STRUCTURAL AND FUNCTIONAL RETINAL CHANGES IN EYES WITH DUSN DIEGO VEZZOLA, MD,* NACIMA KISMA, MD,* ANTHONY G. ROBSON, PHD,*† GRAHAM E. HOLDER, PHD,*† CARLOS PAVESIO, MD* Purpose: To report novel spectral domain optical coherence tomography and electrophysiologic findings in diffuse unilateral subacute neuroretinitis. Methods: Six patients with a diagnosis of diffuse unilateral subacute neuroretinitis were retrospectively ascertained. All patients had received oral treatment with albendazole; resolution of the inflammatory lesions without subsequent relapse was noted. Spectral domain optical coherence tomography was performed using a Spectralis HRA OCT (Heidelberg Engineering). The inner and outer retinal volumes were calculated for the macular area. The contralateral eyes acted as controls. All six patients underwent standardized full-field electroretinography and pattern electroretinography. Some had multifocal electroretinography. Results: Inner retinal volume significantly differed between affected and control eyes (P , 0.02), but there was no significant difference in outer retinal volume. Electroretinography data showed a mixed pattern of inner and outer retinal dysfunction, with inner retinal dysfunction being greater; reduction in b:a ratio of the scotopic bright flash electroretinography was a consistent observation in those patients (5/6) with generalized retinal dysfunction. Two patients showed definite photoreceptor involvement, with probable involvement in a third. Of the four patients in whom serial data are available, there was definite evidence of progressive inner and outer retinal dysfunction in one patient, with inner retinal dysfunction being greater, and probably in a second patient. Conclusion: The data provide anatomical and functional evidence of both inner and outer retinal dysfunction in diffuse unilateral subacute neuroretinitis, even though the worm is usually assumed to be located in the subretinal space. The mechanism is unclear. RETINA 34:1675–1682, 2014
D
has been described.4 A number of nematodes have been reported as potentially causative. In the acute phase, DUSN is characterized by vitritis, swelling of the optic disk, vasculitis and recurrent crops of evanescent, multifocal, white-yellowish lesions at the level of the outer retina and inner choroid. These lesions tend to resolve spontaneously, leaving retinal pigment epithelium (RPE) abnormalities in the affected areas, and typically will reappear elsewhere in the fundus in keeping with movement of the worm. Optic atrophy, arterial narrowing, and diffuse retinal atrophy can develop over time.2 Gass and Braunstein2 suggested that the pathogenesis of DUSN may involve a local toxic tissue effect on the outer retina caused by the worm, as well as a more diffuse reaction affecting both inner and outer retinal structures. Indeed, although the worm is situated between the RPE and the neuroretina, previous electrophysiologic tests have describedinvolvement of both the outer and inner retina, with the latter more
iffuse unilateral subacute neuroretinitis (DUSN) was first described by Gass in 1978.1 It is caused by the presence of a nematode, which results in persistent retinal inflammation and degenerative changes leading to severe visual loss if left untreated. The parasite is usually presumed to be present in the subretinal space,1,2 but the exact location of the worm has not been definitively proven.3 The infestation occurs mainly in healthy children and young adults without significant ocular history. It usually affects only one eye, but bilateral involvement From the *Medical Retina Department, Uevitis Unit, Moorfields Eye Hospital, London, United Kingdom; and †Electrophysiology Department, Institute of Ophthalmology, University College London, London, United Kingdom. This research has received a proportion of its funding from the Department of Health’s NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. None of the authors have any conflicting interests to disclose. Reprint requests: Diego Vezzola, MD, Moorfields Eye Hospital, City Road 162, London, United Kingdom; e-mail: vezzino81@ yahoo.it
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1676 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
affected.1,2,5 Recent studies6–8 report retinal nerve fiber layer (RNFL) atrophy. In particular, time domain optical coherence tomography (OCT) showed that DUSN eyes had a significant decrease in RNFL thickness compared to the fellow eyes6; RNFL thickness was directly proportional to visual acuity. More recently, spectral domain OCT (SD-OCT) changes including central macular and RNFL thinning have been described in eight patients affected by DUSN.8 This study addresses the structure/function relationships in DUSN, in particular the relationship between the structural data shown by SD-OCT and the functional electrophysiologic and perimetric data.
