[Retinal OCT biomarkers and neurodegenerative diseases of the central nervous system beyond Alzheimer's disease]. / Retinale OCT-Biomarker und neurodegenerative Erkrankungen des zentralen Nervensystems jenseits der Alzheimer-Krankheit.

BACKGROUND: Optical coherence tomography (OCT) biomarkers are increasingly used by neurologists, psychiatrists, and ophthalmologists for the diagnosis, prognosis, and follow-up of neurodegenerative diseases. Long-term data on OCT biomarkers of selected primary and secondary neurodegenerative diseases of the central nervous system (CNS), such as multiple sclerosis (MS) or Parkinson's disease, are already available in part. In addition, there are rare neurodegenerative diseases with early disease onset that may show OCT abnormalities. METHODS: A literature review on the association of OCT biomarkers with neurodegenerative diseases of the CNS beyond Alzheimer's disease is presented. Parkinson's disease, MS, Friedreich's ataxia, Huntington's disease, spinocerebellar ataxia, and lysosomal storage diseases are addressed. RESULTS: Relevant OCT biomarkers of neurodegenerative diseases are the macular ganglion cell inner plexiform layer (GCIPL) and the peripapillary retinal nerve fiber layer (pRNFL) thickness. Different sectors may be affected depending on the disease entity in addition to global pRFNL reduction. OCT­angiography (OCT-A) is also increasingly used as a biomarker in neurodegenerative diseases. CONCLUSION: Optical coherence tomography biomarkers are used in an interdisciplinary context. Retinal pathologies should be excluded by an ophthalmologist. While OCT biomarkers are increasingly used clinically in MS, the benefit in other neurodegenerative diseases, especially the rare ones, is less well documented. Further longitudinal studies are required.

Distribution of Pupil Size and Associated Factors: Results from the Population-Based Gutenberg Health Study.

Results: 18,335 eyes of 9,559 participants aged 40 to 80 years were included in the analysis. Median pupil diameter was 4.19 mm in right eyes and 4.12 mm in left eyes. A smaller pupil was associated with older age, hyperopic refractive error, previous cataract surgery, diabetes, obesity, and ACE inhibitor intake, whereas wider pupil was associated with female gender, arterial hypertension, intake of tricyclic antidepressants, and intake of SNRI and tetracyclic antidepressants. Socioeconomic status and smoking were not associated with pupil size. Conclusion: Individuals of older age, after cataract surgery, under therapy with ACE inhibitors and with diabetes have a smaller pupil. This should be taken into account when planning nonmydriatic fundus photography-based screening programs, for instance, for diabetic retinopathy.

Five-Year Cumulative Incidence and Progression of Myopic Maculopathy in a German Population.

PURPOSE: To investigate the 5-year cumulative incidence and progression of myopic maculopathy in the general population in Germany and to analyze potential risk factors. DESIGN: The Gutenberg Health Study (GHS) is a population-based cohort study including 15 010 participants aged 35 to 74 years at baseline. PARTICIPANTS: A total of 494 eyes of 323 participants (mean age, 50.2 ± 9.2 years; median, -7.25 diopters [D] myopic refractive error) without myopic maculopathy at baseline and 34 eyes of 27 subjects (mean age, 56.7 ± 9.1 years; median, -8.75 D myopic refractive error) with myopic maculopathy met the inclusion conditions, phakic eyes with spherical equivalent ≤-6 D (baseline), and had gradable fundus photographs at baseline and 5-year follow-up. METHODS: Myopic maculopathy incidence and progression were assessed by grading of fundus photographs according to a recent international photographic classification system (META-PM). Multivariable logistic regression analysis was used to assess risk factors for progression of myopic maculopathy. MAIN OUTCOME MEASURES: Estimates for incidence and progression of myopic maculopathy. RESULTS: The 5-year cumulative incidence of myopic maculopathy was 0.3% (95% confidence interval [CI], 0.02-1.99; n = 1). Progression occurred in 17 of 34 eyes (50%) with prior myopic maculopathy over 5 years with 4 changes in category. The most common types of progression were enlargement of diffuse and patchy chorioretinal atrophy; a new pathology was present in 8 eyes. Higher intraocular pressure (IOP) (odds ratio [OR], 1.62; 95% CI, 1.51-1.59; P = 0.035) was associated with progression of myopic maculopathy. Female gender (OR, 5.54; 95% CI, 0.93-32.92; P = 0.060) and higher myopic refractive error (OR, 1.62 per diopter; 95% CI, 0.99-1.49; P = 0.063) showed a tendency toward progression. CONCLUSIONS: Incidence of myopic maculopathy is rare in highly myopic eyes in the general population aged 35 to 74 years in Germany. Progression of myopic maculopathy in the German population occurred in 50% of highly myopic eyes. We presented population-based 5-year follow-up data on incidence and progression of myopic maculopathy in Europe.

Retinal thinning in phenylketonuria and Gaucher disease type 3.

