Probable dengue without warning signs
Live in/travel to dengue endemic area with fever and two of the following:
Aches and pains
Positive tourniquet test
Dengue with warning signs a
Dengue as defined above with any of the following:
Abdominal pain or tenderness
Clinical fluid accumulation (ascites, pleural effusion)
Liver enlargement >2 cm
Laboratory: increase in HCT concurrent with rapid decrease in platelet count
Dengue with at least one of the following criteria:
Severe plasma leakage leading to:
Fluid accumulation with respiratory distress
Severe bleeding as evaluated by clinician
Severe organ involvement
Liver: AST or ALT ≥ 1000
CNS: impaired consciousness
Heart and other organs
In addition to encephalopathy, other neurological changes seen in dengue include encephalitis, meningitis, Guillain-Barré syndrome, myelitis, acute disseminated encephalomyelitis, polyneuropathy, mononeuropathy, hypokalaemic paralysis, cerebromeningeal haemorrhage as well as neuro-ophthalmic signs which will be discussed below [20, 24–39].
Pain is the commonest symptom and its severity ranges from a feeling of eye strain (30 %) or foreign body sensation (3 %) to a retro-orbital pain (20 %) . In the majority of patients, it is a non-specific and benign symptom. However, in certain patients, ocular pain in dengue may represent a sight-threatening event such as acute angle closure . In this particular patient though, who was female with fairly short axial length of 22 mm and normal posterior segments on B scan ultrasonography, it is uncertain if the angle closure was a direct complication of dengue infection or a coincidental occurrence. Of greater significance is a 6-year-old child who presented with what was thought to be acute angle closure initially and was subsequently diagnosed as panophthalmitis which resulted in permanent visual loss . Hence, although pain in dengue often has no detrimental outcome, a high index of suspicion needs to be maintained for potentially blinding causes.
Other symptoms commonly reported include blurring of vision (10 %), diplopia (3 %) and floaters and flashes (3 %) . However, a significant proportion of patients with maculopathy may be asymptomatic, and although an abnormal Amsler chart test has high specificity of 95 % for maculopathy, nonetheless its sensitivity is only 30 % [6, 8]. Therefore, the absence of visual symptoms does not exclude the presence of ocular involvement, and systematic screening especially in patients with severe dengue remains the main means of detection.
22.214.171.124 Anterior Segment
Anterior segment lesions in the form of subconjunctival haemorrhage are the commonest reported ocular manifestation of dengue, occurring in about 40 % of all patients [2, 8] and in up to 60 % in patients with severe dengue haemorrhagic fever, usually in association with severe thrombocytopenia . As a consequence of the thrombocytopenia, haemorrhages have also been noted to occur in the periocular tissues, including the retrobulbar space where it may be of such severity as to result in globe perforation [42, 43].
Uveitis occurring as an isolated event is rare in dengue [2, 41, 46], and it is more commonly described in association with the occurrence of dengue maculopathy [19, 22, 45, 47]. The series of patients with isolated uveitis described by Gupta is unusual for a number of reasons. Firstly, these patients were noted to have no ocular lesions during the acute phase and only presented 3 to 5 months later with progressive loss of vision. Secondly, four of the six patients did not experience pain, and ciliary injection was absent or mild in all six patients despite the presence of significant cellular reaction. Only one eye had bilateral involvement. Five patients (six eyes) had only anterior segment involvement with fine to large keratic precipitates and 2 to 4 + anterior chamber cells and flare. The intraocular pressure was normal, and posterior synechiae was absent in all but one patient who also had concomitant vitritis, vasculitis, retinal haemorrhages and macula oedema. The inflammation in all these patients resolved with corticosteroid therapy .
The other two cases of uveitis reported in the literature presented within 1 week of onset of fever with pain and blurring of vision. Both had shallowing of the anterior chambers. In one patient the shallowing was due to bilateral iridocyclitis with choroidal effusions, and the intraocular pressures were low. This patient recovered well following treatment with topical corticosteroids . The other patient was the 6-year-old child mentioned above who was initially diagnosed as having acute angle closure glaucoma in the left eye due to the presence of ciliary injection, hazy cornea and shallow anterior chamber and who had in fact severe panophthalmitis with periocular extension resulting in visual loss .
126.96.36.199 Fundal Changes in Dengue
There is a wide spectrum of fundal changes that have been described in patients with dengue including vitreous haemorrhage, retinal haemorrhages, peripapillary haemorrhages, optic disc hyperaemia, Roth spots, cotton wool spots, intraretinal precipitates, retinal oedema, maculopathy and retinal vasculopathy. There may be a concomitant anterior uveitis and vitritis [3, 18, 19, 21, 22, 35, 45, 47–53].
