Punctate Inner Choroidopathy
|Punctate Inner Choroidopathy|
|Classification and external resources|
Color fundus photograph 3 months after second injection of bevacizumab shows a grayish subfoveal CNV membrane.
Punctate inner choroidopathy (PIC) is an inflammatory disease affecting the choroid and retina which can lead to vision loss, often in young women.
- 1 Disease Entity
- 2 Diagnosis
- 3 Management
- 4 Additional Resources
- 5 References
- ICD9: 363.20 chorioretinitis, unspecified
- ICD10: H30.9 Chorioretinal inflammation, unspecified
- ICD10: H30.1 Disseminated chorioretinal inflammation
Punctate inner choroidopathy (PIC) is an idiopathic inflammatory disorder of the choroid which was first described by Watzke et al in 19841.
EtiologyThe etiology has remained unclear with a wide spectrum of theories proposed. PIC was proposed to be a variant of multifocal choroiditis and panuveitis (MFCPU), a form of limited myopic degeneration or a variant of Multifocal Choroiditis (MFC). Other theories have proposed an inflammatory or infectious thrombosis of the choriocapillary layer by as of yet an unidentified organism. A previous study suggested an association betwee
It predominantly occurs in myopic females (90%), usually aged 18 to 40 years of age although more recent studies have reported a slightly different spectrum with mean age of presentation in one case series reported to be 32 years with a range of 24 to 52 years6. In the original case series by Watzke et al, myopia ranged from -3.25 to - 10.0 Diopters1.
Bilateral white-yellow chorioretinal lesions usually 100-200 microns diameter develop at the level of the inner choroid and retinal pigment epithelium (RPE) which rarely extend to the midperiphery and are never associated with vitritis. They are bilateral in 80% of cases but are usually asymmetric. They progress to atrophic scars, leaving a halo of depigmentation and are deeper and appear punched-out. Subretinal neovascular membranes in this condition occur in between 40 to 75% of cases depending on case examined6.
A recent pathological study examining choroidal neovascular membranes (CNVMs) secondary to PIC showed some intriguing findings7. Light and electron microscopy of the CNVM showed lymphocytes at the level of the inner choroid with sparing of the choriocapillaris. This study provided ultrastructural electron microscopic support to the hypothesis that PIC is an inflammatory disease, with the inflammation originating in the choroid. Pericyte-poor neovascular units have been shown to be more susceptible to one type of treatment (anti-VEGF agents) than pericyte-rich ones. This is the first pathological study employing human tissue that points to pericytes as a potential critical therapeutic target with the aggravating influence of inner choroidal chronic inflammation in PIC7.
There are several theories as to the etiology including those discussed above (eg an inflammatory or infectious thrombosis of the choriocapillary layer by an unidentified organism), however the specific mechanism remains elusive.
There are no known preventive measures for PIC.
Diagnosis is based on clinical examination. Ancillary tests from the options below can be used as adjuncts in difficult cases.
Patients usually complain of blurred vision and floaters at presentation.
Evaluation of patients with suspected punctate inner choroidopathy includes a complete ophthalmological exam.
The initial visual acuity at presentation varies from 20/50 to 20/400. In the original report by Watzke et al, 8 of 12 eyes had VA of 20/50 or better (66.7%), 2 had 20/70, one had 20/500, and another had counting fingers1. Patients tend to be myopic with bilateral white-yellow chorioretinal lesions of the posterior pole in a linear branching pattern. There is no vitritis present. Brown et al reported that 88% of patients with PIC had bilateral disease, compared to 66% in MCP, 100% in DSF, and 25% in MEWDS patients8. Patients present with typical signs of ocular histoplasmosis but have negative serology or skin test for histoplasmosis.
Blurred vision, photopsia, central and/or peripheral scotomatas and metamorphopsias. Studies have reported the commonest reported initial symptoms are unilateral scotoma and blurred vision9.
Diagnosis is based on history and physical.