Materials and Methods A retrospective case series of patients attending a uveitis service at Moorfields Eye Hospital in London with a diagnosis of DUSN. IRB/Ethics Committee ruled that approval was not required for this study. The diagnosis of DUSN was based on patient’s medical and travel history and characteristic retinal lesions on fundus examination, which showed spontaneous resolution and did not recur after systemic therapy with albendazole for 1 month. All other forms of infectious uveitis and known noninfectious uveitis were excluded. All patients received a full ophthalmologic examination including slit-lamp examination, dilated fundus examination, fluorescein and indocyanine
2014 VOLUME 34 NUMBER 8
green angiography, computerized visual field (SITA standard 30-2) and full-field electroretinography (ERG), and pattern electroretinography. Most patients also had multifocal electroretinography. All electrophysiologic recordings were performed in accordance with current ISCEV standards.9–11 Additional On–Off ERGs were obtained with an orange stimulus (duration 200 ms, 620 nm, 560 cdm−2) superimposed on a green background (530 nm, 150 cdm−2). S-cone ERGs were performed using a 5 ms duration blue stimulus (445 nm, 80 cdm −2 ) superimposed on an orange background (620 nm, 560 cdm−2). All patients had SD-OCT following resolution of the active lesions (Spectralis HRA OCT; Heidelberg Engineering, Heidelberg, Germany). Standard volume protocol (19 lines of 6 mm) was used to obtain images and thickness measurements of the retina at the posterior pole. All scans were reviewed by the same ophthalmologist. The volume map was used to establish the volume of the macular area (3 mm of diameter). The inner retina volume was obtained by manually moving the bottom reference line from below the RPE to the junction between the inner nuclear layer and the outer plexiform layer (Figure 1). This reference was used to define the border between inner and the outer retina. The outer retinal volume was obtained by subtraction. The inner, outer, and total volumes in affected and fellow eyes (used as control) were compared using a 2-sample student’s t-test.
Fig. 1. Spectral domain OCT scans and maps of macular volume within the central 3 mm (healthy eye of Patient 1). The total volume was measured from the inner limiting membrane (ILM, upper red line) to the basal side of the RPE (bottom red line) (A); the inner retinal volume was measured from the ILM to the junction between the inner nuclear layer and outer plexiform layer, after manual positioning of the bottom red line (B). Optical coherence tomography maps (C–D) show the morphologic aspect of the retina (in particular, the full thickness volume map permits a 3 dimensional interpretation) and the numeric volume data of specific macular areas (E–F, red numbers).
SPECTRAL DOMAIN OCT AND ERG IN DUSN VEZZOLA ET AL
Results Six eyes of 6 patients were identified for inclusion in the study. The median age of the patients at the time of the diagnosis was 31 years (range, 23–45); 3 patients were male. Three patients had a previous history of travel to Asia (Thailand, China, Malaysia), one to Mexico, one to Brazil, and the last both to SouthEastern Asia and South America. The initial clinical findings appear in Figure 2, Figure 3, and Table 1. The unaffected eye in all patients was clinically unremarkable with visual acuity of 6/6. All patients had received treatment with albendazole 400 mg/day for 30 days, and the mean follow-up after
1677
therapy and resolution of retinal lesions was 23 months (range, 3–63). Electrophysiology Inner retinal involvement was shown by reduction in the b:a ratio of the bright flash ERG and was found in every patient with generalized retinal dysfunction (Patients 1, 2, 3, 4, and 5). All 5 patients showed additional reduction in the b:a ratio of the single flash cone ERG and/or On-response. There were variable degrees of photoreceptor involvement with clear bright flash dark-adapted a-wave reduction (Patients 4 and 5 and progressive but mild a-wave loss in Patient 1).
Fig. 2. Summary data. (A1–A6): Color fundus photographs before treatment show crops of yellow active lesions; the green line corresponds to the SD-OCT section; (B1–B6): Color fundus photographs following resolution of active disease show signs of retinal atrophy only in Patient 5; (C1–C6): Horizontal SD-OCT scans show retinal thickness alterations; red arrow heads: Thinning of the inner plexiform layer; red arrows: Thinning of inner nuclear layer; yellow arrows: Almost normal photoreceptor layer. The OCT across the central macula in C2 was normal.
1678 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 8
Fig. 3. (A1–A6): Visual fields in Cases 1–6 show absolute scotomata consistent with the OCT maps (B1–B6) showing variations in full retinal thickness (green, sky-blue, and blue areas match with retinal thinning in the regions previously affected by the lesions) because of localized inner retinal disruption. (C1, C3, C4, and C6): Multifocal ERGs (shown in field view) show reduction over thinned retinal areas in the affected eyes of the 4 patients that underwent testing (Cases 1, 3, 4, and 6). (D4): Sequential full-field ERGs in Patient 4 from March, July, and November 2005. The initial ERGs are normal. Four months later, there is now a subnormal a-wave amplitude in the bright flash dark-adapted ERG (DA 11.0), in keeping with loss of photoreceptor function, with reduction in the b-wave of the DA 11.0 ERG, suggesting additional inner retinal rod system dysfunction. At the third visit (4 months later and 3 months after treatment with albendazole), there is further reduction in the DA 11.0 b:a ratio in keeping with progressive inner retinal dysfunction but no further deterioration in photoreceptor function. The light-adapted ERGs show progressive reduction in 30 Hz flicker response amplitude accompanied by reduction in the photopic single flash (LA 3.0) b:a ratio, On-response and “S-cone” ERG, in keeping with inner retinal cone system dysfunction. The pattern electroretinography P50 component becomes undetectable over time, consistent with progressive severe macular dysfunction.
