CENTRAL RETINAL VEIN OCCLUSION IN A YOUNG ADULT DURING RISPERIDONE THERAPY Alper Ag˘ca, MD,* Zerrin Bayraktar, MD,* Mehmet C¸akır, MD,* ¨ zalp Ekinci, MD,† O ¨ mer Faruk Yılmaz, MD* S¸u¨kru¨ Bayraktar, MD,* O
Background: Various articles in the literature point out the higher risk of venous thrombosis in patients taking antipsychotic drugs. However, to our knowledge, an association with central retinal vein occlusion (CRVO) has not been reported before. Methods: We describe the clinical and angiographic findings of a patient with CRVO that may have been related to his antipsychotic medication. Results: A 19-year-old patient had been taking risperidone and fluoxetine for the last 7 months. He presented with atypical nonischemic CRVO with atypical deep intraretinal hemorrhages, a swollen optic disk, dilatation and engorgement of retinal veins, and optic disk capillaries. Despite a detailed workup, no systemic or ocular risk factors for a thromboembolic event were found. He had hyperprolactinemia resulting from his medication. Conclusion: The use of risperidone may be a risk factor for CRVO. RETINAL CASES & BRIEF REPORTS 2:199 –201, 2008
Case
From *Beyog˘lu Eye Research and Education Hospital, Eye Clinic; and †Marmara University Medical Faculty, School of Medicine, Department of Child and Adolescent Psychiatry, Istanbul, Turkey.
A 19-year-old man presented to our hospital with the complaint of sudden visual blurring in his left eye. His medical history revealed that he had been on antipsychotic therapy with risperidone (BID) and fluoxetine (BID) for the last 7 months. Visual acuity was 20/20 in the right eye and 20/40 in the left eye. Anterior segment examination and intraocular pressures were normal and there was no afferent pupillary defect. Fundus examination revealed increased tortuosity and engorgement of retinal veins, a hyperemic and edematous optic disk, and peripheral and macular retinal hemorrhages (Figure 1). The fundus of the right eye was normal. His arterial blood pressure was 110/70 mmHg. There was no history of a Valsalva maneuver. He was diagnosed with nonischemic central retinal vein occlusion and laboratory tests were scheduled for the workup of thromboembolism and blood dyscrasias. Two days later, his visual acuity improved to 20/25 although the fundus findings were not altered. Fluorescein angiography showed venous dilatation and tortuosity of the retinal and optic nerve head capillaries (Figure 2). There was fluorescein leakage from optic nerve head but there were no signs of retinal capillary nonperfusion or macular edema. There was minimal staining along the retinal veins where they enter the optic disk (Figure 3). Fifteen days after the initial presentation, visual acuity was 20/25 and most of the hemorrhages were cleared. Neither systemic nor ocular risk factors for thromboembolism could be identified during the follow-up period despite detailed physical/ophthalmologic examination and laboratory studies. The patient and the parents were not able to recall any event that may be associated with a family history of thromboembolism. Complete blood count
C
orneal endothelial deposits, lens opacities, conjunctival melanosis, and retinopathy may occur during therapy with antipsychotics. In addition to those well-known ophthalmologic and systemic side effects, various articles in the literature point to a higher risk of venous thrombosis in patients taking antipsychotic drugs.1 However, an association with central (or branch) retinal vein occlusion has not been reported before. In this report, we present a case of nonischemic central retinal vein occlusion in a 19-year-old patient (with no inherited or environmental risk factors for thromboembolism) during antipsychotic therapy with risperidone and fluoxetine. The patient also had high serum prolactin levels during the same period. No author has a financial or proprietary interest in any product mentioned. Reprint requests: Alper Agca, MD, Cumhuriyet Mahallesi, Arac Sokak, Gokkusagi Sitesi, A1 Blok, D: 16, Uskudar, Istanbul, Turkey; e-mail: [email protected]
199
200
RETINAL CASES & BRIEF REPORTSℜ
●
2008
●
VOLUME 2
●
NUMBER 3
Fig. 1. Fundus photograph of the left eye at presentation. Note the increased tortuosity and engorgement of retinal veins and deep retinal hemorrhages.
with peripheral smear, erythrocyte sedimentation rate, prothrombin time, partial thromboplastin time, serum protein electrophoresis, plasma homocysteine levels, serum biochemistry profile (including fasting glucose, lipid profile, liver and kidney function tests), antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), protein C, protein S, and antithrombin III were all within normal limits. Activated protein C resistance was not present and syphilis serology was negative. Serum prolactin levels were above the normal limit (possibly drug related). Since the use of atypical antipsychotics was reported to be associated with venous thromboembolism, the psychiatrist of the patient was recalled to change the antipsychotic agents. One month after discontinuation of risperidone, the patient was psychiatrically stable and prolactin level returned to normal limits.
