Active Eye Disease Research Articles

The Pupillary Light-Off Reflex in Acute Disorders of Consciousness.

In intensive care patients with disorders of consciousness, the pupillary light reflex is a measure of pupillary parasympathetic function. By contrast, the pupillary light-off reflex leads to pupil dilation in response to an abrupt change from light to darkness ("light-off") and reflects combined parasympathetic and sympathetic pupillary function. To our knowledge, this reflex has not been systematically investigated in patients with disorders of consciousness. We hypothesized that the pupillary light-off reflex correlates with consciousness levels after acute brain injury. From November 2022 to March 2023, we enrolled 100 study participants: 25 clinically unresponsive (coma or unresponsive wakefulness syndrome) and 25 clinically low-responsive (minimally conscious state or better) patients from the intensive care units of a tertiary referral center, and 50 age-matched and sex-matched healthy controls. Exclusion criteria were active or chronic eye disease. We used automated pupillometry to assess the pupillary light-off reflex and the pupillary light reflex of both eyes under scotopic conditions in all study participants. The pupillary light-off reflex was strongly correlated with consciousness levels (r = 0.62, p < 0.001), the increase in pupillary diameters being smallest in unresponsive patients (mean ± standard deviation 20% ± 21%), followed by low-responsive patients (mean ± standard deviation 47% ± 26%) and healthy controls (mean ± standard deviation 67% ± 17%; p < 0.001). Similar yet less pronounced patterns were observed for the pupillary light reflex. Twenty-one of 25 (84%) unresponsive patients had preserved pupillary light reflexes, but only seven (28%) had fully preserved pupillary light-off reflexes (p < 0.0001). Of these 7 patients, five (71%) regained awareness. The pupillary light-off reflex may be more sensitive to consciousness levels than the pupillary light reflex. The clinical implications of this finding seem worthy of further investigation, particularly regarding possible benefits for neuromonitoring and prognostication after brain injury.

Knowledge, Attitude, and Practice of Parents Regarding Children's Eye Care in Al-Qunfudah Governorate, Saudi Arabia.

Visual impairment and blindness have a long-term impact on children. Common causes include refractive error, amblyopia, and cataracts, all of which are preventable. This study aims to evaluate the knowledge, attitude, and practice of parents regarding children's eye care in Al-Qunfudah governorate, Saudi Arabia. A cross-sectional study was carried out on a convenience sample of 403 parents residing in the governorate of Al-Qunfudah. Data were gathered using a validated, self-administered online questionnaire that required participants' consent and ensured data confidentiality. IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States) was used to do the statistical analysis of the data. This study included 403 participants; 41.2% of them were 36-45 years old, 75.9% were female, and 88.8% were married. Most of the participants had had their children undergo eye examinations (65%). A positive attitude about child eye care among the participants was observed in 48.9% of them, while the level of knowledge about eye care and its regular examinations was poor in 60% of the study sample. A significant positive correlation was detected between participants' attitudes and knowledge scores about the eye care of their children (r = 0.238, p-value = <0.001). Older adults (P = 0.004), those with employment (P = 0.004), and those with a history of children suffering from eye problems (P = 0.018) are associated with a positive attitude, while better knowledge is associated with the parent's age (P = 0.007) and higher education level (P = 0.047). The knowledge and attitude of the parents regarding their children's eyecare were suboptimal, and the main reason for conducting eye examinations on their children was the presence of active eye disease and a symptomatic child. Positive attitudes were more prevalent among those aged 36-45 years, employed, and with a higher number of children with eye problems. Those in the age group of 36-45 who had a bachelor's degree were associated with greater knowledge. There is an urgent need to educate parents about routine and recommended eye screening. Family physicians should conduct opportunistic eye screenings for children who attend primary healthcare facilities and provide parents with educational materials about common eye disorders and children's eye care.

Ocular surface and in vivo confocal microscopic findings in patients with active tyhroid eye disease treated with glucocorticoids.

