Predisposition and epidemiology
Age and sex: Mean age 30.6 years, 62.3% female, mostly unilateral
Bilateral involvement: Rare at 9.8%
Recurrence rate: Rare at 3%
Acute Retinal Pigment Epitheliitis (Krill Disease)
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Acute Retinal Pigment Epitheliitis (Krill Disease)?
Section titled “1. What is Acute Retinal Pigment Epitheliitis (Krill Disease)?”Acute retinal pigment epitheliitis (ARPE) is a rare idiopathic, self-limiting inflammatory retinal disease first reported by Alex E. Krill and August F. Deutman in 1972 1, 2, 4). It is also called Krill disease after the discoverer. It is classified as one of the white dot syndromes.
It predominantly affects healthy young adults, with a mean age of 30.6 ± 10.7 years (range 16–55 years) and a female predominance (62.3%) 2). It is mostly unilateral, with bilateral involvement in only 9.8% of cases. Recurrence is rare (3%) 2).
An association with viral infection has been reported in 25.9% of cases 2). Cold-like symptoms may precede the onset. Drug associations include D2 dopamine receptor agonists (bromocriptine, cabergoline) and intravenous bisphosphonates 1). Cases after COVID-19 and influenza vaccination have also been reported 4).
Whether ARPE is an independent disease or a subtype of other diseases such as MEWDS, pachychoroid, or AMN remains a topic of ongoing debate 1).
Q
How rare is acute retinal pigment epithelitis (Krill disease)?
A
It is an extremely rare disease. A literature review identified only 61 cases from 29 papers, and the exact incidence is unknown. Each time a rare case is reported, the disease concept is re-evaluated.
2. Main symptoms and clinical findings
Section titled “2. Main symptoms and clinical findings”Subjective symptoms
Section titled “Subjective symptoms”Onset is acute, presenting with the following symptoms.
- Blurred vision and metamorphopsia: Appears acutely in one eye. This is the most common complaint 2).
- Central scotoma: Appears due to macular lesions 4).
- Color vision abnormality: Blue appears green, yellow appears beige, and red appears gray 1).
- Duration of symptoms: Average 7.5 ± 6.1 days (range 1–30 days) 2).
Clinical findings
Section titled “Clinical findings”Main subjective symptoms
Blurred vision and metamorphopsia: Characterized by acute onset
Central scotoma: Corresponds to macular lesions
Color vision abnormalities: Blue → green, yellow → beige, red → gray
Visual prognosis
Initial visual acuity: ≈20/40 (corrected visual acuity)
Final visual acuity: ≈20/20
Complete recovery rate: Approximately 89% achieve 20/20 within 2 months
No anterior segment abnormalities or intraocular inflammation are observed4). Fundus examination reveals fine pigment spots surrounded by a yellowish-white hypopigmented halo in the macula2, 4). The lesion has a characteristic appearance with a dark central core and a grayish-white halo around it.
Initial visual acuity is approximately 20/40, and in most cases, final visual acuity recovers to about 20/202). Electrophysiological tests show reduced P50 wave amplitude in pERG and decreased response density in mfERG, reflecting macular dysfunction1).
Q
Will vision fully recover?
A
Approximately 89% recover to 20/20 within 2 months. However, cases with persistent EZ (ellipsoid zone) disruption on OCT for more than 12 months or extensive lesions reaching the ONL (outer nuclear layer) have been reported to have incomplete recovery (see OCT findings).
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”The cause of ARPE is unknown, and most cases are considered idiopathic2). Currently known risk factors are as follows.
Viral infection (most common) An association with viral infection has been reported in 25.9% of cases2). Cold-like symptoms may precede the onset.
After vaccination Onset 31 days after the second dose of COVID-19 vaccine has been reported. In that case, the patient had low-grade fever (37.3–37.5°C) and joint pain for 2 days after vaccination, and had also received an influenza vaccine 5 days earlier 4). Bolletta et al. reported cases of ocular inflammation occurring 28–30 days after COVID-19 vaccination 4).
Drug-induced Onset during treatment for hyperprolactinemia with D2 dopamine receptor agonists (bromocriptine, cabergoline) has been reported 1). Cases after intravenous bisphosphonate administration also exist 1).
Q
Can it occur after vaccination?
A
Onset after COVID-19 or influenza vaccination has been reported 4). The immune response triggered by vaccination may be a trigger, but a causal relationship has not yet been established.
4. Diagnosis and examination methods
Section titled “4. Diagnosis and examination methods”
Robert J Contento; Neha Gupta; Mark P Breazzano. Characterization of Syphilitic Chorioretinitis as a White Dot Syndrome with Multimodal Imaging: Case Series. Diagnostics (Basel). 2025 Feb 4; 15(3):369 Figure 2. PMCID: PMC11817950. License: CC BY.
