Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

324 Diabetes and Ocular Disease

glaucoma was found in the African Caribbean Eye Survey [33]. In the Beaver Dam Eye Study, older-onset diabetes (≥30 years of age) was associated with a modest increase in the risk of glaucoma [25]. In the Blue Mountains Eye Study, there was a significant association between diabetes (diagnosed from history or from elevated fasting plasma glaucose level) and open-angle glaucoma [34]. The Rotterdam Study also reported a significant association between diabetes and POAG [35]. The Ocular Hypertension Treatment Study (OHTS) found that diabetes mellitus appeared to be protective against the development of POAG in patients with ocular hypertension [36]. However, the diagnosis of diabetes was not confirmed with blood tests and individuals with diabetic retinopathy were excluded from the OHTS, suggesting that an unrepresentative group of patients with diabetes was enrolled in this study. These factors may explain the paradoxical relationship between diabetes and POAG in the OHTS, which contradicts previously published study results.

When patients are treated medically for POAG, it is important to recognize that the potential side effects of beta-adrenergic antagonists include reduced glucose tolerance and masking of hypoglycemic signs. Therefore, this class of antiglaucoma medications should be used cautiously in diabetic patients.

Angle-Closure Glaucoma. Several observations suggest an association between diabetes and angle-closure glaucoma (ACG). One study found that patients with ACG had a higher prevalence of abnormal glucose tolerance test results compared with POAG patients and controls [37]. Patients with ACG also have a high prevalence of non-insulin-dependent diabetes [38]. It has been hypothesized that, in some cases, ACG may be a symptom of diabetes, perhaps due to autonomic dysfunction [39]. Finally, lens swelling related to hyperglycemia may precipitate ACG [40].

Hyperosmotic agents are commonly included in the medical management of acute episodes of elevated IOP. In diabetic patients, isosorbide is preferred to glycerol because isosorbide is not metabolized into sugar, while glycerol is metabolized into sugar and ketone bodies. Glycerol, therefore, can produce hyperglycemia and, rarely, ketoacidosis in diabetic patients.

Neovascular Glaucoma. Despite the widespread use of panretinal photocoagulation (PRP), proliferative diabetic retinopathy (PDR) remains a leading cause of neovascular glaucoma. In a 1973 report of 56 patients with neovascular glaucoma, 43% were attributed to diabetic retinopathy, 37% to central retinal vein occlusion, and the rest to miscellaneous causes [41]. In 1984, Brown and associates reviewed 208 cases of neovascular glaucoma and reported that 36% were caused by central retinal vein occlusion, 32% by diabetic retinopathy, and 13% by carotid occlusive disease [42].

The reported incidence of any neovascularization of the iris (NVI) among diabetic patients ranges from 1% [43] to 17% [44]. In eyes with PDR, the reported incidence in one study was 65% [45]. In the early stages, NVI usually appears as small vascular tufts either at the pupillary margin or in the anterior chamber angle. As these vessels later spread across the iris surface, they are frequently accompanied by fibrous tissue, which contracts and may cause ectropion uveae (Fig. 16.3)

Figure 16.3. Extensive neovascularization of the iris in a patient with proliferative diabetic retinopathy.

and peripheral anterior synechiae. While angle closure can cause severe glaucoma, IOP may be elevated even before any angle is closed, probably because of leakage of protein and cells from the new iris vessels [46].

It is generally well accepted that NVI is associated with retinal hypoxia and PDR [47], and many authors have reported regression of early NVI following PRP [47–49]. In goniophotocoagulation, argon laser treatment is applied directly to new vessels in the anterior chamber angle. Although performed infrequently, goniophotocoagulation has been proposed as a treatment in the early stages of neovascular glaucoma to prevent progressive angle closure, while PRP facilitates regression of the anterior segment neovascularization.