13.4.3 Dengue Maculopathy
Although macula changes such as cotton wool spots, oedema and haemorrhages may be observed together in association with major changes in the peripheral retina or with an optic neuritis [3, 18, 19, 21, 22, 31, 37, 45, 53], a predominant involvement of the macula with none or minimal peripheral changes is increasingly being reported as a cause of visual symptoms in patients with dengue, occurring in up to 10 % of patients hospitalised with dengue. It is usually a bilateral condition (73 to 80 %), although it may be asymmetrical, manifesting about 1 week after the onset of fever, when the platelet counts are generally at their lowest. Blurring of vision (18 to 100 %) and central scotoma (7 to 90 %) are the most common complaints. Less commonly, the patients may complain of floaters or metamorphopsia (5 %). The presenting visual acuity varied from 20/25 to count fingers closely, corresponding to the extent of macula oedema. In addition to oedema, other features of dengue maculopathy include foveolitis, small white or yellow subretinal dots, intraretinal haemorrhages, retinal epithelial swelling, vascular sheathing, optic disc hyperaemia and vitritis [6, 19, 21, 22, 35, 47, 54, 55] (Figs. 13.1, 13.2 and 13.3).
(a) Fundal photograph showing small yellow dots and mild sheathing of perifoveal vessels. (b) Indocyanine green angiography of the same eye showing mild large vessel hyperfluorescence in the early phase
(a) Fundal photograph showing sheathing of perifoveal venules. (b) Fundal fluorescein angiography of the same eye showing mild staining of the venules in the mid phase. (c) Indocyanine green angiography of the same eye showing large vessel hyperfluorescence in the early phase
(a) Fundal photograph showing exudative detachment of the macula with striae, retinal haemorrhages, small yellow dots and perivascular cuffing. (b) Optical coherence tomography of the same eye showing the presence of subretinal as well as intraretinal fluid
The term foveolitis is used to describe a small, well-circumscribed yellow-orange subretinal lesion localised to the fovea (Fig. 13.4a, b). These lesions measure between 0.2 and 0.5 mm and may be seen as an isolated lesion or in combination with the other findings described above such as retinal haemorrhages and vascular sheathing. Optical coherence tomography (OCT) of these lesions shows a disruption of the outer sensory retina with or without any accompanying elevation of adjacent retina [54, 55]. In addition to foveolitis, other OCT changes that have been seen in eyes with dengue maculopathy include diffuse retinal thickening, cystoid macular oedema and exudative detachment [19, 22, 56]. All these changes resolved within a month, but the visual function was not always similarly restored. Teoh et al. showed that the different types of OCT changes were useful predictors of visual outcome at 2 years. Patients with diffuse retinal thickening had the least visual disturbance at presentation with more than 85 % having 20/40 or better vision and the best visual outcome. Only 30 % had a residual scotoma and all had 20/40 or better vision. In contrast, the majority of eyes with foveolitis (96 %) presented with 20/80 or worse vision, and although the Snellen acuity improved to 20/40 or better in at least 60 %, all eyes still had a visually disturbing scotoma. While 80 % of eyes with cystoid oedema also had poor visual at presentation and extremely swollen maculae, 81 % regained 20/40 or better vision with only 56 % still experiencing a residual scotoma .
(a) Fundal photograph showing macula haemorrhages with a small yellow elevated lesion at the fovea. (b) Optical coherence tomography of the same eye showing focal thickening of subfoveal outer retina with underlying subretinal fluid. The foveal contour is slightly elevated
Fundus fluorescein angiography (FFA) may be normal in up to 70 % of eyes with dengue maculopathy. FFA changes that have been described include the presence of early hyperfluorescence that persists to the late phase, blocked fluorescence, small vessel occlusion or leakage, capillary non-perfusion, knobbly hyperfluorescence of perifoveal arterioles and early pinpoint hyperfluorescence.
Similarly, indocyanine green angiography (ICGA) may be normal in about 60 % of eyes or show mid- or late phase hypofluorescent spots or large vessel hyperfluorescence suggesting that there may be an underlying choroidopathy as well. The predictive value of angiography is uncertain as in the series from Loh et al., although FFA changes were seen only in eyes that had poor presenting visual acuity of 20/400 or worse, all recovered to 20/40 or better vision. Similarly, other authors also found that despite the presence of severe leakage or non-perfusion on angiography, the retinal changes resolved with visual acuity of 20/40 or better in the majority of eyes [19, 22, 47, 54].