Fluorescein angiographyFluorescein angiography (FA) shows early hyperfluorescence, variable late leakage/staining of acute lesions, leakage in presence of cystoid macular edema (CME) and choroidal neovascular membrane (CNVM). PIC lesions are hyperfluorescent in the early arterial phase, with staining observed in the arteriovenous phase. In some cases the lesions blocked fluorescence in the early arterial phase and stained thereafter. More lesions were seen on FA than on clinical examination. As the disease progresses damage to the RPE occurs and FA demonstrates punctate RPE window defects. Leakage of fluorescein into the subretinal space was observed in patients with a serous neurosensory retinal detachment1. Descriptions of both the pathology and clinical features of CNVMs in PIC have also been reported. Olsen et al described the FA characteristics in 6 eyes. PIC CNVMs appeared as focal areas with an irregular, lacy network of neovascularization, with hyperfluorescence in the early phase and leakage in the late phase. Over time the newer vessels linked to form a larger neovascular complex with multiple feeder vessels originating from individual neovascular buds. The subsequent fibrotic response lead to a dumbbell-shaped pattern of subretinal fibrosis10.
Indocyanine green (ICG) shows multiple midphase hypofluorescent lesions in the peripapillary posterior pole, corresponding to those seen on exams. ICG is a useful tool in the diagnosis of PIC. It has been reported to show subclinical hypofluorescent spots in 32% of affected eyes, thereby increasing the diagnostic potential in patients who have evaded clinical diagnosis11. Tiffin et al described unusual abnormalities of the choroidal vasculature in PIC12. Several areas of obvious hypofluorescence corresponded to the site of the visible subretinal lesions; larger choroidal vessels were noted to cross these areas. In addition, several choroidal vessels demonstrated localized points of hyperfluorescence situated close to the vessel wall/border. The authors suggested that the hypofluorescent areas corresponded to localized choroidal hypoperfusion, whereas the localized points of hyperfluorescence on the vessel walls might indicate an associated vasculitis. The presence of larger choroidal vessels running through the hypofluorescent areas could imply that the vasculitic process is confined to smaller choroidal vessels and the choriocapillaris12.
Indocyanine green (ICG)
Electroretinogram (ERG) is typically normal. In one electrophysiological study 7 out of 16 patients with PIC demonstrated a normal full-field electroretinogram. Three of the seven patients (42.8%) had mild asymmetry in b-wave amplitudes between the two involved eyes that correlated with differences in the number of chorioretinal lesions present in each eye13. Electrooculogram (EOG) can demonstrate very mild abnormalities of the Arden ratio due to involvement of the retinal pigment epithelial layer.
Visual fields show enlargement of the blind spot in approximately 41% of cases and central and paracentral scotoma. Watzke cited the occurrence of relative scotomata at the onset of the disease, although no details were given with regards to the type of visual field (VF) defect present or their course over time1. In a report on 25 patients who presented with enlarged blind spots, 17 (68%) had clinical findings compatible with a concomitant chorioretinal disorder, including MEWDS, PIC, MCP, and acute macular neuroretinopathy14. Other studies showed 45% of patients had normal visual fields15.This study showed the most frequent VF defect detected was enlargement of the blind spot in 41% of eyes (nine eyes). Central/paracentral scotomata were detected in 14% (three eyes). No cecocentral or peripheral scotomata were observed. In many patients the blind spot extended towards the macula and the authors theorized this may have been due to the peripapillary clustering of the inflammatory lesions13. Followup of this same group of patients revealed an improvement in most visual fields without treatment which was in contrast to patients with acute idiopathic blind spot enlargement syndrome.
Spectral domain-Ocular coherence tomography (SD-OCT) has been reported to be a useful tool in the diagnostic armentarium as well as for following conditions affecting outer retinal structures. In one recent study of PIC, SD-OCT showed homogenous thickening over the chorioretinal lesions with recurrent inflammatory activity which resolved when the condition became inactive15. Although this test is by no means diagnostic, it may help in following certain aspects of the disease course over time.
The diagnosis of PIC is largely based on clinical findings. Adjunctive testing such as FA and ICG mentioned above are also helpful particularly in less typical or early forms. Histoplasmosis skin testing is negative.
Differential diagnosis includes Acute Posterior Multifocal Plaquoid Pigment Epitheliolopathy, Behcets’ disease, Harada disease, Leukemia, Myopic degeneration, Multiple evanescent white dot syndrome (MWEDS), Pars planitis, Presumed ocular histoplasmosis, Sarcoidosis, Sympathetic ophthalmia, Serpiginous choroiditis, Vogt-Koyanagi-Harada disease or Whipples disease.
