Periphlebitis in Patients With Acquired Immunodeficiency Syndrome With Cytomegalovirus Retinitis Mimics Acute Frosted Retinal Periphlebitis Retinal
Maurice F. Warren M.
Rabb, MD; Lee M. Jampol, MD; Richard H. Fish, MD; Randy Sobol, MD; Norbert M. Becker, MD
frosted retinal periphlebitis is inflammatory condition of unknown origin characterized by marked perivenular infiltration in otherwise healthy patients. We encountered seven patients with acquired immunodeficiency syn\s=b\ Acute
an
drome who exhibited visual loss associated with an unusual diffuse retinal periphlebitis very similar in appearance to acute frosted retinal periphlebitis. Each patient developed a thick inflammatory infiltrate surrounding the retinal venules, creating a frosted appearance. Two cases were bilateral. All patients had areas of more typical cytomegalovirus retinitis in their involved eye(s). Five of six patients treated with ganciclovir sodium showed improvement not only of the cytomegalovirus retinitis but also of the periphlebitis. Although we do not have histopathologic evidence that cytomegalovirus was the cause of these cases of periphlebitis, we believe that periphlebitis may be a previously unrecognized finding of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. So far, there is no evidence implicating cytomegalovirus as the cause of acute frosted retinal periphlebitis in healthy patients.
(Arch Ophthalmol. 1992;110:1257-1260)
periphlebitis is idiopathic unilateral or bilateral inflammatory condition of the posterior pole in otherwise healthy patients.14 These patients develop prominent widespread periphlebitis with intraretcute frosted retinal
"·
an
Accepted
for publication March 16, 1992. From the Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, and Mercy Hospital and Medical Center, Chicago (Dr Rabb); the Department of Ophthalmology, Northwestern University Medical School, Chicago (Dr Jampol); the University of Texas, Southwestern Medical Center, Department of Ophthalmology, Dallas (Dr Fish); Mayo Clinic, Scottsdale, Ariz (Dr Campo); Retina Physicians and Surgeons Inc, Dayton, Ohio (Dr Sobol); and the Division of Ophthalmology, Cook County (Illinois) Hospital, Chicago (Dr Becker). Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Fla, May 3, 1991. Reprint requests to 303 E Chicago Ave, Chicago, IL 60611 (Dr Jampol).
V.
Campo, MD;
inai hemorrhages and visual loss. The visual outcome is excellent in most cases following systemic corticosteroid therapy, which results in resolution of the periphlebitis.5·6 A few patients have had permanent loss of vision in the involved eye. We have recently encoun¬ tered a very similar appearance in the fundus of patients with acquired immu¬ nodeficiency syndrome (AIDS) with cy¬ tomegalovirus (CMV) retinitis. These patients demonstrated classic findings of CMV retinitis, and one or both of their eyes exhibited a "frosted" pe¬
riphlebitis.
REPORT OF CASES
45-year-old man presented in 1989 with a 6-week history of de¬ creased vision in both eyes. Testing for hu¬ man immunodeficiency virus (HIV) yielded positive results. Visual acuity was 20/50 OU. The patient exhibited 2 + aqueous flare and keratic precipitates. Ophthalmoscopic exam¬ ination showed bilateral perivascular infil¬ trates involving peripheral and posterior retinal venules. Areas of classic CMV retini¬ tis with hemorrhage were seen temporal to the right macula as well in the left macular zone (Figs 1 and 2). The patient was hospi¬ talized and received intravenous ganciclovir treatment. He continued to receive 5 mg/kg of ganciclovir sodium 5 days a week, and the periphlebitis and the classic CMV retinitis gradually cleared (Fig 3). Subsequently, the patient developed a rhegmatogenous retinal detachment in the left eye and underwent retinal surgery, which failed. Ganciclovir therapy could then be given only intermit¬ tently because of leukopenia. The CMV re¬ tinitis recurred, and the visual acuity in the right eye gradually decreased to finger counting. The left eye had no light percep¬ tion. Intravitreal ganciclovir was instilled several times in the right eye, but the patient died in October 1989. Case 2.—A 30-year-old man with docu¬ mented AIDS presented in March 1988 with a 2-week history of photophobia and de¬ creased vision in the left eye. His best corrected visual acuity was 20/20 OD and 20/40 OS. The remainder of his ocular exam¬ ination yielded normal findings, with the ex¬ ception of the posterior pole of the left eye, which showed papillitis with associated re¬ tinitis, vitritis, and a marked perivascular infiltrate affecting the retinal venules (Fig CASE 1.—A
April
4). Blood and urine cultures were positive for
CMV. A diagnosis of CMV retinitis with pe¬ riphlebitis was made, and the patient was treated with intravenous ganciclovir. During the next several weeks, his visual acuity im¬ proved to 20/30 OS with some resolution of the perivascular infiltrate, retinitis, and papillitis. After completion of 1 month of treatment, the patient was unavailable for follow-up. Case 3.—A 30-year-old man with a 3-week history of decreased vision in the left eye was
