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BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

The aim of this study was to investigate, for the first time, the effects of high-intensity interval training (HIIT) on retinal microvascular endothelial function in cardiovascular (CV) risk patients. In the randomized controlled trial, middle-aged and previously sedentary patients with increased CV risk (aged 58 ± 6 years) with ≥ two CV risk factors were randomized into a 12-week HIIT (n = 33) or control group (CG, n = 36) with standard physical activity recommendations. A blinded examiner measured retinal endothelial function by flicker light-induced maximal arteriolar (ADmax) and venular (VDmax) dilatation as well as the area under the arteriolar (AFarea) and venular (VFarea) flicker curve using a retinal vessel analyzer. Standardized assessments of CV risk factors, cardiorespiratory fitness, and retinal endothelial function were performed before and after HIIT. HIIT reduced body mass index, fat mass, and low-density lipoprotein and increased muscle mass and peak oxygen uptake (VO2peak). Both ADmax (pre: 2.7 ± 2.1%, post: 3.0 ± 2.2%, P = .018) and AFarea (pre: 32.6 ± 28.4%*s, post: 37.7 ± 30.6%*s, P = .016) increased after HIIT compared with CG (ADmax, pre: 3.2 ± 1.8%, post: 2.9 ± 1.8%, P = .254; AFarea, pre: 41.6 ± 28.5%*s, post: 37.8 ± 27.0%*s, P = .186). Venular function remained unchanged after HIIT. There was a significant association between ∆-change VO2peak and ∆-changes ADmax and AFarea (P = .026, R2 = 0.073; P = .019, R2 = 0.081, respectively). 12-weeks of HIIT improved retinal endothelial function in middle-aged patients with increased CV risk independent of the reduction in classical CV risk factors. Exercise has the potential to reverse or at least postpone progression of small vessel disease in older adults with increased CV risk under standard medication. Dynamic retinal vessel analysis seems to be a sensitive tool to detect treatment effects of exercise interventions on retinal microvascular endothelial function in middle-aged individuals with increased CV risk.

To analyze pulse wave propagation in the ocular circulation and vessel stiffness in untreated eyes of normal tension primary open-angle glaucoma (NTG) patients.Inferotemporal retinal vessels of 22 NTG eyes and 25 controls were examined with a Retinal Vessel Analyzer. Inferotemporal peripapillary retinal nerve fiber layer thickness was measured by ocular coherence tomography. Phase delay between venous trough and arterial peak was assessed at 3 sites centrifugal from the disc and a choroid-to-retina pulse delay was calculated as an estimation of vessel rigidity.There was choroid-to-retina pulse delay of 0.26±0.08, 0.30±0.11, and 0.33±0.11 seconds, respectively, in NTG eyes at proximal, middle, and distal sites; in control eyes, the corresponding values were 0.28±0.10, 0.35±0.12, and 0.40±0.17 seconds. Average choroid-to-retina pulse delay was shorter in NTG eyes (P=0.028). Retinal nerve fiber layer (inferotemporal) showed an opposite correlation with choroid-to-retina pulse delay in controls (r=-0.48, P=0.019) and in NTG eyes (r=0.47, P=0.032 ).Untreated NTG eyes show stiffer retinal vessels. Vessel rigidity correlates with level of glaucomatous damage.

To analyse a response to the therapy switch from the concomitant application of beta-blocker and topical carbonic anhydrase inhibitor to the fixed combination of timolol and dorzolamide (Cosopt) in glaucoma/ocular hypertensive patients under everyday, office-practice conditions.The data source was a survey among practising ophthalmologists in Switzerland assessing their experience with glaucoma patients/ocular hypertensives put for the first time on the fixed combination of timolol and dorzolamide. A total of 98 patients underwent the therapy switch in at least one eye. The intraocular pressure (IOP) change between the baseline visit before switch to the timolol-dorzolamide fixed combination occurred, and the first follow-up control after the switch, served as an indicator of compliance.The IOP decreased on average from 19.43 +/- 5.64 mmHg to 17.97 +/- 3.58 mmHg (p0.01). The time to the follow-up visit ranged from 4 to 354 days, and the magnitude of IOP change demonstrated a significant dependence on the time to the follow-up visit, also when corrected for baseline IOP level. A total of 87 (85.3%) continued on the timolol-dorzolamide fixed combination therapy after the first control visit. In 68 of these 98 patients the contralateral eyes underwent the same therapy switch, and their IOP followed an identical pattern of behaviour.The average IOP decrease of 1.5 mmHg upon therapy switch to the timolol-dorzolamide fixed combination suggests a better efficacy due to improved compliance. Short-term compliance benefit seems to be more pronounced. The high timolol-dorzolamide fixed combination therapy continuation rate reflects an improvement in compliance and subjectively-perceived convenience.

