KYRIELEIS PLAQUES ASSOCIATED WITH ACUTE RETINAL NECROSIS FROM HERPES SIMPLEX VIRUS TYPE 2 Matthew T. Witmer, MD,* Grace A. Levy-Clarke, MD,*† Bradley D. Fouraker, MD,* Brian Madow, MD*
Purpose: To present the case of a 19-year-old woman with acute retinal necrosis syndrome due to herpes simplex virus type 2, who developed segmental periarterial (Kyrieleis) plaques six and one half weeks into her clinical course. Methods: Retrospective case report. Patients: Single patient with the diagnosis of acute retinal necrosis syndrome. Results: The patient’s vitreous biopsy was positive by polymerase chain reaction for herpes simplex virus type 2. Discussion: Kyrieleis plaques have been found in the setting of toxoplasmosis, tuberculosis, syphilis, rickettsial disease, herpes zoster virus, intraocular lymphoma, and idiopathic branch retinal artery occlusions. The differential diagnosis for these periarterial plaques should also include herpes simplex virus type 2. RETINAL CASES & BRIEF REPORTS 5:297–301, 2011
evidence of vascular leakage (Figure 3). Her laboratory workup showed an elevated white blood cell count (12.1) and C-reactive protein (3.414) but normal erythrocyte sedimentation rate (7). Analysis of her cerebrospinal fluid revealed a lymphocyte pleocytosis but negative culture and Gram stain. The patient was diagnosed with panuveitis and papillitis and admitted to the hospital for empiric treatment of unilateral acute retinal necrosis (ARN) syndrome. She was treated with intravenous acyclovir for 10 days and discharged home on oral valacyclovir, 1000 mg thrice daily, and prednisone 60 mg orally daily. Within 6 days of the initiation of treatment, the patient’s vision in the left eye deteriorated to counting fingers at 2 ft. She also received three intravitreal injections of 2.4 mg foscarnet throughout the course of her treatment. Five weeks after presentation, she underwent a vitrectomy with endolaser demarcation. Intraoperatively, she demonstrated no retinal detachment, but had large amounts of necrosis anteriorly. A polymerase chain reaction of the vitreous was positive for herpes simplex virus type 2 (HSV-2). One week later, her optic nerve was pale and swollen, and she presented with Kyrieleis plaques along three retinal arterioles, nasal to the optic nerve (Figure 4). No fluorescein angiogram was performed at this time. Her final visual acuity postoperatively, with an attached retina, was counting fingers at 5 ft. The poor vision was attributed to ARN-associated optic neuropathy.
From the *Department of Ophthalmology, University of South Florida, College of Medicine, Tampa, Florida; and †St. Luke’s Cataract and Laser Institute, Tarpon Springs, Florida.
Case Report
A
19-year-old healthy woman presented with a 4-day history of redness and blurred vision in her left eye. Her visual acuity was 20/ 15 in the right eye and 20/200 in the left eye. Intraocular pressure was 14 in both eyes. The patient demonstrated a relative afferent pupillary defect left eye. The slit-lamp and dilated fundus examinations of the right eye were normal. The slit-lamp examination of the left eye demonstrated 1+ episcleral injection, granulomatous keratic precipitates, 2+ cell and flare in the anterior chamber, and a clear lens. A dilated fundus examination of the left eye revealed 1+ vitreous cells, 3+ optic nerve edema, and central macula edema with a macular star pattern (Figure 1). Her peripheral retinal examination showed 360° of peripheral retinitis, with associated vasculitis and necrosis that was most prominent in the temporal periphery (Figure 2). Fluorescein angiography showed hyperfluorescence of the left optic nerve head but no
The authors have no conflicts of interest to disclose. Presented at Wills Eye Retina Club Meeting 2009, Wills Eye Hospital, Philadelphia, PA, November 13, 2009. Reprint requests: Dr Matthew T. Witmer, MD, Department of Ophthalmology, University of South Florida, College of Medicine, 12901 Bruce B. Downs Boulevard, MDC 21, Tampa, FL 33612; e-mail: [email protected]
Discussion Acute retinal necrosis syndrome is a devastating ocular inflammatory condition that was first described in 1971.1 Subsequently, Holland and the executive 297
298
RETINAL CASES & BRIEF REPORTS´ 2011 VOLUME 5 NUMBER 4
Fig. 1. Color fundus photograph of the left eye demonstrating vitreous inflammation, optic nerve edema, and macular edema with a macular star pattern.