first seen on June 30,1988. He had been HIV positive since November 1987. The patient had Kaposi's sarcoma, Pneumocystis carinii pneumonia, and oral candidiasis. His visual acuity was 20/25 OD and 20/400 OS. There was a left-sided afferent pupillary defect; the right eye was normal. The left eye showed a diffuse retinal periphlebitis with papillitis. A diagnosis of CMV retinitis was made, and on September 1,1988, treatment with 325 mg/d of ganciclovir sodium was begun. The patient did not return for regular follow-up visits and stopped taking his medication. On Janu¬ ary 12, 1989, he returned with an inferior retinal detachment and neovascularization of the left retina. He had also developed CMV retinitis in the right eye, in which his visual acuity was 20/80. He was again treated with 325 mg of ganciclovir sodium twice daily. On February 21, 1989, the visual acuity in his right eye had improved to 20/50. The left eye at this time had a dense vitreous hemor¬ rhage. On March 21, 1989, the visual acuity in his right eye was 20/60, and the retinitis had largely resolved. The patient reduced the dose of medication, after which macular involvement occurred. On July 6,1989, vision in the right eye was counting fingers at 5 ft, and the dose of ganciclovir was again in¬ creased. In September 1988, the visual acu¬ ity in the right eye had returned to 20/60. Diffuse periphlebitis with areas of classic CMV retinitis involved the superotemporal quadrant of the right eye (Fig 5). The left eye showed similar changes (Fig 5), and a retinal detachment was present in the inferonasal portion of the left eye. The patient died in November 1988. Case 4.—A 25-year-old woman was first seen on October 8, 1990; she had tested pos¬ itive for HIV infection in January 1989. At that time, she had carinii pneumonia, pul¬ monary tuberculosis, and a vaginal yeast in¬ fection. She reported loss of vision in the right eye 1 month previously. Her medica¬ tions included zidovudine and aerosolized pentamidine isethionate. Visual acuity was light perception in the right eye and 20/20
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Fig 1.—Case 1. Top, Right eye demonstrates diffuse necrotizing hemorrhagic cytomegalo¬ virus retinitis temporal to the macular area. Note extensive sheathing of retinal venules involving the posterior pole and midperiphery. Preretinal vitreous precipitates are present. Bottom, Left eye demonstrates sim¬ ilar changes with classic cytomegalovirus ret¬ initis temporal to the macula and extensive sheathing of venules throughout the poste¬ rior pole and midperiphery. OS. Examination of the right eye showed papillitis with multiple areas of flame-shaped hemorrhages and deeper hemorrhages in¬ volving the disc and the areas superior and inferior to the optic disc. The changes were believed to be compatible with CMV retini¬ tis. There was evidence of sheathing involv¬ ing most of the retinal venules (Fig 6). Examination of the left fundus showed no definite CMV retinitis or vasculitis. Ganci¬ clovir therapy was recommended, but the patient was unavailable for follow-up and died 6 months later. CASE 5.—A 37-year-old, HIV-positive man, who was an intravenous drug abuser, presented on August, 8, 1990, with a 3-week history of decreasing vision in the right eye. The patient had a history of carinii pneu¬ monia. Medications included clotrimazole and methadone hydrochloride. Visual acuity on initial presentation was 20/400 OD and 20/20 OS. There was a 1+ afferent pupillary defect in the right eye. Slit-lamp examina¬ tion revealed a few keratic precipitates on the endothelium of the right eye with 1 + cell and flare. Fundus examination of the right eye showed papillitis and severe vasculitis with frosted periphlebitis. Some areas of typical CMV retinitis were seen with a char¬ acteristic CMV necrotic rhegmatogenous retinal detachment nasally and inferiorly. The left eye had a few cotton-wool spots but no retinitis. The patient initially refused any surgical procedure for his retinal detach¬ ment. Induction therapy with intravenous ganciclovir mildly reduced the severity of
Fig 2.—Case 1. Fluorescein angiograms of both fundi (top, right eye; bottom, left eye) demonstrate some staining of the retinal venules and areas of blocked fluorescence due to exúdate and hemorrhages. The amount of staining is not as extensive as might be suspected from the clinical appear¬ ance.
the retinitis and vasculitis. Visual acuity de¬ teriorated to light perception due to progres¬ sive retinal detachment and necrosis. The patient eventually consented to a pars plana vitrectomy with silicone oil injection in the right eye, which resulted in retinal reattachment, but visual acuity remained light per¬
ception.
