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10 μm
Mosquito-Borne Uveitis
Emmett T. Cunningham, Jr, MD, PhD, MPHDepartment of Ophthalmology, California Pacific Medical CenterDepartment of Ophthalmology, Stanford University School of MedicineFrancis I. Proctor Foundation, UCSF School of MedicineWest Coast Retina Medical Group
UCSF December Course- 2016San Francisco, CA
Mosquito Proboscis
www.gettyimages.comMosquitos … Aedes aegypti
Aedes albopictus
Global Distribution of Aedes albopictus
Global Distribution of Aedes aegypti
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Global Distribution of Aedes albopictus
Global Distribution of Aedes aegypti
Tropics: 36% of the Earth’s LandmassOne-Third of the Earth’s Population
Tropics: 36% of the Earth’s LandmassOne-Third of the Earth’s Population
http://education.nationalgeographic.org/encyclopedia/tropics/
23.5 o N – Tropic of Cancer
23.5 o S – Tropic of Capriocorn
Equator
Global Air Travel
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Heavily Interconnected • Malaria – 450,000 Deaths/year• Measles• Mumps• Rubella• Filariasis• Pork tapeworm• Hepatitis C
• 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 Zikaviruses)
• Pestivirus• Hepacivirus (hepatitis C viruses)
The Flaviviridae Family
http://www.utmb.edu/discoveringdenguedrugs-together/Diseases/Flaviviridae%20Family.asp
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West Nile VirusWest Nile Virus• Flavivirus genus• Flaviviridae family• Positive-sense, single stranded RNA virus • ~ 12Kb.
WNVLifecycle
US Outbreak1999
Identified in Uganda
1937
Israeli Outbreak1957
West Nile Virus
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Global Distribution of West Nile Virus
Courtesy Mr. Nicholas Jones, Uveitis, 2nd Edition, 2013
1999 2000
2001 2002
http://www.cdc.gov/westnile/resources/pdfs/wnvguidelines.pdf
West Nile Virus – USA, 1999-2012CDC ArboNET
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622166
41569868
25263086
42693630
1356720
1019712
56742469
22051566
0 2000 4000 6000 8000 100001999200020012002200320042005200620072008200920102011201220132014
2015 YTDCases 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, 1999 – 2012, USA CDC ArboNET
More Common in Elderly
Number of Cases of WNV Human Neuroinvasive Disease
by week, 1999 – 2012, USA CDC ArboNET
More Common in Summer / Fall
http://diseasemaps.usgs.gov/mapviewer/West Nile Virus
Human - 1566
Mosquito
2015 To DateCases reported to CDC ArboNET
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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
• 5% WN Encephalitis – Severe headache, meningismus, confusion, stupor/coma, tremors, convulsions, paralysis, death – typically older or debilitated (diabetes).
AsymptomaticSymptomaticEncephalitis
80% 15%5%
Retina 2003; 23(1):97-99Arch Ophthalmol 2003; 121:205-207
Ocular Disease• AC inflammation• Vitreous inflammation• Retinal vasculitis• Retinitis• Choroiditis (ICGA)• Multifocal chorioretinitis
curvilinear pattern
Courtesy Prof. Moncef Khairallah
Early LesionsDeep, Yellow-White
Courtesy Prof. Moncef Khairallah
Multifocal ChorioretinitisOften Curvilinear Pattern
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Ophthalmol 2003; 110:1732-1736
http://www.westcoastretina.com/WestCoastRetina/Feb-2014.html Courtesy West Coast Retina
West Nile Virus Chorioretinitis
Courtesy K. Bailey Freund
West Nile Virus Chorioretinitis
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Courtesy Prof. Moncef Khairallah
FA
ICGA
Multifocal ChorioretinitisOften Curvilinear Pattern
More on ICGA
West Nile Virus LesionsNerve Fiber Layer Distribution?
Spurious . . .?
Courtesy Prof. Moncef Khairallah
Multifocal Chorioretinitis
Often Curvilinear Pattern
FA
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00:56.19 05:45.9620/20
Courtesy Dr. Steve Bennett
Retina. 2006 Mar;26(3):365-7.
Courtesy Prof. Rathinam Sivakumar
Neuroretinitis – RetinitisVascular Occlusion
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Dengue Virus
Dengue• Flavivirus genus• Flaviviridae family• Positive-sense, single stranded RNA virus • ~ 11Kb.