Fig. 3. Fluorescein angiogram of the fundus of the left eye at 43 seconds demonstrating hyperfluorescence of the optic nerve head with normal filling of retinal vasculature.
committee of the American Uveitis Society recommended a definition that required the following clinical characteristics: 1) focal well-demarcated areas of retinal necrosis located in the peripheral retina (outside the major vascular arcades); 2) rapid circumferential progression of necrosis (if no antiviral has been used); 3) evidence of occlusive vasculopathy; and 4) a prominent inflammatory reaction in the anterior chamber and vitreous.2 The identification of the causative agents of ARN syndrome occurred more than a decade after its initial description. In 1986, through the use of immunocytopathologic stains on specimens from an enucleated eye with ARN in the acute phase, varicella zoster virus was identified as the first cause of ARN syndrome.3
Subsequently, Lewis et al4 were the first to present 2 cases of ARN syndrome in which HSV-1 was isolated from the vitreous. Years later, Thompson reported reactivation of HSV-2 as a cause of the ARN syndrome.5 Several case series have reported the percentage of cases of ARN syndrome that are caused by each type of herpes virus. Varicella zoster virus is responsible for between 46.4% and 87% of ARN syndrome cases,6–9
Fig. 2. Color photograph of temporal retinal periphery at presentation. The retina demonstrates peripheral retinal vasculitis and necrosis.
Fig. 4. Color montage photograph of the left eye six and one half weeks after presentation, revealing yellowish periarterial (Kyrieleis) plaques along the length of three retinal arterioles.
KYRIELEIS PLAQUES ASSOCIATED WITH HSV-2
whereas the percentage of cases attributed to HSV has ranged from 17% to 46.4%.6–8 The median age of patients with ARN syndrome from HSV-1 and HSV-2 has been reported as 47 years and 20 years, respectively. In contrast, the median age for patients with ARN syndrome because of varicella zoster virus is 57 years.6 Acute retinal necrosis syndrome may present unilaterally or bilaterally.10,11 Early reports of bilateral cases referred to the condition as bilateral acute retinal necrosis.11 A retrospective review of the treatment of patients with unilateral ARN syndrome with acyclovir demonstrated a reduction in the risk of involvement to the fellow eye compared with patients who did not receive antiviral medication.12 The first case of segmental periarteritis of the retina was reported by Peters in 1929.13 Kyrieleis, however, gave the first description of periarterial plaques occurring in association with uveitis.14 Segmental periarteritis (Kyrieleis plaques) consists of whitish segmented deposits, which are scattered along the retinal arterial branches.15 These plaques do not appear to be intraluminal or endothelial atherosclerotic plaques or emboli but rather are deposits in the outer walls of the retinal arterioles.15,16 Therefore, Kyrieleis plaques should be differentiated from diffuse retinal vessel emboli.16 Retinal artery sheathing in adjacent arteries and arterioles often accompanies the segmental distribution of plaques. Segmental periarteritis is frequently associated with uveitis.17 The inflammation of the uvea may be anterior or posterior in location.15–17 Active or healed chorioretinal foci of inflammation are frequently found near the involved arteries.15,18 The uveal inflammation may be so intense that the arterial plaques can only be visualized once the uveitis has subsided.17 The plaques may disappear when a patch of associated choroiditis heals, or with corticosteroid or antibiotic treatment.15 Some plaques, however, may remain indefinitely.16,17 Fluorescein angiography of Kyrieleis plaques has demonstrated that the arterioles containing the plaques often appear normal, and the plaques themselves do not fluoresce.15 The angiogram also fails to demonstrate any delay in arterial filling in many cases.16 Although fluorescein does not leak from the retinal arterioles, retinal veins in these patients may be dilated and demonstrate fluorescent staining and leakage.15 In some cases, however, the retinal veins may appear normal angiographically.19 The fluorescein angiogram often helps to distinguish the periarterial deposits from diffuse retinal emboli, should the clinical scenario be uncertain. The recognized causes of Kyrieleis plaques have become more numerous throughout time. Kyrieleis
299