Serial data were available in 4 patients (1, 2, 4, and 6). There was evidence of progressive inner and outer retinal dysfunction in 2/4 patients (Patients 1 and 4) even after resolution of the disease, with inner retinal dysfunction being greater (Figure 3D). Multifocal electroretinography (Patients 1, 3, 4, and 6) showed localized signal reduction in the retinal areas affected by yellowish lesions associated with retinal thinning (Figure 3). There was no significant difference between the pre- and post-treatment findings in the 2 patients in whom repeat recording was performed (Patients 4 and 6).
Optical Coherence Tomography Findings All OCT images were obtained after complete resolution of the active disease (median, 10 months after therapy; range, 2–60 months). At the time of the OCT, five patients showed no ophthalmologic sign of retinal atrophy, while one patient had late stage fundus changes with diffuse RPE mottling, arterial narrowing, and disk atrophy. Five eyes had OCT evidence of thinning of the inner nuclear layer at the level of the posterior pole compared with the normal eye (Figure 2C). The
1679
SPECTRAL DOMAIN OCT AND ERG IN DUSN VEZZOLA ET AL Table 1. Medical and Ocular Details of Our Sample Age at Time of Diagnosis
Sex
1
26
M
Unremarkable
2
26
F
Unremarkable
3
23
M
Unremarkable
4
45
F
Unremarkable
5
34
M
Unremarkable
6
34
F
Unremarkable
Patients
Medical History
Trip Mexico
Ocular Findings
Crops of retinal yellowish lesions China Crops of retinal yellowish lesions; pigment mottling Brazil Crops of retinal yellowish lesions Thailand Crops of retinal yellowish lesions Malaysia Crops of retinal yellowish lesions; pigment mottling; optic atrophy; arterial narrowing South America Crops of retinal and Southyellowish lesions Eastern Asia
thinning of the inner nuclear layer was in the areas previously affected by active yellowish DUSN lesions (Figure 2, A and C, Figures 3B and 4). The only eye without morphologic retinal thinning of the posterior pole in OCT had only peripheral
Posterior Pole Involvement
Followup, months
Yes
6
6/18
No
3
6/6
Yes
13
6/36
Yes
63
6/12
Yes
9
Yes
48
Visual Acuity
Hand motion
6/12
involvement during the clinical evaluation (Patient 2) (Figure 2). Inner retinal volume was significantly reduced in the affected eyes (P = 0.02), but there was no significant difference in outer retinal volume (Table 2).
Fig. 4. Patient 4: Fundus photographs show the appearance of new lesions and resolution of previous ones without chorioretinal scarring in the 2 months before treatment (A–C). There was resolution of the lesions after 1 month of oral albendazole (D). The OCT map (E) shows the retina to be thinner in the areas previously affected by the lesions. The visual field performed 2 months after therapy shows absolute scotomata with good anatomical correspondence to the areas of affected retina (F).
OCT Inner Retinal Layers Changes, mm3 Patient
OCT Outer Retinal Layers Changes, mm3
OCT Total Changes, mm3
−0.03
−0.49
2
−0.09
0.03
−0.06
3
−0.08
0.08
4
−0.51
−0.07
−0.58
5
−0.69
−0.17
−0.86
0
Before and Generalized after inner treatment involvement (reduced b:a ratio) (progressive reduction of b-wave . a-wave) After Generalized treatment inner involvement (reduced b:a ratio)
Bright Flash A-Wave (Photoreceptor System)
Pattern ERG P50
MultifocalERG
On-Off ERG and S-Cone ERG
Normal for 2 Generalized times; mild inner retinal a-wave involvement reduction (reduced b:a during the ratio) third test
Severe Localized Electronegative macular abnormality On-response. involvement S-cone ERG subnormal
Normal Mild generalized inner involvement (reduced b:a ratio)
Normal
Not performed
On response smaller than in other eye but within normal limits. S-cone ERG, NA Severe Localized Electronegative macular abnormality On- response. involvement S-cone ERG subnormal
Mild Normal After Generalized generalized treatment inner involvement involvement (reduced b:a ratio) Before and Generalized Localized On b-wave Normal the first Severe Generalized abnormality delayed and macular time, then involvement involvement after subnormal. involvement a-wave (inner . (inner . outer) treatment S-cone ERG reduced but outer) (reduced b:a subnormal stable in the (reduced b:a ratio) next 3 years ratio) (progressive reduction of b-wave . a-wave) a-wave Severe Not Electronegative Severe Before Generalized reduction macular performed On-response generalized treatment involvement involvement and On ainvolvement (inner . outer) wave (inner . (reduced b:a reduction; Off outer) ratio) d-wave (reduced b:a reduced. ratio) S-cone ERG subnormal
2014 VOLUME 34 NUMBER 8
−0.46
Light-Adapted ERG (Cone System)
1
Time of ERG
Dark-Adapted ERG (Predominantly Rod System)
1680 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Table 2. Spectral Domain OCT Thickness Changes in 3 mm Macular Region and Electrophysiologic Findings
Localized Normal abnormality
Central visual fields were performed in all patients after the resolution of the disease. There were absolute scotomata corresponding with the retinal areas previously affected by yellowish lesions. Retinal sensitivity was almost normal in the spared regions, without obvious transition areas (Figures 3 and 4).