To evaluate the effect of treatment with high-dose glucocorticoids (HDG) on ocular surface parameters and in vivo confocal microscopy (IVCM) findings in patients with active thyroid eye disease (TED). This study included 15 active TED patients treated with a cumulative HDG dose of 4.5g (500 mg and then 250 mg for 6 weeks each). Disease activity was assessed by the clinical activity score (CAS), Graves' Orbitopathy-specific Quality of Life (GO-QoL) questionnaire, ocular surface disease index (OSDI), tear break-up time(T-BUT), ocular surface staining and IVCM. The mean follow-up time was 48.6 months. The treatment resulted in a significant improvement in the T-BUT, ocular surface staining values. In comparison to the baseline, a notable reduction in CAS, OSDI and an increase in GO-QoL were seen after one year. IVCM showed a significant decrease in the number of dendritic cells, activated keratocytes, the degree of tortuosity, there was also a significant increase in the number of basal epithelial cells and total nerves over one-year period. All of those changes remained stable during the follow-up period. HDG treatment results in a sustained decrease in corneal inflammatory cells, an increase in tear film stability, and an improvement in disease symptoms and QoL scores for up to 4 years.

Herpes simplex keratitis following Smart Pulse Technology assisted transepithelial photorefractive keratectomy: a case report

BackgroundHerpes simplex keratitis (HSK) is a rare and sight-threatening complication following refractive surgery. SmartSurfACE surgery is the result of combining transepithelial photorefractive keratectomy (trans-PRK) with Smart Pulse Technology (SPT) to diminish surface irregularities of the residual stromal bed after surgery with less pain, faster re-epithelialization, and better postoperative visual acuity. In this article, we report the first case of HSK following SmartSurf ACE without history of herpetic eye disease.Case presentationA 21-year-old woman underwent bilateral SmartSurfACE without history of clinical herpetic infection, active eye disease, or systemic disease. Mild superficial punctate keratitis occurred on the tenth postoperative day. The condition was not improved by ophthalmic drugs of anti-inflammation or epithelial healings. Dendritic corneal ulcer appeared within one month, which is the commonly recognized clinical manifestation of herpes simplex keratitis. The patient was managed with topical and systemic antiviral agents. After nine days of antiviral therapy, the lesion healed up, remaining mild stromal scarring in both eyes ultimately.ConclusionHerpes simplex keratitis is a rare but sight-threatening complication following refractive surgery. For the ocular irritation symptoms of postoperative patients, we should consider the possibility of HSK and give timely treatment.

