THE WESTERN JOURNAL OF MEDICINE THE

WESTERN

JOURNAL

OF

MEDICINE

o

*

JULY 1992 JULY

1992

0 *

157 157

o *

67

1

67

1

addition, vigorous replacement of potassium alone resulted in prompt and complete resolution of symptoms. The mechanism by which this paradoxic effect occurs is subject to speculation and is often clouded in the literature by references to what are probably secondary effects. Specifically, tetany has been frequently reported in patients with potassium repletion presumably due to the unmasking of the effects of concurrent calcium depletion.3'14'15 Attempts to explain how hypokalemia could provoke tetany are purely speculative, and our understanding of the process is confounded by the complexity of the interactions of the various ions in different tissues. It is likely, for instance, that although extracellular values would suggest an isolated profound depletion in the total body stores of potassium, the intracellular ratios of sodium, calcium, and potassium or intracellular-to-extracellular ratios of these ions are not truly reflected in serum values and are contributing to the appearance of tetany. It has been shown that with a reduction of potassium stores, intracellular sodium rises at times to inappropriately high levels in excess of what is needed simply to compensate for potassium losses.11 Similarly, from the Nernst equation (Em = 67.5 x log KjIK0+, where Em is the transmembrane voltage, Ki, is the intracellular potassium, and Ko+ is the extracellular potassium), it would be expected that in the presence of pure hypokalemia, cells would hyperpolarize and become more stable. It has been found, however, that potassium balance is based on a delicate relationship between absolute intracellular and extracellular gradients for potassium and potassium conductance, and severe decreases in extracellular fluid potassium lead to depolarization experimentally. It has been shown in myocardial cells, for example, that as potassium falls to less than 2.7 mmol per liter, resting potentials actually increase due to a marked fall in the potassium conductance.3 Similar phenomena in other muscles may well lead to what would appear to be a paradoxic instability and irritability of cellular membranes. The occurrence of tetany may also be due in part to the differential effects of hypokalemia on muscular versus peripheral nervous tissues. It has been demonstrated that cramps may result from abnormalities involving any structure from the central cerebral and cerebellar structures to the individual muscle fibers.13 Although muscular weakness leading to flaccidity is the usual occurrence, if potassium effects on nervous tissue dominate and cause nervous irritability, tetany may, in fact, be the prominent finding. This could explain the occurrence of tetany in the presence of muscular weakness and could corroborate the frequent finding of latent tetany in previously reported cases.8 Finally, it is interesting to speculate why, in the presence of a common albeit severe metabolic derangement, this patient had rather unusual symptoms. Perhaps her normal serum calcium level contributed to her symptoms. Ordinarily, patients with such severe hypokalemia have hypomagnesemia and, as a consequence, hypocalcemia. It is possible that the vitamins this patient ingested contained calcium, magnesium, or both. In addition, she had mildly abnormal findings on thyroid function tests. Although the derangement was not severe, it is of interest that both hyperthyroid and hypothyroid disorders have been associated with cramping.15 Despite the paucity of information available regarding hypokalemia as a specific cause of tetany, its clinical consequences are clear. Hypokalemia occurs with significantly

