ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Blepharospasm in children and adolescents.

PURPOSE: Benign essential blepharospasm (BEB) generally is considered a disorder of adults; however, it rarely can present in childhood or adolescence. The main purpose of this study was to determine the prevalence of BEB in children and adolescents. Our research question was whether blepharospasm is seen in children or adolescents as well as in the adult population. METHODS: We conducted a retrospective chart review at the University of Utah and Johns Hopkins University. We reviewed our databases for diagnoses of blepharospasm and tic disorder over the past 10 years in patients of all ages. Charts then were reviewed to confirm the diagnosis, and a questionnaire was sent to subjects whose blepharospasm had apparently begun before age 20 years. RESULTS: We identified 26 patients diagnosed with eyelid spasms that had begun while under the age of 20. We confirmed BEB in four of these cases. Of these individuals, all had developed symptoms in adolescence or before and all were still symptomatic but had noted improvement in the severity and frequency of their symptoms. CONCLUSIONS: Although rare, BEB can develop in the first decade of life, producing symptoms and signs that are similar to adults, with persistence into adulthood.

Effect of intraocular lens glistening size on visual quality.

PURPOSE: To determine whether intraocular glistenings have an impact on light scatter and visual function. SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Retrospective cohort study. METHODS: Pseudophakic patients with visual acuity no worse than 0.02 logMAR and no ocular pathology were enrolled. All had received a single-piece high-refractive-index acrylic intraocular lens (IOL). All IOLs were photographed, and glistenings were analyzed for size and density. Outcome measures included logMAR corrected distance visual acuity (CDVA), mesopic 10% contrast logMAR CDVA with and without glare, and straylight determination with a straylight meter (C Quant log). RESULTS: All 79 patients had glistenings within 2 diameter groups: 6 to 25 µm and over 25 µm. Linear regression for the nonstratified group was significant for IOL glistening size versus contrast visual acuity with glare. Linear regression for the 6 to 25 µm group was significant for a measure of severity index (%area) versus the straylight meter measurements, %area/size versus straylight meter measurements, IOL age versus CDVA, IOL age versus contrast visual acuity, and IOL age versus contrast visual acuity with glare. Linear regression for the over 25 µm group was significant for IOL age versus glistening size and %area/size versus contrast visual acuity, and density versus CDVA and contrast visual acuity with glare. CONCLUSIONS: Glistening %area, at a key size, correlated with random light scatter. The age of the IOL likely affects glistening size and visual parameters. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye.

BACKGROUND: We used in vivo corneal confocal microscopy to investigate structural differences in the sub-basal corneal nerve plexus in chronic migraine patients and a normal population. We used a validated questionnaire and tests of lacrimal function to determine the prevalence of dry eye in the same group of chronic migraine patients. Activation of the trigeminal system is involved in migraine. Corneal nociceptive sensation is mediated by trigeminal axons that synapse in the gasserian ganglion and the brainstem, and serve nociceptive, protective, and trophic functions. Noninvasive imaging of the corneal sub-basal nerve plexus is possible with in vivo corneal confocal microscopy. METHODS: For this case-control study, we recruited chronic migraine patients and compared them with a sex- and age-similar group of control subjects. Patients with peripheral neuropathy, a disease known to be associated with a peripheral neuropathy, or prior corneal or intraocular surgery were excluded. Participants underwent in vivo corneal confocal microscopy using a Heidelberg Retinal Tomography III confocal microscope with a Rostock Cornea Module. Nerve fiber length, nerve branch density, nerve fiber density, and tortuosity coefficient were measured using established methodologies. Migraine participants underwent testing of basal tear production with proparacaine, corneal sensitivity assessment with a cotton-tip applicator, measurement of tear break-up time, and completion of a validated dry eye questionnaire. RESULTS: A total of 19 chronic migraine patients and 30 control participants completed the study. There were no significant differences in age or sex. Nerve fiber density was significantly lower in migraine patients compared with controls (48.4 ± 23.5 vs. 71.0 ± 15.0 fibers/mm2 , P < .001). Nerve fiber length was decreased in the chronic migraine group compared with the control group, but this difference was not statistically significant (21.5 ± 11.8 vs. 26.8 ± 5.9 mm/mm2, P < .084). Nerve branch density was similar in the two groups (114.0 ± 92.4 vs. 118.1 ± 55.9 branches/mm2 , P < .864). Tortuosity coefficient and log tortuosity coefficient also were similar in the chronic migraine and control groups. All migraine subjects had symptoms consistent with a diagnosis of dry eye syndrome. CONCLUSIONS: We found that in the sample used in this study, the presence of structural changes in nociceptive corneal axons lends further support to the hypothesis that the trigeminal system plays a critical role in the pathogenesis of migraine. In vivo corneal confocal microscopy holds promise as a biomarker for future migraine research as well as for studies examining alterations of corneal innervation. Dry eye symptoms appear to be extremely prevalent in this population. The interrelationships between migraine, corneal nerve architecture, and dry eye will be the subject of future investigations.

