral gaze paralysis. Although palsy of the sixth and seventh cranial nerves is the minimum diagnostic finding for M?bius syndrome, neuropathologic evidence indicates that this is a more complex syndrome.(1) Clinically, it is characterized by a total absence of facial expression and severe esotropia. Other anomalies may be associated with this syndrome, especially other cranial nerve palsies and Poland syndrome. The etiology of this syndrome has not been clearly established. Brain stem necrosis resulting from a vascular deficiency has been offered as a possible pathogenetic explanation.(2) The strabismus in M?bius syndrome is congenital esotropia with bilateral limitation in abduction. Even though many reports have described the various features of M?bius syndrome, only a few articles have reported the results of strabismus surgery in children, including bimedial rectus muscle recession. (3-5) Some authors report that bilateral medial rectus muscle recession alone has been disappointing; therefore, a combination of a medial rectus muscle recession and a lateral rectus muscle resection was recommended for satisfactory results. (5-7) In more severe cases, muscle transposition was needed to ensure straight position of the eyes in primary gaze. (8-9)     

Stickler's syndrome associated with congenital glaucoma

A case report of Stickler's syndrome associated with congenital glaucoma is presented. Stickler's syndrome is an autosomal dominant disorder characterised by progressive arthropathy, midfacial flattening, Pierre Robin anomaly or cleft palate, sensorineural hearing loss, progressive myopia, vitreoretinal degeneration, and retinal detachment. Congenital glaucoma and Stickler's syndrome are two diagnoses frequently considered in high myopia in infancy. The case report described presents a case of Stickler's syndrome in association with congenital glaucoma. This association is unusual, but important to recognise in the neonatal period. The possibility of coexistence of these clinical entities should be considered in the future.     

Von Pflugk (Dresden): Contribution to the Technique of Strabismus Operations,Suturing Anteriorly and Posteriorly

Up to 25% of the eyes affected with Duane's syndrome show upshoot and/or downshoot in attempted adduction. This is thought to be caused by the tight horizontal muscles both contracting in attempted adduction (leash or bridle effect) due to abnormal firing of the lateral rectus muscle through which the globe slips beneath the muscle. Surgical procedures successful in correcting the very disturbing cosmesis of gaze are posterior fixation, recession of the horizontal rectus muscles or splitting of lateral recti muscles insertion. The authors report on a 27-year-old male with Duane's syndrome type III with extreme upshoot in adduction. After recession of both horizontal muscles the upshoot on attempted adduction was no longer present postoperatively. At one year follow-up a very discrete upshoot in attempted adduction could be documented. The resolving of the upshoot postoperatively could be explained by the bridle mechanism alone. The low grade upshoot in attempted adduction at one year follow-up could have been caused by new adhesions of the check ligaments and Tenon's capsule at the level of the lateral rectus muscle resulting from surgery itself. The possibility of an anomalous cyclovertical innervation playing a role in the vertical anomalous movements as Duane originally hypothetized cannot be excluded.     

Unilateral acquired Brown's syndrome in systemic scleroderma: An unusual cause for diplopia

Brown''s syndrome can be congenital or acquired with multiple causes. It has been described as a ocular complication in various rheumatic and nonrheumatic diseases. We describe a case of 27-year-old female patient with 5 years old history of systemic scleroderma who developed vertical diplopia, a left head tilt, and restriction of left eye on elevation in adduction. The patient responded to systemic steroids with resolution of diplopia.     

A case of spontaneously resolved primary congenital glaucoma

Primary congenital glaucoma usually presents as enlarged and hazy cornea at birth or early childhood. The diagnosis is based on a thorough clinical examination under anesthesia. Most cases require surgical intervention as the definitive treatment. In very rare instances, primary congenital glaucoma may arrest and resolve spontaneously. We describe a case of spontaneously arrested and resolved primary congenital glaucoma in a 37-year-old male presenting with large cornea, Haab''s striae, and normal intraocular pressure in one eye. Such a case has not been previously described from the Indian subcontinent.     

Review of the major findings about Duane retraction syndrome (DRS) leading to an updated form of classification

In view of all the reported evidence by electromyography in the 1970s, by histology in the 1980s, and by cerebral imagery since the 2000s, Duane retraction syndrome (DRS) has been described as the consequence of a congenital anomaly of the 6th cranial nerve nuclei with aberrant innervations by supply from the 3rd cranial nerve. Both genetic and environmental factors are likely to play a role when the cranial nerves and ocular muscles are developing between the 4th and the 8th week of gestation. New data from eye movement recordings contributed to better understanding the binocular control of saccades. Modeling of saccades in DRS seems promising for the quantification of the innervational deficit and the mechanical properties of the eye plant. The usual clinical classification of DRS needs to be updated in order to match more accurately the underlying dysinnervation of the extra ocular muscles and to illustrate the continuum that exists between the various forms. This review aims to summarize the major findings about DRS and to guide the clinician in the surgical management of this particular form of strabismus.     

先天性颅神经异常支配综合征2例

我们报告两例在我们医疗中心治疗的先天性颅神经异常支配综合征(congenital cranial dysinnervation disorders,CCDD)。其中1例是7岁的中国女孩,无内科疾病,其父母注意到从婴孩时起患者习惯性向一侧倾斜头部,并伴有"眼懒惰"。双眼视力为斯内伦视力表6/6,头向右倾斜。水平或垂直注视时双眼外展受限,试图内转向下看时伴眼球内陷。另1例是10岁的马来西亚男孩,无内科疾病,其父母注意到自出生该男孩就"眼球运动差"。双眼视力为6/6,脸向左转并且双眼上睑下垂。在所有注视方位上眼球运动均受限,强制转向试验阳性。两个病例初步诊断均为先天性眼外肌纤维化(congenital fibrosis of extraocularmuscle,CFEOM),后来第一个病例的诊断修订为双侧Duane综合征。虽然Duane综合征和CFEOM都包括在CCDD内,但两种疾病病理不同。CCDD的表现非常多变,然而,治疗往往是有限的,且手术结果不可预测。因此,仍然需要进行大量研究以更深入了解CCDD,改善其治疗和结局。     

The Genetic Basis of Incomitant Strabismus: Consolidation of the Current Knowledge of the Genetic Foundations of Disease

Abstract

In recent years, our understanding of the genetic foundations of incomitant strabismus has grown significantly. Much new understanding has been gleaned since the concept of congenital cranial dysinnervation disorders (CCDDs) was introduced in 2002, and the genetic basis of CCDDs continues to be elucidated. In this review, we aim to provide an update of the genetic and clinical presentation of these disorders. Disorders reviewed include Duane syndrome (DS), HOXA1 and HOXB1 syndromes, Moebius syndrome, congenital fibrosis of the extraocular muscles (CFEOM), and horizontal gaze palsy with progressive scoliosis (HGPPS).