Fig. 2. Fundus fluorescein angiography (0:30 minutes). Capillary nonperfusion is not present.
Fig. 3. Fundus fluorescein angiography (5:30 minutes). Macular edema is not present. Note the optic disk leakage.
His visual acuity was still 20/25 in his left eye, although he had noticed a subjective improvement. Four months later visual acuity was 20/20 in both eyes and the patient was psychiatrically stable. Hemorrhages were completely resorbed.
Discussion Venous obstructive disease of the retina is the second most common retinal vascular disorder after diabetic retinopathy. The exact pathogenesis of central retinal vein obstruction (CRVO) is not known; however, it is believed to be the result of a thrombus in the central retinal vein at or posterior to the lamina cribrosa. Although their relationship to the pathogenesis remains to be speculative, the most common associated diseases are hypertension, diabetes mellitus, and atherosclerotic heart disease and approximately 85% of the affected individuals are above the age of 45. However, CRVO can occur at any age and may be associated with various systemic diseases including blood dyscrasias, clotting disorders, paraproteinemia and dysproteinemias, vasculitic, and autoimmune disorders. Among systemic medications only oral contraceptives (which are well known to increase the incidence of thromboembolic events) were reported 2 to have an association with CRVO. The evidence strongly suggests that pathogenesis of retinal vein occlusion is a multifactorial process.3 The fundus findings of our patient are not typical for a CRVO. However, there is an occlusion (increased tortuosity, marked engorgement of retinal veins, and hemorrhages) to blood flow in central ret-
201
CRVO ASSOCIATED WITH RISPERIDONE
inal vein of our patient, and we do not speculate on other presumed pathophysiologic processes (papillophlebitis, optic disk vasculitis) by using nomenclature other than CRVO because this patient uses a medication that is known to be associated with increased risk of systemic venous thrombosis via an unknown pathophysiologic process and the clinical findings in the eye are unknown. Therefore, we used the broader term (and the result) CRVO. To our knowledge; the development of CRVO in a patient taking risperidone and/or fluoxetine has not been reported before. A case report cannot prove that there is a cause– effect relationship between risperidone or any other drug and CRVO. The aim of this case report is to bring the attention of clinicians to a possible association. The use of risperidone and fluoxetine was the only identified risk factor for CRVO in our patient. He was referred to an internist for proper evaluation of any possible systemic medical problems; however, no systemic or ocular risk factor could be identified other than his current medication and his family history was negative for any thromboembolic event. Fluoxetine has not been reported in association with thromboembolic events before but (although a rare finding) the association between conventional antipsychotics and thromboembolism is not a new concept.1 Risperidone is an atypical antipsychotic with dopamine, serotonin (5-HT), and ␣2 adrenergic receptor blocking properties and fluoxetine is a selective serotonin reuptake inhibitor. The metabolism of risperidone takes place in liver and is largely dependent on cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4. Fluoxetine is an inhibitor of these enzymes so it reduces the clearance of risperidone and this interaction may lead to an increased incidence of adverse effects.4 In addition, some individuals have genetic variants of CYP2D6 with decreased drug oxidation capacity and addition of fluoxetine in these individuals may further increase the incidence of adverse effects related to risperidone. Serum prolactin level (bioactive prolactin, not mac-
roprolactin) in our patient was 30.09 ng/mL. Although not a major elevation, this value is above the normal limits (4 –15 mg/mL). Hyperprolactinemia is a well known side effect of risperidone. Although the studies present conflicting findings, fluoxetine has also been reported to cause hyperprolactinemia. Hyperprolactinemia has been found to cause increased platelet activation via potentiating ADP effects on human platelets and increased prolactin levels are one of the suggested mechanisms by which some antipsychotics increase the incidence of venous thrombosis.5 In our case the psychiatrist was advised to switch to an alternative treatment other than risperidone after the diagnosis of CRVO and documentation of hyperprolactinemia. Four months after the medication change, the patient was psychiatrically stable and his visual acuity was still 20/20 in both eyes. In conclusion, the use of risperidone may be a risk factor for retinal venous occlusion. The mechanism for that association may be via increasing serum prolactin. Ophthalmologists should be aware of the situation and immediately contact the psychiatrist in similar cases for proper management.
References 1.
Hagg S, Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs 2002;16:765– 776. 2. Morley MG, Heier J. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed. St. Louis: Mosby; 2004:862–869. 3. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–66. 4. Spina E, Avenoso A, Scordo MG, et al. Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. J Clin Psychopharmacol 2002;22:419–423. 5. Wallaschofski H, Eigenthaler M, Kiefer M, et al. Hyperprolactinemia in patients on antipsychotic drugs causes ADPstimulated platelet activation that might explain the increased risk for venous thromboembolism: pilot study. J Clin Psychopharmacol 2003;23:479–483.