Neuro-ophthalmic disorders in pregnancy.

PURPOSE OF REVIEW: This review discusses evaluation and treatment of neuro-ophthalmic disorders in the pregnant patient. RECENT FINDINGS: Any neuro-ophthalmic abnormality seen in nonpregnant women can be seen in pregnant women. Pregnancy-specific complications (preeclampsia and eclampsia) cause visual symptoms and can affect the entire visual axis. SUMMARY: Appropriate evaluation and examination is important to preserve the health and vision of the mother and prevent complications in the fetus. Evaluation should proceed in the same way for a pregnant patient as it would for a nonpregnant patient, with few exceptions. Treatment decisions may be influenced by stage of pregnancy.

Adalimumab and Non-Arteritic Anterior Ischaemic Optic Neuropathy: A Case Report.

Sequential anterior ischaemic optic neuropathy was observed in a patient treated with a tumour necrosis factor α (TNF) inhibitor, adalimumab, for ankylosing spondylitis. He developed decreased visual acuity in the right eye after 17 months of treatment. Findings showed right optic disc oedema with haemorrhages and visual field defect. Adalimumab was discontinued and vision stabilised. After restarting adalimumab, he developed optic neuropathy in the left eye. Findings showed optic disc oedema, with haemorrhages and visual field changes in the left eye. Adalimumab may be associated with optic neuropathy; providers prescribing TNF inhibitors should be aware of optic neuropathy as a potential complication.

Correlation of visual quality with satisfaction and function in a normal cohort of pseudophakic patients.

PURPOSE: To select a normal post-cataract-surgery cohort, determine visual quality parameters, and compare these parameters with self-reported satisfaction and visual function. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Retrospective cohort study. METHODS: A cohort of pseudophakic patients was selected based on uneventful surgery, good corrected visual acuity (no worse than logMAR 0.02), and lack of ocular complaints or pathology including dry-eye syndrome or posterior capsule opacification. A single-piece high-refractive-index acrylic intraocular lens, age 50 or older, and at least 1 year out from surgery were other inclusion criteria. Testing included logMAR corrected distance visual acuity (CDVA), mesopic 10% contrast logMAR CDVA with and without glare, straylight determination, Rasch-modified National Eye Institute Visual Function questionnaire 11R (NEI VF-11R), custom pseudophakic dysphotopsia survey, and overall satisfaction question. Correlations were determined between these parameters. RESULTS: Of the 2953 patients considered, 70 patients met all criteria, provided consent, and enrolled. Only pseudophakic dysphotopsia (r = -0.60; P<.0001) and the NEI VF-11R (r = -0.44; P<.0001) correlated with overall satisfaction. In addition, pseudophakic dysphotopsia correlated with the NEI VF-11R (r = 0.58; P<.0001). CONCLUSIONS: When evaluating a highly controlled population with expected high satisfaction after cataract surgery, pseudophakic dysphotopsia was clearly the only significant dissatisfier. Furthermore, dysphotopsia highly correlated with the NEI VF-11R questionnaire; thus, symptoms of dysphotopsia are also seen to have functional significance. A shortened NEI VFQ survey and satisfaction correlated strongly with the full survey.

Comparison of stromal hydration techniques for clear corneal cataract incisions: conventional hydration versus anterior stromal pocket hydration.

Anterior stromal pocket hydration was compared with conventional hydration for preventing wound leak after 2.8 mm uniplanar clear corneal incisions (CCIs) in patients having routine cataract surgery. Conventional hydration involves hydration of the lateral walls of the main incision with visible whitening of the stroma. The anterior stromal pocket hydration technique involves creation of an additional supraincisional stromal pocket overlying the main incision, which is then hydrated instead of the main incision. Sixty-six eyes of 48 patients were included in the data analysis with 33 assigned to each study group. The anterior stromal pocket hydration technique was significantly better than conventional hydration in preventing wound leak due to direct pressure on the posterior lip of the incision.

Comparison of Hanna and Hessburg-Barron trephine and punch systems using histological, anterior segment optical coherence tomography, and elliptical curve fitting models.

