Carl P. Herbort

International Criteria for the Diagnosis of Ocular Sarcoidosis: Results of the First International Workshop on Ocular Sarcoidosis (IWOS)

Aim: To report criteria for the diagnosis of intraocular sarcoidosis, taking into account suggestive clinical signs and appropriate laboratory investigations and biopsy results. Design: Concensus workshop of an international committee on nomenclature. Methods: An international group of uveitis specialists from Asia, Africa, Europe, and America met in a concensus conference in Shinagawa, Tokyo on October 28–29, 2006. Based on questionnaires that had been sent out prior to the conference, the participants discussed potential intraocular clinical signs eligible for a diagnosis of ocular sarcoidosis. A refined definition of clinical signs, which received two-thirds majority of votes, was included in the list of signs consistent with ocular sarcoidosis. Laboratory investigations were similarly discussed and those tests reaching a two-thirds majority were retained for the diagnosis of ocular sarcoidosis. Finally diagnostic criteria were proposed based on ocular signs, laboratory investigations, and biopsy results. Results: The concensus conference identified seven signs in the diagnosis of intraocular sarcoidosis: (1) mutton-fat keratic precipitates (KPs)/small granulomatous KPs and/or iris nodules (Koeppe/Busacca), (2) trabecular meshwork (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS), (3) vitreous opacities displaying snowballs/strings of pearls, (4) multiple chorioretinal peripheral lesions (active and/or atrophic), (5) nodular and/or segmental peri-phlebitis (± candlewax drippings) and/or retinal macroaneurism in an inflamed eye, 6) optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule, and (7) bilaterality. The laboratory investigations or investigational procedures that were judged to provide value in the diagnosis of ocular sarcoidosis in patients having the above intraocular signs included (1) negative tuberculin skin test in a BCG-vaccinated patient or in a patient having had a positive tuberculin skin test previously, (2) elevated serum angiotensin converting enzyme (ACE) levels and/or elevated serum lysozyme, (3) chest x-ray revealing bilateral hilar lymphadenopathy (BHL), (4) abnormal liver enzyme tests, and (5) chest CT scan in patients with a negative chest x-ray result. Four levels of certainty for the diagnosis of ocular sarcoidosis (diagnostic criteria) were recommended in patients in whom other possible causes of uveitis had been excluded: (1) biopsy-supported diagnosis with a compatible uveitis was labeled as definite ocular sarcoidosis; (2) if biopsy was not done but chest x-ray was positive showing BHL associated with a compatible uveitis, the condition was labeled as presumed ocular sarcoidosis; (3) if biopsy was not done and the chest x-ray did not show BHL but there were 3 of the above intraocular signs and 2 positive laboratory tests, the condition was labeled as probable ocular sarcoidosis; and (4) if lung biopsy was done and the result was negative but at least 4 of the above signs and 2 positive laboratory investigations were present, the condition was labeled as possible ocular sarcoidosis. Conclusion: Various clinical signs, laboratory investigations, and biopsy results provided four diagnostic categories of sarcoid uveitis. The categorization allows prospective multinational clinical trials to be conducted using a standardized nomenclature, which serves as a platform for comparison of visual outcomes with various therapeutic modalities.

Posterior sub-Tenon's steroid injections for the treatment of posterior ocular inflammation: indications, efficacy and side effects.

PURPOSE Posterior sub-Tenons steroid injections (PSTSI) are a standard drug delivery method used for the treatment of chronic uveitis of the posterior segment. The aim of this study was to analyse the indications, efficacy and complications of PSTSI in the treatment of chronic uveitis. METHODS During the period 1990-1994, 53 (9.5%) of 558 patients (58 eyes) followed up in the uveitis clinic received a total of 162 PSTSI of triamcinolone acetonide 40 mg in the superior quadrants. Indications for treatment were vision inferior or equal to 0.7 and/or intolerable visual disturbance. Only patients in whom PSTSI were the only treatment parameter changed were analysed. Among the main parameters analysed were visual acuity, aqueous laser flare photometry, intraocular pressure (IOP) and complications. RESULTS Anatomical location of uveitis was as follows: anterior HLA-B27-related uveitis with CME (1 patient/1 eye), intermediate uveitis (28/32), posterior uveitis (10/10) and panuveitis (14/15). Mean duration of follow-up was 448+/-57 days. Visual acuity improved significantly from 0.40+/-0.03 to 0.79+/-0.07, with 59.4% of eyes having a gain of 2-5 Snellen lines and 18.7% a gain of >5 lines. Mean aqueous flare photometry decreased significantly from 29.6+/-3.5 to 13.6+/-2.2 photons/ms. Mean IOP increased significantly from 13.6+/-0.5 to 18.5+/-0.8 mm Hg with a rise of pressure >8 mm Hg in 23 cases (36%), transient in 16 cases, but chronic in 6 cases, needing filtering surgery. Partial superior ptosis was seen in two cases and cataract progressed in seven cases. CONCLUSION PSTSI are very effective in restoring visual acuity in chronic uveitis of the posterior segment, without systemic complications, but at the expense of intraocular hypertension, a complication that was found more frequently than expected.