Background: Various articles in the literature point out the higher risk of venous thrombosis in patients taking antipsychotic drugs. However, to our knowledge, an association with central retinal vein occlusion (CRVO) has not been reported before. Methods: We describe the clinical and angiographic findings of a patient with CRVO that may have been related to his antipsychotic medication. Results: A 19-year-old patient had been taking risperidone and fluoxetine for the last 7 months. He presented with atypical nonischemic CRVO with atypical deep intraretinal hemorrhages, a swollen optic disk, dilatation and engorgement of retinal veins, and optic disk capillaries. Despite a detailed workup, no systemic or ocular risk factors for a thromboembolic event were found. He had hyperprolactinemia resulting from his medication. Conclusion: The use of risperidone may be a risk factor for CRVO. RETINAL CASES & BRIEF REPORTS 2:199 –201, 2008
Case
From *Beyog˘lu Eye Research and Education Hospital, Eye Clinic; and †Marmara University Medical Faculty, School of Medicine, Department of Child and Adolescent Psychiatry, Istanbul, Turkey.
A 19-year-old man presented to our hospital with the complaint of sudden visual blurring in his left eye. His medical history revealed that he had been on antipsychotic therapy with risperidone (BID) and fluoxetine (BID) for the last 7 months. Visual acuity was 20/20 in the right eye and 20/40 in the left eye. Anterior segment examination and intraocular pressures were normal and there was no afferent pupillary defect. Fundus examination revealed increased tortuosity and engorgement of retinal veins, a hyperemic and edematous optic disk, and peripheral and macular retinal hemorrhages (Figure 1). The fundus of the right eye was normal. His arterial blood pressure was 110/70 mmHg. There was no history of a Valsalva maneuver. He was diagnosed with nonischemic central retinal vein occlusion and laboratory tests were scheduled for the workup of thromboembolism and blood dyscrasias. Two days later, his visual acuity improved to 20/25 although the fundus findings were not altered. Fluorescein angiography showed venous dilatation and tortuosity of the retinal and optic nerve head capillaries (Figure 2). There was fluorescein leakage from optic nerve head but there were no signs of retinal capillary nonperfusion or macular edema. There was minimal staining along the retinal veins where they enter the optic disk (Figure 3). Fifteen days after the initial presentation, visual acuity was 20/25 and most of the hemorrhages were cleared. Neither systemic nor ocular risk factors for thromboembolism could be identified during the follow-up period despite detailed physical/ophthalmologic examination and laboratory studies. The patient and the parents were not able to recall any event that may be associated with a family history of thromboembolism. Complete blood count
C
orneal endothelial deposits, lens opacities, conjunctival melanosis, and retinopathy may occur during therapy with antipsychotics. In addition to those well-known ophthalmologic and systemic side effects, various articles in the literature point to a higher risk of venous thrombosis in patients taking antipsychotic drugs.1 However, an association with central (or branch) retinal vein occlusion has not been reported before. In this report, we present a case of nonischemic central retinal vein occlusion in a 19-year-old patient (with no inherited or environmental risk factors for thromboembolism) during antipsychotic therapy with risperidone and fluoxetine. The patient also had high serum prolactin levels during the same period. No author has a financial or proprietary interest in any product mentioned. Reprint requests: Alper Agca, MD, Cumhuriyet Mahallesi, Arac Sokak, Gokkusagi Sitesi, A1 Blok, D: 16, Uskudar, Istanbul, Turkey; e-mail: [email protected]
199
200
RETINAL CASES & BRIEF REPORTSℜ
●
2008
●
VOLUME 2
●
NUMBER 3
Fig. 1. Fundus photograph of the left eye at presentation. Note the increased tortuosity and engorgement of retinal veins and deep retinal hemorrhages.
with peripheral smear, erythrocyte sedimentation rate, prothrombin time, partial thromboplastin time, serum protein electrophoresis, plasma homocysteine levels, serum biochemistry profile (including fasting glucose, lipid profile, liver and kidney function tests), antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), protein C, protein S, and antithrombin III were all within normal limits. Activated protein C resistance was not present and syphilis serology was negative. Serum prolactin levels were above the normal limit (possibly drug related). Since the use of atypical antipsychotics was reported to be associated with venous thromboembolism, the psychiatrist of the patient was recalled to change the antipsychotic agents. One month after discontinuation of risperidone, the patient was psychiatrically stable and prolactin level returned to normal limits.
Fig. 2. Fundus fluorescein angiography (0:30 minutes). Capillary nonperfusion is not present.
Fig. 3. Fundus fluorescein angiography (5:30 minutes). Macular edema is not present. Note the optic disk leakage.