Maintenance therapy with intravenous ganciclovir was continued until March 1991. On the patient's last examination, visual acuity was no light perception in the right
eye and 20/40 OS. Fundus examination showed resolution of the CMV retinitis and
vasculitis, with extensive atrophie chorioretinal scarring in the right eye and no sign of CMV infection in the left eye. The patient developed disseminated Mycobacterium
avium intracellulare infection and died in April 1991. CASE 6.—A 37-year-old man was diag¬ nosed as having AIDS and carinii pneu¬ monia in December 1987. The patient re¬ ceived inhaled pentamidine and oral zidovudine therapies. In January 1990, he developed dyspnea and was found to have CMV pneumonitis. He was given a 1-month course of intravenous ganciclovir sodium therapy (300 mg every 12 hours). In April 1990, he was noted to have CMV retinitis and acute frosted retinal periphlebitis in the left eye (Fig 7). Visual acuity was 20/20 OD and 20/40 OS. Therapy with intravenous ganci¬ clovir sodium (300 mg/d, five days per week) was initiated. By May 1990, visual acuity had decreased to 20/400 OS to involvement of the optic nerve by CMV infection. Intravenous ganciclovir therapy was possible only inter¬ mittently during the next 8 months because
Fig 3.—Case 1. Six months after the initiation of ganciclovir therapy, both eyes (top, right eye; bottom, left eye) show almost complete resolution of the retinal periphlebitis. There is mottling of pigmentation present temporal to the right macula in the area of previous cytomegalovirus retinitis. Scarring is also present temporal to the left macula. of episodes of neutropenia. The patient de¬ veloped septic arthritis and was subse¬ quently unavailable for ophthalmologic follow-up. Two weeks before his death, he could see only shadows in the left eye but retained good visual acuity in the right eye. The patient died in March 1991. CASE 7.—A 22-year-old, HIV-positive man presented on November 30, 1989, with a visual acuity of 20/400 OD and 20/20 OS. The patient had evidence of CMV retinitis involving the superior portion of the right optic disc with some extension along the superotemporal vascular arcade. The patient was treated with ganciclovir, and his visual acuity improved to 20/60 OD, with reduction of the retinitis. The patient's leukocyte count dropped, requiring a decrease in the dosage of ganciclovir. There was a resultant in¬ crease in retinitis extending superiorly from the previous lesion, without a change in visual acuity. The patient was again treated with ganciclovir after his leukocyte count improved. The viral retinitis again re¬ sponded. However, leukopenia recurred, and ganciclovir therapy was stopped on April 27, 1990. The patient returned for follow-up on May 12, 1990, and showed extensive inferotemporal retinal periphlebitis. The leu¬ kocyte count had improved, allowing retreatment with ganciclovir. The periphlebi¬ tis improved within 1 week of the onset of therapy. Visual acuity was maintained at 20/ 80. The patient's overall physical condition
deteriorated, and his viral retinitis extended to involve the entire retina by September 18, 1990, resulting in no light perception. The left eye was never involved. The patient died in November 1990.
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Fig 6.—Case 4. The right eye shows cytome¬ galovirus retinitis involving the peripapillary area and optic nerve head. Note extensive perivenous sheathing.
Fig 4.—Case 2, left eye. Top, Classic cy¬ tomegalovirus retinitis is seen nasal to the optic disc extending to the disc margin. Bot¬ tom, Extensive retinal seen
temporal
to the
venous
infiltration is
optic disc.
COMMENT
describe seven patients Herein, with CMV retinitis and AIDS who ex¬ hibited an unusual diffuse infiltrative retinal periphlebitis mimicking the ap¬ pearance that has been described in healthy patients with acute frosted ret¬ inal periphlebitis. Six of the patients were adult men whose ages ranged from 22 to 45 years, with a single female patient presenting at age 40 years. The patients demonstrated more classic findings of CMV retinitis elsewhere in the fundus in every involved eye. There was no evidence of other opportunistic retinal or choroidal infections, such as we
Pneumocystis, Candida, tuberculosis, toxoplasmosis, suggesting that the retinal findings described in our pa¬ or
tients represent an unusual manifesta¬ tion of CMV infection. Patient 4 was apparently never treated with ganciclo¬ vir. The beneficial response of the pe¬ riphlebitis to ganciclovir therapy in five of the six remaining cases (cases 1, 2, 3, 5, and 7) is further evidence supporting the idea that CMV is the cause of the periphlebitis. Although we cannot pro¬ vide an exact incidence of this finding in patients with CMV retinitis, we believe that it is certainly less than 5% and may be less than 1%. Previously published descriptions of periphlebitis in patients with AIDS can be found in the literature.710 In 1983, Holland et al11 reported a case of unilat¬ eral retinal periphlebitis involving most