,0.05 0.43 0.02 P
−0.02
−0.21
Before and Normal after treatment
Normal
Normal
Normal
Discussion
−0.19
Time of ERG
1681
Visual Field Findings
6
Light-Adapted ERG (Cone System) Dark-Adapted ERG (Predominantly Rod System) OCT Total Changes, mm3 OCT Outer Retinal Layers Changes, mm3 OCT Inner Retinal Layers Changes, mm3 Patient
Table 2. (Continued )
Bright Flash A-Wave (Photoreceptor System)
Pattern ERG P50
MultifocalERG
On-Off ERG and S-Cone ERG
SPECTRAL DOMAIN OCT AND ERG IN DUSN VEZZOLA ET AL
This report presents the results of structure/function correlation in six patients with presumed unilateral DUSN. Each patient had a travel history in endemic areas and had typical clinical features (retinal yellowish lesions and complete resolution of active disease after treatment with albendazole without recurrence). Direct observation of a worm was not achieved in any of the patients; this is not uncommon,8,12,13 especially if the infection is caused by a small nematode like Ancylostoma caninum, extremely difficult to find on clinical examination. After resolution of the active lesions, 5 patients showed no ophthalmologic sign of retinal atrophy (Figure 2B), while 1 patient had late stage fundus changes with diffuse RPE mottling, arterial narrowing, and disk pallor. All OCT data showed the retina to be thinner in the areas previously affected by active yellowish DUSN lesions with change mainly occurring in the inner nuclear layer; the inner retinal volume was significantly reduced without significant difference in outer retinal volume. These observations are consistent with recent studies showing RNFL and central macular thinning in every stage of DUSN using either time or spectral domain OCT.6–8 The computerized visual fields, performed after the resolution of the active disease, showed absolute scotomata that corresponded well with the retinal thinning on OCT. Retinal sensitivity was almost normal in the spared regions. Preservation of visual acuity is possible if there is foveal sparing. Electrophysiologically, five patients with generalized retinal dysfunction showed reduction in the b:a ratio of the bright flash ERG, and all five patients showed evidence of additional reduction in the b:a ratio of the single flash cone ERG or On–Off ERG, consistent with inner retinal involvement in both rod and cone systems. There was additional loss of bright flash a-wave, and thus photoreceptor function, in two of these cases, and evidence of mild loss in a third case. These data are in keeping with the previously described electroretinographic picture of negative ERG in cases of DUSN.1,4,5,14 A previously published longitudinal study of 1 patient showed that both inner and outer
1682 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
retinal dysfunction can occur, with greater involvement at an inner retinal level5; a similar pattern of dysfunction occurred in Patient 4 (Figure 3D). The novel multifocal electroretinography data in this study showed localized signal reduction in the retinal areas affected by yellowish DUSN lesions, consistent with the OCT and computerized visual field data. The retinal thinning seems to be permanent and was present even 5 years after the resolution of the inflammation. The process may be a primary focal retinal impairment followed by generalized retinal dysfunction, dependent on worm migration under the retina. The mechanism of dysfunction has been suggested to be a possible inflammatory and/or toxic effect on retinal bipolar cells.12 In one eye that came to histologic examination, there was a nonspecific inflammatory process, involving the vitreous body, optic nerve, retina, and choroid.1 Histopathologic data were not sufficient to explain the visual loss, leading to speculation about the role of functional mechanisms in causing visual damage. Interestingly, two recent OCT reports showed a worm laying in the inner part of the retina, suggesting possible direct damage of inner retinal structures.3,15 Further reports with SD-OCT should help to clarify the exact anatomical location of the nematode in the retina. Whether the inner retinal involvement is because of direct retinal damage by the worm or toxic retinal reaction remains unclear. In conclusion, DUSN is a rare infestation of the eye, typically seen in humid and warm areas. Because of the rarity of the disorder in Northern Europe, the diagnosis of DUSN may be difficult and/or delayed in those regions. Even expert clinicians will fail to find the worm on fundus examination in approximately 60% of cases.12–15 Nowadays, travel to endemic areas is increasingly common and a comprehensive travel history may assist diagnosis. It may be that inner retinal thinning on SD-OCT in areas affected by inflammation is typical for DUSN, particularly when accompanied by a negative ERG waveform. Further observations with SD-OCT may help confirm that suggestion. Key words: DUSN, SD-OCT, ERG, albendazole.
