DIABETES MELLITUS AND GLAUCOMA

 INTRODUCTION:

A number of studies have analyzed the association of diabetes mellitus with glaucoma. It is assumed that low ocular blood flow and other pathophysiological abnormalities such as damaged microvasculature and reduced nutritional supply to the retinal ganglion cells (RGC), seen in diabetics, would contribute to the development of glaucoma. Others have suggested that increased surveillance of diabetics in hospitals leads to higher chances of such individuals being detected with glaucoma. Since the prevalence rates of glaucoma increase with age, therefore increased healthcare contact could be responsible for the diagnosis of such co-morbidities. However, no clear association between the two conditions has been found based on experimental, clinical and population-based studies.

This post debates the various studies in favor and against such a relationship. 

STUDIES SHOWING POSITIVE ASSOCIATION:

A number of questions arise with respect to the possible association of diabetes and glaucoma. Do patients with diabetes have a greater risk of developing glaucoma? Is glaucoma progression faster and more severe in patients with diabetic glaucoma? If diabetes increases risk for glaucoma, what is the etiology of this increased risk?

Let us take a look at some studies showing evidence of such a relationship.

Experimental studies in the streptozotocin-induced diabetic mouse and rat model have demonstrated RGC loss as well as abnormal morphology and increased numbers of dendritic terminals in the surviving ganglion cells after 3 months. Also, large and medium-type RGCs show reduced retrograde axoplasmic flow suggestive a positive link between increased blood glucose and glaucoma. Elisaf et al studied metabolic abnormalities amongst patients with known POAG and showed that elevated glucose as well as uric acid levels were significantly higher as compared to a matched control group.

Oh et al have reported insulin resistance in patients with the metabolic syndrome was associated with elevated IOP, and that mean IOP increased linearly with the presence of increasing numbers of components for the metabolic syndrome.

Optic disc hemorrhages are frequently seen in primary open angle glaucoma (POAG), with a hazard ratio of 4.4 as compared to nondiabetics.

The prevalence of POAG appears to be higher in the diabetic population by a factor of about 2 in the majority of population-based surveys. (Shields)

In the Latino cohort of the Los Angeles Latino Eye Study, presence of type 2 diabetes and a longer duration of diabetes were independently associated with an increased risk for POAG. The study also reported that those with type 2 diabetes mellitus, defined as having diabetes after the age of 30, the prevalence of glaucoma was 40% higher than those without type 2 diabetes.

In another recent prospective analysis of a cohort of women over 40 years of age from the Nurses’ Health Study observed between 1980 and 2000, Pasquale et al found that type 2 diabetes mellitus was positively associated with development of POAG as confirmed by record review with a relative rate ratio of 1.82.

The Ocular Hypertension Treatment Study (OHTS) initially showed that having diabetes, in fact, was surprisingly protective of the development of glaucoma. However, a follow-up study determined that a history of diabetes mellitus was not statistically significantly predictive for the development of POAG and failed to support the original conclusion that diabetes was protective of glaucoma in patients with ocular hypertension.

A smaller cohort of ocular hypertensives from the Diagnostic Innovations in Glaucoma Study yielded similar hazard ratios as in the OHTS analysis for all reported risk factors for progression, except that diabetics who progressed to glaucoma had an increased hazard ratio as compared to those that did not progress.

In a study conducted in Wisconsin, USA, a predominantly Caucasian population with diabetes was compared to a smaller group of nondiabetics and was found to have a tendency toward a greater mean IOP than nondiabetics and higher rates of a positive history of glaucoma than in diabetic participants.

The Early Manifest Glaucoma Trial (EMGT), Blue Mountain Eye Study, and the Baltimore Eye Study found persons with diabetes appear to have a slightly higher IOP and have been reported to have a higher prevalence of ocular hypertension and incidence of IOP elevation, compared with persons who do not have diabetes.

Finally, some systematic reviews and meta-analysis throw some more light on the issue. In a meta-analysis by Zhao et al, diabetes, fasting glucose and the risk of glaucoma were studied and found to have a positive association. Similarly, Zhou et al, in their meta-analysis of diabetes mellitus as a risk factor for POAG, found it to be a significant risk factor. Recently, Zhao and Chen in their meta-analysis of seven prospective cohort studies found a pooled risk ratio (RR) of 1.36, implying significant association between diabetes and POAG.

STUDIES SHOWING NEGATIVE ASSOCIATION:

In the European Glaucoma Prevention Study (EGPS) only 4.7% of 1,077 randomized participants with ocular hypertension reported diabetes, a number too small to determine prospectively the effect of diabetes on progression to glaucoma.

