Spheroidal degeneration (climatic droplet keratopathy, Bietti’s band-shaped nodular dystrophy, chronic actinic keratopathy or Labrador keratopathy) is a nonhereditary acquired degenerative condition of the eye. Spheroidal degeneration is characterised by sub-epithelial accumulation of spherical opalescent droplets that coalesce to form bands or nodules with elevated corneal epithelium. The degenerative process is mainly seen in the inter-palpebral part of the cornea.
Spheroidal degeneration may have a distribution in the cornea similar to that of band shaped keratopathy, and it also occurs in the conjunctiva.
Bietti et al in 1955, made his initial clinical observation of an unusual degenerative corneal condition characterised by deposition of yellowish globules in the superficial layers of the cornea. Bietti’s description of corneal degeneration, although it has been described by various names, is most commonly referred to as spheroidal degeneration. Fraunfelder and colleagues divided this condition into three basic forms viz.
Frequency of spheroidal degeneration varies with geographic location and increases with age. It occurs most often in areas that have high sunlight exposure and sunlight reflection off snow or sand, in combination with wind-driven corneal damage by snow and sand. Probably it is caused due to micro-trauma from wind and sand or by solar radiations. This degenerative disease occurs due to excessive exposure to ultraviolet (UV) light. Males are more prone to develop spheroidal degeneration, especially those working outdoors, as compared to females.
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Fraunfelder FT, Hanna C. Spheroidal degeneration of cornea and conjunctiva. 3: Incidence, classification and aetiology. Am J Ophthalmol 1973; 76: 41- 50.
Hida T, Akiya S, Kigasawa K, Hosoda Y. Familial band shaped degeneration of the cornea. Br J Ophthalmol 1986; 70: 347- 353.
Kaji Y, Nagai R, Amano S, et al. Advanced glycation end product deposits in climatic droplet keratopathy. Br J Ophthalmol. 2007; 91(1): 85- 88.
Menegay M, Lee D, Tabbara KF, et al. Proteomic analysis of climatic keratopathy droplets. Invest Ophthalmol Iis Sci. 2008; 49(7): 2829- 2837.
Holopainen JM, Serra HM, Sánchez MC, et al. Altered expression of matrix metalloproteinases and their tissue inhibitors as possible contributors to corneal droplet formation in climatic droplet keratopathy. Acta Ophthalmol. 2011; 89(6): 569- 574.
Spheroidal degeneration is asymptomatic in majority of the cases. Visual acuity may be affected if the deposits extend towards the center of the cornea, thereby, blocking the visual axis.
Ocular (eye) symptoms in advanced cases may be:
The exact cause of spheroidal degeneration is not known. It is hypothesized to be due to:
- Traumatic corneal scars.
- Herpetic keratitis.
- Chronic corneal oedema.
- Lattice corneal dystrophy.
Although no definitive gene defect or inheritance pattern is established, it is thought that genetic predisposition to this condition, may play a role in its development along with environmental factors. Familial occurrence is very rare.
Although spheroidal degeneration is classically associated with ageing and ultraviolet exposure, it has also been described in childhood with much less frequency.
Diagnosis depends upon:
Since spheroidal degeneration is associated with UV light exposure, patients may have other systemic findings of exposure to the elements such as history of skin cancer, pigmentary changes, or other actinic disorders.
Examination should be carried out under slit lamp (bio-microscopy) by an eye specialist.
Spheroidal degeneration is characterised by:
A clear zone may exist early on between peripheral edge of lesion and limbus, but is lost later on.
Type I or Primary corneal type: Primary type is characterised by corneal lesions that occur without other ocular or corneal disorders. The lesions are usually symmetrical and bilateral. In the primary form, degeneration begins peripherally and advances toward the center in the palpebral fissure area. As the condition advances, the droplets become larger and more nodular and lift the central corneal epithelium. The conjunctiva may be involved in patients with primary degeneration, especially nasally.
There are three grades of severity of primary form:
Alternative grading of the condition depending on the severity is:
Type II or Secondary corneal type: Secondary corneal type is associated with other ocular disorders, corneal vascularisation and scarring. Secondary corneal type may occur along the edge of corneal scars.