2014 VOLUME 34 NUMBER 8
References 1. Gass JD, Gilbert WR Jr, Guerry RK, Scelfo R. Diffuse unilateral subacute neuroretinitis. Ophthalmology 1978;85:521–545. 2. Gass JD, Braunstein RA. Further observations concerning the diffuse unilateral subacute neuroretinitis syndrome. Arch Ophthalmol 1983;101:1689–1697. 3. Cunha LP, Costa-Cunha LV, Souza EC, Monteiro ML. Intraretinal worm documented by optical coherence tomography in a patient with diffuse unilateral subacute neuroretinitis: case report. Arq Bras Oftalmol 2010;73:462–463. 4. de Souza EC, Abujamra S, Nakashima Y, Gass JD. Diffuse bilateral subacute neuroretinitis: first patient with documented nematodes in both eyes. Arch Ophthalmol 1999;117:1349–1351. 5. Audo I, Webster AR, Kidd MN, et al. Progressive retinal dysfunction in diffuse unilateral subacute neuroretinitis (DUSN). Br J Ophthalmol 2006;90:793–794. 6. Gomes AH, Garcia CA, Segundo Pde S, et al. Optic coherence tomography in a patient with DUSN. Arq Bras Oftalmol 2009; 72:185–188. 7. Casella AM, Farah ME, de Souza EC, et al. Retinal nerve fiber layer atrophy as relevant feature for diffuse unilateral subacute neuroretinitis (DUSN): case series. Arq Bras Oftalmol 2010; 73:182–185. 8. Garcia Filho CA, Soares AC, Penha FM, Garcia CA. Spectral domain optical coherence tomography in diffuse unilateral subacute neuroretinitis. J Ophthalmol 2011;2011:285296. 9. Holder GE, Brigell MG, Hawlina M, et al. ISCEV standard for clinical pattern electroretinography—2007 update. Doc Ophthalmol 2007;114:111–116. 10. Marmor MF, Fulton AB, Holder GE, et al. ISCEV standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol 2009;118:69–77. 11. Hood DC, Bach M, Brigell M, et al; International Society for Clinical Electrophysiology of Vision. ISCEV standard for clinical multifocal electroretinography (mfERG). Doc Ophthalmol 2012;124:1–13. 12. Souza EC, Casella AM, Nakashima Y, Monteiro ML. Clinical features and outcomes of patients with diffuse unilateral subacute neuroretinitis treated with oral albendazole. Am J Ophthalmol 2005;140:437–445. 13. de Amorim Garcia Filho CA, Gomes AH, de A Garcia Soares AC, de Amorim Garcia CA. Clinical features of 121 patients with diffuse unilateral subacute neuroretinitis. Am J Ophthalmol 2012;153:743–749. 14. Oréfice F, Bonfioli AA, Paranhos FRL. Neuroretinite subaguda unilateraldifusa. In: Oréfice F, ed. Uveíte: clínica e cirúrgica. Rio de Janeiro, Brazil: CulturaMédica; 1998:733–756. 15. Tarantola RM, Elkins KA, Kay CN, Folk JC. Photoreceptor recovery following laser photocoagulation and albendazole in diffuse unilateral subacute neuroretinitis. Arch Ophthalmol 2011;129:669–671.
D
has been described.4 A number of nematodes have been reported as potentially causative. In the acute phase, DUSN is characterized by vitritis, swelling of the optic disk, vasculitis and recurrent crops of evanescent, multifocal, white-yellowish lesions at the level of the outer retina and inner choroid. These lesions tend to resolve spontaneously, leaving retinal pigment epithelium (RPE) abnormalities in the affected areas, and typically will reappear elsewhere in the fundus in keeping with movement of the worm. Optic atrophy, arterial narrowing, and diffuse retinal atrophy can develop over time.2 Gass and Braunstein2 suggested that the pathogenesis of DUSN may involve a local toxic tissue effect on the outer retina caused by the worm, as well as a more diffuse reaction affecting both inner and outer retinal structures. Indeed, although the worm is situated between the RPE and the neuroretina, previous electrophysiologic tests have describedinvolvement of both the outer and inner retina, with the latter more
iffuse unilateral subacute neuroretinitis (DUSN) was first described by Gass in 1978.1 It is caused by the presence of a nematode, which results in persistent retinal inflammation and degenerative changes leading to severe visual loss if left untreated. The parasite is usually presumed to be present in the subretinal space,1,2 but the exact location of the worm has not been definitively proven.3 The infestation occurs mainly in healthy children and young adults without significant ocular history. It usually affects only one eye, but bilateral involvement From the *Medical Retina Department, Uevitis Unit, Moorfields Eye Hospital, London, United Kingdom; and †Electrophysiology Department, Institute of Ophthalmology, University College London, London, United Kingdom. This research has received a proportion of its funding from the Department of Health’s NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. None of the authors have any conflicting interests to disclose. Reprint requests: Diego Vezzola, MD, Moorfields Eye Hospital, City Road 162, London, United Kingdom; e-mail: vezzino81@ yahoo.it
1675
1676 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
affected.1,2,5 Recent studies6–8 report retinal nerve fiber layer (RNFL) atrophy. In particular, time domain optical coherence tomography (OCT) showed that DUSN eyes had a significant decrease in RNFL thickness compared to the fellow eyes6; RNFL thickness was directly proportional to visual acuity. More recently, spectral domain OCT (SD-OCT) changes including central macular and RNFL thinning have been described in eight patients affected by DUSN.8 This study addresses the structure/function relationships in DUSN, in particular the relationship between the structural data shown by SD-OCT and the functional electrophysiologic and perimetric data.