Use of adjunctive 5-fluorouracil or mitomycin C has been shown to increase the success rate of filtering surgery in eyes with neovascular glaucoma [50–53]. Glaucoma drainage devices have gained increasing popularity in recent years to achieve IOP control in various refractory glaucomas, including neovascular glaucoma [54]. A traditional approach to the management of patients with neovascular glaucoma is as follows:

PRP is performed to induce regression of NVI.

Adjunctive anti-vascular endothelial growth factor (anti-VEGF) agents may facilitate regression of NVI.

If IOP is not controlled medically and the eye has visual potential, filtering surgery with an adjunctive antimetabolite or implantation of a glaucoma drainage device is performed. Adjunctive anti-VEGF agents at the time of surgery may also be employed.

If IOP is not controlled medically and the eye has limited visual potential, a cyclodestructive procedure may be considered.

For eyes with NVI and opaque media, an alternative approach is combined pars plana vitrectomy, lensectomy with or without intraocular lens implantation, and implantation of a glaucoma drainage device [54].

326 Diabetes and Ocular Disease

Medical management of IOP elevation in neovascular glaucoma principally involves aqueous suppressants, such as alpha-2-agonists, beta-blockers, and topical and oral carbonic anhydrase inhibitors. Miotics are not beneficial when the anterior chamber angle is closed and are avoided, as they can exacerbate intraocular inflammation and may hamper access to the posterior segment. Topical corticosteroids are often useful in treating intraocular inflammation and pain.

Blood-associated Glaucoma. Glaucoma associated with degenerated intraocular blood is not unique to diabetic patients. Ghost-cell glaucoma may occur after vitreous hemorrhage of any cause in an eye with a communication between the vitreous and the anterior segment through a disrupted anterior hyaloid face. Ghost-cell glaucoma was originally observed after early attempts at vitrectomy, when only a core vitrectomy was performed. Blood products in the peripheral vitreous leach out, and degenerated erythrocytes (ghost cells) travel around lens zonules and into the anterior chamber, obstructing the trabecular meshwork and causing elevated IOP within days to weeks postvitrectomy [55].

Slit-lamp examination usually permits differentiation of white inflammatory cells associated with anterior uveitis from khaki-colored ghost cells. In severe cases, it is important to distinguish the white color of a hypopyon due to uveitis or endophthalmitis from the khaki-colored pseudohypopyon characteristic of ghostcell glaucoma. In questionable cases, anterior chamber aspiration, combined with phase-contrast microscopy, may be performed. In ghost-cell glaucoma, degenerated erythrocytes with precipitated hemoglobin (Heinz bodies) adherent to the inner walls of the cells may be evident [56].

Medical treatment focuses on agents that decrease aqueous production— for example, alpha-2 agonists, beta-adrenergic blocking agents, and carbonic anhydrase inhibitors. Because the trabecular meshwork is obstructed by ghost cells, miotics may be unsuccessful in increasing aqueous outflow. In severe cases or if medical therapy is unsuccessful or not tolerated, surgical management may be limited to anterior chamber washout or may include a pars plana vitrectomy.

Hemolytic glaucoma results when macrophages ingest contents of red blood cells and then accumulate in the trabecular meshwork, where they obstruct aqueous outflow [57]. Examination reveals red-tinted blood cells floating in the aqueous, and the anterior chamber angle is usually open, with the trabecular meshwork covered with reddish brown pigment [58]. As the condition is typically selflimited, it is generally managed medically. Occasionally, anterior chamber lavage is required [58].

First described in 1960, hemosiderotic glaucoma is thought to result from obstruction of the aqueous outflow channels by iron deposition, with subsequent degeneration and inflammatory changes [59]. Hemosiderotic glaucoma is reported to have a later onset than that of ghost-cell glaucoma (patients with hemosiderotic glaucoma typically present with elevated IOP years after the initial intraocular hemorrhage), and ghost cells are not present [60].

Because treatment is similar to that of ghost-cell glaucoma, these two entities (hemolytic glaucoma and hemosiderotic glaucoma) may represent part of the broad spectrum of blood-associated glaucoma.

Figure 16.4. “Snowflake” cataract in a patient with type 1 diabetes.

