CASE REPORT

Dengue maculopathy: visual electrophysiology and opticalcoherence tomography

Thaıs Sousa Mendes Æ Edmundo Frota de Almeida Sobrinho ÆAlexandre Antonio Marques Rosa Æ Laiza Medeiros dos Anjos ÆGenilma Matos da Costa Æ Givago da Silva Souza Æ Bruno Duarte Gomes ÆCezar Akiyoshi Saito Æ Manoel da Silva Filho Æ Luiz Carlos de Lima Silveira

Received: 6 January 2009 / Accepted: 8 June 2009 / Published online: 18 June 2009

� Springer-Verlag 2009

Abstract The objective of this study was to eval-

uate the visual loss due to dengue fever using retinal

and cortical electrophysiology and retinal imaging.

The participants were three female patients with low

visual acuity after dengue fever. They were evaluated

by routine ophthalmological investigations, transient

pattern electroretinogram (tPERG), transient pattern

visual evoked cortical potential (tPVECP), and retinal

optical coherence tomography (retinal OCT). tPERG

and tPVECP amplitude (lV) and implicit time (ms)

were the parameters evaluated using OCT retinal

thickness (lm) and reflectivity. All patients presented

low visual acuity and scotomata with or without

changes in the oculus fundus. tPERG from two

patients showed decreased amplitude or absence of

the main components; it was not possible to record a

reliable response in the third patient due to excessive

blinking. tPVECP at 0.5 cpd was normal in all three

patients, while at 2 cpd the main components were

absent in one patient and normal in the other two

patients. OCT image was abnormal in two patients,

one of them with high reflectance areas and another

with decreased retinal thickness (the third patient was

not studied with this technique).The dengue fever can

lead to visual impairment detectable by ophthalmo-

logical exams such as angiography, retinography, and

OCT imaging, as well as retinal and cortical electro-

physiology. Dengue maculopathy which could be

caused by vascular alterations and/or aberrant

immune response after infection may result in

temporary or permanent visual losses.

Keywords Dengue fever � Viral disease �Retinopathy � Electroretinogram � Cortical evoked

potentials � Optical coherence tomography

Introduction

Dengue fever is considered to be the most important

viral disease affecting humans that is transmitted

through mosquito bites. The virus is transmitted by an

infected female Aedes aegypti mosquito (rarely by

Aedes albopictus) which feeds during the day. The

T. S. Mendes � L. M. dos Anjos � G. M. da Costa �G. da Silva Souza � B. Duarte Gomes � C. A. Saito �M. da Silva Filho � L. C. de Lima Silveira

Instituto de Ciencias Biologicas, Universidade Federal do

Para, Campus Universitario do Guama, 66075-110 Belem,

Para, Brazil

E. F. de Almeida Sobrinho � A. A. M. Rosa

Hospital Universitario Bettina Ferro de Souza,

Universidade Federal do Para, Campus Universitario do

Guama, 66075-110 Belem, Para, Brazil

L. C. de Lima Silveira (&)

Nucleo de Medicina Tropical, Universidade Federal do

Para, Av. Generalıssimo Deodoro 92, 66055-240 Belem,

Para, Brazil

e-mail: luiz@ufpa.br

123

Doc Ophthalmol (2009) 119:145–155

DOI 10.1007/s10633-009-9178-5

infection is caused by four related virus serotypes

(DEN-1, DEN-2, DEN-3, and DEN-4) of the genus

Flavivirus (Flaviviridae family). Infection with one

of these serotypes provides serotype-specific immu-

nity for life; there is no cross-protection, and

epidemics occurring by multiple serotypes (hyperen-

demicity) are frequent.

About 2.5 billion people around the world, mainly

inhabitants of tropical regions, are at risk of infection.

The classical clinical findings of the dengue are fever,

photophobia, myalgia, and retrobulbar pain [1–3].

Although it is common for the eyes to become

reddened during some stage of the disease, ocular

manifestations with complaints of visual impairments

are unusual findings, but these have been described

more frequently in the literature over the last few

years. The main retinal manifestations are macular

swelling, macular yellow spots, and macular hemor-

rhages (see [4–22] for details about the symptoms and

the context in which it is inserted). In addition to the

more classical ophthalmological methods, such as

visual field analysis and fundoscopic examination,

electroretinography (ERG) and event electroenceph-

alography (visual evoked potential, VEP) can be used

as valuable tools to evaluate visual system integrity in

many pathophysiologies affecting the visual system

[15, 23–26]. The purpose of this work was to

investigate three patients that had dengue fever using

ERG, VEP, and retinal optical coherence tomography

(retinal OCT).

