Mosquito-Borne Uveitis

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UCSF December Course- 2016 San Francisco, CA Mosquito-Borne

Cunningham, Jr, MD, PhD, MPH Department of Ophthalmology,

Ophthalmology, Stanford University School of Medicine Francis

Retina Medical Group 10 μm Mosquito Proboscis www.gettyimages.

1 UCSF December Course San Francisco, CA Mosquito-Borne Uveitis Emmett T. Cunningham, Jr, MD, PhD, MPH Department of Ophthalmology, California Pacific Medical Center Department of Ophthalmology, Stanford University School of Medicine Francis I. Proctor Foundation, UCSF School of Medicine West Coast Retina Medical Group 10 μm Mosquito Proboscis Mosquitos Aedes aegypti Global Distribution of Aedes albopictus Aedes albopictus Global Distribution of Aedes aegypti 1

2 Global Distribution of Aedes albopictus Global Distribution of Aedes aegypti Tropics: 36% of the Earth s Landmass One-Third of the Earth s Population Global Air Travel 23.5 o N Tropic of Cancer Equator 23.5 o S Tropic of Capriocorn 2

3 Heavily Interconnected Malaria 450,000 Deaths/year Measles Mumps Rubella Filariasis Pork tapeworm Hepatitis C The Flaviviridae Family Enveloped viruses Icosahedral structures A positive sense, single-strand RNA genome (~ 12kb) Transcribed as a single polyprotein More than 100 different members Subdivided into: Flavivirus (including Yellow fever, Japanese Encephalitis, West Nile, dengue, and Zika viruses) Pestivirus Hepacivirus (hepatitis C viruses) 3

4 West Nile Virus West Nile Virus Flavivirus genus Flaviviridae family Positive-sense, single stranded RNA virus ~ 12Kb. West Nile Virus WNV Lifecycle US Outbreak 1999 Israeli Outbreak 1957 Identified in Uganda

5 Global Distribution of West Nile Virus Courtesy Mr. Nicholas Jones, Uveitis, 2 nd Edition, 2013 West Nile Virus USA, CDC ArboNET 5

2015 YTD 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001

1356 2205 2469 2526 3086 3630 4269 4156 5674 < 1 / 100,000 / year Index Cases,

Neuroinvasive Disease by Decile, 1999 2012, USA CDC ArboNET More Common in

USA CDC ArboNET 2015 To Date Cases reported to CDC ArboNET Human - 1566 More

6 2015 YTD Cases of WNV Reported to the CDC by Year < 1 / 100,000 / year Index Cases, NYC Average Annual Incidence of WNV Human Neuroinvasive Disease by Decile, , USA CDC ArboNET More Common in Elderly Number of Cases of WNV Human Neuroinvasive Disease by week, , USA CDC ArboNET 2015 To Date Cases reported to CDC ArboNET Human More Common in Summer / Fall Mosquito West Nile Virus 6

Systemic Disease 2 14 day incubation 80%

limited, ~ 1 week Fever Headache Myalgia

Severe headache, meningismus, confusion,

Arch Ophthalmol 2003; 121:205-207 Retina 2003;

Vitreous inflammation Retinal vasculitis

chorioretinitis curvilinear pattern Early

7 Systemic Disease 2 14 day incubation 80% asymptomatic 15% symptomatic, WN Fever self limited, ~ 1 week Fever Headache Myalgia Arthralgia Malaise Nausea Vomiting Skin Rash Pharyngitis 80% 15% 5% Asymptomatic Symptomatic Encephalitis 5% WN Encephalitis Severe headache, meningismus, confusion, stupor/coma, tremors, convulsions, paralysis, death typically older or debilitated (diabetes). Arch Ophthalmol 2003; 121: Retina 2003; 23(1):97-99 Ocular Disease AC inflammation Vitreous inflammation Retinal vasculitis Retinitis Choroiditis (ICGA) Multifocal chorioretinitis curvilinear pattern Early Lesions Deep, Yellow-White Multifocal Chorioretinitis Often Curvilinear Pattern Courtesy Prof. Moncef Khairallah Courtesy Prof. Moncef Khairallah 7