greater frequency in the usual adult population than do abnormalities of other electrolytes that cause tetany. Furthermore, treatment errors resulting from incorrect empiric therapy could have devastating consequences because of the potentiation of other concurrent electrolyte abnormalities. The patient in this report had, in addition to neuromuscular abnormalities, electrocardiographic evidence of pronounced hypokalemic effects on the cardiac conduction system. Administering calcium with its antagonistic effects on the myocardium would be expected to further worsen this situation, with potentially castastrophic consequences. REFERENCES 1. Narins RG, Jones ER, Stom MC, Rudnick MR, Bastl CP: Diagnostic strategies in disorders of fluid, electrolyte, and acid-base homeostasis. Am J Med 1982; 72:496520 2. Sansone RA: Complications ofhazardous weight-loss methods. Am Fam Physician 1984; 30:141-146 3. Kleeman K, Singh BN: Serum electrolytes and the heart, chap 5, In Maxwell MH, Kleeman CR, Narins RG (Eds): Clinical Disorders of Fluid and Electrolyte Metabolism, 4th Ed. New York, NY, McGraw-Hill, 1987, pp 145-180 4. Knochel JP: Neuromuscular manifestations of electrolyte disorders. Am J Med 1982; 72:521-535 5. Gabow PA, Peterson LN: Disorders of potassium metabolism, In Schrier RW (Ed): Renal and Electrolyte Disorders, 2nd Ed. Boston, Mass, Little, Brown, 1980, pp 196-208 6. Strong JA: Serum potassium deficiency during treatment with sodium paraaminosalicylic acid and liquorice extract. Br Med J 1951; 2:998-1002 7. Roussak NJ: Fatal hypokalaemic alkalosis with tetany during liquorice and paraaminosalicylic acid therapy. Br Med J 1952; 2:360-361 8. Eliel LP, Pearson OH: Postoperative potassium deficit and metabolic alkalosis. N Engl J Med 1950; 243:471-478 9. Ravin IS, Aronson PR, Yules JH: Complications of the diuretic phase of lowernephron nephrosis. N Engl J Med 1951; 244:830-832 10. Follis RH Jr: Effect of exercise on rats fed a diet deficient in potassium. Proc Soc Exp Biol Med 1942; 51:69-70 11. Fourman P: The tetany of potassium deficiency. Clin Sci 1954; 13:93-110 12. Fourman P: Depletion of potassium induced in man with an exchange resin. Clin Sci 1954; 13:93-110 13. Layzer RB, Rowland LP: Cramps. N Engl J Med 1971; 285:31-40 14. Isgreen WP: Nornocalcemic tetany-A problem of erethism. Neurology (Minneap) 1976; 26:825-834 15. McGee SR: Muscle cramps. Arch Intern Med 1990; 150:511-518

Current Management of Diabetic Retinopathy EVERETr Al, MD San Francisco, California

DIABETIC RETINOPATHY is the leading cause of blindness in the United States in persons younger than 60 years. The Diabetic Retinopathy Study demonstrated that photocoagulation therapy is of benefit in preserving vision in patients with the more severe proliferative stages of diabetic retinopathy. Recent data compiled by the Early Treatment Diabetic Retinopathy Study (ETDRS), a National Eye Institute-supported multicenter study, showed that focal photocoagulation therapy can reduce the risk of further vision loss in diabetic patients with clinically significant macular edema. This study also showed that aspirin therapy neither prevents the development of high-risk proliferative retinopathy nor in(Ai E: Current management of diabetic retinopathy. West J Med 1992 Jul; 157:67-70) From the Retina Unit, Department of Ophthalmology, California Pacific Medical Center, San Francisco, Califomia. This work was supported in part by an unrestricted grant from Research to Prevent Blindness and the Pacific Vision Foundation. Reprint requests to Everett Ai, MD, Department of Ophthalmology, California Pacific Medical Center, PO Box 7999, San Francisco, CA 94120.

ALERTS, NOTICES, AND CASE REPORTS

68

Figure 1.-Nonproliferative (background) diabetic retinopathy is manifested by the presence of scattered microaneurysms, retinal hemorrhages, and macular edema with formation of hard exudates.

Figure 2.-Preproliferative diabetic retinopathy is shown, with multiple cotton-wool spots that represent infarcts of the nerve fiber layer.

Figure 3-This eye shows the presence of clinically significant macular edema with a circinate ring of hard exudate.

e 30

oi

_

Control

-20

:>10 -10-

Focal

Treatment

3

LUJO 1

_

Figure 4.-The same eye as depicted in Figure 3 is shown immediately after focal photocoagulatron therapy for clinically significant macular edema.