To investigate the choroidal hemodynamic effects of losartan potassium, a specific angiotensin II subtype AT1 receptor antagonist.In this prospective, randomized, observer-masked, open-label placebo-controlled (lactose), two-period crossover study, the choroidal hemodynamic effects of a single oral 50-mg dose of losartan potassium were evaluated in 12 healthy subjects using choroidal laser Doppler flowmetry.Perfusion pressure and the choroidal laser Doppler flowmetry parameters velocity, volume, and flux did not vary significantly compared with placebo (P = 0.33, 0.31, 0.74, and 0.61, respectively). Correcting choroidal laser Doppler flowmetry parameters for perfusion pressure in a covariance analysis did not change these results.A single oral 50-mg dose of the angiotensin II AT1 receptor antagonist losartan potassium given does not disturb the homeostasis of ocular perfusion pressure or choroidal blood flow in young healthy subjects.

PURPOSE: To evaluate the relationship between the circadian blood pressure rhythm and the retrobulbar blood flow in glaucoma patients. DESIGN: Cross-sectional study. METHODS: Circadian blood pressure measurements and color Doppler imaging (CDI) in the ophthalmic artery as well as the central retinal artery of one randomly selected eye were obtained in 193 primary open-angle glaucoma patients. CDI parameters were compared by means of analysis of covariance between patients with a nocturnal decrease in mean systemic blood pressure (MBP) below 20% of the average daytime MBP (over-dippers), patients with a decrease between 10% to 20% (dippers), and patients with a decrease of less than 10% (nondippers), using age, intraocular pressure (IOP), and MBP during color Doppler measurement as covariates. RESULTS: An analysis of covariance disclosed, after correcting for age, IOP, and MBP during color Doppler imaging, a significantly lower EDV ( P = .0096) and a significantly higher RI ( P = .033) in the central artery of over-dipping glaucoma patients compared with nondippers or dippers. This effect seemed independent of the use of vasoactive drugs. CONCLUSIONS: Glaucoma patients with a marked drop in nocturnal systemic blood pressure seem to have altered retrobulbar blood flow parameters, suggesting that an abnormal systemic blood pressure profile may be the manifestation of some kind of systemic vascular dysregulation relevant for the ocular circulation.

PURPOSE To evaluate the effect of 0.5% timolol maleate on the capillary circulation of the anterior optic nerve head in patients with primary open-angle glaucoma and to compare the results with those obtained in a healthy control group. PATIENTS AND METHODS Twelve patients with nonprogressive glaucoma and 12 age- and sex-matched healthy volunteers were included in this prospective study. Optic nerve head perfusion was examined by the Heidelberg Retina Flowmeter (HRF) in both groups. A 3-week washout period preceded the baseline measurement in the glaucoma group, and ONH blood flow was assessed again after 3 weeks of bilateral topical timolol treatment and 2 hours after timolol application. RESULTS Intraocular pressure decreased significantly with timolol (P < 0.001). The HRF flow values for patients with glaucoma were comparable to those for a control group at baseline (P = 0.25), 3 weeks after timolol therapy (P = 0.09), and 2 hours after timolol instillation (P = 0.15). The glaucoma group showed no statistically significant change in the HRF parameter flow as compared with baseline, either after 3 weeks of timolol treatment or 2 hours after timolol instillation (P = 0.40). The heart rate and arterial systolic and diastolic blood pressure values showed no alteration after timolol therapy. CONCLUSIONS Patients with nonprogressive glaucoma seem not to have an altered optic nerve blood flow as assessed by the HRF, and timolol treatment does not seem to alter the latter blood flow parameter in such patients.