Case 1, left eye (OS). (A): Ultra-widefield fundus pseudocolor photography shows nearly invisible peripheral white spots, fewer in number than the fellow eye, yet without placoid lesions. (B): Late-phase fluorescein angiography demonstrates active optic nerve head leakage. (C): Fundus autofluorescence colocalizes with the white dots seen on fundus examination as discrete foci of hyperautofluorescence (arrows). (D): Swept-source optical coherence tomography of the macula did not show evidence of retinal pigment epithelium or ellipsoid zone disruption.
Diagnosis of ARPE is made by combining multiple imaging examinations. Characteristic findings of each examination are shown below.
OCT findings
Section titled “OCT findings”OCT (optical coherence tomography) is the most important diagnostic and follow-up tool.
The frequency of involvement and healing duration for each retinal layer are shown below.
| Affected layer | Frequency | Healing duration |
|---|---|---|
| IZ (inner/outer segment junction) | 100% | 9.1±8.3 weeks |
| EZ (ellipsoid zone) | 95.6% | 7.2±5.2 weeks |
| ELM (external limiting membrane) | 35.6% | 5.1±4.8 weeks |
The main findings are as follows.
- Dome-shaped hyperreflective lesion: observed from the RPE to the inner/outer segments of photoreceptors 1).
- Disruption of EZ/IZ continuity: An essential finding in the acute phase1, 4).
- Involvement of ONL (outer nuclear layer): Cases with this finding have incomplete visual recovery1).
- ASHH (Angular Sign of Henle Fiber Layer Hyperreflectivity): A new OCT sign appearing as angled hyperreflectivity in the Henle fiber layer3).
- Recovery sequence: Restoration occurs in the order of ELM → EZ → IZ4). IZ restoration takes 3–6 months1).
- Persistent cases: EZ disruption lasting more than 12 months has been reported in 2 cases2).
Other Imaging Tests
Section titled “Other Imaging Tests”Characteristic findings of each imaging modality are shown below.
| Test | Characteristic Findings | Positive Rate |
|---|---|---|
| FA | Transmitted hyperfluorescence, no leakage | 83.6% |
| ICGA | Cockade-shaped hyperfluorescent halo | 84.6% |
| Fundus autofluorescence | Mild hyperautofluorescence in the lesion | 40% |
- FA (fluorescein angiography): 83.6% show transmission hyperfluorescence without leakage 2), suggesting a chronic course without active inflammation.
- ICGA (indocyanine green angiography): 92.3% show hypofluorescence, and 84.6% show a halo of hyperfluorescence in a cockade pattern 2).
- Fundus autofluorescence (FAF): 40% show mild hyperautofluorescence in the lesion 2).
- OCTA (optical coherence tomography angiography): Flow void is observed in the choriocapillaris 3), suggesting involvement of choroidal ischemia.
Differential Diagnosis
Section titled “Differential Diagnosis”It is important to differentiate from the following diseases 3, 4).
- MEWDS (multiple evanescent white dot syndrome): Presents with more extensive white dots, and white dots are visible on FA.
- APMPPE (acute posterior multifocal placoid pigment epitheliopathy): Characterized by placoid lesions showing early hypofluorescence and late hyperfluorescence on FA.
- AMN (acute macular neuroretinopathy): Presents with wedge-shaped reddish-brown lesions on infrared fundus imaging.
- AZOOR (acute zonal occult outer retinopathy): Fundus photographs are nearly normal.
- Solar or laser retinopathy: Check for exposure history.
- Pachychoroid pigment epitheliopathy: Accompanied by choroidal thickening.
5. Standard Treatment
Section titled “5. Standard Treatment”ARPE is a self-limiting disease, with spontaneous resolution expected within 6 to 12 weeks. Basically, active treatment is not necessary 2).
Observation is the mainstay Many reports show natural recovery of vision without treatment. In the case by Kilic (2021), vision recovered to 20/20 after one month without treatment 1). In the post-vaccine ARPE case by Sasajima et al. (2022), vision recovered to 1.5 (equivalent to 20/13) after 5 weeks without treatment 4).
Efficacy of steroids is not established There are reports of cases recovering after 6 months with oral steroids 3), but also reports that the steroid-treated group had slower visual recovery than the untreated group. The basic policy is to decide on treatment initiation and follow-up observation.
Q
Is treatment necessary?
A
Basically, treatment is not necessary, and spontaneous resolution occurs within 6 to 12 weeks. There is no evidence that steroid administration accelerates recovery; rather, there are reports that it may delay recovery. Regular follow-up with OCT is recommended.
6. Pathophysiology and Detailed Mechanism
Section titled “6. Pathophysiology and Detailed Mechanism”The pathophysiology of ARPE is not fully understood, but several hypotheses have been proposed.