Fig 5.—Case 3. Top, The right eye show ex¬ tensive cytomegalovirus retinitis along the superotemporal arcade. Papillitis is present with extensive sheathing of the retinal venules in the posterior pole and midperiphery. Bottom, The left eye shows a similar pattern of diffuse periphlebitis with areas of cytomegalovirus retinitis temporal to the macula. of the branches of the central retinal vein. Kestelyn et al12·13 were the first to report perivasculitis in both adults and children with AIDS. They believed that the perivasculitis in their patients was a manifestation of AIDS retinopathy. Gal et al14 also reported perivascular sheathing in a patient with AIDS and CMV retinitis. In 1988, Turu et al15 re¬ ported that one of 34 patients with AIDS had retinal periphlebitis. A pa¬ tient with AIDS who had unilateral "frosted branch angiitis" was recently described,16 but the authors of the re¬ port did not relate this finding to the CMV retinitis that was present in the same eye. Other common causes of retinal pe¬ riphlebitis include sarcoidosis,17 tuber¬ culosis,18 multiple sclerosis,19 pars plani¬ fie, and possibly other viral infections. In 1975, Lewis and Clark20 described a massive perivenous infiltrative retinop¬ athy in a 48-year-old woman with a well-differentiated lymphocytic lymphoma. Barr and Joondeph21 described periphlebitis in a patient with Hodgkin's disease. It is possible that the changes in these patients repre¬ sented tumor infiltration or perhaps were a manifestation of an opportunis¬ tic infection. The cause of acute frosted retinal pe¬ riphlebitis in healthy patients remains
Fig 7.—Case 6. Top, Cytomegalovirus retini¬ tis is seen involving the left optic disc and na¬ sal retina. Bottom, Extensive perivenous sheathing is seen involving the posterior pole. uncertain.16 Serologie testing for CMV has been
performed in several of these patients and has been inconclusive or negative. At least one patient had a nondiagnostic rise in Epstein-Barr virus titer. The similarity of the appearance of the periphlebitis in our immunosuppressed patients with CMV retinitis to that of idiopathic acute frosted retinal periphlebitis suggests that future pa¬ tients with the idiopathic disease should undergo careful evaluation for CMV and other herpes viruses to determine whether one of these viruses may be the cause in healthy patients as well. How¬ ever, there is no evidence to date sup¬ porting CMV as the cause. Our patients exhibited more hemorrhages than most patients with idiopathic acute frosted retinal periphlebitis, and all had areas of classic CMV retinitis. The "frosted
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branch" picture may turn out to be a se¬ quela of several insults to the eye, in¬ cluding CMV retinitis. Our suggestion that CMV is the cause of the frosted branch appearance in our patients is based on evidence of CMV retinitis without other opportunistic in¬ fections. It is possible that an immune response to CMV antigens was respon¬ sible for this periphlebitis. In healthy patients with idiopathic acute frosted periphlebitis, the prompt response to
therapy suggests immune-mediated, possibly postviral, perivascular sheathing. The more grad¬ ual responses in our patients to ganci¬ clovir therapy suggests successful corticosteroid
treatment of the CMV infection with
a
gradual clearing of an immune reaction.
We have described a manifestation of CMV retinitis in patients with AIDS that, to our knowledge, has been previ¬ ously unrecognized. Additional investi¬ gations of CMV as the possible cause in these patients, including histopatho¬ logic studies and the further use of anti-CMV therapy, are now indicated. This investigation was supported in part by an unre¬ stricted grant from Research to Prevent Blindness, Ine, New York, NY, to Northwestern University, Chi¬ cago, 111. Patient 6 was referred by Rand Spencer, MD.
References 1. Ito Y, Nakano M, Kyo N, Takeuchi M. Frosted branch angiitis in a child. Jpn J Clin Ophthalmol.
1976;30:797-803. 2. Sakanishi Y, Kanagami S, Ohara K. Frosted
retinal angiitis in children. Jpn J Clin Ophthalmol.
1984;38:803-807. 3. Yamane S, Nishiuchi T, Nakagawa Y, Iwase T, Hama M. A case of frosted branch angiitis of the retina. Folia Ophthalmol Jpn. 1985;36:1822-1825. 4. Watanabe Y, Takeda N, Adachi-Usami E. A case
of frosted branch
angiitis.
Br J
Ophthalmol.
1987;71:553-558. 5. Kleiner RC, Kaplan HJ, Shakin JL, Yannuzzi LA, Crosswell HH Jr, McLean WC Jr. Acute frosted retinal periphlebitis. Am J Ophthalmol. 1988;106:27-34. 6. Sugin SL, Henderly DE, Friedman SM, Jampol LM, Doyle WD. Unilateral frosted branch angiitis. Am J Ophthalmol. 1991;111:682-685. 7. Holland GN, Gottlieb MS, Yee RD, Schanker HM, Pettit TH. Ocular disorders associated with
a new severe
nodeficiency syndrome.
acquired cellular immuOphthalmol. 1982;
Am J
93:393-402. 8. Culbertson WW. Infection of the retina in AIDS. Int Ophthalmol Clin. 1989;29:108-118. 9. Henderly DE, Freeman WR, Smith RS, Causey D, Rao NN. Cytomegalovirus retinitis as the initial manifestation of the acquired immune deficiency syndrome. Am J Ophthalmol. 1987;103:316\x=req-\ 320. 10. Jabs DA, Green WR, Fox R, Polk BF, Barlett JG. Ocular manifestations of acquired immune
deficiency syndrome. Ophthalmology. 1989;96; 1092-1099. 11. Holland GN, Pepose JS, Pettit TH, Gottlieb MS, Yee RD, Foos RY. Acquired immune defi-
Currently
ciency syndrome: ocular manifestations. Ophthalmology. 1983;90:859-873. 12. Kestelyn P, Lepage P, Van de Perre P. Perivasculitis of the retinal vessels as an important sign in children with AIDS-related complex. Am J Ophthalmol. 1985;100:614-615. 13. Kestelyn P, Van de Perre P, Sprecher\x=req-\ Goldberger S. Isolation of the human T-cell leukemia/lymphotropic virus type III from aqueous humor in two patients with perivasculitis of the retinal vessels. Int Ophthalmol. 1986;9:247\x=req-\ 251. 14. Gal A, Pollack A, Oliver M. Ocular findings in the acquired immunodeficiency syndrome. Br J
Ophthalmol. 1984;68:238-241.