OBJECTIVE: To assess the impact of fingolimod (FTY720) therapy on magnetic resonance imaging measures of inflammatory activity and tissue damage in patients participating in a 2-year, placebo-controlled, phase 3 study. DESIGN: Patients with active relapsing-remitting multiple sclerosis were randomized to receive fingolimod, 0.5 mg; fingolimod, 1.25 mg; or placebo for 2 years. Standardized magnetic resonance imaging scans were obtained at months 0, 6, 12, and 24 and centrally evaluated for number and volume of T1 gadolinium-enhancing, T2 hyperintense, and T1 hypointense lesions and for percentage of brain volume change. Findings were compared across subgroups by treatment and baseline characteristics. SETTING: Worldwide, multicenter clinical trial. PATIENTS: Patients were part of the fingolimod FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial for relapsing-remitting multiple sclerosis (N=1272). MAIN OUTCOME MEASURES: We measured the effect of therapy on acute inflammatory activity, burden of disease, and irreversible loss of brain volume. RESULTS: Fingolimod therapy resulted in rapid and sustained reductions in inflammatory lesion activity as assessed by gadolinium-enhancing and new/newly enlarged T2 lesions after 6, 12, and 24 months of therapy (P.001, all comparisons vs placebo). Changes in T2 hyperintense and T1 hypointense lesion volume also significantly favored fingolimod (P.05, all comparisons). Fingolimod, 0.5 mg (licensed dose), significantly reduced brain volume loss during months 0 to 6, 0 to 12, 12 to 24, and 0 to 24 (P.05, all comparisons) vs placebo, and subgroup analyses confirmed these effects over 2 years irrespective of the presence/absence of gadolinium-enhancing lesions, T2 lesion load, previous treatment status, or level of disability. CONCLUSION: These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00289978 clinical trial, phase iii journal article multicenter study randomized controlled trial research support, non-u.s. gov't 2012 Oct imported

Devonshire, Virginia Havrdova, Eva Radue, Ernst Wilhelm O'Connor, Paul Zhang-Auberson, Lixin Agoropoulou, Catherine Haring, Dieter Adrian Francis, Gordon Kappos, Ludwig FREEDOMS study group Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't England Lancet neurology Lancet Neurol. 2012 May;11(5):420-8. doi: 10.1016/S1474-4422(12)70056-X. Epub 2012 Apr 10.; BACKGROUND: Fingolimod 0.5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics. METHODS: We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0.5 mg or 1.25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978. FINDINGS: Treatment with fingolimod 0.5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0.76 (95% CI 0.54-1.09; p=0.13) in patients aged over 40 years to 0.29 (0.16-0.52; p

PURPOSE To measure the oscillation phase delay between retinal arterioles and venules in order to analyze pulse wave propagation in the ocular circulation of vasospastic and nonvasospastic subjects and a change thereof during the cold pressor test in another group of healthy subjects. METHODS Twenty-four young, healthy women, 12 vasospastic and 12 nonvasospastic, were analyzed. A retinal vessel analyzer was used to obtain 1-minute recordings of the ocular fundus. A phase delay between the arteriole and venule pulsations was assessed at three sites, one (proximal) in the close retinal vicinity of the disc, one (middle) 1 to 2 disc diameters away from the disc, and a third (distal) 3 to 4 disc diameters away from the disc; and, assuming that venules are counterphased to the choroidal circulation, a choroid-to-retina pulse delay was calculated. In addition, the change in these parameters was analyzed during the modified cold-pressor test in 10 healthy subjects (five women, five men). RESULTS Pulse oscillations in arterioles led those in venules by 95.0 degrees +/- 39.0 degrees , 60.5 degrees +/- 57.5 degrees , and 47.5 degrees +/- 64.0 degrees in vasospastic subjects, and 76.0 degrees +/- 58.0 degrees , 31.5 degrees +/- 60.0 degrees , and 2.5 degrees +/- 80.5 degrees in nonvasospastic subjects in the proximal, middle, and distal measuring sites, respectively. Calculated choroid-to-retina pulse delays in vasospastic subjects were 0.20 +/- 0.10, 0.28 +/- 0.14, and 0.30 +/- 0.11 seconds and in nonvasospastic subjects 0.25 +/- 0.15, 0.35 +/- 0.11, and 0.43 +/- 0.2 seconds at the proximal, middle, and distal measuring sites, respectively. The difference was significant between vasospastic and nonvasospastic subjects (P = 0.033) and among the measuring sites (P = 0.0023). During exposure to cold, the choroid-to-retina pulse delays changed from 0.31 +/- 0.08, 0.40 +/- 0.16, and 0.51 +/- 0.26 seconds to 0.26 +/- 0.12, 0.30 +/- 0.10, and 0.33 +/- 0.14 seconds at the proximal, middle, and distal measuring sites, respectively (P = 0.024 for the change from baseline to cold exposure, and P = 0.022 for measuring sites). CONCLUSIONS Retinal vessels in vasospastic subjects demonstrate an altered pattern of oscillation phase delay between arterioles and venules. Vessels in vasospastic subjects seem to conduct pulse waves faster and are thus stiffer than those in nonvasospastic subjects. The pattern of oscillation demonstrates changes during the cold pressor test in healthy subjects, indicating faster pulse-wave propagation.