-!, :~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Figure 5.-The same eye as depicted in Figures 3 and 4 is shown a year after focal photocoagulation therapy. Note the resolution of the ring of hard exudate.

the risk of hemorrhage into the vitreous body. I review these findings and describe a new project, the goal of which is to eliminate preventable blindness from diabetes by the year 2000. The successful management of diabetic retinopathy is based on the early recognition of fundus abnormalities, careful follow-up, and prompt treatment. The ocular manifestations of diabetes mellitus comprise the same microvascular abnormalities that are found in other organs. The obstruction and leakage of retinal capillaries are the primary basis for the natural history of this disorder. Capillary closure and leakage result in early fundus changes referred to as nonproliferative (or background) retinopathy. The acceleration of these capillary abnormalities and the progression of ischemia eventually affect adjacent arterioles, resulting in arteriolar closure and a clinical disorder called preproliferative retinopathy. These changes indicate the potential for a rapid progression of the retinopathy. As the nonperfusion worsens, a vasoproliferative factor is thought to be released from the ischemic retina. This diffusible substance induces the growth of new abnormal blood vessels, a process referred to as neovascularization. These new vessels herald the third, and final, stage of proliferative retinopathy. This cycle of capillary closure, ischemia, and neovascularization spreads throughout the retina. The management of diabetic retinopathy is based on interrupting this cycle at each clinical stage. creases

Nonproliferative (Background) Diabetic Retinopathy Nonproliferative (background) retinopathy is seen in 25% of all persons with diabetes mellitus, and its prevalence has been shown to be directly related to the duration of diabetes. I Patients who have had diabetes for 15 years or more have a 60% incidence of retinopathy. Nonproliferative retinopathy is the result of capillary closure and leakage. The underlying

2

3

Years of Follow-up Figure 6.-Focal photocoagulation treatment of clinically significant macular edema reduces the risk of vision loss by more than 50% when compared with untreated control eyes.

mechanism for this change is not known. Endothelial changes (thickening of the basement membrane and degeneration of the pericytes) have been demonstrated,2 and hemodynamic abnormalities (erythrocyte and platelet aggregation) have been observed.3 The patient may be asymptomatic, but some patients may experience vision loss due to macular edema, which is discussed later. Examination of the fundus reveals the presence of numerous microaneurysms tiny red dots within the retina that represent saccular capillary outpouchings resulting from a nonspecific response to ischemia. These microaneurysms leak plasma constituents that can later impinge on foveal photoreceptors and result in loss of vision. Also seen are retinal hemorrhages, which may be deep (dot and blot) or superficial (flame shaped) within the retina (Figure 1). Treatment The management of nonproliferative retinopathy is based on maximal medical control of the diabetes. The effect of blood glucose control on the progression of the retinopathy remains controversial. There is accumulating evidence, however, that both the rate and the severity of retinal changes are favorably influenced by controlling blood glucose levels.4 Another important part of the management of nonproliferative retinopathy is frequent (every four to six months) examinations of the fundus.5 It has been shown that the rate of microaneurysmal formation correlates with the rate of progression of the retinopathy. Photographing the fundus is an excellent way of documenting these early changes.

Preproliferative Diabetic Retinopathy As the microvascular changes of capillary closure and leakage progress, ischemia impinges on the walls of larger vessels, the retinal arterioles. Damage to these vessels results in larger areas of nonperfusion and leakage of blood or

o THE WESTERN JOURNAL JULY 1992 0 157 o 1 OF MEDICINE ~ ~ ~ JORADFMDCN

plasma constituents through the defective endothelium. Arteriolar ischemia manifests as a cotton-wool spot, an infarct of the nerve fiber layer of the retina. Bleeding from a damaged vessel is seen as a blot hemorrhage, and the leakage of serum lipoproteins results in a deposition of hard exudates as the fluid is reabsorbed. The hallmark of preproliferative retinopathy is the presence of multiple cotton-wool spots, blot hemorrhages, and venous beading (Figure 2). With progression of the retinopathy, there is continued leakage from microaneurysms and defective small vessels. Fluid then accumulates within the retina, producing retinal thickening that results in a clinical disorder known as macular edema (Figure 3). When this occurs within the central fovea, cellular distortion may lead to vision loss. The impairment that results from the accumulation of fluid may be reversible, but the damage from chronic leakage and the resultant deposition of hard exudate is permanent. Leakage that produces retinal thickening within, or threatening, the central macula has been called clinically significant macular edema by the ETDRS.