Methods

Subjects

Three female patients (MGF, 56 years old; MLT,

37 years old; and TNM, 26 years old) complaining of

low visual acuity after dengue fever were studied

from February 2004 to August 2005. The diagnostic

of dengue fever was made by the presence of typical

clinical features of the disease: sudden onset of

severe headache, high fever ([38�C), myalgias,

arthralgias, and cutaneous rash. The diagnostic was

confirmed by positive specific IgM antibody capture

using MAC-ELISA. Patients reported a sudden visual

loss 2, 7, and 8 days after dengue fever onset

(patients MGF, MLT, and TNM, respectively). All

patients were infected by DEN-3 sorotype as

identified by transcriptase reverse PCR. They

reported that it was their first exposure to dengue.

Electrophysiological and OCT procedures were per-

formed in the first month after infection. For the three

patients both eyes were tested. Careful anamnesis

was performed and none of the subjects reported

previous ocular, neural, or systemic diseases that

could affect the visual system. This research was

performed following the Brazilian and international

regulations of ethics for research with human subjects

(Ministerio da Saude, Brazil, 2000). It was reviewed

and approved by the Human Research Ethics Com-

mittee, Nucleo de Medicina Tropical, Universidade

Federal do Para (Protocol #113/2004, approved in 25/

11/2004).

To compare the results obtained from dengue fever

patients with normal subjects, a control group com-

posed of healthy subjects was evaluated using

transient pattern electroretinogram (tPERG) and

transient pattern visual evoked cortical potential

(tPVECP): tPERG, 39 subjects, 19 males and 20

females, 23.3 ± 6 (16–46) years old; tPVECP, 52

subjects, 22 males and 30 females, 29.7 ± 12.3 (19–

61) years old. For the control group only one eye was

tested, right eye in right-handed and left eye in left-

handed subjects. All control subjects had normal or

corrected-to-normal visual acuity to 20/20 or better

which was assessed by measuring the eye refractive

state with an autorefractor/keratometer (Humphrey

599, Carl Zeiss Meditec, Dublin, CA).

Ophthalmologic examination

All patients were evaluated by using routine ophthal-

mologic procedures including visual acuity measure-

ment using Snellen letters, biomicroscopy of the

anterior segment, ophthalmoscopy, tonometry using

Goldmann applanation tonometer, retinography, and

angiofluoresceinography (Topcon-50Ex model), and

threshold static automatic perimetry using Humphrey

field analyzer II and SITA-fast protocol (Carl Zeiss

Medtec, Dublin, CA).

tVECP and tPERG visual stimulation

Both tPERG and tPVECP were recorded using the

same stimulus. Psycho for Windows v2.36 software

(Cambridge Research System—CRS, Rochester,

England) was used to generate and display the

146 Doc Ophthalmol (2009) 119:145–155

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stimulus in a 2000 FlexScan T662-t (Eizo, Ishikawa,

Japan) CRT monitor (100 Hz frame rate, 800 9 600

pixels). Gamma correction was performed using an

OptiCAL OP200E photometer (CRS) and the Config

software (CRS). The stimulus test consisted of a black

and white checkerboard covering 16 9 16 degrees of

visual angle surrounded by a black field determined

by the residual monitor’s luminance. Two spatial

frequencies were used, 0.5 and 2 cycles per degree

(cpd) with checks subtending 300 and 150 of visual

angle, respectively, when viewed at 50 cm. The

Michelson contrast used was 100% and the presenta-

tion mode was 1 Hz square-wave pattern-reversal

modulation. Mean luminance was constant along all

presentation with a value of 50 cd/m2. A red cross

(1 degree) was used as fixation point.

tVECP and tPERG recordings

Surface electrodes were placed following the Inter-

national 10/20 System of Electrode Placement. For

tPERG, a corneal Dawson, Trick and Litzkow (DTL)

electrode was used as an active electrode coupled

with a gold-cup surface electrode used as a reference

placed at the ipsilateral outer canthus [27]. For

tPVECP, gold-cup surface electrodes were used to

obtain one-channel recordings from Oz (active elec-

trode), Fp (reference electrode), and Fpz (ground)

according to the international 10/20 system [28, 29].