BACKGROUND: This study analyzes the characteristics of donor and recipient tissue preparation between the Hessburg-Barron and Hanna punch and trephine systems by using elliptical curve fitting models, light microscopy, and anterior segment optical coherence tomography (AS-OCT). METHODS: Eight millimeter Hessburg-Barron and Hanna vacuum trephines and punches were used on six cadaver globes and six corneal-scleral rims, respectively. Eccentricity data were generated using measurements from photographs of the corneal buttons and were used to generate an elliptical curve fit to calculate properties of the corneal button. The trephination angle and punch angle were measured by digital protractor software from light microscopy and AS-OCT images to evaluate the consistency with which each device cuts the cornea. RESULTS: The Hanna trephine showed a trend towards producing a more circular recipient button than the Barron trephine (ratio of major axis to minor axis), ie, 1.059 ± 0.041 versus 1.110 ± 0.027 (P = 0.147) and the Hanna punch showed a trend towards producing a more circular donor cut than the Barron punch, ie, 1.021 ± 0.022 versus 1.046 ± 0.039 (P = 0.445). The Hanna trephine was demonstrated to have a more consistent trephination angle than the Barron trephine when assessing light microscopy images, ie, ±14.39° (95% confidence interval [CI] 111.9-157.7) versus ±19.38° (95% CI 101.9-150.2, P = 0.492) and OCT images, ie, ±8.08° (95% CI 106.2-123.3) versus ±11.16° (95% CI 109.3-132.6, P = 0.306). The angle created by the Hanna punch had less variability than the Barron punch from both the light microscopy, ie, ±4.81° (95% CI 101.6-113.9) versus ±11.28° (95% CI 84.5-120.6, P = 0.295) and AS-OCT imaging, ie, ±9.96° (95% CI 95.7-116.4) versus ±14.02° (95% CI 91.8-123.7, P = 0.825). Statistical significance was not achieved. CONCLUSION: The Hanna trephine and punch may be more accurate and consistent in cutting corneal buttons than the Hessburg-Barron trephine and punch when evaluated using elliptical curve fitting models, light microscopy, and AS-OCT.

Femtosecond-assisted preparation of donor tissue for Boston type 1 keratoprosthesis.

We describe a technique for femtosecond laser-assisted preparation of donor tissue for Boston type 1 keratoprosthesis to provide accurate double punching of the donor tissue for optimized alignment in the visual axis. The technique was reproducibly performed in four donor corneas mounted in an artificial anterior chamber. This technique can provide optically centered donor tissue with smooth trephinated edges.

A fluidics comparison of Alcon Infiniti, Bausch & Lomb Stellaris, and Advanced Medical Optics Signature phacoemulsification machines.

PURPOSE: To compare three phacoemulsification machines for measurement accuracy and postocclusion surge (POS) in human cadaver eyes. DESIGN: In vitro comparisons of machine accuracy and POS. METHODS: Tip vacuum and flow were compared with machine indicated vacuum and flow. All machines were placed in two human cadaver eyes and POS was determined. RESULTS: Vacuum (% of actual) was 101.9% +/- 1.7% for Infiniti (Alcon, Fort Worth, Texas, USA), 93.2% +/- 3.9% for Stellaris (Bausch & Lomb, Rochester, New York, USA), and 107.8% +/- 4.6% for Signature (Advanced Medical Optics, Santa, Ana, California, USA; P < .0001). At 60 ml/minute flow, actual flow and unoccluded flow vacuum (UFV) was 55.8 +/- 0.4 ml/minute and 197.7 +/- 0.7 mm Hg for Infiniti, 53.5 +/- 0.0 ml/minute and 179.8 +/- 0.9 mm Hg for Stellaris, and 58.5 +/- 0.0 ml/minute and 115.1 +/- 2.3 mm Hg for Signature (P < .0001). POS in an 32-year-old eye was 0.33 +/- 0.05 mm for Infiniti, 0.16 +/- 0.06 mm for Stellaris, and 0.13 +/- 0.04 mm for Signature at 550 mm Hg, 60 cm bottle height, 45 ml/minute flow with 19-gauge tips (P < .0001 for Infiniti vs Stellaris and Signature). POS in an 81-year-old eye was 1.51 +/- 0.22 mm for Infiniti, 0.83 +/- 0.06 mm for Stellaris, 0.67 +/- 0.01 mm for Signature at 400 mm Hg vacuum, 70 cm bottle height, 40 ml/minute flow with 19-gauge tips (P < .0001). CONCLUSIONS: Machine-indicated accuracy, POS, and UFV were statistically significantly different. Signature had the lowest POS and vacuum to maintain flow. Regarding POS, Stellaris was close to Signature; regarding vacuum to maintain flow, Infiniti and Stellaris were similar. Minimizing POS and vacuum to maintain flow potentially are important in avoiding ocular damage and surgical complications.