Vijaya et al did not find diabetes to be associated with glaucoma in a South Indian population in Chennai, India.

The Baltimore Eye Survey, a predominantly African-American population, failed to show that diabetes was associated in the development of glaucoma. The Rotterdam Study also negated such an association.

Ellis et al in their study of a population in Scotland, UK, (based on the Diabetes Audit Research in Tayside Study [DARTS]), reported the incidence of POAG in diabetes of 1.1/1000 patient years compared to 0.7/1000 patient years in non-diabetics showing a non-significant increase.

In a population-based study in 3280 Malay adults aged 40 to 80 years, diabetes and metabolic abnormalities were associated with a small increase in IOP but were not significant risk factors for glaucomatous optic neuropathy.

Certain old studies such as those by Waite and Beetham (1935), Palomar-Palomar (1956), Armaly and Baloglou (1967), Bankes (1967), as well as Bouzas et al (1971), had refuted a link between diabetes and glaucoma.

CONCLUSION:

The relationship between diabetes and glaucoma is not well established and currently remains the subject of much controversy.  While at least three meta-analyses have shown an association of glaucoma with diabetes, yet, there remain a number of confounding factors regarding this relationship. One study showed that changes in the biomechanical properties of the cornea due to increased glycosylated hemoglobin may artificially influence intraocular pressure measurements leading to a false-positive association between diabetes and elevated intraocular pressure.

Krueger and Ramos-Esteban proposed that corneal stiffening due to glucose-mediated collagen cross-linking may account for higher intraocular pressure readings in diabetics.

On the other hand, some authors have suggested that the diabetes related increase in the thickness of the lens could be responsible for the shallowing of anterior chamber and increased risk of angle-closure glaucoma.

 

VITREO-RETINAL SURGERY AND GLAUCOMA

INTRODUCTION:

Vitreo-retinal surgery (VRS) may be associated with raised intra-ocular pressure (IOP) or even long-term glaucomatous changes. This can be as a result of vitreo-retinal procedures or the presence of concomitant glaucoma in these patients.

Patients with rhegmatogenous retinal detachments (RRD) were found to have a higher prevalence of primary open angle glaucoma (POAG) compared to the general population (4-6% in RRD patients compared to 1-3% in the general population). Glaucoma can also occur due to diverse mechanisms such as neovascularization of the anterior segment from underlying ischemic retinopathy; prolonged steroid treatment and multiple surgical interventions. Studies have reported that ocular hypertension occurs after VRS in 19–28% of cases. 

 

Glaucoma associated with VRS may occur in the following specific situations:

SCLERAL BUCKLE:

 

Placement of scleral buckles may result in acute postoperative elevated IOP or secondary glaucoma from a closed angle mechanism. As many as 14% patients have been reported to develop postoperative narrowed angle following a scleral buckle. In another study, permanent abnormal IOP elevation and narrowing of the angle was reported in 3.75% cases. Yet another study reported the incidence of acute angle-closure glaucoma at 1.4% over a 6-year period following scleral buckle surgery.

Mechanisms in such situations include: Too anterior placement of the scleral buckle, ciliary body congestion, impaired venous drainage from direct pressure of the buckle, swelling and anterior rotation of the ciliary body, and choroidal effusions, leading to anterior movement of the lens–iris diaphragm, and narrowing of the anterior chamber angle or development of peripheral anterior synechiae.

Management: Most cases resolve spontaneously within a few days. Topical or systemic medical treatment may be required during the acute period. Cycloplegics are often employed to deepen the anterior chamber and rotate the ciliary body posteriorly. Adjunctive use of topical steroids may also help to decrease inflammation and prevent the formation of peripheral anterior synechiae. Surgical options include argon laser peripheral iridoplasty, drainage of choroidal effusions, revision of the buckle or loosening of the encircling band. Laser peripheral iridotomy is usually not indicated as pupillary block is uncommon following scleral buckle procedures.

PANRETINAL PHOTOCOAGULATION (PRP): 

 

PRP leads to transfer of transfer of thermal energy causing an inflammatory cascade, leading to ciliochoroidal effusions and detachments from anterior rotation of the ciliary body. Subsequently, there can be forward shifting of the lens–iris diaphragm leading to narrowing of the anterior chamber angle with the potential for angle-closure glaucoma. The mechanism of angle closure is thought to be swelling of the ciliary body or an outpouring of fluid from the choroid to the vitreous with subsequent forward displacement of the lens-iris diaphragm. Usually, such an elevation of IOP resolves within 2 weeks of the procedure.

Management: IOP can be reduced with topical or systemic anti-glaucoma medications with additional requirement of cycloplegics and steroids.