P24 Ankylosing spondylitis &amp; uveitis - challenges in management

Case report - IntroductionAnkylosing spondylitis is a chronic inflammatory condition involving spine, chest and sacroiliac joints. It can be associated with extra spinal manifestations which include uveitis and enthesitis, as well as other features of an inflammatory spondyloarthropathy including psoriasis and inflammatory bowel disease. It is characterised by the presence of inflammatory back pain, limited range of spinal movement, sacroiliitis on imaging, excess spinal bone formation and a high prevalence of HLA-B27. The main aims of treatment are to improve symptoms and retain function as well as to prevent disease complications.Case report - Case descriptionA 49-year-old male diagnosed with ankylosing spondylitis at the age of 23 (HLA-B27 positive, classical radiographic features on plain radiographs and MRI), with background of meningitis and subsequent epilepsy (not on treatment since the age of 13), severe hip osteoarthritis and osteoporosis. He has peripheral elbow and knee synovitis. At the age of 27 he developed sight-threatening bilateral recurrent anterior uveitis complicated by cystoid macular oedema (causing central vision loss). Initial management included anti-inflammatories and steroids. He progressed to biologics but developed a rash on adalimumab. He was switched to infliximab in 2010. In 2015 it was switched due to reduced response to golimumab which was non-beneficial. Subsequently he was switched to etanercept but after 3 months it was discontinued due to eye flare. The patient’s therapy was switched to certolizumab, which was non-beneficial for spine and discontinued. In 2016, infliximab was retried as the patient thought it worked best. Unfortunately, in 2018 patient developed Infliximab antibodies and treatment was changed to secukinumab. After 9 months this was stopped owing to ongoing active eye and spine disease. Adalimumab was re-tried; however, it was discontinued as it was showing no benefit. In 2020 Eeanercept (Benepali) was re-tried; however, only for 4 months because of severe flare of joint and eye disease. Tofacitinib was commenced but was non-beneficial and hence it was discontinued. Currently he continues on ixekizumab, oral prednisolone and also receives steroid eye and joint injections. On commencing biologics he was on methotrexate; however, the patient stopped. He was switched to mycophenolate mofetil which he remained on for 10 years. It was switched to methotrexate to try and control peripheral inflammatory joint disease better (re-tried for the second time) which the patient has recently discontinued as he felt it was non-beneficial.Case report - DiscussionThe case is very challenging. The patient’s disease continues to flare despite changing therapies. He continues to get flares in his back disease, eye disease and peripheral synovitis. His latest BASDI was 5.1 and VAS was 9/10. Measurements: intermalleolar distance 15cm, modified Schober’s 4cm, right lateral flexion 3.8cm and left lateral flexion 11cm. His latest MRI of whole spine and SI joints (in 2020) showed signs of previously active seronegative spondyloarthropathy with established cervical and thoracic ankyloses as well as bilateral sacroiliac joint ankylosis. There is a need for repeated steroid injections to the knees as well as the eyes. He continues on oral prednisolone which was first started in 2006. This is associated with multiple side effects, i.e., osteoporosis. The patient has already completed 8 years of bisphosphonate therapy. He is under regular review with the osteoporosis clinic. His bone density scan showed worsening bone mineral density and bisphosphonates had to be restarted. The patient adjusted medications depending on his symptoms. Recently he also discontinued methotrexate as he felt it was of no benefit to him at all. We are very limited at present to find combined medications to manage both the patient’s inflammatory back disease and inflammatory eye disease.Case report - Key learning pointsThis patient was diagnosed with ankylosing spondylitis 26 years ago. To date he has tried 5 different anti-TNF agents (two of which have also been re-tried at a different time point). This failed to control his disease as he continued to experience flares in either inflammatory back or eye disease. The biologic classes were also changed – he has tried one IL-17A agent as well as a JAK-I. Unfortunately, they both failed to control his disease. He currently continues on a second IL-17A; however, he still requires steroid eye and joint injections as well as systemic steroids. Throughout the years he has tried different DMARDs – most recently methotrexate. Unfortunately, the patient decided to discontinue it as he felt it was of no benefit to him. All of the above indicates that there is still a need to find a collaborative treatment option that will control the patient’s inflammatory back disease, inflammatory eye disease and peripheral synovitis. The aim would be, if possible, to decrease the steroid dose as well (currently on prednisolone 15mg daily) in order to prevent the steroid-associated side effects.

Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial

A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia. We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848. Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02-0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups. Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association. Associazione Allievi Endocrinologia Pisana.

Statins for Graves' orbitopathy: a new tool for prevention and treatment?

Graves' orbitopathy, which affects about 25–30% of newly diagnosed patients with hyperthyroidism due to Graves' disease, 1 Tanda ML Piantanida E Liparulo L et al. Prevalence and natural history of Graves' orbitopathy in a large series of patients with newly diagnosed Graves' hyperthyroidism seen at a single center. J Clin Endocrinol Metab. 2013; 98: 1443-1449 Crossref PubMed Scopus (146) Google Scholar is a multifactorial autoimmune disease causing inflammation and remodelling of orbital tissues, with relevant clinical manifestations heavily effecting the quality of life of affected individuals. 2 Neag EJ Smith TJ A 2021 update on thyroid-associated ophthalmopathy. J Endocrinol Invest. 2021; (published online Aug 20.)https://doi.org/10.1007/s40618-021-01663-9 Crossref PubMed Scopus (1) Google Scholar Considerable progress has been made in our understanding of pathogenesis of the disease 2 Neag EJ Smith TJ A 2021 update on thyroid-associated ophthalmopathy. J Endocrinol Invest. 2021; (published online Aug 20.)https://doi.org/10.1007/s40618-021-01663-9 Crossref PubMed Scopus (1) Google Scholar and in the treatment of severe forms using combination therapies (eg, intravenous glucocorticoids and mycophenolate or orbital irradiation) or novel drugs (teprotumumab, tocilizumab, and rituximab). 3 Bartalena L Kahaly GJ Baldeschi L et al. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur J Endocrinol. 2021; 185: G43-G67 Crossref PubMed Scopus (24) Google Scholar Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trialAddition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association. Full-Text PDF

Methotrexate monotherapy for unilateral moderately active thyroid-related eye disease.