Aims: To investigate the source of ocular blood flow alterations in glaucoma. Methods: In 56 patients with open angle glaucoma, blood flow parameters were obtained from both eyes in the ophthalmic and central retinal artery by means of colour Doppler imaging, as well as in the choroidal circulation and the neuroretinal rim of the optic nerve by means of laser Doppler flowmetry. Based on these haemodynamic parameters, a cluster analysis (two groups) was performed and differences with regard to risk factors were assessed between clusters. Results: Ocular blood flow data in the two clusters indicated that the two groups (cluster 1 = 26 patient with higher blood flow values; cluster 2 = 30 patients with lower blood flow values) differed mainly in choroidal and optic nerve blood flow. No differences in sex distribution, propensity to have normal tension glaucoma, age, endothelin-1 plasma levels, visual field damage, intraocular pressure, or systemic blood pressure parameters were observed between the two clusters. However, 12 patients (46%) from the cluster with high ocular blood flow values showed a vasospastic response in nailfold capillaroscopy, while such a response was observed in 24 patients (80%) of the cluster with low ocular blood flow values. This difference in vasospastic propensity was statistically significant (p = 0.0121). Conclusions: Ocular blood flow alterations in glaucoma patients seem, at least partly, to be related to a systemic vascular dysregulation.

Purpose To assess the impact of vascular dysregulation on choroidal blood flow response to the hand-grip test and the relevance of this response to glaucoma. Methods Eighty healthy volunteers underwent a hand-grip test while choroidal blood flow was measured by means of laser Doppler flowmetry. Blood pressure, heart rate, and intraocular pressure (IOP) were monitored. Choroidal blood flow changes were compared between subjects with a positive history of cold hands and control subjects by means of analysis of variance. The relationship of the vascular response to the level of IOP at which progressive damage occurred was analyzed in 21 patients with primary open-angle glaucoma who had progressive damage despite normal or normalized IOP. Results Blood pressure and heart rate increased and IOP decreased in response to a hand-grip test. Healthy subjects with a positive history of cold hands (n = 36) demonstrated a decrease in choroidal blood flow during the hand-grip test (mean +/- SD: 13.5 +/- 5.8, 12.2 +/- 6.8, and 13.4 +/- 6.9 AU, at baseline, during the test, and 3 minutes after release, respectively), whereas control subjects (n = 44) demonstrated an inverse (12.5 +/- 8.3, 13.7 +/- 9.4, and 11.9 +/- 7.1 AU, respectively) response pattern (P = 0.039). Glaucoma patients with a decrease of at least 10% in choroidal blood flow during the hand-grip test had lower IOP (14.67 +/- 3.83 and 13.50 +/- 2.59 mm Hg in the right and the left eyes, respectively) compared (P = 0.032) with those without such a decrease (16.54 +/- 3.85 and 16.92 +/- 2.95 mm Hg in the right and the left eyes, respectively). Conclusions A hand-grip test elicits a different blood flow response in subjects with vasospasm compared with control subjects. Damage by glaucoma in patients with a decrease in choroidal blood flow during a hand-grip test may progress at a relatively lower IOP.

To assess the variability in choroidal laser Doppler flowmetry (LDF).Five measurements of choroidal blood flow were obtained on 5 days in both eyes of 10 subjects. Reliability, sensitivity, and sample size calculations were performed. Yield, the intensity of the returning light (direct current [DC]) divided by the signal amplification (gain) used during recording, was calculated (yield = DC/gain). The correlation between yield and the LDF parameters velocity, volume, and flux was analyzed. Reliability, sensitivity, and sample size calculations were repeated after correcting for this relationship. The influence of different light-scattering properties on the returning signal was assessed in a model eye.Yield and the LDF parameters, velocity, volume, and flux, correlated significantly in a regression model. After the influence of yield was partialized out, reliability, reproducibility, sensitivity, and statistical power improved markedly. The high reliability of yield in a given eye (87%) suggests, that, besides varying recording settings on different days, individual specific scattering properties within the eye influence LDF measurements. Comparison of model eye data with human data disclosed a low signal-to-noise ratio with decreasing yield. Correcting for yield did not affect the sensitivity to blood flow changes induced by hypercapnia or a suction cup.Tissue-scattering properties alter the characteristics of the returning light, and recording settings affect the outcome of the analysis of the returning light during LDF measurements. Partializing out the influence of yield markedly improves the reproducibility of choroidal LDF.