15. Turu AC, Civera AA, Latorre X. Ophthalmic manifestations of acquired immunodeficiency syndrome: a study of thirty-four patients. Ophthalmo-
logica. 1988;197:113-119.
16. Geier SA, Nasemann J, Klauss V, Kronawitter U, Goebel FD. Frosted branch angiitis in a patient with the acquired immune deficiency syndrome. Am J Ophthalmol. 1992;113: 203-205. 17. Spalton DJ, Sanders MD. Fundus changes in histologically confirmed sarcoidosis. Br J Ophthalmol. 1981;65:348-358. 18. Fountain JA, Werner RB. Tuberculous retinal vasculitis. Retina. 1984;4:48-50. 19. Arnold AC, Pepose JS, Hepler RS, Foos RY. Retinal periphlebitis and retinitis in multiple sclerosis. Ophthalmology. 1984;91:255-262. 20. Lewis RA, Clark RB. Infiltrative retinopathy in systemic lymphoma. Am J Ophthalmol.
1975;79:48-52. 21. Barr CC, Joondeph HC. Retinal periphlebi-
as the initial clinical finding in a patient Hodgkin's disease. Retina. 1983;3:253-257.
tis
in Other AMA Journals
ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE
Rhabdomyosarcoma: A New Classification Scheme Related to Prognosis Maria Tsokos, MD; Bruce L. Webber, MD; David M. Parham, MD; Robert A. Wesley, PhD; Angela Miser, MD; James S. Miser, MD; Erlinda Etcubanas, MD; Timothy Kinsella, MD; Jane Grayson, MD; Eli Glatstein, MD; Philip A. Pizzo, MD; Timothy J. Triche, MD, PhD (Arch Pathol Lab Med. 1992;116:847-855)
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with
Maurice F. Warren M.
Rabb, MD; Lee M. Jampol, MD; Richard H. Fish, MD; Randy Sobol, MD; Norbert M. Becker, MD
frosted retinal periphlebitis is inflammatory condition of unknown origin characterized by marked perivenular infiltration in otherwise healthy patients. We encountered seven patients with acquired immunodeficiency syn\s=b\ Acute
an
drome who exhibited visual loss associated with an unusual diffuse retinal periphlebitis very similar in appearance to acute frosted retinal periphlebitis. Each patient developed a thick inflammatory infiltrate surrounding the retinal venules, creating a frosted appearance. Two cases were bilateral. All patients had areas of more typical cytomegalovirus retinitis in their involved eye(s). Five of six patients treated with ganciclovir sodium showed improvement not only of the cytomegalovirus retinitis but also of the periphlebitis. Although we do not have histopathologic evidence that cytomegalovirus was the cause of these cases of periphlebitis, we believe that periphlebitis may be a previously unrecognized finding of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. So far, there is no evidence implicating cytomegalovirus as the cause of acute frosted retinal periphlebitis in healthy patients.
(Arch Ophthalmol. 1992;110:1257-1260)
periphlebitis is idiopathic unilateral or bilateral inflammatory condition of the posterior pole in otherwise healthy patients.14 These patients develop prominent widespread periphlebitis with intraretcute frosted retinal
"·
an
Accepted
for publication March 16, 1992. From the Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, and Mercy Hospital and Medical Center, Chicago (Dr Rabb); the Department of Ophthalmology, Northwestern University Medical School, Chicago (Dr Jampol); the University of Texas, Southwestern Medical Center, Department of Ophthalmology, Dallas (Dr Fish); Mayo Clinic, Scottsdale, Ariz (Dr Campo); Retina Physicians and Surgeons Inc, Dayton, Ohio (Dr Sobol); and the Division of Ophthalmology, Cook County (Illinois) Hospital, Chicago (Dr Becker). Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Fla, May 3, 1991. Reprint requests to 303 E Chicago Ave, Chicago, IL 60611 (Dr Jampol).
V.
Campo, MD;
inai hemorrhages and visual loss. The visual outcome is excellent in most cases following systemic corticosteroid therapy, which results in resolution of the periphlebitis.5·6 A few patients have had permanent loss of vision in the involved eye. We have recently encoun¬ tered a very similar appearance in the fundus of patients with acquired immu¬ nodeficiency syndrome (AIDS) with cy¬ tomegalovirus (CMV) retinitis. These patients demonstrated classic findings of CMV retinitis, and one or both of their eyes exhibited a "frosted" pe¬
riphlebitis.