LENS ABNORMALITIES

Refractive Error. Reversible swelling in lenses of diabetic patients causes “fluctuating myopia,” which may be a presenting sign of diabetes. It is thought that accumulation of the sugar alcohol sorbitol, an end product of glucose reduction by aldose reductase, exerts an osmotic effect in lens cells [61]. A transient hyperopic shift typically occurs in hyperglycemic patients after such patients improve control of their plasma glucose levels [62]. Because lens shape, and thus refractive error, may fluctuate with blood glucose levels, it is best to prescribe glasses when the blood glucose level is relatively stable. Prior to prescribing glasses in patients with labile blood glucose levels, the clinician may need to evaluate the refractive error on several visits to confirm a stable refractive error.

Cataract. The risk of cataract formation is approximately 2 to 4 times higher in diabetic patients than in nondiabetic persons [63–66]. The risk of cataract increases with duration of diabetes and with poor metabolic control [62,67]. Cataract in diabetic patients usually does not differ morphologically from age-related cataract, but may occur 20 to 30 years earlier than in nondiabetic persons. In young diabetic patients, a rare “snowflake” cataract may develop, with superficial vacuoles and white snowflake opacities (Fig. 16.4) in the subcapsular region, and rapidly progress to a mature cataract.

OPTIC NERVE ABNORMALITIES

Acute Optic Disc Edema. Acute optic disc edema associated with diabetes, or diabetic papillopathy, usually occurs in the second to fourth decades of life and generally shows no correlation with the severity of diabetic retinopathy. It is typically associated with mild loss of vision (≥20/50) [68,69], and the visual field may be normal or may show defects, such as an increased blind spot, arcuate scotoma, or altitudinal scotoma. Fluorescein angiography usually demonstrates diffuse leakage

A

B

Figure 16.6. Diabetic papillopathy with eventual optic atrophy. (A) Disc edema, hemorrhages, and cotton-wool spots in a 52-year-old patient with a 6-year history of diabetes. Visual acuity is 20/25. (B) About 3 years later, diffuse optic atrophy is present. Visual acuity is 20/100.

hypertensive persons with or without diabetes, and is characterized by acute unilateral moderate-to-marked loss of vision, swelling of the optic disc with variable nerve fiber layer hemorrhages, segmental areas of nonperfusion on fluorescein angiography, poor prognosis for visual recovery, and late optic disc pallor [74].

Wolfram Syndrome. Wolfram syndrome refers to type 1 diabetes mellitus and progressive optic atrophy. The clinical spectrum includes multiple other neurologic and systemic abnormalities, such as neurosensory hearing loss, neurogenic bladder, diabetes insipidus, nystagmus, anosmia, and gonadal dysfunction [75]. The inheritance is autosomal recessive or sporadic. The syndrome has been reported to be associated with mutations of the WFS1 gene that encodes wolframin, a putative transmembrane glycoprotein of the endoplasmic reticulum [76]. In a series of nine patients reported by Lessell and Rosman, diabetes was diagnosed between the ages of 2 and 11 years, and progressive loss of vision to ≤20/200 occurred within several years [75].

generally consists of anisocoria of ≤1 mm rather than a fully dilated unreactive pupil [80], and internal ophthalmoplegia is incomplete [81]. Despite what is often reported, cranial nerve palsies caused by microvascular disease may present with orbital pain in up to 20% of cases [79], and pain may precede the palsy by a few days.

Workup for causes other than microvascular disease is indicated if examination reveals involvement of more than one cranial nerve, other neurologic signs, progressive deterioration, or lack of complete recovery within 3 months. Patients younger than 45 years with an isolated cranial nerve palsy usually do not have a microvascular infarct even if they have long-standing diabetes [77]. Recurrences are not rare and may involve the same or another cranial nerve on either side.