8 Ophthalmol 2003; 110: West Nile Virus Chorioretinitis West Nile Virus Chorioretinitis Courtesy West Coast Retina Courtesy K. Bailey Freund 8

9 West Nile Virus Lesions Nerve Fiber Layer Distribution? FA ICGA Multifocal Chorioretinitis Often Curvilinear Pattern More on ICGA Courtesy Prof. Moncef Khairallah Spurious...? Multifocal Chorioretinitis Often Curvilinear Pattern FA Courtesy Prof. Moncef Khairallah 9

10 20/20 00: :45.96 Courtesy Dr. Steve Bennett Neuroretinitis Retinitis Vascular Occlusion Retina Mar;26(3): Courtesy Prof. Rathinam Sivakumar 10

11 Dengue Flavivirus genus Flaviviridae family Positive-sense, single stranded RNA virus ~ 11Kb. Global Distribution of Courtesy Mr. Nicholas Jones, Uveitis, 2 nd Edition, M New Cases per Year 11

Cases of Dengue Reported to the CDC by Year 2015 YTD 2014 364 33 654

554 6169 2011 243 1552 2010 642 10969 0 2000 4000 6000 8000 10000 12000

gov/mapviewer/ Dengue 2015 To Date Cases reported to CDC ArboNET

incubation Asymptomatic Non-specific febrile illness Classic Dengue

12 Cases of Dengue Reported to the CDC by Year 2015 YTD < 1 / 100,000 / year Mostly Florida and Texas Imported Locally Aquired Dengue 2015 To Date Cases reported to CDC ArboNET Locally Acquired 33 Cases Imported 364 Systemic Disease 2 14 day incubation Asymptomatic Non-specific febrile illness Classic Dengue fever High Fever Severe Headache Myalgia Arthralgia Malaise Nausea Vomiting Maculopapular Skin Rash 10% - Dengue Hemorrhagic Fever Shock Syndrome 12

Ocular Disease 75% Bilateral May be Serotype

inflammation Vitreous inflammation Retinal

vascular occlusion Retinitis Deep retinal

Subconjunctival Hemorrhage Platelet Counts <

13 Ocular Disease 75% Bilateral May be Serotype Specific Subconjunctival hemorrhage AC inflammation Vitreous inflammation Retinal hemorrhage Retinal vasculitis Retinal vascular occlusion Retinitis Deep retinal spots / foveolitis RPE mottling Serous retinal detachment Choroiditis (ICGA) Hemorrhage Yellow-White Lesions Subconjunctival Hemorrhage Platelet Counts < 50,000/ul 13

14 Active Lesions Active Lesions FA FA Courtesy Dr. Stephen Teoh Courtesy Dr. Stephen Teoh Active Lesions Active Lesions ICGA ICGA Courtesy Dr. Stephen Teoh Courtesy Dr. Stephen Teoh 14

15 Active Lesions 20/40 Infection CF Foveolitis Courtesy Dr. Stephen Teoh Courtesy Dr. Padmamalini Mahendradas Active Lesions Inactive Lesions Courtesy Prof. Khalid Tabbara Courtesy Prof. Khalid Tabbara 15

16 Active Lesions + 9 Months, Inactive Courtesy Dr. Srinivasan Sanjay Courtesy Dr. Srinivasan Sanjay Active Lesions Retinitis / Intraretinal Hemorrhage Active Lesions Retinitis / Intraretinal Hemorrhage Courtesy Prof. Chee Soon Phaik Courtesy Prof. Chee Soon Phaik 16

17 Active Lesions Vasculitis Active Lesions Vasculitis Courtesy Prof. Chee Soon Phaik Courtesy Prof. Chee Soon Phaik Active Lesions Foveolitis Chikungunya Alphavirus genus Togaviridae family. Positive-sense, single stranded RNA virus ~ 12Kb. Courtesy Prof. Chee Soon Phaik 17

In Makonde, Chikungunya means to walk bent over.