No treatment is advised for the majority of patients with PIC when there is no evidence of CNV as the visual prognosis is excellent. The only exception to this would be those patients with inflammatory lesions very close to fixation in whom medical treatment may be considered. Additionally patients who have developed CNVMs should also be considered for treatment as discussed below.
Systemic corticosteroids have been used alone or indeed combined as part of a multimodal approach. The usual starting dose is 1 mg/kg (60- 80 mg oral daily) for 3-5 days and subsequently tapered16. Lesions may show a marked improvement however this may be without an improvement in visual acuity due to CNVM formation and subsequent subfoveal fibrosis17. One case report showed the value of oral steroids in a 28 year old pregnant female with PIC after intravitreal lucentis and PDT have failed to arrest disease progression18. Interestingly one would expect that inflammatory activity of PIC or other autoimmune inflammatory diseases would be suppressed during pregnancy and exacerbated in the postpartum period19, 20. A case report by Rao et al demonstrated a flare up of choroiditis in the first trimester18.
The multimodal approach to treatment has also been used in the management of PIC. One such study examined 5 patients treated with PDT combined with oral prednisolone (1 mg/kg body weight/day) which was started 5 days before PDT over a 12 month followup period and found a mean improvement in vision of 15 letter following a mean of 2 PDT treatments21.
Intraocular corticosteroid implants and injections
One of the more commonly used methods of administration has been the intravitreal injection of 4 mg of triamcinolone. One recent retrospective study studied fourteen patients (14 eyes) over 12 month follow-up who had PIC and idiopathic CNVM. Patients were treated with combined intravitreal triamcinolone (4 mg) and PDT. The mean logMAR BCVA improved significantly from 0.52 at baseline to 0.20 at 1 year (Wilcoxon signed- ranks test, P = 0.003)22.
Intravitreal dexamethasone implant
More recently an intravitreal implant containing 0.7 mg or 0.35 mg of dexamethasone for posterior uveitis releases the medication over a 6 month period. The implant is biodegradable (containing poly D, L- lactide-co- glycolide polymer (PLGA) matrix) and is administered via a 22-gauge applicator. A recent multicenter trial examined the use of the dexamethasone implant (both 0.35 and 0.70 mg) in posterior and intermediate uveitis and found a significant improvement in degree of inflammation and visual acuity over a 6 month followup compared to sham treatment with a slightly higher incidence of raised IOP in both implants23.
Intravitreal fluocinolone acetonide implants
Injectable, non-biodegradable, intravitreal implants containing 0.59 mg of fluocinolone acetonide releases its contents over 36 months. The medication is released at a nominal initial rate of 0.6 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. The cylindrical device is 3.5 mm in length and 0.37 mm in diameter and injected into the vitreous cavity using a 25-gauge needle. Recently the results of the the MUST trial (Multicenter Uveitis Steroid Treatment trial) were published. This was a multicenter trial across the United States examining the effectiveness of standardized systemic therapy versus the fluocinolone acetonide implant therapy for the treatment of severe non-infectious intermediate, posterior uveitis or panuveitis. Although this in theory includes PIC cases, the specific diagnoses were not discussed in the results. It reported that neither treatment were superior to the other with a detectable degree of power in terms of visual acuity, quality of life or degree of inflammation24. Conversely another study in Europe examined the effectiveness of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious uveitis and found intravitreal injections were superior with no treatment-related side-effects compared with standard of care25.
Mycophenolate mofetil suppresses the immune system by selectively inhibiting the purine biosynthesis enzyme inosine monophosphate dehydrogenase (IMPDH), thereby resulting in depletion of guanosine nucleotides that are essential for purine synthesis used in the proliferation of B and T lymphocytes26. Mycophenolate mofetil has has been shown to decrease the frequency of attacks in recurrent PIC. This was used in conjunction with fundus autofluorescence to monitor and predict the response to treatment27. Other multicenter studies have examined its role in uveitis and found it was effective in approximately 50 % of all patients it was used in 28. This study did not specifically divide its participants into diagnostic categories, it examined patients with anterior uveitis (20.3%), intermediate uveitis (11.9%) and posterior uveitis or panuveitis (39.8%).
Thalidomide has little role in the treatment of CNVM due to PIC although one case report by Ip et al showed that it failed to prevent a recurrence of a choroidal neovascular membrane in a 38 year old patient with bilateral CNVM secondary to PIC29.