The recordings were amplified 50,000X and online

filtered between 0.5 and 100 Hz. For each spatial

frequency, 240–480 epochs, 1 s each, were averaged.

The signal was recorded using a MAS800 differential

amplifier (CRS). A data acquisition card AS-1 (CRS)

allowed signal sampling at 1 KHz, with 12 bits of

resolution. The records were displayed and stored for

further analysis using an IBM Pentium PC and the

Optima for Windows software (CRS).

Waveform analysis

The waveforms were off-line filtered using Fast

Fourier Transform to allow waveform reconstruction

with only even harmonics. The recordings reproduc-

ibility was assessed by comparing mean waveforms

obtained in two sessions of 240 steps. For the final

analysis, the complete set of 480 sweeps was

averaged. All subjects selected showed a clear

reproducibility at the two spatial frequencies used

in both protocols.

Low temporal frequency presentation mode

evokes transient responses, which are characterized

by three main components: for tPERG, the presence

of N35, P50, and N95 components [25, 27]; for

tPVEP, the presence of N75, P100, and N135

components [29, 30]. For each one of these compo-

nents, we measured the time for peak amplitude

(implicit time and latency, respectively) as well as the

baseline-to-peak amplitude. The tPERG N95/P50

ratio was also estimated to evaluate retinal ganglion

cell function [31].

tPERG was obtained from only two patients, TNM

and MGF. An attempt to perform tPERG recording

from the third patient, MLT, was unsuccessful due to

excessive blinking caused by electrode contact with

the cornea. tPVECP was recorded from all three

patients.

Optical coherence tomography (OCT) scanning

TNM and MLT were also evaluated using retinal

Optical Coherency Tomography (retinal OCT) (Zeiss

Stratus C2 M model). Optical Coherence Tomogra-

phy (OCT) is a non-invasive and out of contact

imaging method able to produce cross-sectional slices

from ocular structures in vivo with 10–15 lm reso-

lution [32, 33]. It is comparable, when considering its

functioning, to B-mode ultrasound, but uses light

instead of sound waves to produce images of the

ocular tissues. As it is a digital method, high quality

quantitative measurements can be obtained [32]. By

using short coherence interferometry technique, the

thickness of the tissues can be calculated by multi-

plying the time delay of light by its speed in the

respective tissue, which depends on its refraction

index and the speed of light in vacuum [33].

Statistical analysis

Data from dengue fever patients were compared to

the statistical tolerance intervals for 95% confidence,

90% population coverage. This statistical technique

was used because tolerance intervals allow the

comparison of one subject with a given population

sample with a certain degree of confidence and it is

appropriate for clinical studies [34–41].

Doc Ophthalmol (2009) 119:145–155 147

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Results

Ophthalmoscopy

MGF had a vitreous hemorrhage in the right eye.

After vitrectomy and hemorrhage resolution, retinal

angiofluoresceinography showed cystoid macular

edema and biomicroscopy with mild flare (3–5 cells).

TNM had low visual acuity in the left eye, normal

retinography, and angiofluoresceinography in both

eyes (Fig. 1a–b). MLT had low visual acuity with

either eye and retinography revealed cotton-wool

spots and yellow areas suggesting retinal ischemia in

both eyes (Fig. 1c–d).

Visual field static perimetry

MGF had a temporal superior scotoma in the right

visual field and temporal superior and inferior

scotomata in the left visual field. TNM had normal

right visual field and a central scotoma in the left

visual field. MLT had normal right visual field and

peripheral and parafoveal scotomata in the left visual

field.

Electrophysiological findings: tPERG

Figure 2 illustrates tPERG recordings obtained from

MGF (top panels) and TNM (bottom panels) at two

spatial frequencies, 0.5 and 2 cpd, and the results are

compared with mean recordings obtained from nor-

mal control subjects. In Table 1 numerical values of

amplitude and implicit time for different tPERG

components are compared with normative values

for normal control subjects. Electroretinographic res-

ponses were severely affected in both patients,

making it difficult to measure amplitude and implicit

time of different tPERG components. When mea-

surements were possible, amplitude was generally

decreased for all components with little change in

implicit time.

Fig. 1 Angiofluoresceinography from the right eye (a) and left

eye (b) of patient TNM with normal aspect of the optic nerve

and retinal vessels, and retinography from the right eye (c) and

left eye (d) of patient MLT presenting cotton-wool spots

(arrows)

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Electrophysiological findings: tPVECP

Figure 3 shows tPVECP recordings obtained from all

three patients, MGF, MLT, and TNM, compared with

mean recordings obtained from normal control subjects.