A type 1 diabetic patient with unilateral active thyroid‐related eye disease was intolerant to systemic steroid therapy due to uncontrollable blood sugar levels. She was treated with low‐dose methotrexate monotherapy, which resulted in a marked improvement of her condition with no adverse events.

Barriers and Facilitators to Obtaining Eyeglasses for Vulnerable Patients in a Michigan Free Clinic.

Uncorrected refractive error is the main cause of visual impairment globally. Understanding barriers and facilitators underserved individuals face in obtaining eyeglasses will help address high rates of uncorrected refractive error. The purpose of this study was to understand the barriers and facilitators to obtaining eyeglasses among low-income patients in Michigan. Participants older than 18 years with hyperopia, myopia, or presbyopia and without active eye disease, severe mental illness, or cognitive impairment at Hope Clinic, Ypsilanti, Michigan, were included in this study. The participants answered a sociodemographic survey and underwent autorefraction and an interview. Interviews were audiorecorded, transcribed, and analyzed by two investigators. Interviews were completed by 43 participants, and 30 participants' interviews were analyzed. The mean ± standard deviation age of 30 participants was 55 ± 12 years, 70% were female, 57% were African American, 40% had high school diploma or less, 57% earned less than U.S. $25,000 per year, 93% had worn glasses previously, and 87% had some medical insurance. Uncorrected visual acuity was logMAR 0.73 ± 0.61; best-corrected visual acuity was logMAR 0.16 ± 0.21. Thematic saturation was reached after 25 transcripts. Top barriers to using eyeglasses were cost (312 mentions, 29 participants), negative experiences with eyeglasses (263, 29), and limited access to eye care (175, 27). Top facilitators were positive experiences with glasses (230, 29), easy access to eyeglasses (143, 27), and availability of transportation (65, 27). Most participants (97%, 29) reported being negatively impacted by uncorrected refractive error. Most (97%, 29) were skeptical about obtaining eyeglasses online because of possible prescription problems. Key barriers to correcting uncorrected refractive error in our community span across multiple health domains but are predominately rooted in external factors such as cost and access to vision care. Online eyeglasses may address access issues, but many participants were uncomfortable or unable to obtain glasses online.

Technetium‐99m‐anti‐tumour necrosis factor alpha scintigraphy as promising predictor of response to corticotherapy in chronic active Graves' ophthalmopathy

It has been suggested that technetium-99m (99mTc)-anti-tumour necrosis factor alpha (TNF-α) scintigraphy (SCI) may be a useful diagnostic tool in Graves' ophthalmopathy (GO). This study evaluated whether orbit total radioactivity uptake on SCI could be used to predict corticosteroid therapy (CorT) responses in active-GO patients. A longitudinal study of patients with active GO defined by Clinical Active Score (CAS) >3/7 was done. Clinical, laboratory and SCI evaluations were performed at baseline and 3months after concluding intravenous CorT. SCI (planar and tomographic) was assessed after intravenous injection of 10mCi of 99mTc-anti-TNF-α. Orbits and cerebral hemispheres were defined as regions of interest (ROIs) to enable orbit/hemisphere ROI-ratios of total radioactive uptake. ROI-ratios were considered positive at >2·5. Average total radiation uptake (TRU) was also determined for each orbit (AVGROI ). Clinical, laboratory and SCI data were compared between responders (CAS became inactive) and non-responders to CorT (18 patients). At baseline, AVGROI were higher in active OG orbits (67·3cps) than in inactive ones (33·6cps; P<0·05). AVGROI (absolute values) reduced (-29·9cps) in CorT responders and tended (P=0·067) to differ from variations occurred in non-responders (+6·9 cps in patients with maintained CAS positivity post-treatment). Higher baseline ROI-ratios (4·9 versus 3·3; P=0·056) and its pronounced reductions following CorT (-37% versus +56% in non-responders; P=0·036) tended to be associated with good CorT responses in the subgroup of GO history ≥1year. SCI showed a good association with active eye disease and may be an additional tool to identify CorT responders.