Treatment The introduction and refinement of laser or photocoagulation therapy for diabetic retinopathy have dramatically changed the treatment and morbidity of this disorder. The primary indication for laser therapy in nonproliferative and preproliferative diabetic retinopathy is clinically significant macular edema. The ETDRS, a randomized controlled clinical trial, demonstrated that photocoagulation therapy for clinically significant diabetic macular edema substantially reduces the risk of vision loss.6 Photocoagulation spots are applied directly to leaking microaneurysms or in a grid pattern to areas of diffuse leakage in a treatment known as focal

Figure 7.-Proliferative diabetic retinopathy is shown, as manifested by the proliferation of new vessels and fibrous tissue known as retinal neovascularization.

photocoagulation (Figures 4 and 5). The ETDRS data showed that such treatment reduces the risk of vision loss by more than 50% (Figure 6). Laser therapy also increases the chance of visual improvement and decreases the frequency of persistent macular edema. The results of the study demonstrated that laser therapy is a safe procedure to undergo, although it may be accompanied by some, usually minor, side effects. Of particular note is that the benefits of treatment occur regardless of the level of vision acuity at the time of treatment. As a result, even diabetic persons with normal vision may have macular edema that should be considered for photocoagulation therapy. The ETDRS also studied the use of aspirin to determine whether or not it was effective in altering the course of diabetic retinopathy. The results indicated that a dosage of 650 mg per day did not prevent the development of high-risk proliferative retinopathy. In addition, aspirin therapy did not increase the risk of vitreous hemorrhage and overall had no effect on vision. These results indicate that there is no reason for persons with diabetes to avoid taking aspirin in these doses when it is needed for the treatment of other disorders.

Proliferative Diabetic Retinopathy The proliferative stage of diabetic retinopathy is characterized by the growth of abnormal new vessels and fibrous tissue in response to retinal ischemia. These neovascular vessels may arise from the optic disc and from the retinal vasculature. They appear as delicate lacy fronds of elevated vessels (Figure 7). Unlike normal retinal arteries and veins, these vessels leak fluorescein dye profusely during fluorescein angiography (Figure 8). These proliferative new vessels are also abnormal because of their propensity to bleed into the vitreous cavity and thereby obscure vision. This prolifer-

Figure 8.-A fluorescein angiogram of the same eye as depicted in Figure 7 shows the presence of fluorescein dye leakage (white areas) from the fronds of retinal neovascularization.

Figure 10.-Proliferative diabetic retinopathy is shown, as manifested by the proliferation of new vessels on the optic disc, referred to as disc neovascularization. Note preretinal hemorrhages and laser scars nasal (right of photo) to the disc.

69

Figure 9.-Panretinal photocoagulation treatment consists of applying a scatter pattern of laser burns to the peripheral retina.

Figure 11.-The same eye as in Figure 10 shows regression of the disc neovascularization into a fibroglial strand after panretinal photocoagulation therapy.