All patients had decreased amplitudes of all evoked

potential components at 2 cpd. Patient MLT also had

decreased tPVEP amplitudes at 0.5 cpd. Table 2 shows

a comparison between patients and normative data from

control subjects for the implicit time of different evoked

potential components. tPVEP implicit time was gener-

ally conserved with a few exceptions: at 2 cpd, MGF

had no evoked response from the right eye and a delayed

response from the left eye.

Fig. 2 tPERG recordings at 0.5 cpd (a and c) and 2 cpd (b and

d) for patients MGF and TNM, respectively. The patient

recordings are compared with grand mean recordings for both

spatial frequencies. Both patients showed more alterations in

the tPERG amplitude than in the tPERG implicit time

Doc Ophthalmol (2009) 119:145–155 149

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OCT findings

For patient MLT, a 5 mm scan line over a retinal area

corresponding to the cotton-wool spots was applied .

An increase in optical reflectivity from the inner

retina (arrow) was observed, with discrete signal

attenuation in deeper retina layers. This is a fundo-

scopic finding related to the release of axoplasmic

content secondary to localized ischemia.

Figure 4 shows OCT scans from two patients,

TNM (top panels) and MLT (bottom panels). TNM

left retina had a decrease in the central, nasal,

inferior, and temporal inner macula. OCT scanning of

MLT retina showed cotton-wool spots with high

reflectance signal from the retinal tissue. Figure 5

shows macular color maps for two patients, TNM

(top panels) and MLT (bottom panels).

Patient evolution

One year after the onset of visual impairment,

patients MGF and TNM still presented low visual

acuity with normal ophthalmoscopy. MLT recovered

normal visual acuity for both eyes 2 months after the

dengue fever; at this time, both retinas also recovered

their normal appearance at OCT scanning.

Discussion

Visual disturbances are uncommon findings during

dengue fever, but there are reports of long-term visual

impairment after infection. All patients evaluated in

this study had a decreased visual acuity after

suffering from dengue fever. MGF had vitreous

hemorrhage also described in other patients by other

authors [9, 12, 42]. MLT presented many signals

described in previous works as cotton-wool spots and

retinal ischemic alterations [7, 8, 10, 14, 17]. The

pathogenesis of ocular manifestations is unknown,

but it is probable that they are caused by increased

vascular permeability involved in dengue fever

pathophysiology and postviral immune reaction after

thrombocytopenic state [4, 6, 7, 14, 17, 43, 44].

The maculopathy was the most important finding

in all three patients. tPERG showed more changes

departing from normal values than tPVEP. Clinical

and fundamental experiments that studied the mean-

ing of the electroretinographic response proposed that

tPERG P50 component is generated from retinal

ganglion cells and from other non-ganglion cells of

inner retina, while the N95 component is a contrast-

related component originating from retinal ganglion

cells [23–25, 27, 45]. The N95:P50 ratio has been

proposed as good indicator of retinal ganglion cell

Table 1 tPERG results: comparison between patients and controls

Implicit time (ms) Amplitude (lV)

N35 P50 N95 N35–P50 P50–N95 N95/P50

Tolerance interval

0.5 cpd 26–38 50–62 86–115 2.6–6.2 4.6–10.6 1.1–2.3

2 cpd 28–42 53–67 92–114 1.4–5.0 2.8–8.3 0.7–2.8

MGF

0.5 cpd NM (RE) NM (RE) NM (RE) NM (RE) NM (RE) NM (RE)

28 (LE) 56 (LE) 104 (LE) 1.6 (LE)* 2.3 (LE)* 1.5 (LE)

2 cpd NM (RE) 64 (RE) 105 (RE) 1.7 (RE) 1.8 (RE)* 1.1 (RE)

NM (LE) NM (LE) NM (LE) NM (LE) NM (LE)* NM (LE)

TNM

0.5 cpd NM (RE) 58 (RE) 98 (RE) 1.0 (RE)* 2.1 (RE)* 2.1 (RE)

35 (LE) 58 (LE) 88 (LE) 2.0 (LE)* 2.5 (LE)* 1.2 (LE)

2 cpd NM (RE) NM (RE) NM (RE) NM (RE) NM (RE) NM (RE)

NM (LE) NM (LE) NM (LE) NM (LE) NM (LE) NM (LE)

RE right eye, LE left eye, NM no measurable response

*Value outside the tolerance interval

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Fig. 3 tPVEP recordings at 0.5 cpd (a, c, e) and 2 cpd (b, d, f)for patients MGF, MLT, and TNM, respectively. The patient

recordings are compared with grand mean recordings for both

spatial frequencies. MGF alone showed absence of response at

2 cpd from recording obtained with the right eye stimulated

Doc Ophthalmol (2009) 119:145–155 151

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function.25 Choroidal changes secondary to dengue

fever have also been reported [46].