Purpose: To assess sex difference and parameters possibly accounting for such a difference in healthy subjects evaluated by means of the Langham Ocular Blood Flow (OBF) System. Methods: Pulse amplitude of intraocular pressure (IOP) and pulsatile ocular blood flow (POBF) as measured with the Langham OBF System were assessed in 86 healthy men and 69 healthy women. Results: Compared to men, women showed higher POBF (mean ± SD: 722.6 ± 152.8 versus 647.8 ± 164.9 μL/min; P = .0056) and pulse amplitude (mean ± SD: 2.3 ± 0.7 versus 2.0 ± 0.6 mm Hg; P = .0043) values. Sex difference was still significant after correcting for age, refraction, blood pressure, IOP, and pulse rate. Pulse amplitude correlated negatively with pulse rate, and POBF correlated negatively with IOP. Women had higher readings in pulse amplitude and POBF, even after correcting for age, refraction, IOP, blood pressure, and pulse rate. Conclusions: While using the Langham OBF System, one needs to be aware of sex difference that is independent of other hemodynamic parameters. How the observed difference in POBF is related to ocular blood flow, and how it might influence the preponderance of various ocular diseases in men or women remains to be clarified.

PURPOSE: To evaluate the relationship between ocular perfusion pressure and color Doppler measurements in patients with glaucoma. MATERIALS AND METHODS: Twenty patients with primary open-angle glaucoma with visual field deterioration in spite of an intraocular pressure lowered below 21 mm Hg, 20 age-matched patients with glaucoma with stable visual fields, and 20 age-matched healthy controls were recruited. After a 20-minute rest in a supine position, intraocular pressure and color Doppler measurements parameters of the ophthalmic artery and the central retinal artery were obtained. Correlations between mean ocular perfusion pressure and color Doppler measurements parameters were determined. RESULTS: Patients with glaucoma showed a higher intraocular pressure (P

To test the interocular differences in optic disc topography in normal subjects by means of confocal scanning laser ophthalmoscopy.Topographic measurements of the optic disc were evaluated by means of confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph) in 314 eyes of 157 healthy volunteers. The examination was started randomly either with the right eye or the left eye. Differences between right and left eyes in disc area, cup area, cup volume, cup/disc area ratio, rim area, rim volume, maximum cup depth, cup shape measure, retinal nerve fiber layer thickness, and retinal nerve fiber cross section area for 360 degrees and for the temporal and nasal regions of the optic nerve head were evaluated by means of Student t-test. The same parameters were assessed in a subgroup of 80 elderly (age50 years) healthy subjects. Holm's sequentially rejective method was used for significance correction of multiple comparisons.Significant interocular differences in the average retinal nerve fiber layer thickness (p = 0.0010) and retinal nerve fiber layer cross section area (p = 0.0036) were found, with the right eye showing, on the average, lower values. The left eye showed a larger retinal nerve fiber layer thickness in 94 subjects (59.87%) and a larger retinal nerve fiber cross section area in 101 subjects (64. 33%). In the temporal optic disc area there were no statistically significant differences in topometric data (p0.05). In the nasal area, significant interocular differences in the retinal nerve fiber layer thickness (p = 0.0002) and retinal nerve fiber layer cross section area (p = 0.0003) were found. Similar results were found when the group of subjects older than 50 years was considered.This study demonstrates systematic interocular differences in optic disc topometric data. Such a finding, be it due to methodological or biological reasons, should be taken in consideration in clinical trials.