REPORT OF CASES
45-year-old man presented in 1989 with a 6-week history of de¬ creased vision in both eyes. Testing for hu¬ man immunodeficiency virus (HIV) yielded positive results. Visual acuity was 20/50 OU. The patient exhibited 2 + aqueous flare and keratic precipitates. Ophthalmoscopic exam¬ ination showed bilateral perivascular infil¬ trates involving peripheral and posterior retinal venules. Areas of classic CMV retini¬ tis with hemorrhage were seen temporal to the right macula as well in the left macular zone (Figs 1 and 2). The patient was hospi¬ talized and received intravenous ganciclovir treatment. He continued to receive 5 mg/kg of ganciclovir sodium 5 days a week, and the periphlebitis and the classic CMV retinitis gradually cleared (Fig 3). Subsequently, the patient developed a rhegmatogenous retinal detachment in the left eye and underwent retinal surgery, which failed. Ganciclovir therapy could then be given only intermit¬ tently because of leukopenia. The CMV re¬ tinitis recurred, and the visual acuity in the right eye gradually decreased to finger counting. The left eye had no light percep¬ tion. Intravitreal ganciclovir was instilled several times in the right eye, but the patient died in October 1989. Case 2.—A 30-year-old man with docu¬ mented AIDS presented in March 1988 with a 2-week history of photophobia and de¬ creased vision in the left eye. His best corrected visual acuity was 20/20 OD and 20/40 OS. The remainder of his ocular exam¬ ination yielded normal findings, with the ex¬ ception of the posterior pole of the left eye, which showed papillitis with associated re¬ tinitis, vitritis, and a marked perivascular infiltrate affecting the retinal venules (Fig CASE 1.—A
April
4). Blood and urine cultures were positive for
CMV. A diagnosis of CMV retinitis with pe¬ riphlebitis was made, and the patient was treated with intravenous ganciclovir. During the next several weeks, his visual acuity im¬ proved to 20/30 OS with some resolution of the perivascular infiltrate, retinitis, and papillitis. After completion of 1 month of treatment, the patient was unavailable for follow-up. Case 3.—A 30-year-old man with a 3-week history of decreased vision in the left eye was
first seen on June 30,1988. He had been HIV positive since November 1987. The patient had Kaposi's sarcoma, Pneumocystis carinii pneumonia, and oral candidiasis. His visual acuity was 20/25 OD and 20/400 OS. There was a left-sided afferent pupillary defect; the right eye was normal. The left eye showed a diffuse retinal periphlebitis with papillitis. A diagnosis of CMV retinitis was made, and on September 1,1988, treatment with 325 mg/d of ganciclovir sodium was begun. The patient did not return for regular follow-up visits and stopped taking his medication. On Janu¬ ary 12, 1989, he returned with an inferior retinal detachment and neovascularization of the left retina. He had also developed CMV retinitis in the right eye, in which his visual acuity was 20/80. He was again treated with 325 mg of ganciclovir sodium twice daily. On February 21, 1989, the visual acuity in his right eye had improved to 20/50. The left eye at this time had a dense vitreous hemor¬ rhage. On March 21, 1989, the visual acuity in his right eye was 20/60, and the retinitis had largely resolved. The patient reduced the dose of medication, after which macular involvement occurred. On July 6,1989, vision in the right eye was counting fingers at 5 ft, and the dose of ganciclovir was again in¬ creased. In September 1988, the visual acu¬ ity in the right eye had returned to 20/60. Diffuse periphlebitis with areas of classic CMV retinitis involved the superotemporal quadrant of the right eye (Fig 5). The left eye showed similar changes (Fig 5), and a retinal detachment was present in the inferonasal portion of the left eye. The patient died in November 1988. Case 4.—A 25-year-old woman was first seen on October 8, 1990; she had tested pos¬ itive for HIV infection in January 1989. At that time, she had carinii pneumonia, pul¬ monary tuberculosis, and a vaginal yeast in¬ fection. She reported loss of vision in the right eye 1 month previously. Her medica¬ tions included zidovudine and aerosolized pentamidine isethionate. Visual acuity was light perception in the right eye and 20/20
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Fig 1.—Case 1. Top, Right eye demonstrates diffuse necrotizing hemorrhagic cytomegalo¬ virus retinitis temporal to the macular area. Note extensive sheathing of retinal venules involving the posterior pole and midperiphery. Preretinal vitreous precipitates are present. Bottom, Left eye demonstrates sim¬ ilar changes with classic cytomegalovirus ret¬ initis temporal to the macula and extensive sheathing of venules throughout the poste¬ rior pole and midperiphery. OS. Examination of the right eye showed papillitis with multiple areas of flame-shaped hemorrhages and deeper hemorrhages in¬ volving the disc and the areas superior and inferior to the optic disc. The changes were believed to be compatible with CMV retini¬ tis. There was evidence of sheathing involv¬ ing most of the retinal venules (Fig 6). Examination of the left fundus showed no definite CMV retinitis or vasculitis. Ganci¬ clovir therapy was recommended, but the patient was unavailable for follow-up and died 6 months later. CASE 5.—A 37-year-old, HIV-positive man, who was an intravenous drug abuser, presented on August, 8, 1990, with a 3-week history of decreasing vision in the right eye. The patient had a history of carinii pneu¬ monia. Medications included clotrimazole and methadone hydrochloride. Visual acuity on initial presentation was 20/400 OD and 20/20 OS. There was a 1+ afferent pupillary defect in the right eye. Slit-lamp examina¬ tion revealed a few keratic precipitates on the endothelium of the right eye with 1 + cell and flare. Fundus examination of the right eye showed papillitis and severe vasculitis with frosted periphlebitis. Some areas of typical CMV retinitis were seen with a char¬ acteristic CMV necrotic rhegmatogenous retinal detachment nasally and inferiorly. The left eye had a few cotton-wool spots but no retinitis. The patient initially refused any surgical procedure for his retinal detach¬ ment. Induction therapy with intravenous ganciclovir mildly reduced the severity of
Fig 2.—Case 1. Fluorescein angiograms of both fundi (top, right eye; bottom, left eye) demonstrate some staining of the retinal venules and areas of blocked fluorescence due to exúdate and hemorrhages. The amount of staining is not as extensive as might be suspected from the clinical appear¬ ance.