initially described periarterial deposits in association with ocular tuberculosis.14 Subsequently, Kyrieleis plaques have been described in association with toxoplasmosis,20 syphilis,16,21 Mediterranean spotted fever,22 herpes zoster virus–associated ARN syndrome,23 intraocular lymphoma,24 arterial macroaneurysms,23 and associated with collagen vascular disease.25 The underlying etiology of Kyrieleis plaques may determine the potential for these plaques to present bilaterally. In toxoplasmosis, the plaques are typically found in the same quadrant as the focus of retinochoroiditis and may simulate arterial emboli.20,26 Fluorescein angiography demonstrates no permeability alterations or evidence of artery obstruction in the area of the arterial plaques but demonstrates marked fluorescence in the area of the retinitis.20 The periarterial plaques may fade or persist after resolution of the retinitis. Kyrieleis plaques have also been associated with recurrent episodes of multiple branch retinal artery occlusions.23,27 Patients with this condition are apparently healthy but have recurrent bouts of branch retinal artery occlusions over decades. There is usually an absence of intraocular inflammation and sparing of the central vision.28 Gass et al28 presented nine cases of this condition, and vitreous cells were noted in only one patient. These recurrent obstructions are not believed to be embolic in nature because no visible emboli or source of emboli have been identified in these patients.28 It is believed that focal arteritis and arterioloitis, which may be caused by the deposition of immune complexes into the arterial wall, may be the etiology of the occlusions.23 Sheathing and periarterial yellow-white plaques often develop along the obstructed arterial segment and may remain permanently.23 These plaques have been described as very similar to those that appear as a result of active retinochoroiditis from toxoplasmosis.23 In these patients, the fluorescein angiogram may demonstrate leakage from the retinal arteriole with segmental periarteritis plaques;23,27 however, most sheathed white arterial segments show prompt perfusion and no obvious angiographic abnormalities.28 An association of idiopathic recurrent branch retinal artery occlusion with auditory symptoms, such as tinnitus and hearing loss, and encephalopathy has also been identified.29 This syndrome, known as Susac syndrome, has been most frequently reported in women. These patients may develop yellow to yellowwhite retinal arterial wall plaques, which occur at midarteriolar segments, away from retinal bifurcations.30 In one retrospective case series of four patients with the syndrome, periarterial plaques were reported to occur in six of eight eyes. The plaques resolved in four of these
300
RETINAL CASES & BRIEF REPORTS´ 2011 VOLUME 5 NUMBER 4
eyes after treatment with immunosuppressive agents. On fluorescein angiography, there was no occlusion at the sites of the retinal arterial wall plaques.30 Gass et al had recognized the association of multiple retinal artery occlusions with auditory and central nervous system abnormalities and suggested that the clinical findings were because of the localized immune-mediated reaction in the retinal arterial walls, which were also affecting arteries elsewhere in the body, such as the inner ear and brain.28 Although the exact cause of Kyrieleis plaques is undetermined, several theories have attempted to explain this clinical phenotype. Kyrieleis initially attributed the plaques to a local allergic reaction to the bacteria that causes tuberculosis.14 Additional authors have similarly claimed that the plaques represent an immunologic response to an infectious etiology, which result in the deposition of inflammatory cells within the vascular wall.31 According to this hypothesis, segmental periarteritis is allergic in nature and results from an immune reaction to bacterial antigen or drugs.15,18 An allergic reaction could account for the occasional resolution of these lesions after corticosteroid therapy.18 Others believe that the deposits represent migration of exudate from active areas of choroiditis into the periarterial sheaths.18 This hypothesis, however, has difficulty explaining the presence of these plaques in patients with idiopathic recurrent branch retinal artery occlusions because these patients often do not demonstrate active areas of choroidal inflammation. An additional theory claims that the lesions are nonobstructive atheromatous plaques, which occur at focal sites of retinal arterial wall damage.23 The mechanism by which this would occur involves the slow extravasation of blood lipids into the arterial walls. This theory was supported by histologic findings from a patient with non–Hodgkin large cell lymphoma and multiple yellow retinal arterial wall plaques.24 This patient’s enucleation specimen demonstrated that the lumen of many arteries was narrowed by both tumor infiltration of the arterial wall and subendothelial infiltration of lipid-laden macrophages.24 The authors of this study believed that the lymphomatous infiltration caused damage to the arterial endothelium and allowed passage of serum lipids into the arterial wall. Macrophages responded to this material, and an ‘‘atheroma’’ was formed.24 Incidentally, elevated serum cholesterol has never been firmly associated with this phenotype in the literature. The exact mechanism for the development of Kyrieleis plaques remains unknown. This is partly because of the absence of pathologic studies of these arteriole wall plaques in patients with infectious