Indocyanine green angiography in birdshot chorioretinopathy

OBJECTIVE Birdshot chorioretinopathy (BC) is an ocular inflammatory disease involving both the retina and the choroid. The study goal was to evaluate indocyanine green angiographic features in BC to assess choroidal involvement. DESIGN Retrospective, observational case series. PARTICIPANTS Fifty-two patients with BC documented with at least 1 concomitant fluorescein and indocyanine green angiogram. INTERVENTION Indocyanine green angiography (ICGA) was performed according to a standard protocol used for inflammatory disorders. MAIN OUTCOME MEASURE Indocyanine green angiographic signs were correlated with fundus photographs, fluorescein angiography, degree of inflammatory activity, and stage of disease. RESULTS In active disease, three main features were observed. The principal finding, found in 100% of patients, was the presence of hypofluorescent dark dots during the intermediate phase of angiography; their evolutionary pattern was twofold, becoming either isofluorescent or remaining hypofluorescent at the late phase of angiography. The other two signs were fuzzy, indistinct choroidal vessels and late-diffuse choroidal hyperfluorescence. In chronic longlasting disease, the characteristic finding was the presence of hypofluorescent dark dots that persisted in the late phase of disease and is theorized to correspond either to chorioretinal atrophy (irregular geographic pattern) or to persistent choroidal granulomas (round oval form). CONCLUSIONS Consistent ICGA findings in 52 patients allowed the authors to establish a fairly precise ICGA semiology for BC. This procedure enabled the authors to assess choroidal involvement, and, in selected cases, it also was found to be of diagnostic help and useful to monitor therapeutic intervention.

Necrotizing herpetic retinopathies a spectrum of herpes virus-induced diseases determined by the immune state of the host

PURPOSE Necrotizing herpetic retinopathies (NHR), a new spectrum of diseases induced by viruses of the herpes family (herpes simplex virus, varicella-zoster virus and cytomegalovirus), includes acute retinal necrosis (ARN) occurring in apparently immunocompetent patients and progressive outer retinal necrosis (PORN) described in severely immuno-compromised patients. Signs of impaired cellular immunity were seen in 16% of ARN patients in a review of 216 reported cases, indicating that immune dysfunction is not only at the origin of PORN but might also be at the origin of ARN. The aim of this study was to correlate clinical findings in NHR patients with their immunologic parameters. METHODS Charts from patients with the diagnosis of ARN or PORN seen from 1990 to 1995 were reviewed. Clinical characteristics and disease patterns were correlated with immunological parameters taking into account CD4 lymphocyte rate in AIDS patients and blood-lymphocyte subpopulation determination by flow cytometry, cutaneous delayed type hypersensitivity testing and lymphocytic proliferation rate to seven antigens in HIV-negative patients. RESULTS During the period considered, 11 patients and 7 patients fulfilled the criteria of ARN and PORN respectively. Immune dysfunctions were identified in most patients. Mild type of ARN and classical ARN were associated with discrete immune dysfunctions, ARN with features of PORN was seen in more immunodepressed patients and classical PORN was always seen in severely immunodepressed HIV patients. CONCLUSION Our findings suggest that NHR is a continuous spectrum of diseases induced by herpes viruses, whose clinical expression depends on the immune state of the host going from mild or classical ARN at one end in patients with non-detectable or slight immune dysfunction to PORN in severely immunodepressed patients at the other end and with intermediary forms between these extremes.

