Congenital Cystic Eye
Congenital cystic eye (CCE) is an ophthalmologic condition characterized by an orbital cyst that replaces the eyeball. CCE is caused by a complete or partial failure of invagination of the primary optic vesicle between the 2-mm and the 7-mm stage of embryological development. Patients present in infancy or adolescence with a cystic mass that has replaced the eye. Diagnosis relies on ocular exam, systemic physical exam, ocular imaging, and histopathology of cystic tissue. The gold standard treatment for CCE is excision of the cyst followed by orbital eye implant, and eventual ocular prothesis. CCE cases are best managed by a multidisciplinary team of ophthalmologists, plastic surgeons, pediatricians and neurosurgeons.
Congenital cystic eye. ICD-9 743.03, ICD-10 Q11.0.
HISTORY AND PREVALENCE: Congenital cystic eye (CCE) is an extremely rare orbital and ocular malformation that occurs when an orbital cyst replaces the eyeball.[1,2,3,4,5] The first case of CCE was reported in 1906 by Taylor and Collins in the Ophthalmological Society of the United Kingdom. In 1939, renowned British ophthalmologist Dr. Ida Mann was the first to describe its clinical presentation in detail, establishing the term “anophthalmus with cyst” to describe the cavity lined by neuroglial tissue that is hallmark of CCE.[3,4] Cystic orbital lesions represent 10-30% of all non-thyroid orbital lesions, with CCE being the rarest form of cystic orbital lesion.[4,6] According to the English ophthalmic literature from 1966 to 2022, only 53 cases have been documented that represent CCE.
RISK FACTORS AND PRIMARY PREVENTION: No clear risk factors have been identified or linked to the development of CCE. Moreover, no prevention measures have been identified that reduce the risk of CCE. These include environmental exposures or insults during pregnancy or birth. While no inheritance pattern or genetic mutation for CCE has been identified, one case has been documented in a patient with Turner syndrome (45, X) and one case in a patient with Orbeli syndrome (13q deletion syndrome).[8,9]
AFFECTED PATIENT POPULATIONS:
Patients typically present during infancy with a cystic mass occupying the orbit in place of an eyeball, with associated swelling of the ipsilateral eyelid. However, the presence of a cyst may not be evident initially. In these cases, patients present later in childhood and into early adolescence with absence of eyeball and cystic swelling due to progressive fluid production and accumulation of the proliferating neuroglial tissue that compose the cystic body.[5,6]
DEVELOPMENT OF THE EYE: After the gastrulation stage of embryonic development, the eye primordium, or eye field, originates from the medial anterior neural plate and contains all progenitors of the neural-derived eye structures. The following eye field transcription factors (EFTFs) that are highly conserved among vertebrates are expressed by the cells of the eye field: Pax6, Rax, Six3, and Lhx2.  These EFTFs serve as a regulatory network needed for eye development.  Neural ectoderm transcription factors, OTX2 and SOX2, serve to activate Rax within the eye field, which then upregulates the expression of Pax6, Six3, and Lhx2. Lhx2, in turn, further upregulates the expression of Pax6, Six3, and Rax. When highly expressed, these EFTFs work to delineate the intrinsic and extrinsic pathways that define the optic vesicle along its axes. From there, the optic vesicle goes on to invaginate and form the optic cup that will later become the retina.
Meanwhile, grooves that form along the ventral surface of the optic cup and stalk allow the vessels that would become the central retinal artery and vein to pass through and become entrapped within the optic nerve as the optic cup fuses around them. As for the remaining structures of the eye and its adnexa, neural crest cells contribute to the following: the layers of the cornea, the ciliary body, uveal stroma, melanocytes, sclera, meningeal sheaths, connective tissue of the optic nerve and extraocular muscles, and bones of the orbit. [13,14] Meanwhile, the neuroectoderm yields the retina, posterior iris, and optic nerve, while surface ectoderm yields the lens and the corneal epithelium. Finally, the mesoderm is responsible for the development of the vascular endothelium and extraocular muscles. 
PATHOPHYSIOLOGY: Disruptions to these early stages of eye field differentiation have been reported to yield pathological clinical findings such as anophthalmia, severe bilateral ocular malformation, and microphthalmia. [16,17,18] Based on current literature, however, genetic investigations into the few cases of congenital cystic eye did not unveil any particularly linked genetic mutations responsible for the presentation. [19,20]
CCE is caused by complete or partial failure of invagination of the primary optic vesicle between the 2-mm and the 7-mm stage of embryological development at the 4th week of gestation. [1,2,3,21] While the genetic etiology of CCE remains unknown, some researchers have hypothesized that its etiology is inflammatory-mediated, given the presence of inflammatory cells in the cystic eyeball on histopathology.
The histopathological finding diagnostic of CCE is an irregularly shaped cyst with a connective tissue layer externally and an inner neuroglial tissue layer. On physical exam and imaging studies, there is a lack of ocular structures and surface ectodermal elements, which help differentiate CCE from microphthalmos with a cyst.
CLINICAL PRESENTATION: CCE typically presents as unilateral involvement, although several bilateral presentations have been reported.[19,23,24] Regardless, the most common CCE symptoms that prompt initial presentation are the following: (A) Non-tender, non-pulsatile cystic mass occupying the orbit, with no evidence of globe or ocular structures. (B) Stable or progressive swelling of affected upper and/or lower eyelid, which can cause cosmetic disfigurement. (C) Complete lack of vision from affected eye(s).
MAKING THE DIAGNOSIS: Clinical diagnosis is defined by a work-up that follows three major stages: (A) physical exam of the eye and entire body, (B) imaging of affected eye, and (C) histopathological assessment of cystic tissue. No serum or laboratory testing is utilized or diagnostic for CCE. Only histopathology can be used to confirm the diagnosis, with physical examination and imaging studies helpful in aiding the diagnosis.
