Fig. 15.1
Schema for the pathogenesis of HTLV-1 uveitis
HTLV-1 uveitis is caused by inflammatory cytokines produced by HTLV-1-infected CD4+ T cells that significantly accumulate in the eyes of patients
The amount of integrated virus in the host genome is referred to as the provirus load and is involved in the HTLV-1 disease pathogenesis. Previous studies have shown that peripheral blood of HU patients contains a significantly higher provirus load compared to HTLV-1 asymptomatic carriers [28]. HTLV-1 provirus load in the peripheral blood mononuclear cells was also found to be correlated with intensity of the intraocular inflammation and with history of Graves’ disease [30]. In addition to that, a greater HTLV-1 provirus load in the eye, as compared to peripheral blood suggests a significant accumulation of HTLV-1-infected lymphocytes in eyes with HU [28].
15.4 Clinical Features
15.4.1 Systemic Disease
Most HTLV-1-infected persons are considered to be asymptomatic carriers. HTLV-1 causes HAM/TSP and ATL in a small percentage of infected individuals. HTLV-1-infected subjects, without a diagnosis of HAM/TSP, may also report subjective neurological symptoms such as paresthesia and weakness, or rheumatologic complaints mainly arthralgia. They may also develop oral disorders including gingivitis, periodontitis, and dry oral mucosa, or dermatitis [31]. Interval between HTLV-1 infection and disease manifestations remains unclear.
15.4.2 Ocular Disease
HTLV-1-associated ocular disease includes HU, opportunistic infections/malignant infiltrations of the eye in ATL patients, and keratoconjunctivitis sicca.
HU is usually characterized by a sudden onset with floaters, foggy vision, or moderate visual disturbance, with half of the affected patients developing bilateral HU [20]. HU typically presents with moderate to severe vitreous inflammation accompanied by mild anterior chamber cells and mild retinal vasculitis without any chorioretinal lesions (Fig. 15.2). Fluorescein angiography shows mild dye leakage from the retinal blood vessels (Fig. 15.3).
Fig. 15.2
Color fundus pictures in a typical patient with HTLV-1 uveitis. (a) Moderate vitreous opacities are seen in the right eye. (b) Inflammation is not seen in the left eye
Fig. 15.3
Fluorescein angiographic pictures in a typical patient with HTLV-1 uveitis. (a) Mild dye leakage from the optic disc and retinal blood vessels is seen in the right eye. (b) Leakage is not seen in the left eye
In most individuals, HU presents as an intermediate uveitis. Panuveitis, anterior uveitis and retinal vasculitis without vitreous opacities are less common. Mutton-fat KPs are often seen, but fibrin and hypopyon are extremely rare in the anterior chamber. Vitreous opacities are seen in more than 80 % of the patients, with more than half showing some form of vitreous membranous, lacework-like or dense opacities. Mild non-occlusive retinal vasculitis confirmed by fluorescein angiography is also seen in more than half of the patients. Although optic disc hyperemia may be observed in some patients, it disappears upon recovery from the intraocular inflammation and usually does not lead to atrophy. Cystoid macular edema has been reported to develop in less than 10 % of these patients [20].
15.5 Diagnosis
The diagnosis of HU should be based on seropositivity for HTLV-1 with no systemic evidence of HTLV-1-related diseases such as ATL and exclusion of other uveitis entities with defined causes such as ocular sarcoidosis, Behçet’s disease, or candidiasis [2, 32]. Careful ophthalmic and systemic assessments and laboratory tests are needed. The polymerase chain reaction method on aqueous humor and peripheral blood samples may be used to detect the HTLV-1 provirus [33].
15.6 Differential Diagnosis
As previously mentioned, vitreous opacity and mild vasculitis are the major clinical features observed in HU. When diagnosing patients with vitreous opacities for potential HU, ocular sarcoidosis, Behçet’s disease, pars planitis, and candidiasis must be excluded.
In ocular sarcoidosis, the nature of the vitreous opacities is clinically similar to that during HU. In HU, however, multiple snowball-like opacities are seen to a lesser degree, and typically punched-out-like multiple chorioretinal lesions in the peripheral retina are not seen.
In Behçet’s disease, the vitreous opacity is denser than that observed in HU. Hypopyon, retinal hemorrhages, and infiltrates, which are typical features of Behçet’s uveitis, are not seen in HU. Identification of systemic signs such as recurrent oral aphthous ulcers, and skin lesions are also helpful for differential diagnosis.
In addition to that, HU does not present “string of pearls” or “balls of fluff” patterns seen in candidiasis. The Candida antigens such as β-D-glucan in the peripheral blood will be negative in HU. Moreover, the snowbank-like changes seen in pars planitis are not observed in HU.
Venous sheathing, occlusion, and thrombosis of the retinal vessels typically seen in ocular sarcoidosis are not common in HU. In addition, the obstructive retinal vasculitis seen in Behçet’s disease is not normally found in HU.
15.7 Management
Various inflammatory cytokines are produced by the HTLV-1-infected CD4+ T cells that significantly accumulate in the eyes of HU patients [32]. Therefore, corticosteroid treatment should be effective in treating the intraocular inflammation seen in these patients, as it will suppress the cytokine production of the HTLV-1-infected CD4+ T cells. The effectiveness of corticosteroid administration is supported by an in vitro study which found that addition of corticosteroids to a culture medium suppressed the cytokine production from the infiltrating cells [34].
A mild degree of anterior inflammation in HU can be managed by the use of topical nonsteroidal or corticosteroidal drugs together with mydriatics. A sub-Tenon’s injection of corticosteroids such as triamcinolone acetonide may be an additional option when the patients have only moderate inflammatory activity in the vitreous cavity.
In patients with severe vitreous inflammatory activity and retinal vasculitis, oral corticosteroids should be better prescribed. It has been reported that an initial dosage of prednisolone started at 0.5 mg/kg daily followed by a tapering off of the drug is effective. However, long-term administration oral corticosteroids should be avoided [2, 32].
15.8 Prognosis
A good visual outcome is usually achieved with topical, and/or periocular, or systemic corticosteroids. However, approximately half of the patients experience recurrence of the uveitis [15]. Persistent visual impairment may result from secondary glaucoma, cystoid macular edema, or epiretinal membrane.
Conclusion
There have been clinical, seroepidemiological, molecular, biological, and virological evidence of HTLV-1-associated uveitis. Studies have allowed a better understanding of HU immunopathogenesis. However, many of the mechanisms of HU remain unclear, including how the HTLV-1-infected CD4+ cells are able to breakdown the ocular blood barrier and why the vitreous cavity is the major site of inflammation. Corticosteroids are the mainstay of HU treatment. They are able to suppress the cytokines produced by the infiltrating HTLV-1-infected cells. However, it remains unknown whether long-term corticosteroid treatment is safe or if it will adversely affect patients with HU.
Recent studies have shown new insights into the molecular functions of the HTLV-1 basic leucine zipper factor and Tax [35]. However, at the present time, there have been few studies undertaken to apply these new findings in further HU research. A better understanding of the mechanism of HU will make it possible to potentially find more effective treatments in the future.
Core Messages
A better understanding of HTLV-1 uveitis is of more importance today for ophthalmologists as recent surveys have indicated that HTLV-1 carriers are now thought to be spreading the disease from local endemic areas to non-endemic metropolitan areas.
The diagnosis of HTLV-1 uveitis is made based on positive serology for HTLV-1 and the exclusion of other uveitis entities, which include sarcoidosis, Behçet’s disease, pars planitis, acute retinal necrosis, and candidiasis.
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