Ophthalmological features of Rift Valley Fever Virus
Rift Valley Fever Virus (RVFV) is a single-stranded, negative-sense RNA arbovirus that contains a tripartite genome and is part of the Phlebovirus genus within the Bunyaviridae family. RVFV is the cause of Rift Valley Fever (RVF), an emerging zoonotic illness with associated symptoms including headache, retro-orbital pain, myalgia, arthralgia, neck pain, and mild digestive disorders. Severe expression of RVF occurs in less than 2% of cases and can include manifestations such as acute or delayed encephalitis, vision disorders, hepatitis, jaundice, kidney function deficiencies, and hemorrhagic fever. This Eyewiki will emphasize the ocular findings of RVF. 
Modes of Transmission
The enzootic transmission cycle of RVF occurs through infected Aedes mosquitos serving as both the vector and the reservoir who subsequently feed on wild ungulates. Interestingly during “El Nino”-southern oscillation events (ENSO), an epizootic transmission cycle can occur from increased mosquito breeding zones. Other mosquito species (Anopheles,Culex,Mansonia) may act as secondary vectors which feed on the infected ruminates and subsequently transfer the disease to domesticated livestock (i.e. sheep, goats, camel, cattle). Human infection therefore either occur through handling of infected animals or through an infected mosquito bite. In addition, there is the possibility of vertical transmission which has been documented in a few cases.
Intensive RVF outbreaks and endemic disease in humans have been reported in East and Southern African countries since the 1950s. An epidemiologic shift to a number of West African countries occurred in the 1980s and was theorized to be associated with climate variability. The livestock trade has been postulated to be causative of the geographical spread of the virus to Yemen and Saudi Arabia in the early 2000s. In addition, outbreaks within the 21st century have occurred in Kenya, Somalia, Egypt, Madagascar, Tanzania, the Republic of South Africa, Namibia, Niger, Uganda, Mauritania, and more recently in 2019 in Mayotte and Sudan. A male predominance of a male:female ratio of 3.5:1 has been reported and risk factors include persons that have direct contact with infected animals, exposure to mosquito bites, or both such as farmers or herders. Ocular manifestations occur in 0.5-1.5% of patients with RVF, although visual symptoms have reached 15% of the infected population in an outbreak in southwest Saudi Arabia in 2000.
Whether the mechanism of ocular involvement in RVFV infection results from an immune-mediated response or from direct viral toxicity remains opaque. Reports of retinal pigment epithelium (RPE) degeneration with perivascular cuffing and round cell inflammatory infiltration as well as retinal necrosis in focal areas was suggested on post-mortem examination but viral presence in the ocular tissues could not be proved.
Currently there is no licensed human vaccine protective against RVFV despite the limited antigenic diversity of the virus and it being listed by the World Health Organization as a priority pathogen with high epidemic potential. Therefore, preventive strategies include all-day measures against mosquito vector exposure through the use of bed nets, long-sleeved clothing, and insect repellants. In addition, use of personal protective equipment has been shown effective against nosocomial infection.
Visual symptoms may include photophobia, acute hemorrhagic conjunctivitis, retro-orbital pain, blurred vision, decreased visual acuity, scotomas, and/or seeing floaters. The mean interval of presentation of unilateral or bilateral visual symptoms after onset of RVF is 5-14 days.
On fundoscopic examination with indirect ophthalmoscopy, macular or paramacular retinitis is the most specific and common ocular lesion seen which is visualized as a singular well-defined necrotizing lesion with poorly demarcated patchy creamy-white lesions accompanied with retinal hemorrhages. Slit-lamp biomicroscopy may reveal transient anterior uveitis with non-granulomatous keratic precipitates (range of +1 to +3 cells) and aqueous flare accompanied with posterior uveitis (panuveitis). Fluorescein angiography (FA) during the active phase of RVF may reveal early hypofluorescence of retinitis accompanied by delayed filling of venules and arterioles in association with subsequent late staining of blood vessels and retinal lesions. Retinal vasculitis (phlebitis or less commonly arteritis), arterial occlusions, and sheathing of vessels may also be identified on FA. In addition, vitreous reactions (range of +1 to +2 vitreous cells) with vitritis or vitreal haze as well as optic disc edema or palor may be seen. On FA follow-up, obliterated macular vessels, vascular occlusions, sheathing, angiospasm, and window defects may be seen months after initial symptom onset of RVF.