Molecular mapping of the binding site for a blocker of hyperpolarization-activated, cyclic nucleotide-modulated pacemaker channels.

Hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels mediate rhythmic electrical activity of neural and cardiac pacemaker cells. Drugs that block these channels slow the beating rate of the heart and are used to treat angina. Here, we characterized the effect of the HCN channel blocker, ZD7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride] on HCN2 channels that were heterologously expressed in Xenopus oocytes. A site-directed mutagenesis approach was used to identify specific residues of the mouse HCN2 channel pore that interact with ZD7288. Two residues (Ala425 and Ile432) located in the S6 transmembrane domain were found to be the primary determinants for block of HCN2 channels by ZD7288. I432A mutant HCN2 channels were approximately 100-fold less sensitive to block by ZD7288. Substitution of Ile432 with more hydrophobic residues (Phe, Leu, or Val) caused only modest shifts in the IC(50) for the drug. HCN1 channels have a Val (Val390) in the equivalent position of Ile432 and are less sensitive to block by ZD7288. Accordingly, mutation of this Val390 to Ile in HCN1 increased the sensitivity of these channels to drug block. Mutation of Ala425 and Ile432 also attenuated the block of HCN2 by the more potent blocker cilobradine. An HCN2 homology model based on the bacterial KcsA K(+) channel predicts that the phenyl ring of ZD7288 occupies a hydrophobic cavity formed by Ala425 and Ile432 and that the charged ring aligns with the axis of the inner pore closely corresponding to the localization of K(+) ions observed in the KcsA crystal structure.

Neural reprogramming in retinal degeneration.

PURPOSE: Early visual defects in degenerative diseases such as retinitis pigmentosa (RP) may arise from phased remodeling of the neural retina. The authors sought to explore the functional expression of ionotropic (iGluR) and group 3, type 6 metabotropic (mGluR6) glutamate receptors in late-stage photoreceptor degeneration. METHODS: Excitation mapping with organic cations and computational molecular phenotyping were used to determine whether retinal neurons displayed functional glutamate receptor signaling in rodent models of retinal degeneration and a sample of human RP. RESULTS: After photoreceptor loss in rodent models of RP, bipolar cells lose mGluR6 and iGluR glutamate-activated currents, whereas amacrine and ganglion cells retain iGluR-mediated responsivity. Paradoxically, amacrine and ganglion cells show spontaneous iGluR signals in vivo even though bipolar cells lack glutamate-coupled depolarization mechanisms. Cone survival can rescue iGluR expression by OFF bipolar cells. In a case of human RP with cone sparing, iGluR signaling appeared intact, but the number of bipolar cells expressing functional iGluRs was double that of normal retina. CONCLUSIONS: RP triggers permanent loss of bipolar cell glutamate receptor expression, though spontaneous iGluR-mediated signaling by amacrine and ganglion cells implies that such truncated bipolar cells still release glutamate in response to some nonglutamatergic depolarization. Focal cone-sparing can preserve iGluR display by nearby bipolar cells, which may facilitate late RP photoreceptor transplantation attempts. An instance of human RP provides evidence that rod bipolar cell dendrite switching likely triggers new gene expression patterns and may impair cone pathway function.

Molecular mapping of a site for Cd2+-induced modification of human ether-à-go-go-related gene (hERG) channel activation.

Cd(2+) slows the rate of activation, accelerates the rate of deactivation and shifts the half-points of voltage-dependent activation (V(0.5,act)) and inactivation (V(0.5,inact)) of human ether-à-go-go-related gene (hERG) K(+) channels. To identify specific Cd(2+)-binding sites on the hERG channel, we mutated potential Cd(2+)-coordination residues located in the transmembrane domains or extracellular loops linking these domains, including five Cys, three His, nine Asp and eight Glu residues. Each residue was individually substituted with Ala and the resulting mutant channels heterologously expressed in Xenopus oocytes and their biophysical properties determined with standard two-microelectrode voltage-clamp technique. Cd(2+) at 0.5 mM caused a +36 mV shift of V(0.5,act) and a +18 mV shift of V(0.5,inact) in wild-type channels. Most mutant channels had a similar sensitivity to 0.5 mM Cd(2+). Mutation of single Asp residues located in the S2 (D456, D460) or S3 (D509) domains reduced the Cd(2+)-induced shift in V(0.5,act), but not V(0.5,inact). Combined mutations of two or three of these key Asp residues nearly eliminated the shift induced by 0.5 mM Cd(2+). Mutation of D456, D460 and D509 also reduced the comparatively low-affinity effects of Ca(2+) and Mg(2+) on V(0.5,act). Extracellular Cd(2+) modulates hERG channel activation by binding to a coordination site formed, at least in part, by three Asp residues.