Independently of the spatial frequency used, the

main changes in tPERG were in the amplitude of its

components whereas the N95:P50 ratio was normal.

These findings indicate a general decrease in cell

response, i.e., dengue maculopathy seems to cause an

unspecific impair of different retinal cell types. The

most pronounced tPVECP changes were observed in

patient MGF: absent (right eye) and delayed P100

component (left eye) at 2 cpd. The absence of the

response by right eye stimulation could be partially

explained by vitreous hemorrhage which physically

blocked light to reach the retina. However, the

implicit time increase of the P100 component that

was observed with left eye stimulation indicates an

important neural impairment in the visual system of

this patient.

Previous studies have shown macula thickening

with exudative retinal detachment in dengue fever

patients [14, 18]. In agreement with these previous

reports, OCT scanning of the cotton-wool spots of

patient MLT showed a high reflectivity, indicating

inflammatory infiltrate or exudates.

Lim et al. [7] observed retinal changes restricted

mainly to the macula, but a recent work described

dengue retinopathy as a more widespread inflam-

matory process [14]. We have also found changes

located outside the central retina in patient MLT.

This patient had a better visual recovery after 1 year

Table 2 tPVEP results: comparison between patients and

controls

Implicit time (ms)

N75 P100 N135

Tolerance interval

0.5 cpd 68–86 97–116 126–172

2 cpd 78–96 103–121 135–174

MGF

0.5 cpd NM (RE) 109 (RE) 152 (RE)

66 (LE) 104 (LE) 144 (LE)

2 cpd NM (RE) NM (RE) NM (RE)

88 (LE) 129 (LE)* 172 (LE)

MLT

0.5 cpd NM (RE) 110 (RE) 176 (RE)*

NM (RE) 106 (LE) 147 (LE)

2 cpd 87 (RE) 109 (RE) 147 (RE)

91 (LE) 116 (LE) 167 (LE)

TNM

0.5 cpd 66 (RE) 109 (RE) 156 (RE)

71 (LE) 106 (LE) 144 (LE)

2 cpd 91 (RE) 118 (RE) 154 (RE)

90 (LE) 116 (LE) NR (LE)

RE right eye, LE left eye, NM no measurable response

*Value outside the tolerance interval

Fig. 4 Optical coherence tomography. Patient TNM: 5 mm

scan going through macular region from right eye (a) and left

eye (b), where the foveal depression can be seen. Black arrows

indicate direction and position from where the tomogram was

obtained. Patient MLT: 5 mm scan in right eye (c) and 6 mm

in left eye (d) going through cotton-wool spots. At the

tomogram, a higher optical reflectivity region can be observed

in the inner retinal layers (between white arrows) correspond-

ing to the cotton-wool spots. In d an ‘‘optical shadow’’ caused

by the lesion can be seen

152 Doc Ophthalmol (2009) 119:145–155

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than the other two patients, whose retinopathy was

located mainly in the macula.

Conclusions

Dengue fever can lead to visual impairment detect-

able by ophthalmologic exams as angiography

and retinography, electrophysiological recordings—

tPERG and tVECP—and OCT scanning. Dengue

fever maculopathy could be caused by vascular

alterations and/or aberrant immune response after

the infection. The injury can result in temporary or

permanent visual loss.

Acknowledgments This research was supported by grants

from CNPq-PRONEX/FAPESPA/FADESP #2268, CNPq

#486351/2006-8, #620248/2006-8, and #620037/2008-3, and

FINEP research grant ‘‘Rede Instituto Brasileiro de Neu-

rociencia (IBN-Net)’’ #01.06.0842-00. LCLS and MSF are

CNPq research fellows. BDG and GSS received CAPES-PROF

fellowships for graduate students. GMC, LMA, and TSM

received UFPA fellowships for undergraduate students.

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