(A) Physical Examination Findings:
Physical examination of a patient with CCE begins with thorough ophthalmic examination, followed by a systemic physical examination to identify any non-ocular associations that could put the patient at increased risk for morbidity or mortality.
Starting with gross ophthalmic examination of the orbits, patients will completely lack a globe. Further gross assessment typically reveals cystic mass using eyelid retractors. Upper and lower ipsilateral eyelid bulging is a common finding. Visual acuity and visual field testing are not applicable in assessment of CCE, given complete absence of globe and thus absence of vision-mediating structures.
A systemic physical exam following the initial ophthalmic exam is vital, given the reported ocular and non-ocular associated abnormalities. Common eyelid abnormalities associated with CCE are accessory limbs of the eyelid, skin tags, a notch, and periocular dermal appendages on the same side as the effected eye and colobomatous eyelid defect on the contralateral side. While uncommon, non-ocular findings associated with CCE have been reported. [19,23,25] Common non-ocular findings in CCE are facial clefts, saddle nose deformity, nostril malformations, malformed sphenoid bone, punched-out lesions of the face and scalp, bifid thumb, midbrain deformities, agenesis of corpus callosum, basal encephalocele and microphallus with hydrocele.[5,6,19,23,25] Initial physical examination for associated neurological conditions is vital, but ultimately requires radiological confirmation for diagnosis.
(B) Imaging: Common imaging modalities for work-up of CEE include B-scan ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). B-scan USG is a low-cost, bedside tool that can be implemented in an outpatient ophthalmology clinic to collect valuable data relating to the patient’s cyst, including size and morphology of the cyst, absence or presence of eyeball and an optic stalk-like findings. CT and MRI can be used to visualize the cyst in the orbital cavity, and collect data that can differentiate it from microphthalmic eye.
(C) Histopathology: Histopathology testing involves running analysis on a tissue sample from the cyst. The hallmark histopathological findings of CCE are (1) a lack of normal ocular structures (i.e. cornea, lens, retinal pigment epithelium) and (2) the presence of an intraocular cyst lined by neuroglial tissue.[1,5] Fibrous connective tissue typically surrounds the wall of the cyst. Fluid produced by neuroglial tissue can cause progressive growth of cyst.
DIFFERENTIAL DIAGNOSES: CEE should be differentiated from a more common disorder, microphthalmos with cyst, which is caused by arrests in closure of the fetal fissure in the 7-mm to 14-mm stages.[1,5] Differential diagnosis also includes epithelial cyst, orbital cystic teratoma, heterotopic brain tissue, meningoencephalocele, optic nerve meningocele and lymphangioma.[1,7,8]
MANAGEMENT OF CCE: The goals of treatment for CCE are aimed at comfort and cosmetic rehabilitation, due to progressive accumulation of fluid within the cyst and worsening cosmetic deforming of orbit and eyelid(s).
For both symptomatic treatment of fluid accumulation and cosmetic deformity, surgical intervention is the preferred and prioritized treatment approach. Medical therapy for patients with CCE does not play a role in the long-term management of symptoms and cosmetic deformities associated with CCE. The only significant complication of surgical treatment is rare cerebrospinal fluid leak, which can be avoided by pre-operatively screening the patient for the presence of a meningocele.
One cited alternative to treatment is repeated aspiration of the cyst. An aspiration approach is not curative and consequently requires repeated procedures, but prevents rare cerebrospinal fluid leak associated with surgical treatment.[4,7]
Steps of Surgical Management of CCE:
Typical surgical management involves the following steps in the following order: (1) Completely excise the cyst while preserving the eyelids.
(2) Inserting an orbital implant immediately following excisional surgery. (3) Placing an orbital conformer. (4) Placing an orbital prosthesis for long-term replacement of orbital volume and fulfillment of desired cosmetic needs. [1,5] The surgical intervention is aimed at preventing further fluid accumulation within the cyst by removing the entire mass, and replacing it with an ocular prosthetic that will ameliorate the ocular deformity the cyst has caused. Surgical treatment is not aimed at regenerating ocular structures within the orbit or restoring vision.
Ocular prostheses: Various uses of ocular prosthesis for replacement of orbital volume and cosmetic need have been cited. This includes use of spherical silicone orbital implants, bioceramic implants, and general orbital implants with conformers.[1,5,7]
Post-Operative Follow Up:
The major focus for surgical follow-up addresses possible clinical anophthalmia that persists after surgical excision of cyst. In these cases, patients may benefit from insertion of an orbital expander before a long-term ocular prosthesis is placed.
Given the rare risk for cerebrospinal fluid leak due to surgical excision treatment, follow-up for systemic symptoms post-operatively is recommended.
No cases have reported need for screening biopsy for metaplasia or malignancy, thus no follow-up with oncology services has been recommended as part of the clinical course.
Post-Surgical Complications: No life-threatening complications during or after surgical intervention for CCE have been reported in the English literature. Several researchers have noted clinical anophthalmia that has persisted following initial surgery, which was monitored with close follow-up.
PROGNOSIS: Once treated with surgical intervention, patients with CCE have noted to have favorable outcomes regarding symptom control and cosmetic satisfaction.
CONCLUDING REMARKS: Prompt diagnosis for patients with CCE is recommended given functional and cosmetic benefits early intervention can provide to patients and their families. Several cases report the discomfort and impairment patients can experience with delayed diagnoses due to progressive cystic fluid accumulation. Greater understanding regarding disease process and surgical management can allow ophthalmologists to initiate care and recruit a multidisciplinary team to minimize symptom severity and cosmetic impact patients can experience.
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