Indocyanine green angiographic features in ocular sarcoidosis

OBJECTIVE To determine indocyanine green (ICG) angiographic features and evaluate the extent of choroidal involvement in proven cases of posterior ocular sarcoidosis. DESIGN Nonrandomized controlled trial. PARTICIPANTS Nineteen patients (14 females, 5 males; average age, 56 +/- 4 years) with clinically typical posterior sarcoidosis (biopsy-proven in 6 cases and fulfilling the other diagnostic criteria in 13 cases) participated, with 10 control subjects (average age, 48 +/- 7 years). Criteria for the diagnosis of sarcoidosis were a positive biopsy result or the presence of at least three of the following four criteria: elevated serum angiotensin-converting enzyme, elevated lysozyme, cutaneous anergy, and hilar lymph node enlargement. INTERVENTION Indocyanine green angiography was performed according to a standard angiographic protocol used in inflammatory disorders. MAIN OUTCOME MEASURES Indocyanine green angiographic features and proportion of choroidal inflammatory involvement were measured. RESULTS Indocyanine green angiographic features could be classified into four main patterns. The first pattern is hypofluorescent choroidal lesions in the early and intermediate phases, irregularly distributed, invisible on funduscopy or fluorescein angiography, and localized in the midperiphery (63% of patients), in the macula (11%) or in both regions (26%) with an average dot diameter of 0.31 +/- 0.03 disc diameters. These lesions either became isofluorescent in the late phase of the angiogram (Type 1, present in all patients) or remained hypofluorescent (Type 2, present in 84% of patients). The second pattern is focal hyperfluorescent pinpoints visible in the intermediate and late phases (in 89% of patients). The third pattern is fuzzy choroidal vessels with leakage in the intermediate phase of the angiogram, and the fourth pattern is diffuse late zonal choroidal hyperfluorescence with staining in the late phase of the angiogram, both features being present in all patients. CONCLUSIONS Indocyanine green angiography allowed the authors to assess and quantify the hitherto unknown extent of choroidal involvement in ocular sarcoidosis. Furthermore, characteristic ICG findings might represent an additional valuable tool for diagnosing and monitoring this disease.

Use of Laser Flare Photometry to Assess and Monitor Inflammation in Uveitis

PURPOSE Laser flare photometry (LFP) is a new quantitative method for the evaluation of aqueous flare, making flare the only inflammatory parameter that can be evaluated precisely and objectively. The aim of this study was to characterize the inflammatory pattern of acute human leukocyte antigen-B27 (HLA-B27)-related anterior uveitis and to determine further clinical use and limitations of LFP in posterior inflammation. METHODS In the first part of the study, 78 episodes of HLA-B27-related acute anterior uveitis were analyzed to determine mean pretreatment (initial) flare, mean flare evolution, need for additional periocular steroids, and mean duration of an episode. In the second part of the study, the use of LFP was further tested in posterior inflammation, first by analyzing the predictive value of a subclinical LFP-detected flare increase for disease recrudescence in posterior scleritis, and then by exploring clinical applications for LFP in posterior uveitis, where LFP was essential either in the establishment of a diagnosis or in guiding therapeutic decisions. RESULTS Mean initial flare in HLA-B27-related acute anterior uveitis was 160 +/- 22 photons/msec, and mean duration of an episode was 18.5 +/- 15 days. A 50% and 90% flare reduction occurred after 2 and 8 days, respectively. In posterior scleritis, LFP was accurate in monitoring response to systemic steroid therapy and a small flare increase was predictive for disease recrudescence in five of six cases (predictive value 0.83, sensitivity 100%). In posterior uveitis, LFP was sensitive to monitor systemic treatments and to establish a diagnosis in unclear cases by measuring the effect of a selective therapy (therapeutic trial) on the flare level. CONCLUSION In acute anterior HLA-B27-associated uveitis, LFP represented a potential improvement in management by allowing precise adjustment of therapy. In uveitis of the posterior segment, our data confirm the validity of LFP to monitor response and adjust systemic therapy and to detect disease recurrence in patients with a sufficient pretreatment level of associated blood-aqueous barrier disruption (flare).

Dexamethasone versus diclofenac sodium eyedrops to treat inflammation after cataract surgery

Abstract We compared the postoperative anti‐inflammatory effect of diclofenac sodium 0.1 % and dexamethasone phosphate 0.1% in a prospective, randomized, doublemasked pilot study. Anterior chamber inflammation was evaluated by measuring aqueous flare and cells with a laser flare‐cell meter at one, three, 12, 30, and 60 days after cataract surgery. Flare values in the two groups did not significantly differ at any time, nor did aqueous cell counts at one, three, 12, and 60 days after surgery. At 30 days, however, cell count was significantly lower in the diclofenac group. Diclofenac sodium seems to be as potent as dexamethasone phosphate, as good an anti‐inflammatory agent, and may replace corticosteroid therapy after cataract surgery.

