Multimodal Analysis and Electroretinogram in VKH From Acute Onset - a Prospective Study
Phase: NA
Conditions: Uveomeningoencephalitic Syndrome, Inflammation, Choroid Disease, Visual Impairment
Sponsor: University of Sao Paulo

 
 
 
Multimodal Analysis and 
Electroretinogram in VKH 
From Acute Onset - Part I 
 
NCT03811366 
 
03/26/2025 
 
 
 
 

STUDY PROTOCOL  
Prospective cohort study on VKH disease conducted from June 2011 through 
January 2017 at Uveitis Service, Hospital das Clinicas HCFMUSP, Faculdade de 
Medicina, Universidade de Sao Paulo, SP, BR. The local institutional review board 
approved the full protocol, which follows the tenets of the declaration of Helsinki 
(clinicaltrials NCT03811366).  
The inclusion criteria consisted of: diagnosis of VKH disease in the acute phase 
according to the International Committee in 2001 [1]. The exclusion criteria were: less 
than a 24-month follow-up period and contraindication to corticosteroid therapy. 
Treatment protocol included a three-day course of intravenous methylprednisolone 
(1000 mg per day) followed by a high dose of oral prednisone (1.0 mg/kg/day) with a 
slow tapering with dose equal or less than 0.1mg/kg/day after 10 months. The 
prednisone dose was scheduled to be reduced in a 0.1 mg/kg-step ladder until it reaches 
0.3 mg/kg (i.e., for an individual with 60 kg, dose would be 20 mg): from 1 to 0.8 
mg/kg every two to three weeks; at 0.7 mg/kg for 4 weeks; at 0.6 mg/kg for two to three 
weeks; from 0.5 mg/kg every 4 weeks; from 0.3 to 0.15 mg/kg every 6 weeks; and 0.1 
mg/kg, 0.075 mg/kg and 0.05 mg/kg for 8 weeks each. Oral corticosteroid dose increase 
was prescribed in case of persistent clinical inflammation signs in two steps and at least 
0.5 mg/kg/d. For example, if a patient with 60 kg presents worsening of inflammatory 
signs while in use of 0.4 mg/kg/d, oral corticosteroid should be increased to 0.6 
mg/kg/d. On the other hand, if a patient with 60 kg presented a clinical flare while using 
0.2 mg/kg/d, the oral corticosteroid should be increased to at least 0.5 mg/kg/d. 
Subsequent tapering would be performed as previously scheduled. Additional non-
steroidal immunosuppressive therapy (IMT) would be prescribed if the patient 
presented intolerance due to side effects (e.g., psychosis) or prednisone monotherapy-
refractory inflammation. IMT use would be considered as an additional therapy if 
implemented for at least six months and if includes cyclosporine A, azathioprine, or 
mycophenolate mofetil. 
Examinations were performed at inclusion, 1, 2, 4, 6 months (M), and, thereafter, 
every 3 months. Each visit included complete clinical and imaging examinations (e.g., 
fundus color photography, ICGA, fluorescein angiography – FA and EDI-OCT). ff-
ERG was performed at inclusion; at 30 days and at 6 months intervals thereafter, using 
RETI-port system (Roland Consult; Electrophysiological Diagnostic Systems, 
Brandenburg, Germany). Fundus color photography was performed using the Topcon 

