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Case report

A 7-year-old boy presented after 3 days of blurred vision and floaters in both eyes, preceded by an upper respiratory tract infection treated with oral amoxycillin. There was no other significant medical history. On examination, visual acuities were right 6/60 and left 2/36. There was a mild right relative afferent pupillary defect. There was bilateral diffuse conjunctival injection with mild nongranulomatous anterior uveitis and vitritis. Intraocular pressures were right 12 mmHg and left 8 mmHg. Fundal examination (Figure 1) revealed symmetrical widespread retinal vasculitis, including prominent sheathing affecting both venules and arterioles. There was bilateral moderate papillitis, severe macular oedema, and scattered small retinal haemorrhages. The patient had submandibular lymphadenopathy, but no other abnormality on general examination.

Figure 1
figure 1

Bilateral primary idiopathic frosted branch angiitis in a 7-year-old boy. There is extensive, translucent perivascular ‘exudate’, disc and mascular oedema, and scattered intraretinal haemorrhages.

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Full blood count and differential cell count were normal, as were erythrocyte sedimentation rate, C-reactive protein, chest X-ray, angiotensin-converting enzyme, immunoglobulins, and liver function tests. There was no evidence of cellular or humoral immune deficiency. An auto-antibody screen was negative, as was the Paul Bunnell test. Serology for cytomegalovirus (CMV), herpes simplex, varicella zoster and Epstein–Barr viruses, rubella, and syphilis were negative. Fluorescein angiography (FA, Figure 2) revealed normal blood flow, but late diffuse staining and leakage of the affected vessels and the optic discs. A diagnosis of primary frosted branch angiitis (FBA) was made. Within 24 h visual acuity had deteriorated to counting fingers at 1 m in both eyes. He was treated with oral prednisolone 1 mg/kg/day, with topical steroid and mydriatic. Response was rapid, with resolution of all clinical signs and improvement in visual acuity to 6/9 in both eyes, by day 15. Systemic steroid treatment was tapered and discontinued after 4 weeks.

Figure 2
figure 2

Fluorescein angiography is frosted branch angiitis showing extensive vascular leakage and retinal oedema. The same patient as in Figure 1.

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After 4 weeks, uveitis with mild macular oedema recurred, without angiitis. Topical steroid was recommenced. An MRI scan of orbits and brain was normal, as was electrophysiology. The Goldmann fields showed generalised constriction. The disease course fluctuated in the early stages, accompanied by an inferior punctate retinitis, but subsided 14 months later, leaving fine retinal pigment epithelial changes at both maculae, but visual acuity of better than 6/6 in both eyes.

Discussion and review of the literature

In 1976 Ito1 reported a 6-year-old Japanese boy with panuveitis and widespread retinal vasculitis. The florid translucent perivascular exudate inspired the descriptive term ‘frosted branch angiitis’. The phenomenon is rare and probably a new entity, only 57 cases2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46 having been recorded in the world literature (Table 1). The great majority (75%) of patients are Japanese; indeed, it was not until 198813 that any patient outside Japan was reported. A total of 9 cases have subsequently been reported from the USA13,25,27,32,44 and single cases from Turkey,37 Korea,40 India,41 and Spain.46 Our patient is the first to be described in the UK.

Table 1 Reported cases of primary idiopathic frosted branch angiitis 1976–2003
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FBA predominantly affects the young and fit. There appears to be a bimodal age distribution (Figure 3), with one peak in childhood and a second in the third decade. The youngest patient reported to date was 2 years16 and the oldest 42 years.28 There has been a preponderance of females (61%) to males (39%).

Figure 3
figure 3

Age distribution at presentation (possibly bimodal) for all published cases of primary frosted branch angiitis.

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The most common presenting symptoms of FBA are subacute visual loss, floaters or photopsiae. The visual acuity may be substantially reduced (Table 1), even to perception of light.4,17 Most patients (75%) have bilateral disease.