Sirolimus is a macrolide antibiotic and potent immunosuppressive agent and was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample sample from Easter Island- an island also known as Rapa Nui. Its mode of action involves inhibiting the binding of the cytosolic protein FK-binding protein 12 (FKBP12) and thereby inhibiting the secretion of IL-2. It has been reported to be used successfully in a patient with juxtafoveal PIC-associated CNVM30.
One study reported the resolution of disease activity following the treatment of chronic recurrent PIC with interferon B-1A31. There has been scant reports on this specific modality of treatment for PIC in the literature.
Intravitreal bevacizumab and ranibizumab
Several case series have reported the successful treatment of CNVM with anti-VEGF treatments32, 33. Although anti-VEGF agents have not been examined in pregnant patients with PIC, it has been successfully used in the treatment of CNVM with good results34. Rouvas et al followed a cohort of 16 patients including 5 with PIC over a period of 70 weeks following intravitreal injection of ranibizumab35. They found an improvement in mean foveal thickness and visual acuity as well as significant regression in CNVM over the course of the study35. It remains to be seen whether the advent of VEGF-TRAP holds the key to widening the anti-VEGF spectrum for the white dot syndromes, including PIC. Without treatment CNV is inevitably progressive36, 37.
Several reports have substantiated PDT as an effective treatment option in extrafoveal or juxtafoveal CNV due to PIC. PDT has been advocated as a viable option if outcome without treatment is likely to be poor, and preliminary success in ocular histoplasmosis syndrome, angioid streaks, idiopathic, and other conditions has been reported38, 39, 40, 41, 42, 43, 44, 45. With the widespread use of anti-VEGF treatment its role continues to decline. Studies of subfoveal CNVs which had failed to improve with a single dose of immunosuppressive therapy showed an improvement in visual acuity after they were treated with PDT46. A multimodal approach using a combination of PDT and intravitreal triamcinolone have also been used for the treatment of CNV47. This was described in a cohort of 15 patients who showed a significant improvement in visual acuity at 3 and 6 months but a worsening at 12 months47. Although PDT can be useful in selective circumstances, its role remains limited in CNV secondary to PIC.
Medical follow up
Patients are followed at periodic intervals by a uveitis/retinal specialist depending on level of inflammation/pathology.
Submacular translocation surgery Although currently submacular translocation surgery is no longer advocated for ARMD related CNVM, recent studies have examined its use in a cohort of patients with progressive use from non-ARMD submacular diseases including PIC. They primarily examined final visual acuity and found a large percentage of subjects gained >3 lines of visual acuity (38%) and achieved a final visual acuity of ≥ 20/50 (31%) over a mean followup of 28 months48. The submacular surgery trial examined a cohort of patients following submacular surgery and recurrent CNV developed in 58 % of patients. One recent publication examined the ultrastructural and pathological features of CNVMs in PIC in a patient with PIC who initially had intravitreal bevacizumab followed by submacular surgery when this failed50. This study noted recurred in on eye of a PIC patient with bilateral CNVMs who had submacular surgery in both eyes. This was consistent with the study by Olsen et al in which four out of six eyes developed a recurrence of CNV following surgical excision10.
Surgical follow up
Close follow up after surgical intervention is necessary. Patients should be monitored for recurrence of disease.
CNVM as well as subretinal fibrosis can develop leading to poorer visual outcomes.
Visual prognosis is good in the absence of CNVM with 50-75% of eyes having visual acuity better than 20/25. The course is usually self-limited with recurrences common, usually in the first 3 months 49. The two major causes of visual loss are CNVM and subretinal fibrosis. One study of 136 patients noted CNVM in 74 (66%) of cases. In eyes with choroidal neovascularization, the mean logMAR visual acuity was 0.63 at study entry, 0.63 at 12 months, 0.61 at 2 years, and 0.71 at final review (mean, 6.1 years). Brown et al reported a cohort with a mean length of followup of 51 months. The final average VA was 20/40 or better in 77% of eyes (23 eyes) and 20/50 or worse in 23% (7 eyes). In 20% of eyes (6 eyes) it was 20/200 or worse8.
- American Academy of Ophthalmology. Uveitis: Punctate inner choroidopathy Practicing Ophthalmologists Learning System, 2017 - 2019 San Francisco: American Academy of Ophthalmology, 2017.
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