TRC-50DX (Tokyo, Japan); FA, ICGA and EDI-OCT were performed using 
Spectralis® HRA+OCT (Heidelberg Engineering, Germany). Fundus findings were 
graded according to a previously described analytical framework [2]. The development 
of sunset glow fundus was classified as either present or absent based on the fundus 
color photography. Imaging examinations were read by two well-trained examiners. In 
case of instances of disagreement, the senior reader would classify the images and 
would be responsible for the final decision. The FA and ICGA reading charts were 
adapted from Tugal-Tutkun et al [3]. Dark dots (DD) were evaluated based on a semi-
quantitative score for the posterior pole and each quadrant: sparse and/or faint and 
numerous and/or pronounced. The total score varies from 0 to 8. Fluctuation was 
defined as a change in DD quantity (e.g., sparse to numerous or vice versa) according to 
the Tugal-Tutkun et al score and whether the DD in the posterior pole or in each 
quadrant [3]. Objectively, DD fluctuation was defined as a final score variation ≥ 0.5 
between two different points in time. ff-ERG recordings were performed in accordance 
with the International Society for Clinical Electrophysiology of Vision guidelines with 
the RETI-port system (Roland Consult) using ERG-jet electrodes (Universe SA, La 
Chaux-deFons, Switzerland) [4]. Scotopic ERG responses were recorded after a period 
of 20 minutes of dark adaptation, and photopic ERG responses were recorded after 10 
minutes of light adaptation. The recording sequence was scotopic rod response, scotopic 
cone–rod combined response, scotopic oscillatory potentials, photopic cone response, 
and 30-Hz flicker cone response. The normal value limits for each specific ERG 
response were established at 95% confidence intervals. Amplitude and implicit time of a 
and b wave of eight averaged stimulus response for each phase were analyzed, and the 
results were compared with a normative database. The worsening of the ERG 
parameters was defined as value reduction  30% in any scotopic ERG parameter, 
which needed to be confirmed in two consecutive examinations [5]. ff-ERG scotopic 
parameters obtained at 12 and 24 months were compared; all included eyes were 
grouped based on the worsening or stabilization of the scotopic parameters from 12th to 
24th month.  
After the acute inflammatory phase (six months following disease onset), disease 
activity was systematically evaluated based on both clinical and subclinical signs. 
Specifically, clinical signs included anterior chamber cells (ACC) of at least 1+ cells, 
exudative retinal detachment, and macular edema confirmed on FA and/or OCT. Visual 
acuity measurement with a Snellen chart was converted to LogMAR values. Subclinical 

signs are those detected exclusively in posterior segment imaging (PSI) and included 
optic disc leakage/hyperfluorescence (ODH) and/or perivascular leakage on FA; 
hypofluorescent DD on ICGA; and, increase of at least 30% in subfoveal choroidal 
thickness (CT) in two consecutive EDI-OCT examinations. Perivascular leakage was 
observed as an increase in hyperfluorescence around retinal vasculature over time on 
FA exam at midperiphery. Isolated subclinical signs of activity did not infer change in 
treatment schedule, whereas clinical signs led to either an increase in a daily oral 
prednisone dosage of 0.2 mg/kg (up to at least 0.5 mg/kg/day) or the introduction of 
non-steroidal IMT (i.e., azathioprine, cyclosporine, or mycophenolate mofetil). Any 
intolerance to corticosteroid also determined a switch in treatment to non-steroidal IMT. 
Based on the predefined protocol, the term “flare” was used to describe the appearance 
or worsening of inflammatory signs observed at least sixth months after disease onset. 
During the 24-month follow-up period, the presence of ocular complications (i.e., 
cataract [6], ocular hypertension/glaucoma [7,8], choroidal neovascularization (CNV) 
[9], or SGF) was recorded. Cataract was defined as any lens opacification greater than 
nuclear or cortical 2+/4 or subcapsular 1+/4 [6]. Ocular hypertension was defined as an 
intraocular pressure (IOP) above 21mmHg [7,8]. The CNV membrane was diagnosed 
when increasingly localized hyperfluorescence at the posterior pole is detected on FA or 
a hyperreflective subretinal lesion associated with sub or intraretinal fluid on OCT. 
The main outcomes measures included clinical and subclinical flares, presence of 
sunset glow fundus, and ff-ERG results from 12 to 24 months of follow-up. 
 
STATISTICAL ANALYSIS PLAN WITH RESULTS INFORMATION 
Twelve patients (24 eyes, 10 female) with acute VKH disease were included in the 
study. For descriptive data analysis, medians and ranges were calculated. Table 1 
summarizes the data regarding clinical and subclinical signs of inflammation, 
complications and ff-ERG results during the 24-month follow-up.

 
 
 
 
 
 
 
 
 
 
 
 
 

For the comparison of qualitative and quantitative data between the stable ERG and 
worsening ERG groups, the Fisher exact test and Mann Whitney test, respectively, was 
used (Tables 2 and 3). Furthermore, Kappa statistics was used to test interrater 
reliability between subnormal ERG and SGF. P values ≤ 0.05 were considered 
statistically significant. Generalized estimated equations (GEE) were used for analyzing 
binary ocular data. (Tables 2 and 3) Data analysis and statistical tests were conducted 
using SPSS 20.0 (SPSS Science, Chicago, IL, USA).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

 

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