disease. Additional histologic examinations of eyes with these arterial lesions would provide a more precise identification of the composition of these plaques and help to elucidate the true etiology and mechanism for the development of these lesions. The differential diagnosis of segmental retinal periarteritis has become extensive. This is the first case to our knowledge of HSV-2 retinitis to present with Kyrieleis plaques. This case underscores the importance of including HSV-2–associated ARN syndrome on the differential diagnosis of segmental retinal periarteritis. Key words: acute retinal necrosis syndrome, herpes simplex virus, Kyrieleis plaques, retinal arterial wall plaques, segmental periarteritis. References 1. Urayama A, Yamada N, Sasaki T. Unilateral acute uveitis with periarteritis and detachment. Jpn J Clin Ophthalmol 1971;25: 607–619. 2. Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol 1994;117:663–667. 3. Culbertson WW, Blumenkranz MS, Pepose JS, Stewart JA, Curtin VT. Varicella zoster virus is a cause of the acute retinal necrosis syndrome. Ophthalmology 1986;93:559–569. 4. Lewis ML, Culbertson WW, Post JD, Miller D, Kokame GT, Dix RD. Herpes simplex virus type 1. A cause of the acute retinal necrosis syndrome. Ophthalmology 1989;96:875–878. 5. Thompson WS, Culbertson WW, Smiddy WE, Robertson JE, Rosenbaum JT. Acute retinal necrosis caused by reactivation of herpes simplex virus type 2. Am J Ophthalmol 1994;118:205– 211. 6. Ganatra JB, Chandler D, Santos C, Kuppermann B, Margolis TP. Viral causes of the acute retinal necrosis syndrome. Am J Ophthalmol 2000;129:166–172. 7. Hillenkamp J, Nolle B, Bruns C, Rautenberg P, Fickenscher H, Roider J. Acute retinal necrosis: clinical features, early vitrectomy, and outcomes. Ophthalmology 2009;116:1971,5.e2. 8. Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis features, management, and outcomes. Ophthalmology 2007;114:756–762. 9. Muthiah MN, Michaelides M, Child CS, Mitchell SM. Acute retinal necrosis: a national population-based study to assess the incidence, methods of diagnosis, treatment strategies and outcomes in the UK. Br J Ophthalmol 2007;91:1452–1455. 10. Willerson D Jr, Aaberg TM, Reeser FH. Necrotizing vasoocclusive retinitis. Am J Ophthalmol 1977;84:209–219. 11. Young NJ, Bird AC. Bilateral acute retinal necrosis. Br J Ophthalmol 1978;62:581–590. 12. Palay DA, Sternberg P Jr, Davis J, et al. Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol 1991;112:250–255. 13. Peters H. Metastase nach scheeiwerotlauf. im auge. Klin Mbl Augenheilk 1929;83:25. 14. Kyrieleis W. Uber atypische gerfaesstuberkulose der netzhaut (periarteritis ‘‘nodosa’’ tuberculosa). Arch Augenheilkd 1933; 107:182–190. 15. Orzalesi N, Ricciardi L. Segmental retinal periarteritis. Am J Ophthalmol 1971;72:55–59.
KYRIELEIS PLAQUES ASSOCIATED WITH HSV-2 16. Crouch ER Jr, Goldberg MF. Retinal periarteritis secondary to syphilis. Arch Ophthalmol 1975;93:384–387. 17. Blach RK. Segmental lesions of the retinal arteries. Br J Ophthalmol 1960;44:562–566. 18. Griffin AO, Bodian M. Segmental retinal periarteritis; a report of three cases. Am J Ophthalmol 1959;47:544–548. 19. Rask JA. Periarteritis retinalis segmentalis. Acta Ophthamol 1969;47:234. 20. Gass J. Toxoplasmosis retinitis. In: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. St Louis, MO: Mosby; 1997:614–622. 21. Krishnamurthy R, Cunningham ET. Atypical presentation of syphilitic uveitis associated with Kyrieleis plaques. Br J Ophthalmol 2008;92:1152–1153. 22. Khairallah M, Ladjimi A, Chakroun M, et al. Posterior segment manifestations of Rickettsia conorii infection. Ophthalmology 2004;111:529–534. 23. Gass J. Idiopathic recurrent branch retinal arterial occlusion. In: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. St Louis, MO: Mosby; 1997:458–462.
301 24. Gass JD, Trattler HL. Retinal artery obstruction and atheromas associated with non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol 1991;109:1134–1139. 25. Gass J. Occlusive retinal arterial and arteriolar diseases. In: Stereoscopic Atlas of Macular Diseases; Diagnosis and Treatment. 3rd ed. St Louis, MO: Mosby; 1987:348–355. 26. Baglivo E, Safran AB. Haemorrhagic toxoplasmic retinochoroiditis: description of an unusual clinical presentation. Br J Ophthalmol 2003;87:1051–1052. 27. Kayazawa F, Sonoda K. Segmental retinal periarteritis with branch arterial occlusion. Ann Ophthalmol 1983;15: 584–586. 28. Gass JD, Tiedeman J, Thomas MA. Idiopathic recurrent branch retinal arterial occlusion. Ophthalmology 1986;93:1148–1157. 29. Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain and retina. Neurology 1979;29:313–316. 30. Egan RA, Ha Nguyen T, Gass JD, Rizzo JF 3rd, Tivnan J, Susac JO. Retinal arterial wall plaques in Susac syndrome. Am J Ophthalmol 2003;135:483–486. 31. Rodenhauser J. Clinical findings and pathogenesis of Kyrieleis’ discontinuous reversible arteriopathy in uveitis. Klin Monatsbl Augenheilkd 1969;155:234–243.