Increased serum VEGF and b-FGF in Graves' ophthalmopathy.

BackgroundGraves’ ophthalmopathy (GO) is thought to be an inflammatory disorder of autoimmune background. The aim of this study is to investigate the involvement of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) in patients with Graves’ ophthalmopathy (GO).MethodsSerum concentrations of VEGF and b-FGF of 48 GO patients, 30 Graves’ hyperthyroid disease (GD) patients without ophthalmopathy, and 30 healthy controls were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Patients with GO were subdivided into two groups according to clinical activity scores (CAS): a score of 3 or less is considered as inactive (CAS ≤ 3, inactive GO, n = 14), and 4 or more is considered active eye disease (CAS ≥ 4, active GO; n = 34). All of the patients with active GO underwent corticosteroid therapy.ResultsThe concentrations of serum VEGF and b-FGF were significantly higher in patients with GO and in those with GD than in controls. The serum levels of VEGF and b-FGF in patients with active GO were higher than those in patients with inactive GO and those in GD patients (P < 0.05). Moreover, serum VEGF and b-FGF concentratison were significantly correlated with CAS in GO patients (p < 0.01). Mean VEGF and b-FGF levels in corticosteroid-responsive patients (CAS decreases ≥3 after treatment) decreased significantly after corticosteroid treatment (P < 0.05), and these changes were accompanied by a decrease of CAS (P < 0.05).ConclusionThe results suggest that serum VEGF and b-FGF levels were increased in patients with active GO and could reflect the degree of ocular inflammatory activity.

The relationship between serum levels of angiogenin, bFGF, VEGF, and ocular involvement in patients with Behçet’s disease

The aim of this study was to investigate the possible role of angiogenin, vascular endothelial growth factor, (VEGF) and basic fibroblast growth factor (bFGF) in the pathogenesis of BD. Sixty-five patients with BD and 21 healthy control subjects were included in the study, and serum angiogenin, bFGF, and VEGF concentrations were measured by using in-vitro enzyme immunoassay (ELISA) kits according to the manufacturer's instructions. The median serum angiogenin level was significantly higher in patients with BD (391.8; range:151.6-594.8pg/ml) than controls (298.8; range:241.9-449.6pg/ml) (p = 0.001). The levels were similar in both ocular and non-ocular BD patients (p = 0.537). The mean serum bFGF level was higher in patients with BD (38.8 ± 12.3pg/ml) than controls (33.2 ± 11.3pg/ml); the median serum VEGF level was also higher in BD patients (239.7; range:53-991.3pg/ml) than controls (189.4; range:53.6-357.9pg/ml). But these differences were not statistically significant. Serum bFGF and VEGF levels were also not different statistically in ocular and non-ocular Behçet's patients. There was no statistically significant relationship between serum angiogenin, bFGF, and VEGF levels and the presence of active eye disease or anatomic location of uveitis. While there was a correlation of borderline significance in angiogenin levels between the patients with anterior uveitis and panuveitis (p = 0.053), we did not obtain any correlation between serum angiogenin, bFGF, and VEGF levels and the duration of BD. This study suggests that angiogenin may be associated with pathophysiology of BD, and highlights the need of further investigation of the role of angiogenin, bFGF, and VEGF serum levels in BD susceptibility and its clinical manifestations.

A Randomized Controlled Trial to Evaluate the Effectiveness of 2 Regimens of Fixed Iodine (131I) Doses for Graves Disease Treatment