Secondary corneal type is characterised by the presence of corneal scars and vascularisation with large and small yellow globules invading the epithelium, basement membrane, Bowman’s layer and superficial stroma. There may be scarring within the adjacent layers of the cornea. The location of the globules depends on the degree of Bowman’s layer disruption and the location of the corneal scars. Scars may be peripheral or central. The deposition is not always in a band-shaped configuration and can occupy the areas of the corneal scar. The disease may be either unilateral or bilateral. In cases with unilateral vascularized corneal scars, the degeneration occurs in the eye with corneal scars and may not occur in the other eye with clear cornea.
Recurrence of degeneration may occur in patients undergoing penetrating keratoplasty. Globular aggregates may occur in the corneal graft and usually in the center of the graft.
Type III or Conjunctival type: Conjunctival type may also show similar deposits on conjunctiva as are seen in corneal type. The conjunctival lesions may have engorged blood vessels.
Histopathology and Electron microscopy:
Primary spheroidal degeneration:
Staining for fat with oil red O and for calcium with Von Kossa stain is usually negative. Von Kossa stain may show positive staining for calcium in any associated calcification, but is rare.
Secondary spheroidal degeneration:
Haematoxylin and Eosin (H&E) stained sections of cornea: Haematoxylin and Eosin (H&E) stained sections of cornea show evidence of corneal scarring and vascularisation with homogeneous sub-epithelial globular deposits of variable sizes. Spherules may reach the superficial and even deeper layers of the stroma.
Electron microscopic study:
Electron microscopic study of the globules in patients with spheroidal degeneration reveals aggregates of extracellular electron dense round to oval globules among the collagen fibrils of the superficial stroma. The globules are of different sizes and cause disruption of Bowman’s layer and the basement membrane of the epithelium.
Proteomic analysis and Pathogenesis:
Approximately 105 different proteins have been identified using proteomic analysis. Primary degeneration shows irregular collagen from abnormal fibroblasts. Secondary degeneration shows protein deposits from the interaction of UV light and plasma proteins (diffusing through the cornea from limbal vessels under normal conditions).
Spheroidal degeneration may be caused by an aggregation of advanced glycation end products (AGEs) and modified proteins resulting from UV radiation and ageing.
Corneal globular deposits show protein deposits having amino acids such as tryptophan, tyrosine, cysteine and cystine, which are not normally found in the corneal stroma.
Matrix metalloproteinases (MMPs) and Tissue inhibitors of metalloproteinases (TIMPs): One study detected an up-regulation and increase in the level of MMP-9 and MMP-2 in the tear fluids in patients with spheroidal degeneration. TIMPs (inhibitors of MMP), where found as part of complexes in the TIMP-1, were significantly lower in patients. This study demonstrated that MMP-2 and MMP-9 tear levels were significantly elevated and may have resulted in delay in corneal re-epithelialisation and corneal scarring. The reduced expression of TIMP-1 in spheroidal degeneration, such as deficient anti-proteolytic shield, which may lead to rendering the corneas of patients vulnerable to enhanced MMP activity.
Annexin and Glyceraldehyde 3-phosphate dehydrogenase (GAPDH): Annexin and Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) are the proteins identified in patients with spheroidal degeneration using monoclonal antibodies. Annexin is found in the periphery but not in the center of cornea, while in spheroidal degeneration, it is found in abundance in the central portion of the cornea. Annexin and GAPDH are known for membrane fusion and allows cells to adhere to the collagen. The increased accumulation of Annexin and GAPDH in spheroidal degeneration as compared to normal cornea requires further investigation.
Spheroidal degeneration may be differentiated from:
There do not appear to be other corneal conditions that resemble spheroidal degeneration of the cornea. However, conditions which may be considered are:
Management should be carried out under medical supervision.
The majority of patients of spheroidal degeneration are asymptomatic.
Management of patients with spheroidal degeneration is mainly symptomatic. There is no specific treatment available for the resolution of spherules.
Most of the time, spheroidal degeneration pathology is located nasally and temporally, and observation alone is required.
General medical therapy:
Patients with corneal scarring and globules involving anterior central part of cornea compromising vision, or causing pain, may require surgical intervention.
The spheroidal degeneration recurs after conjunctival resection.
Long standing keratopathy may lead to visual impairment caused by involvement of visual axis due to secondary scarring.
Spheroidal degeneration may be prevented by: