Is There A Significant Relationship Of Central Corneal Thickness To Glaucoma?
Written by Larry J Alexander OD FAAO Sunday, 24 March 2013
Certainly, central corneal thickness (CCT) and peripheral corneal characteristics impact significantly on outcomes in all refractive surgery including premium intraocular lens implants. Likewise the corneal thickness relates very strongly to the outcomes in corneal replacement procedures. A lot of time is spent in the clinical work up of all surgical patients to ensure the maximal possible outcome. Clinical experience and research supports this hypothesis. But then what is the generally accepted attitude toward the importance of central corneal thickness and glaucoma?
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The often quoted definition of glaucoma, “Progressive optic neuropathy with characteristic structural damage that is frequently accompanied by a specific type of vision field defect”1-2 does NOT necessarily address central corneal thickness. Is there an important and relevant relationship between thin corneas and glaucoma? As a clinician must you make a correction to your applanation tonometry for corneal thickness? Could that relationship perhaps be a manifestation of the collagen composition of the eye and it’s alteration in these cases. Does a weakened collagen network lend to the development of a “long eye” and a “thin cornea?” Would that logic then transfer to include the integrity of the lamina cribrosa making it more susceptible to pressure perfusion issues? Let’s take a look at glaucoma as it relates to corneal thickness. This paper was developed to assess these issues and develop a reasonable approach to the clinical application.
ASSESSMENT OF THE STUDIES
The Ocular Hypertension Treatment Study (OHTS) brought to the forefront the importance of central corneal thickness in regard to the progression of ocular hypertension. Central corneal thickness was found to be a powerful predictor for the development of POAG. 3-4 The European Glaucoma Prevention Study (EGPS) results corroborated the findings of the Ocular Hypertension Treatment Study and supported the need for a thorough evaluation of patients with ocular hypertension including corneal thickness considerations. 5 As early as 1999 it was suggested that patients with low-tension glaucoma may have thinner corneas than patients with COAG and healthy subjects. The supposition was that this finding resulted in underestimation of their IOP. The conclusion was that corneal thickness should be taken into account when managing these patients to avoid under-treatment. 6 Likewise it appears that other factors may be related to central corneal thickness. Another study projected that people with thinner corneas, which purportedly slightly underestimate the true IOP, may also have larger and more deformable optic discs.7 Other results also indicate a relationship to the genetic model for glaucoma. The authors report that PITX2/Pitx2 mutation results in reduced corneal thickness and provides the first example of reduced CCT in a genetic subtype of glaucoma. 8 Another more recent study corroborated the relationship of corneal thickness to congenital glaucoma. This study showed that patients with congenital glaucoma have lower central corneal thickness than normal subjects. 9 Alpeza-Dunato et al report “Patients with pseudoexfoliative glaucoma and also patients with open angle glaucoma had significantly lower values of central cornea thickness compared with normal subjects in control group.” 10
One report boldly suggested that variations of central corneal thickness lead to mis-estimation of intraocular pressure with Goldmann applanation tonometry. The report also posited that the under-estimation of intraocular pressure may lead to under-diagnosis and consequently under-treatment of glaucoma. 11 Another work suggested the association of thin corneas also includes systemic disorders. They found “CCT is associated with higher IOP, longer axial length, and greater radius of corneal curvature, as well as higher BMI, metabolic syndrome, and CKD.” 12
Numerous studies correlate the CCT to the issue of risk of glaucoma and hint that there should be some correction of applanation IOP for corneal thickness. The revelation of the relationship of CCT to glaucoma diagnosis and progression launched the pachymetry industry in eyecare and became a career for a number of research persons. The following studies add to the indications that CCT is a definite risk for progression in glaucoma.
Implications of CCT Assessment
It has been suggested that there is strong and consistent level I and level II evidence that CCT is a risk factor for progression from ocular hypertension to POAG. The conclusion of one study was that CCT measurement should be included in the examination of all patients with ocular hypertension. 13 Recent work suggested that CCT correlated with disease (glaucoma) severity: the more advanced the disease, the thinner the cornea. 14 Patwardhan et al reported that CCT and adjusted IOP measurement can influence glaucoma management in a clinical context. They added that CCT attributed risk and hence aids patient management decisions. 15
All of the OHTS- related studies fostered even more tangential applications of the central corneal thickness readings. A scoring system was developed to indicate risk with central corneal thickness under 500 microns carrying three times the risk as a central corneal thickness over 500 microns (Corneal central thickness:<500 micro m (3X),>500 micro m (0X); ) 16 It has also been suggested that central corneal thickness must be considered when establishing a treatment goal. The report went so far as to say that central corneal thickness is a risk factor for development of visual field loss among patients diagnosed with pre-perimetric glaucomatous optic neuropathy (GON). They posited that it is important to consider CCT when establishing target intraocular pressure of patients with GON. 17 In the Kim case-control patient population, visual field progression in patients with open-angle glaucoma was significantly associated with thinner CCT. 18 One other study suggested that worse visual field changes tend to occur in the eye with the thinner cornea. 19 It also appears that this correlation carries over to angle-closure variations as well. Patients with chronic primary angle-closure glaucoma (CPACG) with a thinner cornea are at greater risk for visual field progression even if they maintain a low IOP after treatment. 20 One study showed that based on the pachymetry values for central corneal thickness, patients with thinner corneas more often progressed to glaucoma (P<0.0001). 21 Guedes reported that CCT <520 microns was a significant indicator of the presence of glaucoma. 22 In yet another report it was found that “Ocular hypertensives with CCT < or =555 micron may represent patients who have either very early undetected glaucoma or an inherent structural predisposition to glaucomatous damage.” This was related to the fact that “RNFL in ocular hypertensives with CCT < or =555 microns was significantly thinner than in those with thick corneas…” 23 In another study it was reported that for patients with thinner corneas, pressure reduction may potentially be of even greater importance to help avoid glaucomatous progression. 24 Coleman summarized that “Prognostic factors for the progression of open-angle glaucoma in individuals who already have the condition include older age at baseline, higher IOP at baseline, and thinner central corneal thickness.” 25
There were also suggestions in the literature that the central corneal thickness measurements may be associated with increased vascular risk factors in glaucoma. Central corneal thickness in normal tension glaucoma (NTG) was significantly lower than in POAG and corneas were thinner in NTG patients with vascular risk factors than in those without. Vascular risk factors were significantly more common in patients with thin corneas. 26 A 2010 report also related the fact that central retinal vein occlusion fellow eyes have thinner CCT than controls hinting the relationship to laminar thinning. 27 A recent report relates optic nerve head morphology to branch retinal vein pathogenesis. 28 In an attempt to create a new “nomogram” there were even attempts to create a pressure-to-cornea vascular index (PCVI) to relate progression of NTG visual field loss. 29
All of the research work then spawned numerous studies to create nomograms to actually correct for IOP measurements based on CCT. These reports attempt to manipulate the importance of central corneal thickness measurements. Conclusions included that the IOP corrected by CCT may change or influence a decision to initiate or modify treatment. CCT measurement has also proved to be crucial in patients who have undergone laser refractive surgery. 30 One more caveat reported was the importance of consistency and repeatability regarding thickness measurements. In 2005 it was reported that the measurements of CCT taken within a clinical setting by a trained observer may show significant variability. For CCT to become a valuable addition to the assessment of glaucoma suspects, more than one reading may be required. Failure to do so may result in misclassification and, thus, an inaccurate assignment of risk. 31
Conflicting Reports Regarding Significance
There are, however, conflicting reports regarding the association of central corneal thickness and progression in glaucoma. In one cohort of patients with established glaucoma, CCT was not a useful index in the risk assessment of visual field and optic disc progression. 32 In another it was reported that “Progression of glaucomatous optic nerve neuropathy was independent of central corneal thickness, suggesting that central corneal thickness may not play a major role in the pathogenesis of progressive glaucomatous optic nerve damage.” 33 In yet another it is reported that patients with thinner corneas initially present with a greater visual field defect, indicating that thin corneas may contribute to advanced glaucomatous damage at the time of diagnosis. However, CCT does not seem to be a significant risk factor for progression of the disease. 34 Cao concluded that no relationship was found between CCT and VF loss in treated patients with primary open-angle glaucoma or normal-tension glaucoma with asymmetrical CCT. Specifically, the thin eye did not have the more advanced VF loss or more rapid VF progression. 35 To add to the confusion, an article also published in 2012 concluded that “Higher mean IOP, thinner central corneal thickness (CCT), and presence of progressive optic disc damage were associated with faster rates of MD change.” 36 Mansouri also reported that there is a weak relationship between corneal biomechanical parameters and measures of structural and functional damage in glaucoma. 37
In the arena of genetics, reports indicate that when evaluating the genetics of the situation there no evidence is reported in the studies of a relationship of CCT to POAG. 38 Charlesworth concluded “CCT did not correlate genetically with disease and is unlikely to be a useful surrogate endophenotype for POAG.” 39 Yet a 2010 Dimasi study looking at Osteogenesis imperfecta implicated type 1 callagen in the determination of CCT providing the first evidence of a trait loci that influences CCT. They posited “potential implications for investigating genes involved in glaucoma pathogenesis, a common eye disease in which the severity and progression is influenced by CCT.” 40 Interestingly enough it has been proposed that patients with thinner corneas have larger and more deformable optic discs. 7 Contrast that study with the statement that “The CCT is NOT a surrogate marker for abnormal scleral or laminar thickness as an independent cause of increased glaucoma risk” 41 The issue of the relationship of genetics to CCT and thus to glaucoma and thus to underlying collagen disorders is suggestive but far from resolved.
CONCLUSION-AKA THE “TAKE HOME”
To summarize all of this you must ask the question “what does this mean to the practitioner?” Must a nomogram be applied to correct for corneal thickness to IOP measurements? Is pachymetry important? Is a thin cornea a risk indicator for glaucoma? The issue suffers from analysis paralysis with no definitive guidelines. A number of careers and an entire industry has been built on the issue of CCT and glaucoma. However, one cannot ignore that the Early Manifest Glaucoma Trial (EMTG) with an eleven year follow-up stated that, “CCT was a significant predictive factor for glaucoma progression in patients with higher baseline IOP but not in those with lower baseline IOP.” 42-43 A more recent report states “CCT correlated with disease severity: the more advanced the disease, the thinner the cornea.” 14 Herndon et al point to the fact that CCT is a powerful clinical factor in the determination of the severity of glaucoma at the initial evaluation. 44 In 2013 Viswanathan again pointed to the importance of CCT and the correlation with damage at presentation. 45
To put the issue in perspective, tonometry is only a small part of the diagnosis of glaucoma. This fact has been demonstrated in numerous studies and in clinical practice. Tonometry is a relative number and should be viewed as such especially when considering time of day, diet, presence of a necktie in males, and a number of other issues. Tonometry is somewhat instrument dependent, realizing that the same instrument should be used in following patient’s IOP. Application of any nomogram must take all of these issues into account. The following study in Ophthalmology 2012 summarized the relative importance of correcting IOP for CCT. The authors used the Pascal Dynamic Contour Tonometer as the reference standard. The full conclusion of the article is “Adjusting IOP using CCT-based formulae resulted in poorer agreement with Pascal Dynamic Contour Tonometer (PDCT) IOP when compared with unadjusted Goldmann Applanation Tonometry (G AT) IOP. If PDCT is the closest measure we have to intracameral IOP, there is a risk of creating clinically significant error after adjustment of GAT IOP with CCT-based correction formulae, especially in thicker corneas. This study suggests that although CCT may be useful in population analyses, CCT-based correction formulae should not be applied to individuals.” 46
Hundreds of studies have been generated regarding the topic of CCT and glaucoma. The variations of the studies indicate a pretty common theme. The conclusion is that measurements of central corneal thickness are important to the differential diagnosis and management of glaucoma and hint at the suggestion that they may be predictive of the possibility of progression. This measurement is especially critical at the first visit prior to initiating therapy and there is a relationship to severity at presentation. One study indicates that 555 microns is the cutoff while another states that 520 microns is the cutoff for concern with CCT and predictability of glaucoma. Should a patient have had LASIK, the only hope of establishing a relationship is recovery of the original CCT from the LASIK pre-operative work up. It should also be noted that a thin CCT has a relationship to the development of retinal vascular disease but the totality of the significance is yet to be determined. A general statement may be condensed to the fact that the thinner the CCT the more the positive predictive value should push the diagnosis toward glaucoma and possibly toward the progression of glaucoma. To say more than that would dilute the importance of all of the other factors in glaucoma diagnosis and management.
CCT is a critical component of the glaucoma work up but has to be put into context with the following risk factors:
- Patients who are offspring of patients who were identified with glaucoma
- Patients with siblings with glaucoma
- Patients with axial length over 25 mm
- Patients with myopia over 5 diopters—Be on the alert for normotensive glaucoma as well
- Patients with high hyperopia-Narrow Angle
- Ethnicity considerations
- History of ocular trauma
- Patients who are known steroid responders
- Patients who are obese-Inflammation
- Patients who are smokers
- Patients with erectile dysfunction-Vascular Flow
- Patients with dementia
- Patients with sleep apnea and sleep deprivation-Vascular Flow and Inflammation
There is definitely a genetic link to glaucoma. There is probably some sort of genetic link to collagen and perhaps this transfers over to the overall collagen health of the eye including the lamina cribrosa. It also appears that the application of correction nomograms is of minimal use in the diagnosis and management of glaucoma assuming that the same type of IOP testing device is used for each follow-up measurement and timing of the follow-up is consistent with the concept of diurnal variation. The RAND Study Group chose age, life expectancy, intraocular pressure (IOP), central corneal thickness, cup-to-disc ratio, disc size, and family history as the variables to consider when deciding whether to treat glaucoma suspects. 47
It is also important to realize that for patients with thinner corneas, pressure reduction may potentially be of even greater importance to help avoid glaucomatous progression. 48
In summary the glaucoma diagnosis and management algorithm must include but not be limited to all of the following components:
Considerations for Diagnosis and Managemen
- For diagnosis after risk assessment
- First and Foremost…ASSESS ALL ASPECTS OF THE PATIENT HISTORY AND BEHAVIOR
- Assess and photograph optic nerve
- Assess RNFL
- Assess angle measurement(OCT) and debris in angle(Gonioscopy)
- Perform pachymetry..remember also that thicker corneas occur in diabetes 49
- There is no need to apply a nomogram to correct for IOP and CCT.
- Assess corneal health…Corneal dystrophy and Lasik will give false CCT
- Rely on newer technologies such as Ganglion Cell Complex assessment that is less dependent on optic nerve head architecture and easier to acquire because of fixation advantages.
- Perform threshold perimetry
- Recheck extremes for accuracy
- Consider serial tonometry
- For treatment
- Realize that the patient with thinner corneas will be potentially more difficult to manage with therapeutic intervention and will be more difficult to follow because of testing issues.
- Do not use Carbonic Anhydrase Inhibitors in Fuchs dystrophy. Also remember that glaucoma occurs more often in eyes with Fuchs compared to unaffected eyes.50
Konan Cellchek endothelial cell count
- Use the same type of tonometer for follow-up and try to perform at the same time during the day
HOWEVER REMEMBER THAT THE THINNER THE CCT, THE MORE LIKELY GLAUCOMA AND THE MORE LIKELY THE PATIENT WILL EXPERIENCE MORE RAPID PROGRESSION
CCT IS A MARKER FOR GLAUCOMA
- Measure The Angle And Get Pachymetry On All Glaucoma And Glaucoma Suspects
- Macular Ganglion Cell Loss In Ocular Disorders
- SDOCT Imaging Of The Anterior Chamber And Cornea
- The Importance Of SDOCT In Differential Diagnosis
About the Author(s)
Dr. Alexander (1948-2016) was a 1971 graduate of Indiana University School of Optometry. He served in the US Navy then served as a Professor at the University of Alabama Birmingham School of Optometry. Larry contributed to a number of chapters in textbooks and has published three editions of Primary Care of the Posterior Segment, as well as contributed to the professional literature. He also lectured extensively in the area of ocular and systemic disease. His areas of special interest included dysfunctional tear syndrome, glaucoma and macular degeneration. His lessons are the basis for this site and he will be dearly missed.