Global Distribution of Chikungunya Described in 1953, East

Nicholas Jones, Uveitis, 2 nd Edition, 2013 2015 To Date Cases

18 In Makonde, Chikungunya means to walk bent over. A reference to the stooped posture of many sufferers. Global Distribution of Chikungunya Described in 1953, East Africa Tanzania Mozambique Chikungunya Courtesy Mr. Nicholas Jones, Uveitis, 2 nd Edition, To Date Cases reported to CDC ArboNET Locally Acquired 152 Imported Chickunugnya 18

Systemic Disease In Makonde, Chikungunya means to walk bent

pain Severe joint pain Myalgia Malaise Nausea Vomiting

Disease AC inflammation +/- high IOP Vitreous inflammation

occlusion Retinitis Neuroretinitis Serous retinal

19 June 2, June 2, 2015 Systemic Disease In Makonde, Chikungunya means to walk bent over day incubation Acute Fever Headache Low back pain Severe joint pain Myalgia Malaise Nausea Vomiting Severe multi-organ failure, CNS involvement, death Ocular Disease AC inflammation +/- high IOP Vitreous inflammation Retinal hemorrhage Retinal vasculitis Retinal vascular occlusion Retinitis Neuroretinitis Serous retinal detachment Choroiditis (ICGA) Courtesy Dr. Padmamalini Mahendradas 19

20 Chikungunya Fever 20/30 20/50 Am J Ophthalmol 2007; 144: Common AC / Vitreous cell Neuritis Retinitis +/- SRD Courtesy Prof. Richard Rosen Chikungunya Fever + Two Months Oral CST, Topical CST, Topical Cyloplegic / Mydriatic 20/30 20/50 1:11 2:16 Courtesy Prof. Richard Rosen 20/20 20/20 Courtesy Prof. Richard Rosen 20

21 Chikungunya Fever Courtesy Prof. Rathinam Sivakumar Courtesy Dr. Padmamalini Mahendradas Presentation Chikungunya Fever 4 WEEKS 16 WEEKS 20/20 20/40 Am J Ophthalmol 2007; 144: /20 20/30 Courtesy Dr. Annie Mathai and Dr. Nidhi Relhan Vision at Last Visit Variable 21

22 Zika Virus Zika Virus Flavivirus genus Flaviviridae family Positive-sense, single stranded RNA virus ~ 12Kb. Uganda Monkeys 22

How Zika Spread 70-year Migration 1970s 2007

day incubation Non-specific febrile illness

23 How Zika Spread 70-year Migration 1970s Africa Southeast Asia Pacific Islands Americas New England Journal of Medicine; January 13, 2016 DOI: /NEJMp Systemic Disease Maculopapular Rash 1 in 5 symptomatic 2 to 10 day incubation Non-specific febrile illness Fever Arthralgias Maculopapular Skin Rash

Testing Risk of Local Zika Transmission: Year Round Seasonal

24 Testing Risk of Local Zika Transmission: Year Round Seasonal Serum PCR within 7 days Thereafter serum PRNT (Plaque Reduction Neutralization Technique) assay. Antibody crossreactivity with Dengue, WNV, etc Areas Susceptible to Spread of Zika Zika Risk US Brazil Travel Routes 24

25 Zika Risk Maculopapular Rash Conjunctivitis Child with Microcephaly, Recife, Brazil 25

Atrophy 15% Optic Disc Pallor 40% Exopharia

Alterations Atrophic Lesions Atophic Lesion

Foundation in Recife, Brazil Courtesy Dr.

26 10 Microcephalic Infants Severe Macular Neuroretinal Atrophy 25% 10% 15% 10% 10% 75% 25% 40% 15% 15% Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil 65% RPE Alterations 25% Optic Disc Hypoplasia 15% RPE Atrophy 15% Optic Disc Pallor 40% Exopharia 20% Esophoria 10% Horizontal Nystagmus RPE Alterations Atrophic Lesions Atophic Lesion RPE Alterations Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil 26

RPE Alterations Atrophic Lesions Optic Disc Hypoplasia -

Double-ring sign 3) +/- Vascular tortuosity Courtesy Dr.