Typical FBA has a striking fundal appearance (Figures 1 and 2); the retinal vasculitis is widespread and bilateral with a ‘frosted’ quality to the perivascular exudate. Mild-to moderate iritis with vitritis is common, as is retinal oedema. Intraretinal haemorrhages and punctate hard exudates are only occasionally seen. Papillitis, if present, is usually mild; marked disc oedema has been noted only by us. FA is near normal in the early phase, but there is late leakage from the larger affected retinal vessels. In the recovery phase, microaneurysms have been described.3 The vasculitis is usually nonocclusive. Visual field analysis reveals constriction or relative central defects that improve after clinical resolution1.6,7,9,10,19,20,36,37,41,43 The latter are thought to result from macular oedema.9,37

Electrophysiology has shown a reduction in the amplitudes of the electroretinogram (ERG), electro-oculogram (EOG), and visually evoked response (VER). This would be consistent with a widespread dysfunction of the retina, pigment epithelium, and optic nerve.9,47 The EOG and VER may return to normal,1,4,9 but the ERG changes have generally persisted beyond convalescence, suggesting permanent retinal damage.

Most patients with FBA have been treated with systemic steroids and have rapidly resolved with good visual recovery (Table 1). Less frequently, recovery has taken place over many months. Aciclovir has been used11,17,21,23,24,26,40 with unknown effect. Recurrence is rare.4,48

The prognosis in FBA has not always been favourable. Macular scarring has severely limited vision in 3 patients.13,25,37 Complications include retinal vein13,49 or artery occlusion,24 macular epiretinal membrane formation,38 diffuse retinal fibrosis,37 retinal tear formation,13 vitreous haemorrhage,50 optic disc atrophy1 and peripheral atrophic retinal lesions.1,9,16,30,37 The final visual acuity has been 6/60 or worse in 10% of affected eyes thus far reported (cases 1, 14, 34, 42, 46, 48, 52, 55, 56, Table 1), nine of which received systemic steroid treatment. In contrast, five patients (eight affected eyes) with severe visual loss (cases 7,23,24,32,37, Table 1) did not receive systemic steroid treatment, yet regained high acuity.

The cause of FBA is unknown. The typical onset of FBA after a multifactorial prodromal illness has led to the suggestion of a hypersensitivity reaction to various infective agents,23 which may initiate FBA via a common pathway, possibly of immune-complex deposition.13,38 This would support the use of systemic corticosteroids for those with substantial visual loss. However, the visual results with or without systemic steroid treatment thus far provide no clear guidance on treatment.

Other causes of retinal vasculitis should be excluded, especially viral retinitis, sarcoidosis, multiple sclerosis, toxoplasmosis, syphilis, and Behçet's disease. Infiltrative causes such as lymphoma and leukaemia may occasionally mimic FBA. However, the distinctive clinical appearance is usually pathognomonic. Tentative suggestions31 of a link to HLA-A2 are inadequately supported. A presumed viral illness has preceded the onset in 33% of cases including our own.2,3,4,5,7,13,17,19,22,23,25,27,29,31,35,39,41,42 No consistent aetiological agent has been identified, but positive serology results have been reported for: herpes simplex virus (HSV),11,13,26,34,35,41 varicella zoster virus (VZV),2,5,11,13,21 tuberculoprotein,1,5,34 antistreptolysin O,4,13,39 Epstein-Barr virus,25 CMV,34 Coxsackie virus A10,31 adenovirus,34 measles34 and rubella.41

The cases listed in Table 1 and referred to above appear, with limited variation, to adhere to Ito's original description of a primary idiopathic FBA. However, other cases of FBA, often localised, have been described, which appear either to be secondary to intraocular infection by CMV,51,52,53,54,55,56,57,58 HSV (confirmed by aqueous PCR),59,60 herpesvirus hominis,61 toxoplasmosis62 or Fusarium dimerium,63 or in association with systemic lupus erythematosus,64 Crohn's disease,65 lymphoma,66 leukaemia67 and Behçet's disease (our own unpublished case, Figure 4).

Figure 4
figure 4

Occlusive hemispheric retinal vasculitis in a 22-year-old woman with Behçet's disease. In addition to widespread retinal haemorrhage, venous tortuosity, and disc oedema, there is a frosted branch appearance to much of the involved venous tree.

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In summary, Frosted branch angiitis in typical form, unassociated with preexisting intraocular inflammation, is likely to be a primary immunological process in response to a number of provoking antigens. As discussed by Kleiner,13,68 an apparently different form exists, which is secondary to concurrent inflammation, most commonly in association with CMV retinitis.51,52,53,54,55,56,57,58 Kleiner classifies the form seen in association with intraocular lymphoma or leukaemia differently, which may mimic FBA but is probably an infiltrative process. Our review of the world literature to date suggests that this proposal is sound. However, in order to distinguish classical FBA, as originally described by Ito1 from secondary forms and masquerades, we propose the descriptive term ‘primary idiopathic frosted branch angiitis’.