Current management of diabetic retinopathy Recently diabetes has become a leading cause in new cases of blindness.1 In contrast to the other main cause of blindness, senile macular degeneration, which affects individuals over 65 years of age, blindness caused by diabetes most often affects the young or middleaged adult. In many such patients the nonocular effects of diabetes are minimal or are well controlled; nevertheless patients are unable to lead normal lives because of poor vision. One dramatic consequence of blindness in persons with diabetes is that their average life span following onset of blindness is less than 6 years.2 Although it is widely recognized now that diabetic retinopathy is a major health problem, effective methods of management have not been found for a number of reasons. Until recently, for example, there was no accurate information on the natural history of diabetic retinopathy. Without this knowledge, proof of the effectiveness of such treatments as hypophysectomy, photocoagulation, and systemic and ocular medications has come largely from anecdotal reports. Despite these difficulties progress is being made in clarifying a few of the misunderstandings concerning diabetic retinopathy. A first step has been the widespread acceptance of a classification of the condition. With standard photographs that depict all diabetic retinal changes it is now possible to categorize retinopathy as proliferative or nonproliferative and thus to identify those patients who are at greatest risk of becoming blind.1 The three main causes of blindness in diabetic retinopathy are macular edema, vitreous hemorrhage and retinal detachment. Macular edema, prob-
ably the most common cause, occurs in ness. In 1971 a diabetic retinopathy both proliferative and nonproliferative study was set up by the National Eye retinopathy. It is identified ophthalmo- Institute of the United States as a scopically or by stereoscopic photo- nationwide, randomized, controlled, graphy as a swelling of the retina in the clinical trial to test the hypothesis that macula caused by accumulation of in- a certain method of photocoagulation, traretinal fluid. Fluorescein angio- namely panretinal photocoagulation, graphy visualizes the origin of this could prevent loss of vision in proliferfluid as points of leakage arising from ative diabetic retinopathy. From 15 retinal capillaries, microaneurysms, or clinical centres approximately 1700 paintraretinal microvascular abnormalities tients with symmetric proliferative diaimmediately adjacent to the fovea. Ma- betic retinopathy were registered in cular edema is treated by sealing the the study. All aspects of pretreatment points of leakage with a photocoagulat- visual assessment, documentation of ing beam to prevent further accumula- fundus findings, treatment protocol and tion of fluid in the macula. Although postoperative examinations were carethe technique yields good results in fully controlled from a coordinating many patients, no controlled study has centre by a team of ophthalmologists, been done to prove its effectiveness. epidemiologists and biostatisticians. Vitreous hemorrhage and retinal de- Only one eye, randomly chosen, was tachment occur only in proliferative treated with panretinal photocoaguladiabetic retinopathy. In retinitis proli- tion. At specific intervals following ferans neovascular channels grow out treatment both eyes were carefully of pre-existing retinal capillaries onto studied. the inner surface of the retina or the In April 1976, after 2 years of foloptic nerve. When the overlying vit- low-up, the results of this study demreous separates from the retina and onstrated significantly fewer episodes optic nerve the new vessels with the of loss of vision in treated eyes comdetaching vitreous are pulled forward pared with untreated eyes, the effect towards the centre of the eye. Since becoming more pronounced the longer neovascular channels have fragile walls, the follow-up. Subsequently the diabetic bleeding often develops both behind retinopathy study research group recand into the vitreous gel, resulting in ommended that all previously untreated opacification of the ocular media. Al- eyes should also receive photocoagulaternatively these neovascular channels tion.3 Based on the findings of this transmit the pull of the detaching vit- study, panretinal photocoagulation is reous back onto the retina, where the now considered to offer a notable dechannels originated, thus producing a gree of prophylaxis against blindness traction detachment of the retina. in eyes with proliferative diabetic retiBlindness results when the retinal de- nopathy. tachment spreads to involve the macula. In patients in whom vitreous hemUntil 1976 there was no effective orrhage or retinal detachment occurs method to prevent or modify the events because of lack of, or in spite of adthat occurred from the onset of proli- ministration of, panretinal photocoaguferative diabetic retinopathy to blind- lation, microscopic techniques of vitCMA JOURNAL/JULY 9, 1977/VOL. 117 7