Purpose: To present the case of a 19-year-old woman with acute retinal necrosis syndrome due to herpes simplex virus type 2, who developed segmental periarterial (Kyrieleis) plaques six and one half weeks into her clinical course. Methods: Retrospective case report. Patients: Single patient with the diagnosis of acute retinal necrosis syndrome. Results: The patient’s vitreous biopsy was positive by polymerase chain reaction for herpes simplex virus type 2. Discussion: Kyrieleis plaques have been found in the setting of toxoplasmosis, tuberculosis, syphilis, rickettsial disease, herpes zoster virus, intraocular lymphoma, and idiopathic branch retinal artery occlusions. The differential diagnosis for these periarterial plaques should also include herpes simplex virus type 2. RETINAL CASES & BRIEF REPORTS 5:297–301, 2011
evidence of vascular leakage (Figure 3). Her laboratory workup showed an elevated white blood cell count (12.1) and C-reactive protein (3.414) but normal erythrocyte sedimentation rate (7). Analysis of her cerebrospinal fluid revealed a lymphocyte pleocytosis but negative culture and Gram stain. The patient was diagnosed with panuveitis and papillitis and admitted to the hospital for empiric treatment of unilateral acute retinal necrosis (ARN) syndrome. She was treated with intravenous acyclovir for 10 days and discharged home on oral valacyclovir, 1000 mg thrice daily, and prednisone 60 mg orally daily. Within 6 days of the initiation of treatment, the patient’s vision in the left eye deteriorated to counting fingers at 2 ft. She also received three intravitreal injections of 2.4 mg foscarnet throughout the course of her treatment. Five weeks after presentation, she underwent a vitrectomy with endolaser demarcation. Intraoperatively, she demonstrated no retinal detachment, but had large amounts of necrosis anteriorly. A polymerase chain reaction of the vitreous was positive for herpes simplex virus type 2 (HSV-2). One week later, her optic nerve was pale and swollen, and she presented with Kyrieleis plaques along three retinal arterioles, nasal to the optic nerve (Figure 4). No fluorescein angiogram was performed at this time. Her final visual acuity postoperatively, with an attached retina, was counting fingers at 5 ft. The poor vision was attributed to ARN-associated optic neuropathy.
From the *Department of Ophthalmology, University of South Florida, College of Medicine, Tampa, Florida; and †St. Luke’s Cataract and Laser Institute, Tarpon Springs, Florida.
Case Report
A
19-year-old healthy woman presented with a 4-day history of redness and blurred vision in her left eye. Her visual acuity was 20/ 15 in the right eye and 20/200 in the left eye. Intraocular pressure was 14 in both eyes. The patient demonstrated a relative afferent pupillary defect left eye. The slit-lamp and dilated fundus examinations of the right eye were normal. The slit-lamp examination of the left eye demonstrated 1+ episcleral injection, granulomatous keratic precipitates, 2+ cell and flare in the anterior chamber, and a clear lens. A dilated fundus examination of the left eye revealed 1+ vitreous cells, 3+ optic nerve edema, and central macula edema with a macular star pattern (Figure 1). Her peripheral retinal examination showed 360° of peripheral retinitis, with associated vasculitis and necrosis that was most prominent in the temporal periphery (Figure 2). Fluorescein angiography showed hyperfluorescence of the left optic nerve head but no
The authors have no conflicts of interest to disclose. Presented at Wills Eye Retina Club Meeting 2009, Wills Eye Hospital, Philadelphia, PA, November 13, 2009. Reprint requests: Dr Matthew T. Witmer, MD, Department of Ophthalmology, University of South Florida, College of Medicine, 12901 Bruce B. Downs Boulevard, MDC 21, Tampa, FL 33612; e-mail: [email protected]
Discussion Acute retinal necrosis syndrome is a devastating ocular inflammatory condition that was first described in 1971.1 Subsequently, Holland and the executive 297
298
RETINAL CASES & BRIEF REPORTS´ 2011 VOLUME 5 NUMBER 4
Fig. 1. Color fundus photograph of the left eye demonstrating vitreous inflammation, optic nerve edema, and macular edema with a macular star pattern.
