1. Case Report:Dengue-Associated Retinopathy in Puerto Rico Juan G. Santiago, MD Ophthalmology Fellow Beetham Eye Institute Joslin Diabetes Center

2. Age/Gender: Ethnicity: Occupation: Last Eye Exam: Location: 22 y/o Male Hispanic (PR) Inmate 1 yr before PR Medical Center San Juan, PR Presentation

3. Chief Complaint “ Blurry vision in both eyes since 1 day”

4. History of Present Illness • A 22-year-old inmate male was hospitalized for dengue fever. On the third day of admission (7 days after fever onset), he complained of acute onset of painless decrease of vision in both eyes and was referred for ophthalmic evaluation. He denied associated photopsias, floaters, photophobia or diplopia.

5. History • Past Ocular Hx : Myopia • Systemic med : Acetaminophen IV drip • Drug Allergy : NKDA • Family Hx : Non-contributory • Social Hx : (+) Smoking (-) Alcohol x 3 yrs (-) Drugs

6. Review of Systems

7. Exam Vital Signs Pulse 84, BP 123/76, Resp 14, Temp 38.7 ◦C, Pain 4/10 Visual Acuity OD: CF @ 4 FT OS: 20/400 CPH 20/70 Ancillary Tests Pupils PERRLA OU EOMs F/S OU VF Confrontation Full OU IOP 15 OD / 16 OS

8. External and Anterior Segment Exam OD OS External Normal OU Conjunctiva Clear OU Cornea Clear OU AC Deep and Quiet OU Lens Clear OU

9. Posterior Segment Exam OD OS Vitreous Clear OU CDR C/D = 0.2 OU Optic nerve WNL OU Macula Dot-Blot Hemes, CWS, Ret Thickening Vessels Arterial sheathing Periphery Dot-Blot Hemes, CWS

10. Fundus Photo – Right Eye

11. Fundus Photo – Left Eye

12. FA • Blocked fluorescence consistent with retinal hemes. • Areas of venular and arteriolar leakage in the posterior pole of both eyes (right > left).

13. OCT OD Findings: Retinal thickening with cystic changes (Cystoid Macular Edema)

14. OCT OS Findings: Retinal thickening with cystic changes (Cystoid Macular Edema)

15. Labs • HIV (ELISA) test - Negative • Dengue titers IgM - Positive (5.62) IgG - Negative (0.43) • CBC • WBC 2.3, RBC 4.20, HGB 13.6, HCT 39 • Plat 77,000 • Amylase / Lipase – WNL • LFT – WNL • Toxicologies- Negative

16. Fort San Felipe del Morroin Old San Juan

17. Purtscher’s Retinopathy Purtscher’s-Like Retinopathy Cocaine or IVDA Retinopathy Collagen Vascular Diseases Leukemia Differential Diagnosis • Dengue Retinopathy • HIV Retinopathy • Diabetic Retinopathy • Hypertensive Retinopathy • Retinal Vascular Events

18. Dengue Fever • Most prevalent form of flavivirus infection in humans • 4 Serotypes • DEN-1, DEN-2, DEN-3, or DEN-4 • Transmitted generally by Aedesaegyptimosquito • Usually self-limiting illness with minimal systemic sequelae.

19. Dengue Fever • Endemic in the tropics and warm temperate regions in the world • Highest incidence • South-East Asia • Western Pacific • Latin and Central America • 500,000 cases/year require hospitalization • Most prevalent during rainy seasons when standing water provides an ideal breeding ground for mosquitoes

20. World Distribution of Dengue (2005) PR

21. Dengue in Latin America and the Caribbean

22. Dengue Fever in PR (2007) • More than 3,200 suspected dengue cases were reported in Puerto Rico from January to August 2007. • Most since the dengue fever epidemic of 1994.

23. Dengue in USA • Cases of dengue fever are confirmed every year in travelers returning to USA after visits to tropical and subtropical areas. (1) • Studies of military and relief workers placed the estimated risk for travelers returning from dengue-endemic areas near one illness per 1000 travelers. (2) • CDC. Travel-associated dengue - US, 2005. MMWR Morbid Mortal Wkly Rep. 2006;55:22:700-2. • O’Leary DR, et al. Assessment of Dengue risk in relief workers in PR after Hurricane Georges. Am J Trop Med Hyg. 2002;66:35-39

24. USA – Aedesalbopictus

25. Dengue Fever Symptoms • Abrupt onset of fever after 2-7 day incubation period, with temp reaching 41◦ C • Several malaise, headaches, and retroburbal and lumbo-sacral pain

26. Dengue Fever Symptoms • Patients also experience: • Sore throat, rhinitis, cough • Nausea • Anorexia • Altered taste sensation • Transient macular rash on day 1 to day 2 of illness • Secondary rash on days 3-6 of illness that involves the trunk, limbs, and face.