reous surgery have been developed that can improve vision: a small, needle-like instrument is inserted through the side of the eye into the vitreous cavity, where the surgeon, by looking with an operating microscope through the cornea, can observe and control the cutting, sucking and infusing functions of the intraocular instrument. Thus intravitreal blood is removed and simultaneously replaced with an equal volume of saline. Modifications include techniques to peel away membranes on the surface of the retina and cauterize actively bleeding stalks of retinitis proliferans, and to inject materials into the vitreous cavity to provide an internal tamponade effect to push back detached retinas that do not reattach following cutting of visible traction bands. In May 1976 the results of a study of vitreous surgery in 100 eyes followed up for at least 6 months disclosed that vision was substantially improved in 50 eyes.4 Although surgical complications accounted for failures in 10 eyes the end result was determined more often by the degree of damage to the retina caused by diabetes than by technical difficulties at operation. Conversely, many patients obtained reading vision after having been blind for several years, since in these cases a relatively normal macula was found upon removal of intravitreal blood. The development of both effective prophylaxis against the complications of proliferative diabetic retinopathy and surgical treatment to correct some forms of blindness in persons with diabetes has improved the outlook for many who were threatened with blindness. Nevertheless, the finding of methods to prevent proliferative diabetic retinopathy and the understanding of the perplexing relation between diabetic retinopathy and systemic diabetes remain among the many mysteries still to be solved in the management of the ocular complications of diabetes. MARK MANDELCORN, MD, CM, FRC5[C] Department of ophthalmology Mount Sinai Hospital Toronto, Ont.
References 1. KAmI HA, MoomsRsn HB: Statistics on Blindness In the Model Reporting Area, 19691970, Us Dept of Health, Education, and Welfare, publ no (NIH) 73427, Washington, US Govt Printing Office, 1973 2. GOLDBERG MF, FINE SL (eds): Symposium on the Treatment of Diabetic Retinopathy, US Pubi Health Sery, no 1890, Washington, US Govt Printing Office, 1969 3. The Diabetic Ratinopathy Study Research Group: Preliminary report on the effects of photocoagulation. Am I Ophihalmol 81: 383, 1976 4. MANDELCOIN MS, BLANKENSHIP G, MACHEMER
R: Pars plana vitrectomy for the management of severe diabetic retinopathy. Ibid, p 561
(levodopa and carbidopa combination) INDICATIONS Treatment of Parkinson's syndrome with exception of drug induced parkinsonism. CONTRAINDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to starting SINEMET*; in uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucoma; in patients with suspicious, undiagnosed skin lesions or a history or melanoma. WARNINGS When given to patients receiving levodopa alone, discontinue levodopa at least 12 hours before initiating SINEMET* at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chorea. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon may appear earlier with combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored conti nuously during period of initial dosage adjustment in patients with arrhythmias. Safety of SINEMET* in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not be given to nursing mothers. Effects on human pregnancy and lactation unknown. PRECAUTIONS General: Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET* to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptomatic postural hypotension has been reported occasionally, give cautiously to patients on antihypertensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypertensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Mest Cemmen: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be early signs of excessive Aiosage. Othr SerIous Reactlens: Oscillations in parformance: diurnal variations, independent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, akinesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Rarely convulsions (causal relationship not established). Cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness.