Fig. 3. Fluorescein angiogram of the fundus of the left eye at 43 seconds demonstrating hyperfluorescence of the optic nerve head with normal filling of retinal vasculature.
committee of the American Uveitis Society recommended a definition that required the following clinical characteristics: 1) focal well-demarcated areas of retinal necrosis located in the peripheral retina (outside the major vascular arcades); 2) rapid circumferential progression of necrosis (if no antiviral has been used); 3) evidence of occlusive vasculopathy; and 4) a prominent inflammatory reaction in the anterior chamber and vitreous.2 The identification of the causative agents of ARN syndrome occurred more than a decade after its initial description. In 1986, through the use of immunocytopathologic stains on specimens from an enucleated eye with ARN in the acute phase, varicella zoster virus was identified as the first cause of ARN syndrome.3
Subsequently, Lewis et al4 were the first to present 2 cases of ARN syndrome in which HSV-1 was isolated from the vitreous. Years later, Thompson reported reactivation of HSV-2 as a cause of the ARN syndrome.5 Several case series have reported the percentage of cases of ARN syndrome that are caused by each type of herpes virus. Varicella zoster virus is responsible for between 46.4% and 87% of ARN syndrome cases,6–9
Fig. 2. Color photograph of temporal retinal periphery at presentation. The retina demonstrates peripheral retinal vasculitis and necrosis.
Fig. 4. Color montage photograph of the left eye six and one half weeks after presentation, revealing yellowish periarterial (Kyrieleis) plaques along the length of three retinal arterioles.
KYRIELEIS PLAQUES ASSOCIATED WITH HSV-2
whereas the percentage of cases attributed to HSV has ranged from 17% to 46.4%.6–8 The median age of patients with ARN syndrome from HSV-1 and HSV-2 has been reported as 47 years and 20 years, respectively. In contrast, the median age for patients with ARN syndrome because of varicella zoster virus is 57 years.6 Acute retinal necrosis syndrome may present unilaterally or bilaterally.10,11 Early reports of bilateral cases referred to the condition as bilateral acute retinal necrosis.11 A retrospective review of the treatment of patients with unilateral ARN syndrome with acyclovir demonstrated a reduction in the risk of involvement to the fellow eye compared with patients who did not receive antiviral medication.12 The first case of segmental periarteritis of the retina was reported by Peters in 1929.13 Kyrieleis, however, gave the first description of periarterial plaques occurring in association with uveitis.14 Segmental periarteritis (Kyrieleis plaques) consists of whitish segmented deposits, which are scattered along the retinal arterial branches.15 These plaques do not appear to be intraluminal or endothelial atherosclerotic plaques or emboli but rather are deposits in the outer walls of the retinal arterioles.15,16 Therefore, Kyrieleis plaques should be differentiated from diffuse retinal vessel emboli.16 Retinal artery sheathing in adjacent arteries and arterioles often accompanies the segmental distribution of plaques. Segmental periarteritis is frequently associated with uveitis.17 The inflammation of the uvea may be anterior or posterior in location.15–17 Active or healed chorioretinal foci of inflammation are frequently found near the involved arteries.15,18 The uveal inflammation may be so intense that the arterial plaques can only be visualized once the uveitis has subsided.17 The plaques may disappear when a patch of associated choroiditis heals, or with corticosteroid or antibiotic treatment.15 Some plaques, however, may remain indefinitely.16,17 Fluorescein angiography of Kyrieleis plaques has demonstrated that the arterioles containing the plaques often appear normal, and the plaques themselves do not fluoresce.15 The angiogram also fails to demonstrate any delay in arterial filling in many cases.16 Although fluorescein does not leak from the retinal arterioles, retinal veins in these patients may be dilated and demonstrate fluorescent staining and leakage.15 In some cases, however, the retinal veins may appear normal angiographically.19 The fluorescein angiogram often helps to distinguish the periarterial deposits from diffuse retinal emboli, should the clinical scenario be uncertain. The recognized causes of Kyrieleis plaques have become more numerous throughout time. Kyrieleis
299