To investigate the effectiveness of 2 fixed iodine (¹³¹I) doses for the treatment for Graves hyperthyroidism and their impact on eye disease. We prospectively examined 76 patients who received a fixed dose of 370 MBq (group 1) and 52 patients who received 555 MBq ¹³¹I (group 2). Patients were followed up for 12 months and considered in remission when they were in a stable euthyroid or hypothyroid state in the absence of antithyroid drugs 12 months after ¹³¹I administration. Eight patients with active eye disease received a daily dose of 0.5 mg/kg prednisone per kilogram of body weight at the time of radioiodine therapy for 1 month. The remission rate obtained was similar in groups 1 (73.7%) and 2 (80.8%; P = 0.35). Hypothyroidism was diagnosed in 56.5% of the 370-MBq group and 71.1% of the 555-MBq group patients (P = 0.13). There was no correlation among clinical features, thyroid uptake, antibody levels, serum hormones levels, and outcome. However, logistic regression analysis demonstrated that patients with large thyroid glands had 2.4 times less chance to go into remission (odds ratio; 95% confidence interval = 1.18-4.96). None of the patients developed eye disease during any fixed-dose treatment regimen or worsened their previously diagnosed ophthalmopathy. Fixed doses of 370 MBq and 555 MBq ¹³¹I provided similar remission rates; however, outcome was influenced by the thyroid size. We propose that 370 MBq ¹³¹I should be the routine treatment dose for all Graves disease patients, reserving a dose of 555 MBq ¹³¹I to palpable large goiters, without any additional concern to eye disease.

Silent central nervous system involvement in Egyptian Behçet's disease patients: clinical, psychiatric, and neuroimaging evaluation

Behçet's disease (BD) is an idiopathic multisystem disorder. Involvement of CNS occurs in 4-48% of cases. This study was designed to evaluate the prevalence of subclinical neuropsychiatric affection in asymptomatic Egyptian BD patients using psychometric tests and brain imaging with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), also to assess possibly associated clinical predictive variables. Twenty-five BD patients without overt CNS involvement and ten healthy controls matched for age, education, and sex completed a comprehensive neuropsychological battery including Hamilton scales for anxiety and depression and Wechsler memory scale-revised. Disease activity was assessed using Behçet's Disease Current Activity Form (BDCAF). SPECT was done for all subjects, and 12 patients underwent brain MRI. Compared to controls, 23 (92%) and 24 (96%) patients had anxiety and depression scores respectively above normal range; also, BD patients had significantly lower memory quotient (MQ). SPECT revealed abnormalities in 16/25 (64%), while in 3/12 patients (25%), MRI was abnormal. Subjects with abnormal SPECT had significantly higher ages than those with normal SPECT (P = 0.02) and were more frequently males (P = 0.03). No statistically significant differences between cases with normal or abnormal SPECT were found regarding disease duration, frequency of headache, BDCAF, frequency of active eye disease, major vascular involvement, mean Hamilton anxiety and depression scores, and mean MQ. Early diagnosis of neurological involvement in BD is important in reducing or preventing complications. Neuropsychiatric evaluation and HMPAO brain SPECT were found to be useful for detecting subclinical neurological abnormalities in BD patients.

Deficient activation and different expression of transforming growth factor-beta isoforms in active proliferative diabetic retinopathy and neovascular eye disease.

An increased expression and secretion of angiogenic growth factors was proposed to occur in proliferative diabetic retinopathy and other neovascularizing retinal diseases. However, a loss of anti-angiogenic factors also might promote retinal neovascularization. Therefore we investigated the active and latent vitreous levels of the subtypes of the endothelial anti-mitogen transforming growth factor-beta in vitreous of 58 patients. Four groups of patients were compared: Controls without retinal hypoxia, patients with quiescent and active proliferative diabetic retinopathy (PDR), and patients with severe retinal hypoxia resulting in rubeosis iridis. Whereas the amount of total TGF-beta in the four groups did not differ significantly, latent TGF-beta isoform expression showed complex alterations in ocular vitreous. Levels of active TGF-beta of patients with active PDR (79.5 +/- 28 pg/ml; n = 8) were decreased to 20% of the control levels (378 +/- 55 pg/ml; n = 12; p = 0.0005) and 25% of the mean concentration in quiescent PDR (346 +/- 64 pg/ml; n = 9; p = 0.0021). Levels in rubeosis (52 +/- 10 pg/ml; n = 10) did not differ significantly from those found in active PDR but were decreased to 15% of those in patients with quiescent PDR (p = 0.0004). Furthermore a highly significant inverse correlation between active TGF-beta and alpha2-antiplasmin, a liver produced inhibitor of the activation of TGF-beta by plasmin was noted (r = -0.59; n = 28; p = 0.001). We conclude that deficient activation of TGF-beta occurs in active proliferative diabetic retinopathy and in hypoxic angiogenesis most likely as a consequence of a blood retina barrier breakdown and influx of alpha2-antiplasmin from serum. The disinhibition of endothelial cell proliferation may be a central component in the process of neovascularization.