70

ation of fibrous and vascular tissue may also form firm adhesions at the interface between the retina and vitreous body. As the vitreous undergoes further changes over time, traction on the underlying retina can occur, resulting in a tractional retinal detachment. Treatment The proliferative stage of diabetic retinopathy is initially managed by laser photocoagulation. The large areas of nonperfusion that result from arteriolar closure are thought to release a vasoproliferative factor that stimulates neovascularization. The laser is used to ablate the ischemic retina, thereby preventing release of the vasoactive substance. The technique for the application of laser spots to the entire peripheral retina is called panretinal photocoagulation (Figure 9). This form of laser therapy helps to prevent further growth of neovascularization and has been shown to induce regression of established new vessels (Figures 10 and 1 1).' Nevertheless, some patients may still suffer a vitreous hemorrhage. Most ofthese hemorrhages clear spontaneously over a period of weeks to months, thereby allowing the application of additional laser therapy. In a patient whose hemorrhage has not cleared after several months, a pars plana vitrectomy may be indicated to remove the blood from the vitreous cavity, thereby improving vision and enabling the necessary laser treatments.8 When a traction retinal detachment complicates proliferative diabetic retinopathy, it may become necessary to excise the tractional fibrovascular adhesions that are responsible for the retinal detachment. Advances in surgical instrumentation also enable the application of intraocular laser photocoagulation during the operation.

Summary Diabetic retinopathy progresses through three distinct stages. A rational approach to management is based on an understanding of the pathophysiology of each stage. Based on the results of national multicentered clinical trials of laser photocoagulation and other treatments, advances in our understanding of the pathogenesis and treatment can now make a dramatic impact on blindness in the

diabetic population: * Panretinal laser photocoagulation treatment can reduce

ALERTS, NOTICES, AND CASE REPORTS

ALERTS,

NOTICES,

AND

CASE

REPORTS

the risk of vision loss from high-risk proliferative diabetic retinopathy by at least 50%. * Laser photocoagulation treatment of clinically significant diabetic macular edema can reduce the risk ofvision loss by more than 50%. * Vitrectomy can restore useful vision to some patients with severe diabetic retinopathy and vitreous hemorrhage with or without an accompanying traction retinal detachment. Diabetes 2000 is a new project sponsored by the American Academy of Ophthalmology, the goal of which is to eliminate preventable blindness from diabetes by the year 2000. As its name implies, Diabetes 2000 will be a long-term project aimed at a specific disease-diabetic retinopathy and its complications. It will provide the latest research findings to ophthalmologists and primary care physicians as the first priority, followed by the education of patients and the general public. Recent advances and treatment guidelines for the medical and surgical treatment of diabetic eye disease will be emphasized through the continuing education of ophthalmologists, other physicians, and allied health professionals. In later phases, educational programs for diabetic persons and the public will be developed. Ultimately, improved access of diabetic patients to ophthalmologic care and a close working relationship between ophthalmologists and primary care physicians will ensure the early detection of diabetic retinopathy and the timely delivery of state-of-the-art treatments. REFERENCES 1. Kahn HA, Bradley RF: Prevalence of diabetic retinopathy: Age, sex and duration of diabetes. Br J Ophthalmol 1975; 59:345-349 2. Ashton N: Vascular basement membrane changes in diabetic retinopathy. Br J Ophthalmol 1974; 58:344-366 3. deVenecia G, Davis MD, Engerman R: Clinicopathologic correlations in diabetic retinopathy: I. Histology and fluorescein angiography of microaneurysms. Arch Ophthalmol 1976; 94:1766-1773 4. Friberg TR, Rosenstock K, Sanborn G, Vaghefi A, Raskin P: The effect of longterm near-normal glycemic control on mild diabetic retinopathy. Ophthalmology 1985; 92:1051-1058 5. Coonan P, Ai E: The early treatment of diabetic retinopathy, In Ai E, Freeman WR (Eds): New Developments in Retinal Disease. Philadelphia, Pa, WB Saunders, 1990 6. Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema-ETDRS Report No. 1. Arch Ophthalmol 1985; 103:1796-1806 7. The Diabetic Retinopathy Study Research Group: Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976; 81:383-396 8. The Diabetic Retinopathy Vitrectomy Study Research Group: Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy: Two-year results of randomized trial-DRVS Report No. 2. Arch Ophthalmol 1985; 103:1644-1652

Current management of diabetic retinopathy.

Diabetic retinopathy progresses through three distinct stages. A rational approach to management is based on an understanding of the pathophysiology o...
1MB Sizes 0 Downloads 0 Views