Definitive diagnoses of RVF requires one of the following according recommendation by the WHO:
1. Virus RNA detection in plasma or serum via RT-PCR
2. Anti-RVFV IgM and IgG antibodies detection via ELISA and molecular assays
3. RFVF virus antigen detection via ELISA and molecular assays
4. RVFV isolation
Challenges with diagnosis include the broad overlap of symptomology with other hemorrhagic fevers and the lack of a point-of-care diagnostic tool. Commercially available RT-PCR kits can confirm cases but the transient period of viremia requires an additional serological assy to ensure reliable case detection.
Macular retinitis, paramacular retinitis, retinal hemorrhage, vitreous reactions, optic disc edema, retinal vasculitis, anterior uveitis, posterior uveitis
Photophobia, hemorrhagic conjunctivitis, retro-orbital pain, blurred or decreased vision, scotomas, floaters
Table 1 lists the different diagnoses that should be taken into consideration in relation to specific RVF manifestations.
|RVF manifestation||Time of onset||Frequency||Lethality||Sequelae||Differential infectious diagnoses|
|50–90% of infected people||Prolonged asthenia||Arboviruses, influenza virus, HIV (primary infection)
Rickettsia spp., Coxiella burnetii, Salmonella spp., bacterial sepsis
|Acute hepatitis||Day 2–21||1–2% of symptomatic cases||High in icteric hepatitis||None||EBV, CMV, HIV, hepatitis viruses A, B, C, D, E, arboviruses (yellow fever, dengue, chikungunya)
Mycoplasma, Leptospirosa spp., Coxiella burnetii, Brucella, Bartonella, Babesia, Pneumococcus, Clostridium perfringens
|Hemorrhagic fever||Day 2–14 (day 2–4)||1–25% of symptomatic cases||25–65%||None||Hemorrhagic viral fevers, Leptospira spp.|
|Ocular signs including RVF retinitis||Day 4–20||0.5–15% of symptomatic cases||Reduced or lost vision||Measles, rubella, influenza, CMV, HSV, VZV, West Nile, chikungunya, dengue and various encephalitis viruses|
|Acute encephalitis||Day 2–10||< 1% of symptomatic cases||
|1–5% of symptomatic cases||< 50%||
|Same diagnoses as acute encephalitis|
Source: Javelle E, Lesuer A, Pommier de Santi V, de Laval F, Lefebvre T, Holweck G, Durand G, Leparc-Goffart I, Texier G, Simon F. The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal. Ann Clin Microbiol Antiomicrob 2020;19:4.
General management includes supportive therapy with fluid replacement and implementation of infection prevention and control (IPC) measures.
Presently there is no FDA-approved treatment for RVF infection. Iatrogenic use of aspirin, non-steroid anti-inflammatory drugs, and hepatotoxic analgesics need be avoided in order to reduce the risk of hemorrhagic complications. In addition, use or ribavirin is currently not advised due to a lack of proven efficacy in vivo and increased risk of neurological disease complications. Management of ocular symptoms include artificial tear preparations and topical ophthalmic steroids.
The prognosis of RVF is variable. Severe ocular morbidity may occur. Spontaneous resolution of active ocular lesions (retinitis, retinal hemorrhage, vitreous reaction) typically occurs within 10 to 12 weeks with subsequent scar formation as the most common complication. In addition, anterior uveitis typically resolves within 2 to 3 weeks without treatment. Poor visual acuity outcomes are the result of central scarring in association with macular/paramacular scarring, occlusive retinal vasculitis and post-infectious optic atrophy. In summary, between 40%-50% of infections with retinal complications have permanent vision loss and up to 71% of patients with ocular manifestations reached the criteria for legal blindness. 
RVF can produce ophthalmic findings in the anterior (acute hemorrhagic conjunctivitis) or posterior segement (retinitis). There is no vaccine or proven effective treatment for RFV and primary prevention centers on reducing exposure and mosquito bite. Travel to or from an endemic area for RVF is the main epidemiologic risk factor.
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