Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
2000-03-03
2002-08-20
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
active
06438398
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a diagnostic kit for measuring tear clearance and a method of measuring tear clearance from a mammalian eye.
2. Description of Related Art
Ocular irritation is one of the most common complaints of patients presenting to the eye care practitioners. The exact mechanism by which eye irritation symptoms develop has been not established. Most patients presenting with ocular irritation have a reduced tear break-up time indicating the presence of tear film instability. This may be due to decreased aqueous tear production, meibomian gland disease that leads to lipid tear deficiency or undefined causes. Pathological changes of the meibomian glands are known to be present in many asymptomatic, elderly patients. Accordingly, the exact pathogenic role of these changes remains unclear.
The National Eye Institute/Industry Workshop on dry eye proposed a classification scheme that stratified dry eye patients into those with aqueous tear deficiency due to lacrimal gland disease or dysfunction and those with evaporative tear loss. Development of this classification scheme represented an important step in standardizing the diagnosis and classification of dry eye. While some patients present with clearly defined dry eye conditions such as Sjögren's syndrome aqueous tear deficiency or meibomian gland disease following Accutane™ therapy, many patients present with a combination of clinical problems contributing to their tear film deficiency (e.g. aqueous tear deficiency, meibomian gland disease, incomplete blink, lid laxity and conjunctivochalasis).
Pflugfelder et al. previously observed that delayed clearance of fluorescein dye instilled into the tear film is frequently found in patients complaining of ocular irritation, even in those with normal aqueous tear production (See Pflugfelder S C, Tseng S C G, Sanabria O, et al.
Cornea.
1998; 17:38-56). Furthermore, as tear clearance decreases, the concentration of pathological factors in the tear film capable of inciting inflammation, for example, Il-1&agr;, and tissue destruction, for example, matrix metalloproteinase (MMP-9), increases. These findings suggest that delayed tear clearance leads to chronic ocular surface inflammation, which in turn could sensitize the nerves that are responsible for the irritation symptoms.
A number of different techniques are known in the art for measuring the clearance or turnover of fluorescein instilled into the tears, including direct fluorometric measurement of fluorescein in the pre-corneal tear film or the inferior tear meniscus (See Benedetto D A, Clinch T E, Laibson P R.
Arch Ophthalmol
1984; 102,410-2). A more practical method is to visually compare the fluorescein concentration in tear fluid collected on Schirmer test strips to photographic standards (See Nava A, Barton K, Monroy D C, Pflugfelder S C.
Cornea
1997; 16:430-438). This Schirmer strip method has been reported to have excellent correlation with in vivo fluorometric measurement of basal tear turnover and tear flow. Nevertheless, this semiquantitative technique is not optimal for correlating tear clearance with the concentration of pathogenic factors in the tear fluid (e.g. IL-1) or for monitoring small changes in tear clearance that may occur in therapeutic clinical trials. Previous studies evaluating patients complaining of ocular irritation reported poor correlation between the severity of irritation symptoms and the Schirmer test (either the Schirmer 1 or the basic secretion test) and only moderate correlation with corneal or ocular surface dye staining (See Afonso A A, Monroy D, Stern M E, Feuer W J, Tseng S C, Pflugfelder S C.
Ophthalmology
1999;4:803-810). This may be due in part to the fact that symptomatic patients with meibomian gland disease often have normal or only minimally reduced aqueous tear production. This suggests that factors other than aqueous tear deficiency play a role in the pathogenesis of dry eye. Afonso and colleagues have observed better tear fluorescein clearance correlation with ocular irritation symptoms than with the Schirmer 1 test (See Afonso et al., supra). Jones and associates reported a technique of obtaining tear fluid from the inferior meniscus with a polyester rod. These low protein-binding rods have been used to obtain well-mixed tear fluid from the inferior tear meniscus for measuring tear cytokine concentrations (See Nava et al., supra). In dry eye patients, the pre-comeal tear layer may break-up rapidly and overlies a diseased corneal epithelium that is excessively permeable to fluorescein, making it difficult to determine whether fluorescein readings are from tear fluid or corneal tissue.
Regardless of the underlying cause, patients with tear film deficiencies complain of irritation symptoms and often show ocular surface epithelial, eyelid marginal and meibomian gland diseases. Even though the cause of these problems has not been established, better means of detecting such ocular abnormalities affecting tear flow are needed.
SUMMARY OF THE INVENTION
The inventive technique eliminates well-known problems associated with assessing fluorescein concentration in the precorneal tear film in vivo.
An embodiment of the invention provides a method of measuring tear clearance from a mammalian eye, comprising:
(a) instilling an effective amount fluorescein dye solution into the inferior conjunctival sac of an eye;
(b) incubating the fluorescein dye solution in the conjunctival sac for a period of time sufficient to allow the dye to mix with tear fluid;
(c) collecting a sample of tear fluid from the eye;
(d) determining the volume of tear fluid collected; and
(e) measuring the amount of fluorescence present in the tear fluid.
Another embodiment of the invention provides for a process of detecting at least one ocular abnormality affecting tear flow, said process comprising:
(a) instilling an effective amount fluorescein dye solution into the inferior conjunctival sac of an eye;
(b) incubating the fluorescein dye solution in the conjunctival sac for a period of time sufficient to allow the dye to mix with tear fluid;
(c) collecting a sample of tear fluid from the eye;
(d) determining the volume of tear fluid collected; and
(e) measuring the amount of fluorescence present in the tear fluid,
wherein preferably said at least one ocular abnormality comprises a member selected from the group consisting of meibomian gland disease, conjunctivochalasis, lid laxity, tear outflow obstruction and blink abnormalities.
Another preferred embodiment is a process of detecting at least one ocular abnormality affecting tear flow, said process comprising:
(a) instilling an effective amount of fluorescein dye solution into the conjunctival sac of an eye;
(b) incubating the fluorescein dye solution in the conjunctival sac for a period of time sufficient to allow the dye to mix with tear fluid;
(c) examining the eye surface with a biomicroscope to observe corneal fluorescein staining in each of four corneal quadrants;
(e) measuring the amount of fluorescence observed to obtain a corneal fluorescein staining score; and
(f) correlating the corneal fluorescein staining score with results from a Fluorescein Clearance Test (FCT) corrected according to correction formula I:
FCT
(corrected)=
FCT
+Schirmer score
y
I
wherein coefficient y is calculated from a corresponding area under the Receiver Operating Characteristic (ROC) curve, and the Schirmer score is obtained using Schirmer test strips placed over an eyelid margin.
Still another embodiment of the invention provides for a diagnostic kit for measuring tear clearance. The kit may comprise an indicator that may be directly measured in the inferior tear meniscus of the eye. The kit may contain, for example, a fluorescein dye as an indicator.
Yet another embodiment of the invention provides for a diagnostic kit for measuring tear clearance comprising:
(a) a fluorescein dye solution suitable for introduction into the inferior conjunctival sac of an eye;
(b) optionally, a substrate
Afonso Adolfo
Macri Angelo
Pflugfelder Stephen C.
Tseng Scheffer C. G.
McCrosky David
Pillsbury & Winthrop LLP
The University of Miami
Winakur Eric F.
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