jpg Increased Frequency First Trimester Exposure Smaller

symptomatic) 37 eyes (46%) of 22 patients (55%) with

27 RPE Alterations Atrophic Lesions Optic Disc Hypoplasia - Signs 1) Small disc (Disc-foveal distance > 3 DD) 2) Double-ring sign 3) +/- Vascular tortuosity Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil Increased Frequency First Trimester Exposure Smaller Cephalic Perimeter JAMA Ophthalmol Aug 1;134(8): Infants with Microcephaly Zika + Mothers (64% symptomatic) 37 eyes (46%) of 22 patients (55%) with findings RPE Atrophy RPE Mottling (28%) Optic Disc Hypoplasia (18%) Increased cip/disc (11%) RPE Atrophy (8%) Optic Disc Pallor (8%) Vaso- Obliteration RPE Alterations Tortuosity 27

N Engl J Med. 2016 Jul 28;375(4):394-396.

40 mmhg OD; 28 mmhg OS 1+ AC reaction OU Cleared with topical CST and

PRNT +; AC PCR + Zika 20/20 OD; 20/40 OS IOP normal Tr + AC reaction OD; 2+ OS Cleared

Furtado, MD February, 2016 20/20 64-year-old man erythematous rash / arthritis for 10 days

28 N Engl J Med Jul 28;375(4): year-old Male Physician Known Zika Infection Blurred vision one week later 20/40 OU IOP 40 mmhg OD; 28 mmhg OS 1+ AC reaction OU Cleared with topical CST and cycloplegic/mydriatic 40s-year-old man Rash and Conjunctivitis x 2 days Serum PCR, IgM, PRNT +; AC PCR + Zika 20/20 OD; 20/40 OS IOP normal Tr + AC reaction OD; 2+ OS Cleared with topical CST and cycloplegic/mydriatic Courtesy Dr. João M. Furtado, MD February, /20 64-year-old man erythematous rash / arthritis for 10 days after mission work in Haiti Courtesy Dr. Will Parke Ophthalmology 2016; Jul 27. pii: S (16) doi: /j.ophtha [Epub ahead of print] Courtesy Dr. Will Parke 28

29 12/2/2016 February, /200 for 3 days IOP Normal February, /200 for 3 days RPE Alterations Courtesy Dr. Will Parke Ring of Gray Perifoveal Coloration in Roughly a Bull s-eye shape 00:28.36 Courtesy Dr. Will Parke 02:33.14 Courtesy Dr. Will Parke Courtesy Dr. Will Parke 29

April, 2016 20/20 Presentation 3/200 + 2 Months

Optic Disc Hypoplasia (Neonates) UAIM-like

Conjunctivitis RPE Alterations Anterior Uveitis

30 April, /20 Presentation 3/ Months 20/20 Courtesy Dr. Will Parke Courtesy Dr. Will Parke Unilateral Acute Idiopathic Maculopathy (+Coxsackie) Ocular Disease Conjunctivitis AC inflammation (+/-hypertensive) RPE Alterations / Atrophy Optic Disc Hypoplasia (Neonates) UAIM-like outer retinal inflammation Neonates Adults Conjunctivitis RPE Alterations Anterior Uveitis RPE Alterations UAIM Courtesy Dr. J. Michael Jumper, West Coast Retina RPE Atrophy Disc Hypoplasia 30

31 Zika Ophthalmic Images Courtesy of Rubens Belfort, Jr, MD São Paulo, Brazil Camila V. Ventura, MD Racife, Brazil João M. Furtado, MD São Paulo, Brazil Darius Moshfeghi, MD Stanford, CA, USA D. Wilkin (Will) Parke, III, MD Minneapolis, MN, USA West Coast Retina, San Francisco, CA 31

Public Health Image Library. CDC/ Cynthia Goldsmith. Image #

Public Health Image Library. CDC/ Cynthia Goldsmith. Image # Zika Virus Fredrick M. Abrahamian, D.O., FACEP, FIDSA Clinical Professor of Medicine UCLA School of Medicine Director of Education Department of Emergency Medicine Olive View-UCLA Medical Center Sylmar,