Materials and Methods A retrospective case series of patients attending a uveitis service at Moorfields Eye Hospital in London with a diagnosis of DUSN. IRB/Ethics Committee ruled that approval was not required for this study. The diagnosis of DUSN was based on patient’s medical and travel history and characteristic retinal lesions on fundus examination, which showed spontaneous resolution and did not recur after systemic therapy with albendazole for 1 month. All other forms of infectious uveitis and known noninfectious uveitis were excluded. All patients received a full ophthalmologic examination including slit-lamp examination, dilated fundus examination, fluorescein and indocyanine
2014 VOLUME 34 NUMBER 8
green angiography, computerized visual field (SITA standard 30-2) and full-field electroretinography (ERG), and pattern electroretinography. Most patients also had multifocal electroretinography. All electrophysiologic recordings were performed in accordance with current ISCEV standards.9–11 Additional On–Off ERGs were obtained with an orange stimulus (duration 200 ms, 620 nm, 560 cdm−2) superimposed on a green background (530 nm, 150 cdm−2). S-cone ERGs were performed using a 5 ms duration blue stimulus (445 nm, 80 cdm −2 ) superimposed on an orange background (620 nm, 560 cdm−2). All patients had SD-OCT following resolution of the active lesions (Spectralis HRA OCT; Heidelberg Engineering, Heidelberg, Germany). Standard volume protocol (19 lines of 6 mm) was used to obtain images and thickness measurements of the retina at the posterior pole. All scans were reviewed by the same ophthalmologist. The volume map was used to establish the volume of the macular area (3 mm of diameter). The inner retina volume was obtained by manually moving the bottom reference line from below the RPE to the junction between the inner nuclear layer and the outer plexiform layer (Figure 1). This reference was used to define the border between inner and the outer retina. The outer retinal volume was obtained by subtraction. The inner, outer, and total volumes in affected and fellow eyes (used as control) were compared using a 2-sample student’s t-test.
Fig. 1. Spectral domain OCT scans and maps of macular volume within the central 3 mm (healthy eye of Patient 1). The total volume was measured from the inner limiting membrane (ILM, upper red line) to the basal side of the RPE (bottom red line) (A); the inner retinal volume was measured from the ILM to the junction between the inner nuclear layer and outer plexiform layer, after manual positioning of the bottom red line (B). Optical coherence tomography maps (C–D) show the morphologic aspect of the retina (in particular, the full thickness volume map permits a 3 dimensional interpretation) and the numeric volume data of specific macular areas (E–F, red numbers).
SPECTRAL DOMAIN OCT AND ERG IN DUSN VEZZOLA ET AL
Results Six eyes of 6 patients were identified for inclusion in the study. The median age of the patients at the time of the diagnosis was 31 years (range, 23–45); 3 patients were male. Three patients had a previous history of travel to Asia (Thailand, China, Malaysia), one to Mexico, one to Brazil, and the last both to SouthEastern Asia and South America. The initial clinical findings appear in Figure 2, Figure 3, and Table 1. The unaffected eye in all patients was clinically unremarkable with visual acuity of 6/6. All patients had received treatment with albendazole 400 mg/day for 30 days, and the mean follow-up after
1677
therapy and resolution of retinal lesions was 23 months (range, 3–63). Electrophysiology Inner retinal involvement was shown by reduction in the b:a ratio of the bright flash ERG and was found in every patient with generalized retinal dysfunction (Patients 1, 2, 3, 4, and 5). All 5 patients showed additional reduction in the b:a ratio of the single flash cone ERG and/or On-response. There were variable degrees of photoreceptor involvement with clear bright flash dark-adapted a-wave reduction (Patients 4 and 5 and progressive but mild a-wave loss in Patient 1).
Fig. 2. Summary data. (A1–A6): Color fundus photographs before treatment show crops of yellow active lesions; the green line corresponds to the SD-OCT section; (B1–B6): Color fundus photographs following resolution of active disease show signs of retinal atrophy only in Patient 5; (C1–C6): Horizontal SD-OCT scans show retinal thickness alterations; red arrow heads: Thinning of the inner plexiform layer; red arrows: Thinning of inner nuclear layer; yellow arrows: Almost normal photoreceptor layer. The OCT across the central macula in C2 was normal.
1678 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 8
Fig. 3. (A1–A6): Visual fields in Cases 1–6 show absolute scotomata consistent with the OCT maps (B1–B6) showing variations in full retinal thickness (green, sky-blue, and blue areas match with retinal thinning in the regions previously affected by the lesions) because of localized inner retinal disruption. (C1, C3, C4, and C6): Multifocal ERGs (shown in field view) show reduction over thinned retinal areas in the affected eyes of the 4 patients that underwent testing (Cases 1, 3, 4, and 6). (D4): Sequential full-field ERGs in Patient 4 from March, July, and November 2005. The initial ERGs are normal. Four months later, there is now a subnormal a-wave amplitude in the bright flash dark-adapted ERG (DA 11.0), in keeping with loss of photoreceptor function, with reduction in the b-wave of the DA 11.0 ERG, suggesting additional inner retinal rod system dysfunction. At the third visit (4 months later and 3 months after treatment with albendazole), there is further reduction in the DA 11.0 b:a ratio in keeping with progressive inner retinal dysfunction but no further deterioration in photoreceptor function. The light-adapted ERGs show progressive reduction in 30 Hz flicker response amplitude accompanied by reduction in the photopic single flash (LA 3.0) b:a ratio, On-response and “S-cone” ERG, in keeping with inner retinal cone system dysfunction. The pattern electroretinography P50 component becomes undetectable over time, consistent with progressive severe macular dysfunction.