MerTK Deficiency Hypothesis
POS phagocytosis disorder: MerTK deficiency → POS accumulation → outer layer hyperreflectivity → photoreceptor degeneration
Three-step disorder: recognition/binding (αvβ5 + MFG-E8), uptake (MerTK activation), lysosomal digestion
Related disease: MerTK mutations cause retinitis pigmentosa in humans
Choroidal ischemia hypothesis
Circadian rhythm disruption hypothesis
Dopamine system disturbance: D2 receptor agonists suggested to cause ARPE
POS shedding abnormality: Retinal circadian clock controls POS disc shedding
D2 receptor stimulation: Inhibits cone-rod gap junctions → reduced photoreceptor light sensitivity
Details of the MerTK deficiency hypothesis
Section titled “Details of the MerTK deficiency hypothesis”Phagocytosis of photoreceptor outer segments (POS) by RPE proceeds in three steps 2).
- Recognition and binding: αvβ5 integrin and MFG-E8 cooperate to recognize POS.
- Engulfment: POS is internalized via αvβ5 → FAK/Rac1 GTPase → MerTK activation pathway.
- Lysosomal digestion: Internalized POS is degraded in lysosomes.
Acute transient MerTK deficiency is presumed to be central to the pathogenesis of ARPE 2). MerTK mutations are known to cause retinitis pigmentosa in humans, suggesting a disease continuum with ARPE.
Details of the Choroidal Ischemia Hypothesis
Section titled “Details of the Choroidal Ischemia Hypothesis”Flow voids in the choriocapillaris on OCTA suggest a mechanism similar to APMPPE 3). A mechanism has been proposed in which primary choroidal ischemia secondarily damages photoreceptors and the Henle fiber layer (HFL), and OCT findings indicate that the main lesion of ARPE is in the outer retinal layers rather than in the “pigment epitheliopathy.”
Q
Is the main location of the lesion the retinal pigment epithelium?
A
Although the disease is named “pigment epitheliopathy,” OCT findings show that the main location is the outer retinal layers such as the IZ (inner/outer segment junction) and EZ (ellipsoid zone). The IZ is affected in 100% and the EZ in 95.6% of cases, while abnormalities of the RPE/Bruch membrane are limited to 8.9% 2). RPE changes are likely secondary.
7. Latest Research and Future Perspectives (Investigational Reports)
Section titled “7. Latest Research and Future Perspectives (Investigational Reports)”Controversy over the Disease Concept of ARPE
Section titled “Controversy over the Disease Concept of ARPE”Whether ARPE is an independent disease entity remains under debate. There are opposing positions: one denies its independent disease nature as a “diagnostic myth,” and the other supports it as “not a diagnostic myth” 1, 3). Its relationship with MEWDS, AMN, and APMPPE, as well as the possibility of inclusion in the pachychoroid spectrum, are being considered.
ASHH: A New OCT Sign of ARPE
Section titled “ASHH: A New OCT Sign of ARPE”Sen et al. (2025) reported the ASHH (Angular Sign of Henle Fiber Layer Hyperreflectivity) in presumed ARPE cases 3).
Sen et al. (2025) identified ASHH and choriocapillaris flow voids on OCTA in presumed ARPE cases, suggesting that choroidal ischemia may be involved in the pathogenesis of ARPE 3). It was proposed to position ARPE as one of the differential diagnoses of pachychoroid pigment epitheliopathy.
Post-Vaccination ARPE and Immune Mechanisms
Section titled “Post-Vaccination ARPE and Immune Mechanisms”Sasajima et al. (2022) reported a case of ARPE that developed 31 days after the second dose of COVID-19 vaccine 4). The EZ/IZ disruption on OCT was repaired within 5 weeks, and visual acuity recovered to 1.5. It has been hypothesized that the post-vaccination immune response targets the RPE or outer retina, triggering inflammation.
Verification of the MerTK Deficiency Hypothesis
Section titled “Verification of the MerTK Deficiency Hypothesis”The MerTK deficiency hypothesis remains at the hypothesis stage and requires direct verification in human cases 2). However, the fact that ARPE can also be induced by drugs (D2 receptor agonists) has drawn attention to the mechanism by which dopamine-mediated retinal circadian rhythm disruption disturbs POS shedding 1, 2).
8. References
Section titled “8. References”- Kowalik-Jagodzinska M, Czajor K, Turno-Krecicka A. Acute retinal pigment epitheliitis during treatment of hyperprolactinaemia. BMC Ophthalmol. 2024;24:96.
- Kiliç R. Acute retinal pigment epitheliitis: a case presentation and literature review. Arq Bras Oftalmol. 2021;84(2):186-90.
- Sen A, Kala U, Chowdhury R, Shambhawi P, Juneja A, Divya NS, et al. Angular sign of Henle fiber layer hyperreflectivity in presumed acute retinal pigment epitheliitis. J Curr Ophthalmol. 2025;37:129-32.
- Sasajima H, Zako M, Aoyagi A, Ueta Y, Suzuki T. Acute retinal pigment epitheliitis following vaccination. Case Rep Ophthalmol. 2022;13:832-7.
- Fouad YA, et al. Revisiting acute retinal pigment epitheliitis (Krill disease). Surv Ophthalmol. 2024;69(6):916-923.
- Heutinck PAT, et al. Acute retinal pigment epitheliitis using adaptive optics imaging: a case report. BMC Ophthalmol. 2024;24(1):507.