A Prospective Study of the Effects of Radioiodine Therapy for Hyperthyroidism in Patients with Minimally Active Graves’ Ophthalmopathy

Radioiodine is an effective and safe treatment for hyperthyroidism but has been implicated as a risk factor for deterioration or new presentation of Graves' ophthalmopathy (GO). Prophylactic glucocorticoids appear to prevent this effect. The objective of this study was to document the course of GO after radioiodine therapy. This was a prospective observational study. Patients were assessed at baseline and 2, 4, 6, and 12 months after radioiodine therapy. The study was conducted at a tertiary referral center. Seventy-two GO patients with minimally active eye disease participated in the study. A fixed dose of radioiodine was administered. T(4) was commenced 2 wk later to prevent hypothyroidism. Change in activity and severity of GO were analyzed. Exophthalmometer readings, the width of the palpebral aperture, diplopia scores, and the clinical activity score improved significantly. By clinically significant criteria, the eye disease improved in four patients (transiently in three of the four cases), most likely attributable to the natural course of the disease. No patient's eyes deteriorated. Radioiodine is not associated with deterioration of GO in patients with minimally active eye disease when postradioiodine hypothyroidism is prevented.

Multi-center study on the characteristics and treatment strategies of patients with Graves' orbitopathy: the first European Group on Graves' Orbitopathy experience.

To improve management of patients with Graves' orbitopathy, a multi-center collaborative approach is necessary in order to have large enough sample sizes for meaningful randomized clinical trials. This is hampered by a lack of consensus on how to investigate the eye condition. The European Group on Graves' Orbitopathy aims to overcome this and has designed a preliminary case record form (CRF) to assess Graves' orbitopathy patients. This form was used in this first multi-center study. To investigate patient characteristics and treatment strategies in 152 new consecutively referred patients with thyroid eye disease seen in nine large European referral centers. Newly referred patients with Graves' orbitopathy were included who were seen between September and December 2000. Demographic data and a complete ophthalmological assessment were recorded. One-hundred and fifty-two patients (77% females) were included. Diabetes was present in 9%, and glaucoma or cataract in 14% of patients. Forty percent were current smokers, 9% also had dermopathy, and only 33% reported a positive family history of thyroid disease. Mild eye disease was seen in 40%, moderately severe eye disease was seen in 33% and severe eye disease was seen in 28% of patients. Soft tissue involvement was the most frequent abnormality (seen in 75%), proptosis > or =21 mm was found in 63%, eye motility dysfunction in 49%, keratopathy in 16% and optic nerve involvement was found in 21% of patients. According to the clinical impression, 60% had active eye disease. Immunosuppressive treatment was planned more frequently in active patients (57/86; 66%) than in inactive patients (5/57, 9%; Chi-square 46.16; P<0.02). There were no important differences among the eight centers regarding the severity and the activity of their patients. In view of the large number of patients recruited in only 4 months, multi-center studies in the eight EUGOGO centers appear to be feasible.

Octreoscan in thyroid-associated ophthalmopathy.

Until recently, there was no imaging technique available that could be considered as a reliable measure of inflammation in thyroid-associated opthalmopathy (TAO). Pentetreotide (a synthetic derivative of somatostatin) labeled with 111In has been used to visualize somatostatin receptors in endocrine-related tumours in vivo. It has also been used to measure the orbital uptake in patients with TAO. An increased uptake in the orbit was found in patients with active disease. It was suggested that it is caused by the expression of somatostatin receptors on activated T-lymphocytes. Thus, a positive orbital octreoscan indicates clinically active eye disease in which immunosuppressive treatment might be of therapeutic benefit, in contrast to the fibrotic end stage. Indeed, successful immunosuppression with prednisone, orbital irradiation, or very recently with somatostatin analogues, has been demonstrated in patients with TAO and positive octreoscan. It is inferred that an orbital octreoscan is mainly indicated to select patients with TAO who will benefit from immunosuppression. However, limitations such as cost, nonnegligible radiation burden, nonspecific examination for TAO, and finally, lack of evaluation of eye muscle swelling restrict the widespread use of this technique. It remains to be seen if orbital octreoscan will become a widely available tool in the management of patients with TAO.