initially described periarterial deposits in association with ocular tuberculosis.14 Subsequently, Kyrieleis plaques have been described in association with toxoplasmosis,20 syphilis,16,21 Mediterranean spotted fever,22 herpes zoster virus–associated ARN syndrome,23 intraocular lymphoma,24 arterial macroaneurysms,23 and associated with collagen vascular disease.25 The underlying etiology of Kyrieleis plaques may determine the potential for these plaques to present bilaterally. In toxoplasmosis, the plaques are typically found in the same quadrant as the focus of retinochoroiditis and may simulate arterial emboli.20,26 Fluorescein angiography demonstrates no permeability alterations or evidence of artery obstruction in the area of the arterial plaques but demonstrates marked fluorescence in the area of the retinitis.20 The periarterial plaques may fade or persist after resolution of the retinitis. Kyrieleis plaques have also been associated with recurrent episodes of multiple branch retinal artery occlusions.23,27 Patients with this condition are apparently healthy but have recurrent bouts of branch retinal artery occlusions over decades. There is usually an absence of intraocular inflammation and sparing of the central vision.28 Gass et al28 presented nine cases of this condition, and vitreous cells were noted in only one patient. These recurrent obstructions are not believed to be embolic in nature because no visible emboli or source of emboli have been identified in these patients.28 It is believed that focal arteritis and arterioloitis, which may be caused by the deposition of immune complexes into the arterial wall, may be the etiology of the occlusions.23 Sheathing and periarterial yellow-white plaques often develop along the obstructed arterial segment and may remain permanently.23 These plaques have been described as very similar to those that appear as a result of active retinochoroiditis from toxoplasmosis.23 In these patients, the fluorescein angiogram may demonstrate leakage from the retinal arteriole with segmental periarteritis plaques;23,27 however, most sheathed white arterial segments show prompt perfusion and no obvious angiographic abnormalities.28 An association of idiopathic recurrent branch retinal artery occlusion with auditory symptoms, such as tinnitus and hearing loss, and encephalopathy has also been identified.29 This syndrome, known as Susac syndrome, has been most frequently reported in women. These patients may develop yellow to yellowwhite retinal arterial wall plaques, which occur at midarteriolar segments, away from retinal bifurcations.30 In one retrospective case series of four patients with the syndrome, periarterial plaques were reported to occur in six of eight eyes. The plaques resolved in four of these
300
RETINAL CASES & BRIEF REPORTS´ 2011 VOLUME 5 NUMBER 4
eyes after treatment with immunosuppressive agents. On fluorescein angiography, there was no occlusion at the sites of the retinal arterial wall plaques.30 Gass et al had recognized the association of multiple retinal artery occlusions with auditory and central nervous system abnormalities and suggested that the clinical findings were because of the localized immune-mediated reaction in the retinal arterial walls, which were also affecting arteries elsewhere in the body, such as the inner ear and brain.28 Although the exact cause of Kyrieleis plaques is undetermined, several theories have attempted to explain this clinical phenotype. Kyrieleis initially attributed the plaques to a local allergic reaction to the bacteria that causes tuberculosis.14 Additional authors have similarly claimed that the plaques represent an immunologic response to an infectious etiology, which result in the deposition of inflammatory cells within the vascular wall.31 According to this hypothesis, segmental periarteritis is allergic in nature and results from an immune reaction to bacterial antigen or drugs.15,18 An allergic reaction could account for the occasional resolution of these lesions after corticosteroid therapy.18 Others believe that the deposits represent migration of exudate from active areas of choroiditis into the periarterial sheaths.18 This hypothesis, however, has difficulty explaining the presence of these plaques in patients with idiopathic recurrent branch retinal artery occlusions because these patients often do not demonstrate active areas of choroidal inflammation. An additional theory claims that the lesions are nonobstructive atheromatous plaques, which occur at focal sites of retinal arterial wall damage.23 The mechanism by which this would occur involves the slow extravasation of blood lipids into the arterial walls. This theory was supported by histologic findings from a patient with non–Hodgkin large cell lymphoma and multiple yellow retinal arterial wall plaques.24 This patient’s enucleation specimen demonstrated that the lumen of many arteries was narrowed by both tumor infiltration of the arterial wall and subendothelial infiltration of lipid-laden macrophages.24 The authors of this study believed that the lymphomatous infiltration caused damage to the arterial endothelium and allowed passage of serum lipids into the arterial wall. Macrophages responded to this material, and an ‘‘atheroma’’ was formed.24 Incidentally, elevated serum cholesterol has never been firmly associated with this phenotype in the literature. The exact mechanism for the development of Kyrieleis plaques remains unknown. This is partly because of the absence of pathologic studies of these arteriole wall plaques in patients with infectious