Serial data were available in 4 patients (1, 2, 4, and 6). There was evidence of progressive inner and outer retinal dysfunction in 2/4 patients (Patients 1 and 4) even after resolution of the disease, with inner retinal dysfunction being greater (Figure 3D). Multifocal electroretinography (Patients 1, 3, 4, and 6) showed localized signal reduction in the retinal areas affected by yellowish lesions associated with retinal thinning (Figure 3). There was no significant difference between the pre- and post-treatment findings in the 2 patients in whom repeat recording was performed (Patients 4 and 6).
Optical Coherence Tomography Findings All OCT images were obtained after complete resolution of the active disease (median, 10 months after therapy; range, 2–60 months). At the time of the OCT, five patients showed no ophthalmologic sign of retinal atrophy, while one patient had late stage fundus changes with diffuse RPE mottling, arterial narrowing, and disk atrophy. Five eyes had OCT evidence of thinning of the inner nuclear layer at the level of the posterior pole compared with the normal eye (Figure 2C). The
1679
SPECTRAL DOMAIN OCT AND ERG IN DUSN VEZZOLA ET AL Table 1. Medical and Ocular Details of Our Sample Age at Time of Diagnosis
Sex
1
26
M
Unremarkable
2
26
F
Unremarkable
3
23
M
Unremarkable
4
45
F
Unremarkable
5
34
M
Unremarkable
6
34
F
Unremarkable
Patients
Medical History
Trip Mexico
Ocular Findings
Crops of retinal yellowish lesions China Crops of retinal yellowish lesions; pigment mottling Brazil Crops of retinal yellowish lesions Thailand Crops of retinal yellowish lesions Malaysia Crops of retinal yellowish lesions; pigment mottling; optic atrophy; arterial narrowing South America Crops of retinal and Southyellowish lesions Eastern Asia
thinning of the inner nuclear layer was in the areas previously affected by active yellowish DUSN lesions (Figure 2, A and C, Figures 3B and 4). The only eye without morphologic retinal thinning of the posterior pole in OCT had only peripheral
Posterior Pole Involvement
Followup, months
Yes
6
6/18
No
3
6/6
Yes
13
6/36
Yes
63
6/12
Yes
9
Yes
48
Visual Acuity
Hand motion
6/12
involvement during the clinical evaluation (Patient 2) (Figure 2). Inner retinal volume was significantly reduced in the affected eyes (P = 0.02), but there was no significant difference in outer retinal volume (Table 2).
Fig. 4. Patient 4: Fundus photographs show the appearance of new lesions and resolution of previous ones without chorioretinal scarring in the 2 months before treatment (A–C). There was resolution of the lesions after 1 month of oral albendazole (D). The OCT map (E) shows the retina to be thinner in the areas previously affected by the lesions. The visual field performed 2 months after therapy shows absolute scotomata with good anatomical correspondence to the areas of affected retina (F).
OCT Inner Retinal Layers Changes, mm3 Patient
OCT Outer Retinal Layers Changes, mm3
OCT Total Changes, mm3
−0.03
−0.49
2
−0.09
0.03
−0.06
3
−0.08
0.08
4
−0.51
−0.07
−0.58
5
−0.69
−0.17
−0.86
0
Before and Generalized after inner treatment involvement (reduced b:a ratio) (progressive reduction of b-wave . a-wave) After Generalized treatment inner involvement (reduced b:a ratio)
Bright Flash A-Wave (Photoreceptor System)
Pattern ERG P50
MultifocalERG
On-Off ERG and S-Cone ERG
Normal for 2 Generalized times; mild inner retinal a-wave involvement reduction (reduced b:a during the ratio) third test
Severe Localized Electronegative macular abnormality On-response. involvement S-cone ERG subnormal
Normal Mild generalized inner involvement (reduced b:a ratio)
Normal
Not performed
On response smaller than in other eye but within normal limits. S-cone ERG, NA Severe Localized Electronegative macular abnormality On- response. involvement S-cone ERG subnormal
Mild Normal After Generalized generalized treatment inner involvement involvement (reduced b:a ratio) Before and Generalized Localized On b-wave Normal the first Severe Generalized abnormality delayed and macular time, then involvement involvement after subnormal. involvement a-wave (inner . (inner . outer) treatment S-cone ERG reduced but outer) (reduced b:a subnormal stable in the (reduced b:a ratio) next 3 years ratio) (progressive reduction of b-wave . a-wave) a-wave Severe Not Electronegative Severe Before Generalized reduction macular performed On-response generalized treatment involvement involvement and On ainvolvement (inner . outer) wave (inner . (reduced b:a reduction; Off outer) ratio) d-wave (reduced b:a reduced. ratio) S-cone ERG subnormal
2014 VOLUME 34 NUMBER 8
−0.46
Light-Adapted ERG (Cone System)
1
Time of ERG
Dark-Adapted ERG (Predominantly Rod System)
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Table 2. Spectral Domain OCT Thickness Changes in 3 mm Macular Region and Electrophysiologic Findings
Localized Normal abnormality
Central visual fields were performed in all patients after the resolution of the disease. There were absolute scotomata corresponding with the retinal areas previously affected by yellowish lesions. Retinal sensitivity was almost normal in the spared regions, without obvious transition areas (Figures 3 and 4).