Global Distribution of Dengue Virus
Courtesy Mr. Nicholas Jones, Uveitis, 2nd Edition, 201350-100M New Cases per Year
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10969
1552
6169
8253
551
33
642
243
554
772
654
364
0 2000 4000 6000 8000 10000 12000
2010
2011
2012
2013
2014
2015 YTD
Cases of Dengue Reported to the CDC by Year
Imported Locally Aquired
< 1 / 100,000 / yearMostly Florida and Texas
http://diseasemaps.usgs.gov/mapviewer/Dengue
Locally Acquired33 Cases
Imported364
2015 To DateCases reported to CDC ArboNET
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
https://viraldiseasesd.wikispaces.com/Dengue+Fever
https://microbewiki.kenyon.edu/index.php/Dengue_transmission
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Ocular Disease75% BilateralMay 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)
HemorrhageYellow-White Lesions
Dengue VirusSubconjunctival HemorrhagePlatelet Counts < 50,000/ul
https://openi.nlm.nih.gov/detailedresult.php?img=2566568_1757-1626-1-204-1&req=4
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Courtesy Dr. Stephen Teoh
Dengue VirusActive Lesions
Dengue VirusActive Lesions
Courtesy Dr. Stephen Teoh
FAFA
Courtesy Dr. Stephen Teoh
Dengue VirusActive Lesions
ICGAICGA
Dengue VirusActive Lesions
Courtesy Dr. Stephen Teoh
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Dengue VirusActive Lesions
“Foveolitis” Courtesy Dr. Stephen Teoh Courtesy Dr. Padmamalini Mahendradas
Dengue Virus Infection20/40
CF
Dengue VirusActive Lesions
Courtesy Prof. Khalid Tabbara
Dengue VirusInactive Lesions
Courtesy Prof. Khalid Tabbara
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Dengue VirusActive Lesions
Courtesy Dr. Srinivasan Sanjay
Dengue Virus+ 9 Months, Inactive
Courtesy Dr. Srinivasan Sanjay
Dengue VirusActive Lesions – Retinitis / Intraretinal Hemorrhage
Courtesy Prof. Chee Soon Phaik
Dengue VirusActive Lesions – Retinitis / Intraretinal Hemorrhage
Courtesy Prof. Chee Soon Phaik
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Dengue VirusActive Lesions – Vasculitis
Courtesy Prof. Chee Soon Phaik
Dengue VirusActive Lesions – Vasculitis
Courtesy Prof. Chee Soon Phaik
Dengue VirusActive Lesions – Foveolitis
Courtesy Prof. Chee Soon Phaik
Chikungunya• Alphavirus genus• Togaviridae family. • Positive-sense, single stranded RNA virus • ~ 12Kb.
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Described in 1953, East AfricaTanzaniaMozambique
In “Makonde,” Chikungunya means “to walk bent over.”
A reference to the stooped posture of many sufferers.
Chikungunya
Global Distribution of Chikungunya
Courtesy Mr. Nicholas Jones, Uveitis, 2nd Edition, 2013
http://diseasemaps.usgs.gov/mapviewer/Chickunugnya
Locally Acquired152
Imported538
2015 To DateCases reported to CDC ArboNET
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https://www.sciencenews.org/article/chikungunya-move June 2, 2015 https://www.sciencenews.org/article/chikungunya-move June 2, 2015
Systemic Disease• 2 – 14 day incubation• Acute
• Fever• Headache• Low back pain• Severe joint pain• Myalgia• Malaise• Nausea• Vomiting
• Severe – multi-organ failure, CNS involvement, death
In “Makonde,” Chikungunya means “to walk bent over.”
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
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Am J Ophthalmol 2007; 144:552-556
Common• AC / Vitreous cell• Neuritis• Retinitis +/- SRD
Courtesy Prof. Richard Rosen
20/30 20/50Chikungunya Fever
Courtesy Prof. Richard Rosen
20/30 20/50
1:11 2:16
Chikungunya Fever
Courtesy Prof. Richard Rosen20/20 20/20
+ Two MonthsOral CST, Topical CST, Topical Cyloplegic / Mydriatic
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Courtesy Prof. Rathinam Sivakumar
Chikungunya Fever
Courtesy Dr. Padmamalini Mahendradas
4 WEEKS 16 WEEKS
20/30
20/4020/20
20/20
Presentation
Courtesy Dr. Annie Mathai and Dr. Nidhi Relhan
Chikungunya Fever
Am J Ophthalmol 2007; 144:552-556
Vision at Last Visit Variable
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Zika Virus
Zika Virus• Flavivirus genus• Flaviviridae family• Positive-sense, single stranded RNA virus • ~ 12Kb.