PARSPLANA VITRECTOMY (PPV):

 

In one study, 43.3% of patients undergoing PPV had IOP above 30 mmHg in the acute postoperative period. However, patients with pre-existing glaucoma did not have an overall increased rate of IOP elevation following PPV. Mechanisms include gas expansion (most frequent cause), followed by inflammation, silicone oil related (without pupillary block), corticosteroid response, hyphema/ghost cell glaucoma and retained lens material with phacolytic glaucoma. Closed angle mechanisms include ciliary body edema causing pupillary block as the most common mechanism followed in descending order by pupillary block secondary to fibrin, gas, and, lastly, silicone oil.

Risk factors for IOP elevation delineated in a study include intraoperative or previous scleral buckling, intraoperative scatter endophotocoagulation, intraoperative lensectomy, and postoperative fibrin formation.

Management: Medical treatment is usually sufficient to reduce IOP. Han et al reported the need for surgical treatment in 11.3% of subjects. Surgical options include anterior chamber paracentesis, laser peripheral iridotomy, and laser iridoplasty or membranectomy.

INTRAVITREAL GAS:

Postoperative expansion of intravitreal gas can induce acute elevation of IOP. Studies have reported 43-52% incidence of IOPs above 25 mmHg in patients after intravitreal gas injection. This can have sight threatening complications in individuals with advanced glaucoma and serious retinal diseases. Gases with expansile property can cause spikes in IOP, related to the final volume reached by the intra-ocular gas bubble. Elevated pressure after the use of intravitreal gas develops by both open and closed angle mechanisms. Angle closure with pupillary block occurs when the anterior displacement of the lens–iris diaphragm results in iris bombe and iridocorneal touch. This mechanism can occur despite the patient assuming a prone position. Open angle glaucoma occurs when the rate of expansion of the gas exceeds the rate of egress of the aqueous humor through the trabecular meshwork.

Nitrous oxide, when used as an anesthetic, elutes from the blood stream into adjacent gas filled spaces and increases the volume of these spaces. Patients with intraocular gas who receive nitrous oxide during surgery can develop IOP in excess of 70 mmHg, which can result in artery occlusion, retinal ischemia, and/or infarction. Patients should be advised against travel in conditions where the atmospheric pressure may decrease significantly. Generally, heights above 2500 feet and air travel should be avoided until the gas is completely absorbed.

Risk factors for increased IOP after intravitreal gas tamponade include the concentration of gas used, elderly patients, postoperative fibrin in the anterior chamber, concurrent use of a scleral buckle, and intraoperative endophotocoagulation.

Management: Elevated IOP related to retinal surgery should be managed by treatment of the underlying cause. If pupillary block is present, an inferior laser peripheral iridotomy is necessary. Angle closure without pupillary block resulting in iridocorneal touch must be treated promptly to prevent the establishment of peripheral anterior synechiae. This can be accomplished by partial removal of the intravitreal gas and reformation of the anterior chamber with the help of a viscoelastic. In addition, a paracentesis can immediately lower pressures in the setting where topical medications are ineffective.

SILICONE OIL:

Almost 25-50% of the cases treated with silicone oil develop elevated IOP in the post-operative period. Oil tends to migrate into the anterior chamber/angle, producing an “inverse pseudohypopyon” (see image above). Pupillary block can be avoided by an inferior iridectomy. A prone position postoperatively, prevents forward movement of the lens–iris diaphragm.

Management: Raised IOP is usually amenable to topical and/or systemic anti-glaucoma medications. Trabeculectomy usually fails due to migration of the oil as well as extensive conjunctival scarring. A glaucoma drainage device is more successful in the event anti-glaucoma medications are ineffective. Trans-scleral diode laser cyclophotocoagulation is another modality being developed in such cases.

Removal of silicone oil to reduce IOP is controversial. Studies reported 91-75% of the cases did not show any reduction in IOP following the procedure. Decisions to surgically manage glaucoma in these patients must be thoroughly discussed with the retinal specialist, because removal of silicone oil prematurely is associated with a re-detachment rate of 11–33% of eyes. In uncontrolled cases, glaucoma drainage device implant surgery can control the IOP in the majority of eyes, when implanted in the inferonasal or inferotemporal quadrant.

CONCLUSION:

With the improvement in the diagnosis and management of retinal disorders, there has been a concomitant increase in the appearance of glaucoma, related to these surgical modalities. Increased IOP and glaucomatous changes may develop as a result of VRS procedures or the glaucoma could be secondary to the changes brought about by vitreo-retinal disorders. These glaucomas are frequently difficult to manage, especially as they carry a risk of affecting the outcome of a successful VRS performed on the eye. Management of such patients has to be preventive as far as possible and individualized to a large extent.