Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome.

Pseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this study, we analyzed the role of the retinoic acid (RA) signaling pathway in the PEX-associated matrix metabolism and evaluated its targeting as a potential candidate for an anti-fibrotic intervention. We provided evidence that decreased expression levels of RA pathway components and diminished RA signaling activity occur in an antagonistic crosstalk with TGF-ß1/Smad signaling in ocular tissues and cells from PEX patients when compared with age-matched controls. Genetic and pharmacologic modes of RA pathway inhibition induced the expression and production of PEX-associated matrix components by disease-relevant cell culture models in vitro. Conversely, RA signaling pathway activation by natural and synthetic retinoids was able to suppress PEX-associated matrix production and formation of microfibrillar networks via antagonization of Smad-dependent TGF-ß1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-ß1/Smad signaling is a driver of PEX-associated fibrosis, and that restoration of RA signaling may be a promising strategy for anti-fibrotic intervention in patients with PEX syndrome and glaucoma.

Posttranscriptional Regulation of LOXL1 Expression Via Alternative Splicing and Nonsense-Mediated mRNA Decay as an Adaptive Stress Response.

Purpose: Alternative mRNA splicing coupled to nonsense-mediated decay (NMD) is a common mRNA surveillance pathway also known to dynamically modulate gene expression in response to cellular stress. Here, we investigated the involvement of this pathway in the regulation of lysyl oxidase-like 1 (LOXL1) expression in response to pseudoexfoliation (PEX)-associated pathophysiologic factors. Methods: Transcript levels of LOXL1 isoforms were determined in ocular tissues obtained from donor eyes without and with PEX syndrome. Pseudoexfoliation-relevant cell types, including human Tenon's capsule fibroblasts (hTCF) and trabecular meshwork cells (hTMC), were exposed to puromycin, caffeine, TGF-ß1, homocysteine, IL-6, retinoic acid, UV-B radiation, oxidative stress, and mechanical stress for up to 48 hours. Western blot analysis was carried out using antibodies against LOXL1, (phosphorylated-) eukaryotic initiation factor 2-α (eIF2-α), and regulator of nonsense transcripts 2 (UPF2). RNA interference was used to knockdown UPF1-3 and Serine/threonine-protein kinase (SMG1). Results: Constitutive expression of wild-type LOXL1 and alternatively spliced LOXL1-a transcripts was detected in all ocular tissues showing highest levels in trabecular meshwork and differential expression between PEX and control specimens. LOXL1-a transcripts were upregulated in hTCF and hTMC by NMD inhibitors puromycin and caffeine (≥6-fold; P < 0.01) or after knockdown of NMD core factors (≥2-fold; P < 0.05), whereas mRNA and protein levels of LOXL1 were reduced (≤0.8 fold; P < 0.05). Exposure of cells to various PEX-associated (stress) factors, including TGF-ß1, UV-B light, oxidative stress, mechanical stress, and retinoic acid enhanced LOXL1-a transcript levels (≥1.5-fold; P < 0.05), while partially downregulating LOXL1 levels (≤0.7-fold; P < 0.05). Stress-induced inhibition of NMD was dependent on phosphorylation of eIF2α. Conclusions: These findings provide evidence for a functional role of alternative splicing coupled to NMD in the posttranscriptional regulation of LOXL1 gene expression and suggest this mechanism to represent a dynamic mode of adapting LOXL1 expression to PEX-associated environmental and nutritional cues.

Implantation of a new accommodative posterior chamber intraocular lens.

PURPOSE: A new, potentially accommodative posterior chamber lens (PCIOL) was designed based on principles elaborated by Hanna using finite element computer simulation methods. We report 3-month postoperative results in patients. METHODS: In a prospective study, 12 eyes of 12 patients (age 45 to 87 yr) underwent phacoemulsification for cataracts and PCIOL implantation. The PCIOL, 1 CU, has haptics designed for anterior optic movement following ciliary muscle contraction. Patients were examined postoperatively after 1 and 2 days, 1, 2 and 6 weeks, and 3 months, and results were compared with a control group of 12 eyes that received standard PMMA or acrylic PCIOLs. RESULTS: Surgery was uncomplicated and all PCIOLs were well-tolerated and stable with good centration in the capsular bag. The results were (mean +/- SD [range] and median; 1 CU versus control PCIOL): near visual acuity (Birkhäuser reading chart at 35 cm) with best distance correction 0.34 +/- 0.17 (0.2 to 0.6), 0.3 (J10-J1, median J7) versus 0.15 +/- 0.07 (0.1 to 0.3), 0.15 (J16-J7, median J13), P=.001; subjective near point 59 +/- 10 cm (40 to 100 cm), 53.5 cm versus 93 +/- 20 cm (64 to 128 cm), 86 cm, P=.004; retinoscopic accommodative range 1.2 +/- 0.4 D (0.63 to 1.5 D), 1.2 D versus 0.2 +/- 0.19 D (-0.25 to 0.5 D), 0.25 D, P < .001; decrease of anterior chamber depth after 2% pilocarpine 0.63 +/- 0.16 mm (0.40 to 0.91 mm), 0.63 mm versus 0.15 +/- 0.05 mm (0.08 to 0.20 mm), 0.17 mm, P < .001. CONCLUSIONS: The new PCIOL appears to be safe at short to medium term. Our results indicate pseudophakic accommodation secondary to focus shift with this PCIOL. Additional larger and long-term studies are necessary for exact evaluation of safety and accommodative power of this new PCIOL.