INFECTIOUS DISEASES

Endophthalmitis. Several studies suggest that patients with diabetes may have an increased risk of developing postoperative endophthalmitis (Fig. 16.8) compared to nondiabetic persons [82–85]. In one study of the 5-year incidence rates of endophthalmitis following intraocular surgery, a statistically significant increased incidence of endophthalmitis occurred in diabetic patients (0.163%) compared with nondiabetic patients (0.055%) who underwent extracapsular cataract extraction with or without intraocular lens implantation [82]. In a case-control study of endophthalmitis following secondary intraocular lens implantation, 50% of patients had a history of diabetes compared with 5.9% of control patients [84]. In a report of 162 consecutive patients treated for acute postoperative endophthalmitis, 21% had diabetes [83].

The increased risk of postoperative endophthalmitis among diabetic patients is not surprising, because patients with diabetes have been demonstrated to have impaired cellular and humoral immune responses, as well as altered phagocytic capabilities [86]. Further, it is well known that diabetic patients are more likely than nondiabetic patients to experience delayed wound healing [87]. Thus, diabetic patients may be predisposed to wound breakdown or persistent wound defects or both, which, in turn, may increase their risk of developing endophthalmitis. Finally, vitrectomy for complications of PDR often requires longer surgical time and more instrument changes passing through the pars plana sclerotomies compared with vitrectomy for other diseases.

The Endophthalmitis Vitrectomy Study reported that only 39% of diabetic patients compared with 55% of nondiabetic patients achieved a final visual acuity of 20/40 or better [88]. Both diabetic and nondiabetic patients who presented with vision of only light perception had better visual acuity results with immediate vitrectomy. For those who presented with better than light perception vision, diabetic patients achieved a final visual acuity of 20/40 or better more often with vitrectomy (57%) than with vitreous tap/biopsy (40%), but (perhaps due to small numbers) this difference was not statistically significant. Patients without diabetes did equally well with vitrectomy or vitreous tap/biopsy. In the diabetic group, small numbers did not permit adequate statistical power to test treatment difference.

332 Diabetes and Ocular Disease

A

B

Figure 16.8. (A) Staphylococcus epidermidis endophthalmitis in an 86-year-old diabetic man 1 week after small-incision phacoemulsification with posterior chamber intraocular lens implantation. Visual acuity is hand motions at 1 foot. (B) About 5 months later and after pars plana vitrectomy with intraocular antibiotics, visual acuity is 20/40.

Mucormycosis. Mucormycosis is a rare orbital infection that affects diabetic patients, especially those with ketoacidosis. In fact, it is estimated that 50% of mucromycosis cases occur in diabetic patients [89]. The diagnosis should be suspected in any diabetic, immunosuppressed, or debilitated patient who develops facial or orbital pain, diplopia, or other neurologic signs and symptoms, and in diabetic patients with ketoacidosis who remain obtunded after correction of the underlying ketoacidosis.

Orbital mucormycosis usually originates in adjacent sinuses and presents with complete internal and external ophthalmoplegia, decreased vision, proptosis, ptosis, and chemosis. Histopathologic hallmarks of the disease are vascular invasion and tissue necrosis. Clinically, affected areas are characterized by black eschars (Fig. 16.9) and discharge, although this may be a late finding. Mucormycosis is associated with a significant risk of mortality [90,91], which underscores the importance of prompt diagnosis and treatment with tissue debridement and amphotericin B.

Figure 16.9. Mucormycosis with characteristic black eschar in a patient with uncontrolled diabetes.

CONCLUSION

Diabetes is associated with myriad nonretinal ocular abnormalities. The most common of these include corneal diseases (decreased corneal sensitivity, infectious and neurotrophic ulcers, and epithelial defects and erosions), glaucoma (openangle, angle-closure, neovascular, and blood-associated), refractive changes, and cataract. Optic and cranial nerve abnormalities are not rare. Endophthalmitis and mucormycosis occur less frequently and are associated with a guarded prognosis, especially if not detected and treated promptly. Care of the diabetic patient usually includes referral to an appropriate primary care physician to ensure optimal metabolic control, with the goal of reducing the rates of ocular and systemic complications from diabetes.

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