8 CMA JOURNAL/JULY 9, 1977/VOL 117
Other adverse reactions that may occur: Psychiatric: increased libido with serious antisocial behavior, euphoria, lethargy, sedation, stimulation, fatigue and malaise, confusion, insomnia, nightmares, hallucinations and delusions, agitation and anxiety. Nourologic: ataxia, faintness, impairment of gait, hoadache, increased hand tromor, akinotic episodes, 'akinesiaparadoxica', increase in the frequency and duration of the oscillations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, sialorrhea; difficulty in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific ECG changes, flushing, phlebitis. Hematologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskeletal: low beck pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, postnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. SpecialSenses: blurred vision, diplopia, dilated pupils, activation of latent Homers syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SINEMET*: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombs tests reported both with SINEMET* and with levodopa alone, but hemolytic anemia extremely rare. DOSAGE SUMMARY In order to reduce the incidence of adverse reactions and achieve maximal benefit, therapy with SINEMET* must be individualized and drug administration continuously matched to the needs and tolerance of the patient. Combined therapy with SINEMET* has a narrower therapeutic range than with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and recommended dosage ranges not be exceeded. Appearance of involuntary movements should be regarded as a sign of levodope toxicity and an indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias. Therapy in Patients not receiving Levodopa: Initially 1/2 tablet once or twice a day, increase by 'A tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy in Patients receiving Levodopa: Discontinue levodopa for at least 12 hours, then give approximately 20% of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRIBING INFORMATION, PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REQUEST. HOW SUPPLIED Ca8804-TabletsSl NEMET* .50, dapple-blue, oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100. MERCK
.Trademark
& DOHME CANADA LIMITED POINTE CLAIRE QUEBEC (5NM-7-487-JA)
ably the most common cause, occurs in ness. In 1971 a diabetic retinopathy both proliferative and nonproliferative study was set up by the National Eye retinopathy. It is identified ophthalmo- Institute of the United States as a scopically or by stereoscopic photo- nationwide, randomized, controlled, graphy as a swelling of the retina in the clinical trial to test the hypothesis that macula caused by accumulation of in- a certain method of photocoagulation, traretinal fluid. Fluorescein angio- namely panretinal photocoagulation, graphy visualizes the origin of this could prevent loss of vision in proliferfluid as points of leakage arising from ative diabetic retinopathy. From 15 retinal capillaries, microaneurysms, or clinical centres approximately 1700 paintraretinal microvascular abnormalities tients with symmetric proliferative diaimmediately adjacent to the fovea. Ma- betic retinopathy were registered in cular edema is treated by sealing the the study. All aspects of pretreatment points of leakage with a photocoagulat- visual assessment, documentation of ing beam to prevent further accumula- fundus findings, treatment protocol and tion of fluid in the macula. Although postoperative examinations were carethe technique yields good results in fully controlled from a coordinating many patients, no controlled study has centre by a team of ophthalmologists, been done to prove its effectiveness. epidemiologists and biostatisticians. Vitreous hemorrhage and retinal de- Only one eye, randomly chosen, was tachment occur only in proliferative treated with panretinal photocoaguladiabetic retinopathy. In retinitis proli- tion. At specific intervals following ferans neovascular channels grow out treatment both eyes were carefully of pre-existing retinal capillaries onto studied. the inner surface of the retina or the In April 1976, after 2 years of foloptic nerve. When the overlying vit- low-up, the results of this study demreous separates from the retina and onstrated significantly fewer episodes optic nerve the new vessels with the of loss of vision in treated eyes comdetaching vitreous are pulled forward pared with untreated eyes, the effect towards the centre of the eye. Since becoming more pronounced the longer neovascular channels have fragile walls, the follow-up. Subsequently the diabetic bleeding often develops both behind retinopathy study research group recand into the vitreous gel, resulting in ommended that all previously untreated opacification of the ocular media. Al- eyes should also receive photocoagulaternatively these neovascular channels tion.3 Based on the findings of this transmit the pull of the detaching vit- study, panretinal photocoagulation is reous back onto the retina, where the now considered to offer a notable dechannels originated, thus producing a gree of prophylaxis against blindness traction detachment of the retina. in eyes with proliferative diabetic retiBlindness results when the retinal de- nopathy. tachment spreads to involve the macula. In patients in whom vitreous hemUntil 1976 there was no effective orrhage or retinal detachment occurs method to prevent or modify the events because of lack of, or in spite of adthat occurred from the onset of proli- ministration of, panretinal photocoaguferative diabetic retinopathy to blind- lation, microscopic techniques of vitCMA JOURNAL/JULY 9, 1977/VOL. 117 7
reous surgery have been developed that can improve vision: a small, needle-like instrument is inserted through the side of the eye into the vitreous cavity, where the surgeon, by looking with an operating microscope through the cornea, can observe and control the cutting, sucking and infusing functions of the intraocular instrument. Thus intravitreal blood is removed and simultaneously replaced with an equal volume of saline. Modifications include techniques to peel away membranes on the surface of the retina and cauterize actively bleeding stalks of retinitis proliferans, and to inject materials into the vitreous cavity to provide an internal tamponade effect to push back detached retinas that do not reattach following cutting of visible traction bands. In May 1976 the results of a study of vitreous surgery in 100 eyes followed up for at least 6 months disclosed that vision was substantially improved in 50 eyes.4 Although surgical complications accounted for failures in 10 eyes the end result was determined more often by the degree of damage to the retina caused by diabetes than by technical difficulties at operation. Conversely, many patients obtained reading vision after having been blind for several years, since in these cases a relatively normal macula was found upon removal of intravitreal blood. The development of both effective prophylaxis against the complications of proliferative diabetic retinopathy and surgical treatment to correct some forms of blindness in persons with diabetes has improved the outlook for many who were threatened with blindness. Nevertheless, the finding of methods to prevent proliferative diabetic retinopathy and the understanding of the perplexing relation between diabetic retinopathy and systemic diabetes remain among the many mysteries still to be solved in the management of the ocular complications of diabetes. MARK MANDELCORN, MD, CM, FRC5[C] Department of ophthalmology Mount Sinai Hospital Toronto, Ont.