disease. Additional histologic examinations of eyes with these arterial lesions would provide a more precise identification of the composition of these plaques and help to elucidate the true etiology and mechanism for the development of these lesions. The differential diagnosis of segmental retinal periarteritis has become extensive. This is the first case to our knowledge of HSV-2 retinitis to present with Kyrieleis plaques. This case underscores the importance of including HSV-2–associated ARN syndrome on the differential diagnosis of segmental retinal periarteritis. Key words: acute retinal necrosis syndrome, herpes simplex virus, Kyrieleis plaques, retinal arterial wall plaques, segmental periarteritis. References 1. Urayama A, Yamada N, Sasaki T. Unilateral acute uveitis with periarteritis and detachment. Jpn J Clin Ophthalmol 1971;25: 607–619. 2. Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol 1994;117:663–667. 3. Culbertson WW, Blumenkranz MS, Pepose JS, Stewart JA, Curtin VT. Varicella zoster virus is a cause of the acute retinal necrosis syndrome. Ophthalmology 1986;93:559–569. 4. Lewis ML, Culbertson WW, Post JD, Miller D, Kokame GT, Dix RD. Herpes simplex virus type 1. A cause of the acute retinal necrosis syndrome. Ophthalmology 1989;96:875–878. 5. Thompson WS, Culbertson WW, Smiddy WE, Robertson JE, Rosenbaum JT. Acute retinal necrosis caused by reactivation of herpes simplex virus type 2. Am J Ophthalmol 1994;118:205– 211. 6. Ganatra JB, Chandler D, Santos C, Kuppermann B, Margolis TP. Viral causes of the acute retinal necrosis syndrome. Am J Ophthalmol 2000;129:166–172. 7. Hillenkamp J, Nolle B, Bruns C, Rautenberg P, Fickenscher H, Roider J. Acute retinal necrosis: clinical features, early vitrectomy, and outcomes. Ophthalmology 2009;116:1971,5.e2. 8. Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis features, management, and outcomes. Ophthalmology 2007;114:756–762. 9. Muthiah MN, Michaelides M, Child CS, Mitchell SM. Acute retinal necrosis: a national population-based study to assess the incidence, methods of diagnosis, treatment strategies and outcomes in the UK. Br J Ophthalmol 2007;91:1452–1455. 10. Willerson D Jr, Aaberg TM, Reeser FH. Necrotizing vasoocclusive retinitis. Am J Ophthalmol 1977;84:209–219. 11. Young NJ, Bird AC. Bilateral acute retinal necrosis. Br J Ophthalmol 1978;62:581–590. 12. Palay DA, Sternberg P Jr, Davis J, et al. Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol 1991;112:250–255. 13. Peters H. Metastase nach scheeiwerotlauf. im auge. Klin Mbl Augenheilk 1929;83:25. 14. Kyrieleis W. Uber atypische gerfaesstuberkulose der netzhaut (periarteritis ‘‘nodosa’’ tuberculosa). Arch Augenheilkd 1933; 107:182–190. 15. Orzalesi N, Ricciardi L. Segmental retinal periarteritis. Am J Ophthalmol 1971;72:55–59.
KYRIELEIS PLAQUES ASSOCIATED WITH HSV-2 16. Crouch ER Jr, Goldberg MF. Retinal periarteritis secondary to syphilis. Arch Ophthalmol 1975;93:384–387. 17. Blach RK. Segmental lesions of the retinal arteries. Br J Ophthalmol 1960;44:562–566. 18. Griffin AO, Bodian M. Segmental retinal periarteritis; a report of three cases. Am J Ophthalmol 1959;47:544–548. 19. Rask JA. Periarteritis retinalis segmentalis. Acta Ophthamol 1969;47:234. 20. Gass J. Toxoplasmosis retinitis. In: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. St Louis, MO: Mosby; 1997:614–622. 21. Krishnamurthy R, Cunningham ET. Atypical presentation of syphilitic uveitis associated with Kyrieleis plaques. Br J Ophthalmol 2008;92:1152–1153. 22. Khairallah M, Ladjimi A, Chakroun M, et al. Posterior segment manifestations of Rickettsia conorii infection. Ophthalmology 2004;111:529–534. 23. Gass J. Idiopathic recurrent branch retinal arterial occlusion. In: Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. St Louis, MO: Mosby; 1997:458–462.
301 24. Gass JD, Trattler HL. Retinal artery obstruction and atheromas associated with non-Hodgkin’s large cell lymphoma (reticulum cell sarcoma). Arch Ophthalmol 1991;109:1134–1139. 25. Gass J. Occlusive retinal arterial and arteriolar diseases. In: Stereoscopic Atlas of Macular Diseases; Diagnosis and Treatment. 3rd ed. St Louis, MO: Mosby; 1987:348–355. 26. Baglivo E, Safran AB. Haemorrhagic toxoplasmic retinochoroiditis: description of an unusual clinical presentation. Br J Ophthalmol 2003;87:1051–1052. 27. Kayazawa F, Sonoda K. Segmental retinal periarteritis with branch arterial occlusion. Ann Ophthalmol 1983;15: 584–586. 28. Gass JD, Tiedeman J, Thomas MA. Idiopathic recurrent branch retinal arterial occlusion. Ophthalmology 1986;93:1148–1157. 29. Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain and retina. Neurology 1979;29:313–316. 30. Egan RA, Ha Nguyen T, Gass JD, Rizzo JF 3rd, Tivnan J, Susac JO. Retinal arterial wall plaques in Susac syndrome. Am J Ophthalmol 2003;135:483–486. 31. Rodenhauser J. Clinical findings and pathogenesis of Kyrieleis’ discontinuous reversible arteriopathy in uveitis. Klin Monatsbl Augenheilkd 1969;155:234–243.