Measurement of accommodation after implantation of an accommodating posterior chamber intraocular lens.

PURPOSE: To analyze techniques of measuring accommodation after implantation of an accommodating posterior chamber intraocular lens (PC IOL). SETTING: Department of Ophthalmology and University Eye Hospital, University Erlangen-Nürnberg, Erlangen, Germany. METHODS: This prospective study analyzed 23 eyes of 23 patients (aged 41 to 87 years) after cataract surgery and PC IOL implantation (1 CU, HumanOptics) 4 weeks and 3 and 6 months after surgery. The results were compared to those in an age-matched control group (n = 20) 6 months after surgery. The following methods were used to measure accommodation: dynamic with objective techniques (PlusOptix PowerRefractor videorefractometry, streak retinoscopy) and subjective techniques (subjective near point [push-up test, accommodometer], defocusing); static with pharmacologic stimulation after pilocarpine 2% eyedrops directly (conventional refractometry); indirectly (change in the anterior chamber depth [ACD] with Zeiss IOLMaster). RESULTS: Results at 6 months, given as mean +/- SD (range), in the study and control groups, respectively, were as follows: near visual acuity (Birkhäuser reading charts at 35 cm) with distance correction, 0.32 +/- 0.11 (0.20 to 0.60) and 0.14 +/- 0.10 (0.05 to 0.30); accommodation amplitude (diopters) by PowerRefractor, 1.00 +/- 0.44 (0.75 to 2.13) and 0.35 +/- 0.26 (0.10 to 0.65), by retinoscopy, 0.99 +/- 0.48 (0.13 to 2.00) and 0.24 +/- 0.21 (-0.13 to +0.75), by subjective near point, 1.60 +/- 0.55 (0.50 to 2.56) and 0.42 +/- 0.25 (0.00 to 0.75), and by defocusing, 1.46 +/- 0.53 (1.00 to -2.50) and 0.55 +/- 0.33 (0.25 to 0.87). The mean ACD decrease (mm) was 0.78 +/- 0.12 (0.49 to 1.91) and 0.16 +/- 0.09 (0.00 to 0.34) after pilocarpine 2% eyedrops, indicating a mean accommodation of 1.40 D and 0.29 D, respectively, based on Gullstrand's model eye (P =.001). The lowest fluctuation between follow-ups was with the subjective near point and the defocusing techniques followed by ACD decrease with the IOLMaster. CONCLUSIONS: Accommodation after implantation of an accommodating PC IOL should be assessed with several techniques, including subjective and objective, to differentiate true pseudophakic accommodation from pseudoaccommodation. Researchers should be aware of the different variability and consistency of measurements with each technique over time.

Annular crystalline keratopathy in association with immunoglobulin therapy for pyoderma gangrenosum.

PURPOSE: To report on a patient with a clinical presentation of annular crystalline keratopathy after immunoglobulin therapy for pyoderma gangrenosum. METHODS: Case report of a 6-year-old boy with biopsy-proven history of pyoderma gangrenosum who had undergone several cycles of systemic immunoglobulin therapy. The literature on ocular manifestations associated with pyoderma gangrenosum was reviewed. RESULTS: One year after the last cycle, the patient complained of the sudden onset of photophobia. Slit-lamp biomicroscopy revealed bilateral symmetric crystalline deposits in an annular region of the cornea. Because visual acuity was not reduced, specific therapy was not initiated. Symptoms could be reduced by the prescription of medical edged filter lenses. CONCLUSIONS: Annular crystalline corneal deposits may be associated with immunoglobulin therapy or represent a hitherto unknown ocular complication of pyoderma gangrenosum.

[Ocular myasthenic syndrome and systemic lupus erythematosus]. / Okuläres myasthenes Syndrom bei systemischem Lupus erythematodes.

BACKGROUND: Reports on association of systemic lupus erythematosus (SLE) and myasthenia gravis are sparse. CASE REPORT: An 40-year old woman complained of sudden onset of diplopia. A SLE was known for 6 years. Both eyes showed a deficit in upgaze, the right eye showed a deficit in abduction and a slight ptosis. Further ophthalmologic and neurologic status were normal. Magnetic resonance tomographic imaging of the brain and the results of the spinal fluid examination were unremarkable. Sonographic imaging and magnetic resonance tomographic imaging studies showed normal extraocular muscles. The edrophonium test (short acting inhibitor of acetylcholinesterase) was positive (elevation of the ptotic lid after injection of edrophonium). Acetylcholine receptor antibodies were elevated to 70 nmol/l (norm: < 0.25 nmol/l). Thoracic computed tomographic scan showed no evidence of a thymoma/thymus hyperplasia or thymus carcinoma. Systemic steroid treatment resolved the complaints within weeks. CONCLUSIONS: The patient with SLE had an ocular myasthenic syndrome. The etiology of the association of the two autoimmune diseases is not clear. SLE patients showing fatigue signs or pareses should be examined for myasthenia gravis. Patients with isolated ocular myasthenic syndromes should be examined for a generalized immunological disorder.