27. Dengue Fever

28. Laboratories • Compatible with Dengue: • ↓ Platelets • ↑ Hematocrit • ↓ WBC • CONFIRMATION TESTS • Dengue IgM + IgGSerologies • PCR

29. Tourniquet Test • Measure blood pressure • Inflate the cuff for 5 minutes to a pressure exactly half way between systolic and diastolic pressures. • If there are ≥ 10 petechiaes in 1 square inch area, then the test is positive.

30. Dengue Hemorrhagic Fever • More severe form of the disease • Associated with: • Multisystem hemorrhagic manifestations • Skin hemes, epistaxis, gingival bleed, hemoptysis, GI bleeding, hematuria, menorrhagia • Thrombocytopenia (<100,000) • Hemoconcentration (>20% above baseline) • Increased vascular permeability • Plasma leakage

31. El Yunque National Forest

32. Ophthalmic Complications • Rarely associated with ocular manifestations, but have been reported in the literature as isolated case reports since the 1970s • Onset of visual symptoms closely correlated with the nadir of thrombocytopenia.

33. Ophthalmic Complications • Symptoms • Blurring of vision • Central scotoma • Micropsia/Metamorphopsia • Visual field defect • Floaters • Near vision disturbance • Redness

34. Signs Macular hemorrhage Macular edema Retinal vasculitis Intermediate uveitis Subconjunctival hemorrhage Inflammatory optic neuropathy Ophthalmic Complications

35. Pathophysiology… • The pathophysiologic mechanisms responsible for dengue effects are not completely understood. • Several authors report an interval between the systemic manifestations of dengue fever and the onset of visual symptoms. • This delay is consistent with the hypothesis that the ocular manifestations could be an immune-mediated process rather than a direct viral infection. Lim WK, Mathur R, Koh A, et al. Ocular manifestations of dengue fever. Ophthalmology 2004;111:2057– 64.

36. Literature Review • Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007; 125:501-510 • Published a report series of 41 patients (71 eyes) with Dengue Maculopathy at the Singapore National Eye Centre between Jan/02 and Dec/05. *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

37. Literature Review • Symptoms were noted a mean±SD of 6.9±4.0 days after the onset of fever. • Blurred vision 87% • Scotoma 63% • Floaters 1% *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

38. Literature Review • Posterior Segment Findings • Retinal hemes 45% • Venular sheathing 45% • Arteriolar sheathing 3% • Yellow subretinal dots 28% • Round foveal swelling 15% • Disc edema 11% • Optic disc hyperemia 14% • RPE mottling 17% • Intraretinal precipitates 1% • Vitreous hemorrhage 1% *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

39. Literature Review • FA Characteristics • Blocked fluorescence 33% • Venular occlusion 25% • Venular leakage 13% • Venular leakage with occlusion 5% • Knobby capillary hyperfluorescence 13% • Arteriolar occlusion 2% • Arteriolar leakage 3% • RPE window defect 3% • RPE hyperfluorescence 10% • Capillary nonperfusion 2% *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

40. Literature Review *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

41. Patient A Bilateral swollen and hyperemic optic discs, venular and arteriolar sheathing in the posterior pole, and small vitreous hemorrhage in the right eye. *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

42. Patient A Severe venular and arteriolar leakage over the entire posterior pole. *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

43. Patient A Severe neurosensory retinal detachments in both eyes. *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

44. Patient A (2 weeks later) *Bacsal KE, et al. Dengue Associated Maculopathy. Arch Ophthalmol 2007

45. Patient B Areas of blot hemorrhages temporal to the right fovea *Chan D, et al. Ophthalmic Complications of Dengue. Emerging Infectious Diseases 2006

46. Patient B Bilateral dye leakage from the retinal veins (right > left) *Chan D, et al. Ophthalmic Complications of Dengue. Emerging Infectious Diseases 2006

47. Patient B Retinal thickening both sides. Red arrow  exudative retinal detachment. *Chan D, et al. Ophthalmic Complications of Dengue. Emerging Infectious Diseases 2006

48. Patient B Central scotoma of the right visual field *Chan D, et al. Ophthalmic Complications of Dengue. Emerging Infectious Diseases 2006

49. Literature Review • Kapoor HK, et al. Ocular manifestations of dengue fever in an East Indian epidemic. Can J Ophthalmol 2006; 41:741-6 • Report of 134 patients hospitalized with dengue fever in Northern India from Oct/2003 to Nov/2003. *Kapoor HK, et al. Ocular manifestations of dengue fever. Can J Ophthalmol 2006.

50. Literature Review • Ocular findings in patients with dengue fever • Subconjunctival hemorrhage • Petechial-type 42% • Diffuse-type 8% *Kapoor HK, et al. Ocular manifestations of dengue fever. Can J Ophthalmol 2006.