Both Th1- and Th2-derived cytokines in serum are elevated in Graves' ophthalmopathy.

Increased serum cytokine levels have been reported in patients with autoimmune thyroid disease, but less is known about their levels in patients with Graves' ophthalmopathy (GO). It is not known whether GO is a cell-mediated or humoral autoimmune disease. We investigated whether serum cytokines are elevated in GO patients and whether the cytokines were Th1- or Th2-derived. In addition, elevated cytokines might reflect the activity of GO, and thus we investigated whether cytokine levels could predict the clinical response to orbital radiotherapy. We studied 62 consecutive patients with moderately severe untreated GO and 62 healthy controls, matched for sex, age and smoking habits. Serum concentrations of IL-1RA, sIL-2R, IL-6, sIL-6R, tumour necrosis factor-alpha (TNF-alpha) RI and II and sCD30 were measured using highly sensitive ELISAs, in the patients before and 3 and 6 months after radiotherapy. All patients were euthyroid, with anti-thyroid drugs, before and during the entire study period. All baseline cytokine and cytokine receptor levels were significantly elevated in GO patients compared with healthy controls, except for IL-1RA. The levels did not correlate with parameters of the thyroid disease, nor with the duration, activity or severity of GO. However, backward logistic regression analysis showed that IL-6, sCD30 and TNFalphaRI were able to predict a beneficial response to orbital radiotherapy. We therefore conclude that both Th1- and Th2-derived cytokines are elevated in GO patients compared with its controls. IL-6, sCD30 and TNFalphaRI had some value for predicting therapeutic outcome to orbital irradiation, and may thus reflect active eye disease.

Octreotide-scintigraphy is a disease-activity parameter in Graves' ophthalmopathy.

It is thought that immunosuppressive treatment of Graves' ophthalmopathy should be restricted to patients with active eye disease, but assessing disease activity is difficult. Octreotide scintigraphy has been claimed to differentiate active from inactive disease. Here we study the intraobserver variability and diagnostic accuracy of the quantitative measurement of orbital octreotide uptake. Twenty-two consecutive patients with moderately severe ophthalmopathy were treated with retrobulbar radiotherapy. Pretreatment octreotide scintigraphic data were related to the response at six months after radiotherapy, using Receiving-Operator-Characteristic curves. Octreotide uptake was measured at 4 and 24 h after i.v. injection of approximately 3 mCi (= 111 MBq; range 75-150 MBq) 111Indium-DTPA-Octreotide with a neuro-SPECT camera. Counts were measured in fixed regions-of-interest in 4 transversal slices of the orbit, the temporal and the occipital area. Measurements were done twice and intraobserver variability was analysed by coefficients of variations (CV). Uptake is expressed as orbital/background ratio. The nature of the temporal uptake was studied by matching an octreoscan with a technetium scan and MRI. Intra-observer variability of measuring octreotide uptake was acceptable, and the coefficient of variation slightly better using the orbital/occipital ratio (11%), than the orbital/temporal ratio (16%). From matching studies it appears that the temporal uptake takes place, in part, in the parotid gland. The orbital/occipital ratio was used to predict the outcome of radiotherapy. Mean (+/- SD) uptake on the 4 h scan was higher in responders (2.2 +/- 0.66) than in nonresponders (1.7 +/- 0.39; P = 0.04). From the Receiving-Operator-Characteristic curve we determined a cut-off value of 1.85, which yielded a positive predictive value of 92% and a negative predictive value of 70%. The 24 h scan could not predict a response. Quantitative measurement of orbital octreotide uptake is possible. Using the orbital/occipital ratio on the 4 h scan, the octreoscan seems useful in predicting response to subsequent radiotherapy. The 24 h scan seems not to be useful in predicting therapeutic outcome.