References 1. KAmI HA, MoomsRsn HB: Statistics on Blindness In the Model Reporting Area, 19691970, Us Dept of Health, Education, and Welfare, publ no (NIH) 73427, Washington, US Govt Printing Office, 1973 2. GOLDBERG MF, FINE SL (eds): Symposium on the Treatment of Diabetic Retinopathy, US Pubi Health Sery, no 1890, Washington, US Govt Printing Office, 1969 3. The Diabetic Ratinopathy Study Research Group: Preliminary report on the effects of photocoagulation. Am I Ophihalmol 81: 383, 1976 4. MANDELCOIN MS, BLANKENSHIP G, MACHEMER
R: Pars plana vitrectomy for the management of severe diabetic retinopathy. Ibid, p 561
(levodopa and carbidopa combination) INDICATIONS Treatment of Parkinson's syndrome with exception of drug induced parkinsonism. CONTRAINDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to starting SINEMET*; in uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucoma; in patients with suspicious, undiagnosed skin lesions or a history or melanoma. WARNINGS When given to patients receiving levodopa alone, discontinue levodopa at least 12 hours before initiating SINEMET* at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chorea. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon may appear earlier with combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored conti nuously during period of initial dosage adjustment in patients with arrhythmias. Safety of SINEMET* in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not be given to nursing mothers. Effects on human pregnancy and lactation unknown. PRECAUTIONS General: Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET* to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptomatic postural hypotension has been reported occasionally, give cautiously to patients on antihypertensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypertensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Mest Cemmen: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be early signs of excessive Aiosage. Othr SerIous Reactlens: Oscillations in parformance: diurnal variations, independent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, akinesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Rarely convulsions (causal relationship not established). Cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness.
8 CMA JOURNAL/JULY 9, 1977/VOL 117
Other adverse reactions that may occur: Psychiatric: increased libido with serious antisocial behavior, euphoria, lethargy, sedation, stimulation, fatigue and malaise, confusion, insomnia, nightmares, hallucinations and delusions, agitation and anxiety. Nourologic: ataxia, faintness, impairment of gait, hoadache, increased hand tromor, akinotic episodes, 'akinesiaparadoxica', increase in the frequency and duration of the oscillations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, sialorrhea; difficulty in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific ECG changes, flushing, phlebitis. Hematologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskeletal: low beck pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, postnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. SpecialSenses: blurred vision, diplopia, dilated pupils, activation of latent Homers syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SINEMET*: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombs tests reported both with SINEMET* and with levodopa alone, but hemolytic anemia extremely rare. DOSAGE SUMMARY In order to reduce the incidence of adverse reactions and achieve maximal benefit, therapy with SINEMET* must be individualized and drug administration continuously matched to the needs and tolerance of the patient. Combined therapy with SINEMET* has a narrower therapeutic range than with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and recommended dosage ranges not be exceeded. Appearance of involuntary movements should be regarded as a sign of levodope toxicity and an indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias. Therapy in Patients not receiving Levodopa: Initially 1/2 tablet once or twice a day, increase by 'A tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy in Patients receiving Levodopa: Discontinue levodopa for at least 12 hours, then give approximately 20% of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRIBING INFORMATION, PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REQUEST. HOW SUPPLIED Ca8804-TabletsSl NEMET* .50, dapple-blue, oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100. MERCK
.Trademark
& DOHME CANADA LIMITED POINTE CLAIRE QUEBEC (5NM-7-487-JA)