[Myokymia of the obliquus superior muscle and cryptogenetic epilepsy]. / Myokymie des Musculus obliquus superior und kryptogene Epilepsie.

BACKGROUND: Myokymia of the obliquus superior muscle is a rare episodic microtremor caused by uncontrolled activities of the trochlearis nerve fibres. Epilepsy is also caused by spontaneous discharges of neurons. In our report we present an associated epilepsy which to the best of our knowledge is described for the first time. PATIENT: An 61-year old man with twitches of the right eye for 6 weeks and a subjective feeling of eye movement was investigated at our hospital. His history was void of any ophthalmologic diseases. However, he suffered from cryptogenetic epilepsy known since childhood. The morphological and orthoptical findings of his eyes were normal. During the slit-lamp investigation a unilateral rotating microtremor of the right eye induced by looking downward was seen. The neurologic investigation, magnetic resonance imaging and assessment of the thyreoid function did not show further pathological results. The patient underwent treatment with carbamazepine. Under this therapy he did not show any symptoms of myokymia during follow-up. SUMMARY: To the best of our knowledge this is the first case of myokymia of the obliquus superior muscle associated to epilepsy. To our opinion, any case of this syndrome should be investigated for epilepsy. A causal relation is unlikely since the most probable etiologies are either spontaneous discharges of trochlear nucleus neurons or a close contact between vessel and nerve analogously to trigeminal neuralgia.

[Hemiatrophia faciei progressiva and tonic pupil]. / Hemiatrophia faciei progressiva und Pupillotonie.

BACKGROUND: A variety of infectious and autoimmune diseases are described in association with pupillotonia. To our knowledge there is only one report on pupillotonia associated with hemiatrophia faciei. We describe another patient with this rare association. The aim is to investigate possible associations between both diseases. PATIENT: A twenty five-year-old male patient with hemiatrophia faciei, epilepsy and pupillotonia of the right eye since his twelfth birthday was presented for the first time at the age of fourteen at our institution. The patient underwent a complete neurological and paediatric as well as otolaryngological investigation; there was also an investigation by the internist. The patient also underwent a complete serological investigation for infectious and autoimmune disorders as well as an investigation of the local and systemic vascular reactivity by the "Ocular cold pressor test". The follow-up time is 11 years. RESULTS: The clinical picture of our patient was an association of hemiatrophia faciei, epilepsy and pupillotonia. There was no evidence of a local hyperactivity of the sympathetic nervous system. The serological investigation showed an elevated value of antinuclear antibodies. CONCLUSIONS: We assume that in our case the pupillotonia as well as the hemiatrophia faciei and the epilepsy is caused by a common autoimmune factor. All other aetiologies for these three diseases were excluded. Furthermore, the occurrence of pupillotonia, hemiatrophia faciei and epilepsy was simultaneous.

Comparison of 6-month results of implantation of the 1CU accommodative intraocular lens with conventional intraocular lenses.

OBJECTIVE: To evaluate the clinical results of implantation of the new 1CU accommodative intraocular lens (IOL) in cataract patients and to compare results with those of conventional IOLs. DESIGN: Nonrandomized comparative trial. PARTICIPANTS: Twenty eyes of 20 patients (mean age = 65.8+/-13.3 years) in the 1CU group and 20 eyes of 20 patients (mean age = 67.4+/-11.6 years) in the control group. METHODS: All patients underwent phacoemulsification and IOL implantation. The 1CU accommodative lens was used in 20 eyes, and conventional IOLs (polymethyl methacrylate, hydrophilic or hydrophobic acrylate) were used in the control group. Patients were observed prospectively, and 6-month data were analyzed. MAIN OUTCOME MEASURES: Accommodative ranges determined by 3 different methods (near point, defocusing, and retinoscopy). Secondary outcome measures were (1) increase of anterior chamber depth after topical application of 1% cyclopentolate eyedrops and (2) distance-corrected near visual acuity with Birkhäuser reading charts at 35 cm. RESULTS: We observed a higher accommodative range with all 3 methods (mean = 1.83+/-0.49 vs. 1.16+/-0.27 diopters [D] [near point], 1.85+/-0.43 vs. 0.64+/-0.21 D [defocusing], and 0.98+/-0.55 vs. 0.17+/-0.22 D [retinoscopy]), a larger increase of anterior chamber depth after cyclopentolate eyedrops (mean = 0.42+/-0.18 vs. 0.11+/-0.06 mm), and better distance-corrected near visual acuity (median = 0.4 vs. 0.2) in the 1CU group relative to the control group. All differences between the 2 groups were statistically highly significant (P<0.001). CONCLUSIONS: In the present study, the 1CU accommodative IOL showed increased accommodative range and better near visual acuity than a control group with conventional IOLs. Further research is necessary to confirm these results in masked, randomized, prospective studies and to confirm further the accommodative power of this group of new IOLs.