,0.05 0.43 0.02 P
−0.02
−0.21
Before and Normal after treatment
Normal
Normal
Normal
Discussion
−0.19
Time of ERG
1681
Visual Field Findings
6
Light-Adapted ERG (Cone System) Dark-Adapted ERG (Predominantly Rod System) OCT Total Changes, mm3 OCT Outer Retinal Layers Changes, mm3 OCT Inner Retinal Layers Changes, mm3 Patient
Table 2. (Continued )
Bright Flash A-Wave (Photoreceptor System)
Pattern ERG P50
MultifocalERG
On-Off ERG and S-Cone ERG
SPECTRAL DOMAIN OCT AND ERG IN DUSN VEZZOLA ET AL
This report presents the results of structure/function correlation in six patients with presumed unilateral DUSN. Each patient had a travel history in endemic areas and had typical clinical features (retinal yellowish lesions and complete resolution of active disease after treatment with albendazole without recurrence). Direct observation of a worm was not achieved in any of the patients; this is not uncommon,8,12,13 especially if the infection is caused by a small nematode like Ancylostoma caninum, extremely difficult to find on clinical examination. After resolution of the active lesions, 5 patients showed no ophthalmologic sign of retinal atrophy (Figure 2B), while 1 patient had late stage fundus changes with diffuse RPE mottling, arterial narrowing, and disk pallor. All OCT data showed the retina to be thinner in the areas previously affected by active yellowish DUSN lesions with change mainly occurring in the inner nuclear layer; the inner retinal volume was significantly reduced without significant difference in outer retinal volume. These observations are consistent with recent studies showing RNFL and central macular thinning in every stage of DUSN using either time or spectral domain OCT.6–8 The computerized visual fields, performed after the resolution of the active disease, showed absolute scotomata that corresponded well with the retinal thinning on OCT. Retinal sensitivity was almost normal in the spared regions. Preservation of visual acuity is possible if there is foveal sparing. Electrophysiologically, five patients with generalized retinal dysfunction showed reduction in the b:a ratio of the bright flash ERG, and all five patients showed evidence of additional reduction in the b:a ratio of the single flash cone ERG or On–Off ERG, consistent with inner retinal involvement in both rod and cone systems. There was additional loss of bright flash a-wave, and thus photoreceptor function, in two of these cases, and evidence of mild loss in a third case. These data are in keeping with the previously described electroretinographic picture of negative ERG in cases of DUSN.1,4,5,14 A previously published longitudinal study of 1 patient showed that both inner and outer
1682 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
retinal dysfunction can occur, with greater involvement at an inner retinal level5; a similar pattern of dysfunction occurred in Patient 4 (Figure 3D). The novel multifocal electroretinography data in this study showed localized signal reduction in the retinal areas affected by yellowish DUSN lesions, consistent with the OCT and computerized visual field data. The retinal thinning seems to be permanent and was present even 5 years after the resolution of the inflammation. The process may be a primary focal retinal impairment followed by generalized retinal dysfunction, dependent on worm migration under the retina. The mechanism of dysfunction has been suggested to be a possible inflammatory and/or toxic effect on retinal bipolar cells.12 In one eye that came to histologic examination, there was a nonspecific inflammatory process, involving the vitreous body, optic nerve, retina, and choroid.1 Histopathologic data were not sufficient to explain the visual loss, leading to speculation about the role of functional mechanisms in causing visual damage. Interestingly, two recent OCT reports showed a worm laying in the inner part of the retina, suggesting possible direct damage of inner retinal structures.3,15 Further reports with SD-OCT should help to clarify the exact anatomical location of the nematode in the retina. Whether the inner retinal involvement is because of direct retinal damage by the worm or toxic retinal reaction remains unclear. In conclusion, DUSN is a rare infestation of the eye, typically seen in humid and warm areas. Because of the rarity of the disorder in Northern Europe, the diagnosis of DUSN may be difficult and/or delayed in those regions. Even expert clinicians will fail to find the worm on fundus examination in approximately 60% of cases.12–15 Nowadays, travel to endemic areas is increasingly common and a comprehensive travel history may assist diagnosis. It may be that inner retinal thinning on SD-OCT in areas affected by inflammation is typical for DUSN, particularly when accompanied by a negative ERG waveform. Further observations with SD-OCT may help confirm that suggestion. Key words: DUSN, SD-OCT, ERG, albendazole.
2014 VOLUME 34 NUMBER 8
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