Uganda1947 - Monkeys
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How Zika Spread – 70-year Migration
Africa Southeast Asia Pacific Islands Americas
1947
20072016
1970s
New England Journal of Medicine; January 13, 2016 DOI: 10.1056/NEJMp1600297
Systemic Disease
• 1 in 5 symptomatic• 2 to 10 day incubation• Non-specific febrile illness• Fever• Arthralgias• Maculopapular Skin Rash
https://en.wikipedia.org/wiki/Zika_virus#/media/File:Zika.Virus.Rash.Arm.2014.jpg
Maculopapular Rash
http://www.memeornah.com/trending/zika-virus-rash/887/
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Testing
• Serum PCR within 7 days• Thereafter serum PRNT
(Plaque ReductionNeutralization Technique) assay.
• Antibody crossreactivitywith Dengue, WNV, etc
http://www.medscape.com/viewarticle/862671
Areas Susceptible to Spread of Zikahttp://www.nytimes.com/interactive/2016/02/06/science/air-travel-from-countries-affected-by-zika.html
Risk of Local Zika Transmission: Year Round Seasonal
http://www.nytimes.com/interactive/2016/02/06/science/air-travel-from-countries-affected-by-zika.html
US – Brazil Travel Routes
Zika Risk
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Zika Risk
Maculopapular RashConjunctivitis
www.eurosurveillance.com
Child with Microcephaly, Recife, Brazilhttp://www.who.int/emergencies/zika-virus/situation-report-26-02-2016.pdf
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“Severe Macular Neuroretinal Atrophy”
Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil
25%10%15%10%10%75%25%40%15%15%
10 Microcephalic Infants
• 40% Exopharia• 20% Esophoria• 10% Horizontal Nystagmus
• 65% RPE Alterations• 25% Optic Disc Hypoplasia• 15% RPE Atrophy• 15% Optic Disc Pallor
Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil
RPE AlterationsAtophic Lesion
Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil
RPE AlterationsAtrophic Lesions
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Courtesy Dr. Camila Ventura of the Altino Ventura Foundation in Recife, Brazil
RPE AlterationsAtrophic Lesions
http://www.nature.com/eye/journal/v19/n5/images/6701857f15.jpg
Optic Disc Hypoplasia - Signs1) Small disc
(Disc-foveal distance > 3 DD)2) “Double-ring sign”3) +/- Vascular tortuosity
JAMA Ophthalmol. 2016 Aug 1;134(8):912-918.
40 Infants with MicrocephalyZika + Mothers (64% symptomatic)
37 eyes (46%) of 22 patients (55%) with findings
Increased Frequency• First Trimester Exposure• Smaller Cephalic Perimeter
• RPE Mottling (28%)• Optic Disc Hypoplasia (18%)• Increased cip/Disc (11%)• RPE Atrophy (8%)• Optic Disc Pallor (8%)
RPE Alterations
RPE Atrophy
TortuosityVaso-
Obliteration
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39-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
N Engl J Med. 2016 Jul 28;375(4):394-396.
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
Ophthalmology 2016; Jul 27. pii: S0161-6420(16)30507-3. doi: 10.1016/j.ophtha.2016.06.039. [Epub ahead of print]
64-year-old manerythematous rash / arthritis
for 10 days aftermission work in Haiti
Courtesy Dr. Will Parke
February, 201620/20
Courtesy Dr. Will Parke
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February, 20163/200 for 3 days
IOP Normal
“Ring of Gray Perifoveal Coloration in Roughly a ‘Bull’s-Eye’ shape”Courtesy Dr. Will Parke
February, 20163/200 for 3 days
RPE Alterations
Courtesy Dr. Will Parke
00:28.36
Courtesy Dr. Will Parke
02:33.14
Courtesy Dr. Will Parke
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April, 201620/20
Courtesy Dr. Will Parke
20/20
Courtesy Dr. Will Parke
3/200Presentation
+ 2 Months
Unilateral Acute Idiopathic Maculopathy (+Coxsackie)
Courtesy Dr. J. Michael Jumper, West Coast Retina
RPE Alterations
Ocular Disease• Conjunctivitis• AC inflammation (+/-hypertensive)• RPE Alterations / Atrophy• Optic Disc Hypoplasia (Neonates)• UAIM-like outer retinal inflammation
AnteriorUveitis
Conjunctivitis
UAIM
Adults
NeonatesRPE
Alterations
RPE Atrophy Disc Hypoplasia
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Zika Ophthalmic Images Courtesy of
Camila V. Ventura, MDRacife, Brazil
Rubens Belfort, Jr, MDSão Paulo, Brazil
Darius Moshfeghi, MDStanford, CA, USA
João M. Furtado, MDSão Paulo, Brazil
D. Wilkin (Will) Parke, III, MDMinneapolis, MN, USA
West Coast Retina, San Francisco, CA
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