Objective To evaluate normal choroidal blood flow and its relationship with various factors such as age, systemic blood pressure, and intraocular pressure (IOP). Methods A total of 70 healthy subjects were recruited. Choroidal blood flow was assessed using a method based on laser Doppler flowmetry (LDF) technique. The LDF parameters of velocity, volume, and flux were obtained. The influence of age, mean systemic blood pressure, IOP, smoking, and sex on choroidal hemodynamic parameters was assessed in a multiple linear regression model. The correlations between interocular difference in IOP and interocular differences in the LDF parameters were assessed by means of the Pearson linear correlation factor. Results Velocity decreased significantly ( P = .03) with advancing age of the subjects and volume increased significantly ( P = .02) with increasing IOP. Mean blood pressure, smoking, and sex had no influence on the choroidal LDF parameters. Interocular difference in IOP correlated significantly with interocular difference in volume ( R = 0.34, P Conclusion Choroidal blood flow velocity decreased with increasing age of the subjects, while the volume of moving erythrocytes decreased with lower IOP.

To evaluate the correlation of blood-flow velocities in the ophthalmic artery and corneal temperature in normal subjects and glaucoma patients.Corneal temperature was measured on both eyes by means of the THI-500 non-contact infrared thermometer in 18 healthy volunteers and in 18 age and sex matched open-angle glaucoma patients. In these subjects, blood flow velocity was assessed by means of color Doppler imaging (CDI) in both ophthalmic arteries. Peak systolic velocity (PSV), end diastolic velocity (EDV), and resistivity index (RI = [(PSV-EDV)/ PSV]) were computed.Corneal temperature values correlated positively with the ipsilateral values of EDV (R(2) = 0.13, p = 0.028, and R(2) = 0.16, p = 0.017 in the left and the right eyes respectively) and negatively with the ipsilateral values of RI (R(2) = 0.11, p = 0.046 and R(2 ) = 0.11, p = 0.044 in the left and the right eyes respectively) in the ophthalmic artery. In addition, the interocular difference in corneal temperature values were significantly correlated positively with the difference in EDV(R( 2) = 0.30, p = 0. 0005) and negatively with the difference in RI (R( 2) = 0.20; p: 0. 0056). All regression models were statistically comparable between normals and glaucoma patients, as well as between right eyes and left eyes. PSV did not contribute to corneal temperature.The present study suggests that retrobulbar hemodynamics influence corneal temperature, and that this relationship is comparable in normal subjects and glaucoma patients.

The etiology of glaucoma is most probably multifactorial. This study intended to investigate the asymmetry in intraocular pressure (IOP) and that in retinal nerve fiber layer (RNFL) thickness in normal-tension glaucoma patients. Two diurnal tension curves, obtained within 3 months and counting at least five IOP readings each, including an early morning IOP measurement upon awaking, were obtained in 15 normal-tension glaucoma patients. None of the patients received IOP-lowering therapy. IOP asymmetry was present in at least three readings and was always in the same direction. The optic nerve was imaged in both eyes in each patient by means of confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph). The interocular difference in RNFL thickness and the RNFL cross-sectional area were correlated with the interocular difference in IOP by means of Spearman’s rank correlation factor. Nine female and 6 male normal-tension glaucoma patients (mean ± SD age was 62.4 ± 16.9 years) were included in this study. Interocular IOP asymmetry varied between 0.30 and 4 mm Hg. Strong negative correlations were found between interocular asymmetry in IOP and interocular asymmetry in RNFL thickness asymmetry (R = –0.652, p = 0.0083) and interocular asymmetry in RNFL cross-sectional area (R = –0.702, p = 0.0034). The present results demonstrate for the first time a more marked thinning of the neuroretinal nerve fiber layer in the eye with the higher IOP in normal-tension glaucoma patients.