the retinitis and vasculitis. Visual acuity de¬ teriorated to light perception due to progres¬ sive retinal detachment and necrosis. The patient eventually consented to a pars plana vitrectomy with silicone oil injection in the right eye, which resulted in retinal reattachment, but visual acuity remained light per¬
ception.
Maintenance therapy with intravenous ganciclovir was continued until March 1991. On the patient's last examination, visual acuity was no light perception in the right
eye and 20/40 OS. Fundus examination showed resolution of the CMV retinitis and
vasculitis, with extensive atrophie chorioretinal scarring in the right eye and no sign of CMV infection in the left eye. The patient developed disseminated Mycobacterium
avium intracellulare infection and died in April 1991. CASE 6.—A 37-year-old man was diag¬ nosed as having AIDS and carinii pneu¬ monia in December 1987. The patient re¬ ceived inhaled pentamidine and oral zidovudine therapies. In January 1990, he developed dyspnea and was found to have CMV pneumonitis. He was given a 1-month course of intravenous ganciclovir sodium therapy (300 mg every 12 hours). In April 1990, he was noted to have CMV retinitis and acute frosted retinal periphlebitis in the left eye (Fig 7). Visual acuity was 20/20 OD and 20/40 OS. Therapy with intravenous ganci¬ clovir sodium (300 mg/d, five days per week) was initiated. By May 1990, visual acuity had decreased to 20/400 OS to involvement of the optic nerve by CMV infection. Intravenous ganciclovir therapy was possible only inter¬ mittently during the next 8 months because
Fig 3.—Case 1. Six months after the initiation of ganciclovir therapy, both eyes (top, right eye; bottom, left eye) show almost complete resolution of the retinal periphlebitis. There is mottling of pigmentation present temporal to the right macula in the area of previous cytomegalovirus retinitis. Scarring is also present temporal to the left macula. of episodes of neutropenia. The patient de¬ veloped septic arthritis and was subse¬ quently unavailable for ophthalmologic follow-up. Two weeks before his death, he could see only shadows in the left eye but retained good visual acuity in the right eye. The patient died in March 1991. CASE 7.—A 22-year-old, HIV-positive man presented on November 30, 1989, with a visual acuity of 20/400 OD and 20/20 OS. The patient had evidence of CMV retinitis involving the superior portion of the right optic disc with some extension along the superotemporal vascular arcade. The patient was treated with ganciclovir, and his visual acuity improved to 20/60 OD, with reduction of the retinitis. The patient's leukocyte count dropped, requiring a decrease in the dosage of ganciclovir. There was a resultant in¬ crease in retinitis extending superiorly from the previous lesion, without a change in visual acuity. The patient was again treated with ganciclovir after his leukocyte count improved. The viral retinitis again re¬ sponded. However, leukopenia recurred, and ganciclovir therapy was stopped on April 27, 1990. The patient returned for follow-up on May 12, 1990, and showed extensive inferotemporal retinal periphlebitis. The leu¬ kocyte count had improved, allowing retreatment with ganciclovir. The periphlebi¬ tis improved within 1 week of the onset of therapy. Visual acuity was maintained at 20/ 80. The patient's overall physical condition
deteriorated, and his viral retinitis extended to involve the entire retina by September 18, 1990, resulting in no light perception. The left eye was never involved. The patient died in November 1990.
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Fig 6.—Case 4. The right eye shows cytome¬ galovirus retinitis involving the peripapillary area and optic nerve head. Note extensive perivenous sheathing.
Fig 4.—Case 2, left eye. Top, Classic cy¬ tomegalovirus retinitis is seen nasal to the optic disc extending to the disc margin. Bot¬ tom, Extensive retinal seen
temporal
to the
venous
infiltration is
optic disc.