Oral Acyclovir for Herpes Zoster Ophthalmicus

BACKGROUND Reports on the natural history of herpes zoster ophthalmicus stress its high morbidity related to vicious scars on eyelids, ocular complications, and post-herpetic neuralgia. Early treatment with oral acyclovir is effective, but the optimal duration of treatment has not been defined. METHODS The authors performed a bicentric, prospective, randomized, double-masked study of 86 patients with acute herpes zoster ophthalmicus, within 72 hours of skin eruption, who received oral acyclovir (800 mg 5 times daily), either for 7 days (plus 7 days oral placebo) or for 14 days. All patients concomitantly received ophthalmic 3% acyclovir ointment; follow-up was at least 6 months. RESULTS Statistical analyses of subjective symptoms, skin lesions, and ocular complications showed no significant differences between the groups, suggesting that a 7-day course of treatment was sufficient. Drug tolerance was good. Pooled data from both groups corroborated earlier reports that prompt treatment with oral acyclovir reduces the severity of the skin eruption, the incidence and severity of late ocular manifestations, and the intensity of postherpetic neuralgia. At 6 months, late ocular inflammatory complications were seen in 29.1% of our 86 patients, versus 50% to 71% of untreated patients described by others. Only 13% of our patients experienced post-herpetic neuralgia, which in no case required the use of analgesics. CONCLUSION The authors believe it is not useful to prolong treatment with 800 mg of oral acyclovir 5 times daily for more than 7 days in herpes zoster ophthalmicus. This study confirms the efficacy of oral acyclovir not only against skin lesions and ocular complications, but also against postherpetic neuralgia in herpes zoster ophthalmicus.

Immunohistochemical Characterization of Human Retinoblastomas in Situ with Multiple Markers

We studied paraffin-embedded specimens from 18 surgically enucleated eyes with retinoblastoma by peroxidase-antiperoxidase immunohistochemistry with antibodies against glial fibrillary acidic protein, S-100 protein, Leu 7 epitopes, neuron-specific enolase, the 200-kilodalton subunit of the neurofilament triplet polypeptide, and retinal S-antigen. We found that (1) glial fibrillary acidic protein, S-100 protein, and Leu 7 epitopes were detected only in well-differentiated glial cells that were interpreted as reactive and not neoplastic, (2) undifferentiated neoplastic cells expressed both neuron-specific enolase and retinal S-antigen immunoreactivity, and (3) differentiated cells forming Flexner-Wintersteiner rosettes were found to express neuron-specific enolase, retinal S-antigen, and, occasionally, neurofilament protein. These results support the view that retinoblastomas are composed of neuron-committed cells and favor the origin of these tumors from photoreceptor progenitor cells. We did not find any morphologic or immunohistochemical evidence of glial differentiation from tumor cells that would support the concept that retinoblastoma arises from a primitive neuroectodermal cell capable of divergent differentiation along neuronal and glial lines.

Indocyanine green angiographic features in tuberculous chorioretinitis

PURPOSE To determine choroidal involvement in presumed tuberculous posterior uveitis by examining indocyanine green angiographic features. METHODS Indocyanine green angiography was performed according to a standard uveitis angiographic protocol in eight consecutive patients (15 eyes) with presumed posterior tuberculous uveitis. RESULTS In 100% of the 15 examined eyes, indocyanine green angiography disclosed choroidal lesions that were subclinical, not detected by fundus examination or fluorescein angiography, in six (40%) of 15 eyes. Findings were classified into four main angiographic signs: (1) irregularly distributed, hypofluorescent areas in the early and intermediate phases of angiography that either became isofluorescent (type 1 hypofluorescence) or remained hypofluorescent (type 2 hypofluorescence) in the late phase; (2) numerous, small, focal, hyperfluorescent spots; (3) choroidal vessels that appeared fuzzy in the intermediate phase because of leakage, leading in the late phase to (4) diffuse choroidal hyperfluorescence. Type 1 hypofluorescent lesions, fuzzy choroidal vessels, and diffuse choroidal hyperfluorescence tended to regress after the initiation of antituberculous and corticosteroid treatment. Focal hyperfluorescence tended to be associated with longstanding disease. CONCLUSIONS Indocyanine green angiography was useful in assessing and quantifying the as yet unknown extent of choroidal involvement in tuberculous posterior uveitis. Its characteristic appearance may be a valuable contribution to the diagnosis and monitoring of treatment response.