The vasculopathy in dengue affects mainly the venules and arterioles and is usually evident clinically as sheathing of the involved vessels. In a few cases, however, the vasculopathy may only be obvious on FFA (Fig. 13.5a, b and c) . Occlusion of the main retinal arteries have also been described with the patients presenting clinically as a branch or central retinal arterial occlusion with corresponding changes FFA [57, 58].
(a) Fundal photograph showing swelling of the macula with cotton wool spots. (b) Fundal fluorescein angiography of the same eye showing leakage from perifoveal venules in the mid phase. (c) Indocyanine green angiography of the same eye showing large vessel hyperfluorescence in the early phase
188.8.131.52 Neuro-Ophthalmic Involvement
Optic nerve involvement in dengue is a rare event, and of the 14 patients reported, ten (70 %) had bilateral disease with visual loss being the main presenting complaint [20, 30–37]. The initial visual acuity may range from 6/6 to no light perception, and colour vision and visual field defects are present unless the visual loss was too profound to permit their recording together with a relative afferent pupillary defect in unilateral cases. The optic nerve involvement is usually in the form of a papillitis with disc swelling and accompanying peripapillary haemorrhages and cotton wool spots. It may also appear as a retrobulbar neuritis with a normal fundal examination with only the observation of dilated sluggishly reactive pupils in the presence of poor vision to suggest an optic nerve lesion [20, 33]. Seventy percent of the eyes eventually regained 20/40 or better vision, but some patients may have persistent colour vision and field defects, and disc pallor may be seen [20, 30–37]. One of the patients with optic neuropathy also had bilateral exudative retinal detachment. Although the disc and retinal swellings are resolved, there were residual intraretinal lipid deposits which limited her visual recovery from an initial 20/250 in both eyes to 20/100 in one eye and 20/30 in the other . Another of these patients presented as a neuroretinitis with macular star exudates. However, this patient had complete resolution with no residual visual deficits . Three eyes (12.5 %) continued to progress to an eventual hand movement or worse vision.
Optic disc hyperaemia has also been observed in eyes with maculopathy , and in these cases, it can be difficult to exclude a concomitant neuropathy without ancillary tests such as FFA and electrophysiological tests as a severe maculopathy can also give rise to colour vision deficits, visual field defects as well as a relative afferent pupil defect . There have also been sporadic cases of isolated palsies of the cranial nerves supplying the external ocular muscles all of which resolved spontaneously by 3 months [33, 38, 39].
In addition to OCT, FFA and ICGA, ancillary tests that may be required include perimetry and electrophysiology.
Conventional perimetry with kinetic or static perimeter is useful in documenting the field defects in dengue optic neuropathy as well as the scotomas seen in eyes with maculopathy. However, as the maculopathy resolves, the subsequent changes in the scotomas may be subtle, and microperimetry may better able to monitor these changes .
Various modalities of electroretinography (ERG) may be used in combination with the visual evoked potential (VEP) to distinguish between retinal and optic nerve dysfunction in cases where the causes of poor vision are not clinically apparent.
The full-field ERG reflects the global retinal response and hence may be normal even when maculopathy is present with a reduction in scotopic b-wave amplitude, maximal b-wave implicit time delay or amplitude reduction being seen in only 50 % of patients with dengue maculopathy . The pattern ERG which measures macular function specifically showed a decrease in the P50 amplitude with preservation of the N95:P50 ratio in 57 % of the eyes in the series by Chia et al. and in both patients studied by Mendes et al. [59, 61]. The N95 component of the pattern ERG is selectively decreased in eyes with retina ganglion cell dysfunction and hence an abnormal N95:P50 ratio serves as an indicator of optic nerve involvement. The multifocal ERG provides a topographical map of central retinal function and was found to be abnormal in 73 % of Chia et al.’s eyes  and is also useful in the evaluation of macular function when clinical examination, OCT, FFA and ICGA are normal .
A delay in the P100 latency is non-specific and may occur as a result of both optic nerve and macular pathology. However, a delayed P100 in the presence of a normal pattern ERG or fundal examination serves to support a diagnosis of optic neuropathy in eyes with poor vision and abnormal pupillary response .
The laboratory tests used to confirm a diagnosis of dengue fever are determined by the timing as well as local availability of the tests. Prior to day 5, when the patient is still febrile, the virus may be detected by means of polymerase chain reaction for viral RNA, ELISA or rapid tests for viral antigen, in particular the nonstructural protein 1 (NS1) antigen, or virus cell culture. Subsequently, as the fever settles when the viral load decreases in tandem with an increase in antibodies production, immunoglobulin (Ig)M or a rise in paired sera IgG immunoassays is preferred. Although NS1 antigen levels are highest during the first week, it may still be detectable in some patients even up to the second week of onset [63, 64].