His visual acuity was still 20/25 in his left eye, although he had noticed a subjective improvement. Four months later visual acuity was 20/20 in both eyes and the patient was psychiatrically stable. Hemorrhages were completely resorbed.
Discussion Venous obstructive disease of the retina is the second most common retinal vascular disorder after diabetic retinopathy. The exact pathogenesis of central retinal vein obstruction (CRVO) is not known; however, it is believed to be the result of a thrombus in the central retinal vein at or posterior to the lamina cribrosa. Although their relationship to the pathogenesis remains to be speculative, the most common associated diseases are hypertension, diabetes mellitus, and atherosclerotic heart disease and approximately 85% of the affected individuals are above the age of 45. However, CRVO can occur at any age and may be associated with various systemic diseases including blood dyscrasias, clotting disorders, paraproteinemia and dysproteinemias, vasculitic, and autoimmune disorders. Among systemic medications only oral contraceptives (which are well known to increase the incidence of thromboembolic events) were reported 2 to have an association with CRVO. The evidence strongly suggests that pathogenesis of retinal vein occlusion is a multifactorial process.3 The fundus findings of our patient are not typical for a CRVO. However, there is an occlusion (increased tortuosity, marked engorgement of retinal veins, and hemorrhages) to blood flow in central ret-
201
CRVO ASSOCIATED WITH RISPERIDONE
inal vein of our patient, and we do not speculate on other presumed pathophysiologic processes (papillophlebitis, optic disk vasculitis) by using nomenclature other than CRVO because this patient uses a medication that is known to be associated with increased risk of systemic venous thrombosis via an unknown pathophysiologic process and the clinical findings in the eye are unknown. Therefore, we used the broader term (and the result) CRVO. To our knowledge; the development of CRVO in a patient taking risperidone and/or fluoxetine has not been reported before. A case report cannot prove that there is a cause– effect relationship between risperidone or any other drug and CRVO. The aim of this case report is to bring the attention of clinicians to a possible association. The use of risperidone and fluoxetine was the only identified risk factor for CRVO in our patient. He was referred to an internist for proper evaluation of any possible systemic medical problems; however, no systemic or ocular risk factor could be identified other than his current medication and his family history was negative for any thromboembolic event. Fluoxetine has not been reported in association with thromboembolic events before but (although a rare finding) the association between conventional antipsychotics and thromboembolism is not a new concept.1 Risperidone is an atypical antipsychotic with dopamine, serotonin (5-HT), and ␣2 adrenergic receptor blocking properties and fluoxetine is a selective serotonin reuptake inhibitor. The metabolism of risperidone takes place in liver and is largely dependent on cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4. Fluoxetine is an inhibitor of these enzymes so it reduces the clearance of risperidone and this interaction may lead to an increased incidence of adverse effects.4 In addition, some individuals have genetic variants of CYP2D6 with decreased drug oxidation capacity and addition of fluoxetine in these individuals may further increase the incidence of adverse effects related to risperidone. Serum prolactin level (bioactive prolactin, not mac-
roprolactin) in our patient was 30.09 ng/mL. Although not a major elevation, this value is above the normal limits (4 –15 mg/mL). Hyperprolactinemia is a well known side effect of risperidone. Although the studies present conflicting findings, fluoxetine has also been reported to cause hyperprolactinemia. Hyperprolactinemia has been found to cause increased platelet activation via potentiating ADP effects on human platelets and increased prolactin levels are one of the suggested mechanisms by which some antipsychotics increase the incidence of venous thrombosis.5 In our case the psychiatrist was advised to switch to an alternative treatment other than risperidone after the diagnosis of CRVO and documentation of hyperprolactinemia. Four months after the medication change, the patient was psychiatrically stable and his visual acuity was still 20/20 in both eyes. In conclusion, the use of risperidone may be a risk factor for retinal venous occlusion. The mechanism for that association may be via increasing serum prolactin. Ophthalmologists should be aware of the situation and immediately contact the psychiatrist in similar cases for proper management.
References 1.
Hagg S, Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs 2002;16:765– 776. 2. Morley MG, Heier J. Venous obstructive disease of the retina. In: Yanoff M, Duker JS, eds. Ophthalmology, 2nd ed. St. Louis: Mosby; 2004:862–869. 3. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–66. 4. Spina E, Avenoso A, Scordo MG, et al. Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. J Clin Psychopharmacol 2002;22:419–423. 5. Wallaschofski H, Eigenthaler M, Kiefer M, et al. Hyperprolactinemia in patients on antipsychotic drugs causes ADPstimulated platelet activation that might explain the increased risk for venous thromboembolism: pilot study. J Clin Psychopharmacol 2003;23:479–483.