PURPOSE To investigate the response of the optic nerve head and the choroidal circulation to blood gas perturbations in otherwise healthy subjects with a history of cold hands. METHODS Thirty-five healthy subjects were selected and grouped according to the related history of cold hands. All 12 selected male subjects, aged 21 to 38 years (mean +/- SD = 28 +/- 5.2 years) had a negative history of cold hands. Female subjects were almost equally divided between the groups with a negative (11 subjects, aged 18-36 years; mean, 25.7 +/- 5.5) or positive (12 subjects, aged 19-45 years; mean, 25 +/- 6.8) history of cold hands. Blood gas perturbations were created by having subjects breath a gas mixture consisting of 21% O(2), 74% N(2), and 5% CO(2). The partial pressures pCO(2) and pO(2) were continuously monitored transcutaneously. Choroidal and optic nerve head blood flow response was evaluated by means of laser Doppler flowmetry. RESULTS Systolic and diastolic blood pressure (SBP/DBP at baseline, three-group average: 111.2/71.9 mm Hg), heart rate (HR; 70.3 bpm), and intraocular pressure (IOP; 14.7 mm Hg) increased during the blood gas perturbation phase (123.1/77.7 mm Hg, 78.5 bpm, and 15.6 mm Hg, respectively) and returned to baseline in the recovery phase (109.9/73.4 mm Hg, 69.5 bpm, and 13.5 mm Hg, respectively). There was no difference between groups (one-way ANOVA of the percentage change from baseline for SBP, P = 0.75; DBP, P = 0.36; HR, P = 0.95; and IOP, P = 0.72). pCO(2) increased from 5.52 to 6.59 kPa and returned to 5.50 kPa. pO(2) increased from 10.64 to 13.12 kPa and returned to 10.73 kPa. Again, there was no difference between groups (one-way ANOVA for the percentage change: pCO(2), P = 0.17; pO(2), P = 0.78). In the women with vasospasm, optic nerve head blood flow increased 17.1% and the choroidal blood flow decreased -3.6%, whereas in the women and men without vasospasm the optic nerve head blood flow decreased -5.8% and -4.8%, and the choroidal blood flow increased 13.3% and 18.3%, respectively (two-way ANOVA interaction; P = 0.001). CONCLUSIONS The pCO(2) increase was accompanied by a pO(2) increase. Blood pressure and HR increased comparably in all groups, indicating sympathetic arousal. The women with vasospasm demonstrated an inverse response pattern of choroidal and optic nerve head circulation to blood gas perturbation compared with the women without vasospasm and compared with the men.

To assess the relationship between ocular perfusion pressure and blood flow in the choroid in subjects with acral vasospasm.Twenty otherwise healthy subjects with acral vascular dysregulation and 55 age-matched nonvasospastic healthy volunteers were recruited. After a 20-minute rest in a sitting position, intraocular pressure and choroidal blood flow were determined by means of applanation tonometry and choroidal laser Doppler flowmetry, respectively. The laser Doppler flowmetry variables velocity, volume, and flux were assessed. The correlations between mean ocular perfusion pressure ([23 x [(23 x diastolic blood pressure) + (13 x systolic blood pressure)]] -intraocular pressure) and blood flow measures were determined by means of the Pearson linear correlation factor. The t test was used to evaluate differences between normal subjects and patients with vasospasm.Apart from a slight difference in systolic blood pressure (mean +/- SD, 113.70 +/- 11.88 mm Hg in the vasospastic group and 121.09 +/- 14.58 mm Hg in the control group; P =.05), the 2 study groups were completely comparable. Velocity and flux correlated significantly with the mean ocular perfusion pressure (r = 0.76, P.001; r = 0.64, P =.002, respectively) in vasospastic subjects. Such correlations did not occur in the control group, and the difference between vasospastic patients and control subjects with regard to these correlations was statistically significant (P.001 and P =.003, respectively).Choroidal blood flow seems, to some degree, to be independent of perfusion pressure, but not in subjects with acral vasospasm.

Objective To assess the relation between ocular perfusion pressure and blood flow velocity in the central retinal artery in patients with acral vasospasm. Subjects and Methods Eighteen otherwise healthy subjects with acral vascular dysregulation, as demonstrated by nail-fold capillaroscopy, and 18 age- and sex-matched healthy volunteers without vasospasm were recruited. After subjects had rested for 20 minutes in a supine position, intraocular pressure and blood flow velocity in the central retinal artery were determined by applanation tonometry and color Doppler imaging, respectively. The peak systolic velocity, end-diastolic velocity, and resistivity index were assessed. Correlations between the mean ocular perfusion pressure (2/3×[2/3×diastolic blood pressure+1/3×systolic blood pressure]−intraocular pressure) and blood flow velocities in the central retinal artery were determined by the Pearson linear correlation factor. The Studentttest was used to evaluate differences between controls and subjects with vasospasm. Results The mean±SD ocular perfusion pressure was 42.0±7.4 mm Hg in the group with vasospasm and 47.1±6.5 mm Hg in the control group (P=.04). In the subjects with vasospasm, the peak systolic and end-diastolic velocities and the resistivity index of the central retinal artery correlated significantly with the mean ocular perfusion pressure (R=0.49,P=.04;R=0.58,P=.01; andR=−0.67,P=.002, respectively). Such correlations were not found in the control group. Conclusion An altered blood flow regulation is suggested in the ocular circulation of patients with acral vasospasm.