COMMENT
describe seven patients Herein, with CMV retinitis and AIDS who ex¬ hibited an unusual diffuse infiltrative retinal periphlebitis mimicking the ap¬ pearance that has been described in healthy patients with acute frosted ret¬ inal periphlebitis. Six of the patients were adult men whose ages ranged from 22 to 45 years, with a single female patient presenting at age 40 years. The patients demonstrated more classic findings of CMV retinitis elsewhere in the fundus in every involved eye. There was no evidence of other opportunistic retinal or choroidal infections, such as we
Pneumocystis, Candida, tuberculosis, toxoplasmosis, suggesting that the retinal findings described in our pa¬ or
tients represent an unusual manifesta¬ tion of CMV infection. Patient 4 was apparently never treated with ganciclo¬ vir. The beneficial response of the pe¬ riphlebitis to ganciclovir therapy in five of the six remaining cases (cases 1, 2, 3, 5, and 7) is further evidence supporting the idea that CMV is the cause of the periphlebitis. Although we cannot pro¬ vide an exact incidence of this finding in patients with CMV retinitis, we believe that it is certainly less than 5% and may be less than 1%. Previously published descriptions of periphlebitis in patients with AIDS can be found in the literature.710 In 1983, Holland et al11 reported a case of unilat¬ eral retinal periphlebitis involving most
Fig 5.—Case 3. Top, The right eye show ex¬ tensive cytomegalovirus retinitis along the superotemporal arcade. Papillitis is present with extensive sheathing of the retinal venules in the posterior pole and midperiphery. Bottom, The left eye shows a similar pattern of diffuse periphlebitis with areas of cytomegalovirus retinitis temporal to the macula. of the branches of the central retinal vein. Kestelyn et al12·13 were the first to report perivasculitis in both adults and children with AIDS. They believed that the perivasculitis in their patients was a manifestation of AIDS retinopathy. Gal et al14 also reported perivascular sheathing in a patient with AIDS and CMV retinitis. In 1988, Turu et al15 re¬ ported that one of 34 patients with AIDS had retinal periphlebitis. A pa¬ tient with AIDS who had unilateral "frosted branch angiitis" was recently described,16 but the authors of the re¬ port did not relate this finding to the CMV retinitis that was present in the same eye. Other common causes of retinal pe¬ riphlebitis include sarcoidosis,17 tuber¬ culosis,18 multiple sclerosis,19 pars plani¬ fie, and possibly other viral infections. In 1975, Lewis and Clark20 described a massive perivenous infiltrative retinop¬ athy in a 48-year-old woman with a well-differentiated lymphocytic lymphoma. Barr and Joondeph21 described periphlebitis in a patient with Hodgkin's disease. It is possible that the changes in these patients repre¬ sented tumor infiltration or perhaps were a manifestation of an opportunis¬ tic infection. The cause of acute frosted retinal pe¬ riphlebitis in healthy patients remains
Fig 7.—Case 6. Top, Cytomegalovirus retini¬ tis is seen involving the left optic disc and na¬ sal retina. Bottom, Extensive perivenous sheathing is seen involving the posterior pole. uncertain.16 Serologie testing for CMV has been
performed in several of these patients and has been inconclusive or negative. At least one patient had a nondiagnostic rise in Epstein-Barr virus titer. The similarity of the appearance of the periphlebitis in our immunosuppressed patients with CMV retinitis to that of idiopathic acute frosted retinal periphlebitis suggests that future pa¬ tients with the idiopathic disease should undergo careful evaluation for CMV and other herpes viruses to determine whether one of these viruses may be the cause in healthy patients as well. How¬ ever, there is no evidence to date sup¬ porting CMV as the cause. Our patients exhibited more hemorrhages than most patients with idiopathic acute frosted retinal periphlebitis, and all had areas of classic CMV retinitis. The "frosted
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branch" picture may turn out to be a se¬ quela of several insults to the eye, in¬ cluding CMV retinitis. Our suggestion that CMV is the cause of the frosted branch appearance in our patients is based on evidence of CMV retinitis without other opportunistic in¬ fections. It is possible that an immune response to CMV antigens was respon¬ sible for this periphlebitis. In healthy patients with idiopathic acute frosted periphlebitis, the prompt response to
therapy suggests immune-mediated, possibly postviral, perivascular sheathing. The more grad¬ ual responses in our patients to ganci¬ clovir therapy suggests successful corticosteroid
treatment of the CMV infection with
a
gradual clearing of an immune reaction.
We have described a manifestation of CMV retinitis in patients with AIDS that, to our knowledge, has been previ¬ ously unrecognized. Additional investi¬ gations of CMV as the possible cause in these patients, including histopatho¬ logic studies and the further use of anti-CMV therapy, are now indicated. This investigation was supported in part by an unre¬ stricted grant from Research to Prevent Blindness, Ine, New York, NY, to Northwestern University, Chi¬ cago, 111. Patient 6 was referred by Rand Spencer, MD.
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tis
in Other AMA Journals
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