PURPOSE: Retinal alterations in inherited metabolic diseases associated with neurodegeneration are poorly studied. The objective was to study retinal thickness, specifically the components of the ganglion cell complex (GCC)-nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)-using spectral-domain optical coherence tomography (SD-OCT) in two different diseases with potential dopaminergic depletion, phenylketonuria (PKU) and Gaucher disease type 3 (GD3). METHODS: Retinal layers in 19 patients with PKU, 15 patients with GD3, and 93 healthy individuals were measured using peripapillary ring scan and macular SD-OCT. Linear mixed models were computed including an adjustment for age, sex, and spherical equivalent. We calculated Spearman's rank correlations between retinal layer measurements and clinical and/or laboratory parameters. RESULTS: Thinning of total retinal thickness was found in the macular inner ring (p = 0.002), and outer ring (p = 0.012), sparing the fovea (p = 0.12) in PKU, while in GD3, all subfields were thinned (fovea p < 0.001, inner ring p = 0.047, outer ring 0.07). In both conditions, thinning was most evident in the NFL, GCL, and IPL, while OPL (outer plexiform layer) was thickened. Peripapillary retinal nerve fiber layer measurements remained normal. GCL and IPL in PKU correlated with tyrosine serum concentration. CONCLUSION: Thinning of the NFL, GCL, and IPL, with thickened OPL, are both found in PKU and in GD3. Low dopamine concentrations in the retina might promote these effects. However, these data do not give evidence that retinal measurements can be used as a biomarker for disease severity in patients with GD3.

Impact of intraocular pressure fluctuations on progression of normal tension glaucoma.

AIM: To investigate short- and long-term intraocular pressure (IOP) fluctuations and further ocular and demographic parameters as predictors for normal tension glaucoma (NTG) progression. METHODS: This retrospective, longitudinal cohort study included 137 eyes of 75 patients with NTG, defined by glaucomatous optic disc or visual field defect with normal IOP (<21 mm Hg), independently from therapy regimen. IOP fluctuation, mean, and maximum were inspected with a mean follow-up of 38mo [standard deviation (SD) 18mo]. Inclusion criteria were the performance of minimum two 48-hour profiles including perimetry, Heidelberg retina tomograph (HRT) imaging, and optic disc photographs. The impact of IOP parameters, myopia, sex, cup-to-disc-ratio, and visual field results on progression of NTG were analyzed using Cox regression models. A sub-group analysis with results from optical coherence tomography (OCT) was performed. RESULTS: IOP fluctuations, average, and maximum were not risk factors for progression in NTG patients, although maximum IOP at the initial IOP profile was higher in eyes with progression than in eyes without progression (P=0.054). The 46/137 (33.5%) eyes progressed over the follow-up period. Overall progression (at least three progression confirmations) occurred in 28/137 eyes (20.4%). Most progressions were detected by perimetry (36/46). Long-term IOP mean over all pressure profiles was 12.8 mm Hg (SD 1.3 mm Hg); IOP fluctuation was 1.4 mm Hg (SD 0.8 mm Hg). The progression-free five-year rate was 58.2% (SD 6.5%). CONCLUSION: Short- and long-term IOP fluctuations do not result in progression of NTG. As functional changes are most likely to happen, NTG should be monitored with visual field testing more often than with other devices.

Vertical saccadic palsy and foveal retinal thinning in Niemann-Pick disease type C.

INTRODUCTION: Niemann-Pick type C (NPC) is a lysosomal storage disease that is progressive and life-limiting, with an estimated incidence of 1:120,000 live births. In addition to systemic manifestation with (hepato-)splenomegaly, there are a number of neurological manifestations (ataxia, dysarthria, dementia, cataplexy, epileptic seizures, and psychiatric disorders). Characteristic is vertical supranuclear gaze palsy, which is often overlooked. Early diagnosis and start of therapy improve quality of life. This study aimed to characterize oculomotor dysfunction of NPC patients, and to provide ophthalmologic data including retinal imaging. METHODS: Eighteen patients with biochemically or genetically diagnosed NPC completed oculomotor and ophthalmologic examination. Ten of them performed saccadometry by infrared based video-oculography. Saccadic parameters were compared to 100 healthy controls, and were correlated with clinical variables. Another subgroup of eight patients received optical coherence tomography (OCT) of the optic disc and the macula, of which the segmented layers were analysed using a crude linear mixed model, and one adjusted for age, sex, and spherical equivalent. RESULTS: Saccadometry revealed slowed peak velocity compared to controls most evident vertically. Peak velocity correlated negatively with SARA-Score, but correlation with clinical assessment of saccades was not significant. Clinical features in the assessment of vertical saccades were intensive blinking and head movements to initiate gaze changes, and lateral trajectory of the eyes. Macular OCT revealed significant total retinal thinning in the fovea, specifically of the outer nuclear layer and outer retinal layer. Para- and perifoveal retinal thicknesses, as well as peripapillary retinal nerve fibre layer were normal. CONCLUSIONS: Foveal thinning was revealed in NPC. It remains to be shown, whether OCT will prove to be useful to monitor progression. Saccadic impairment reflects CNS involvement and therefore is a parameter to demonstrate the progression of NPC, and potentially also the efficacy of new therapies. Saccadometry, in contrast to clinical investigation, allows the precise evaluation of saccades.

Brimonidine-associated uveitis - a descriptive case series.

BACKGROUND: Anterior uveitis secondary to topical brimonidine administration is rare and not well-defined. In glaucoma patients using brimonidine, one must consider this phenomenon to avoid mis-diagnosis and over-treatment with topical steroids which in turn may increase intraocular pressure (IOP). This is the largest case series including the longest patient follow-up in the current literature. METHODS: Sixteen patients (26 eyes) with consultant diagnosed brimonidine-associated anterior uveitis in a tertiary referral glaucoma clinic presenting between 2015 and 2019 were included in this retrospective case series. Clinical records were taken for descriptive analysis. Main outcome measures were the key clinical features, and disease course (therapy, IOP control, patient outcome). RESULTS: Key features were conjunctival ciliary injection and mutton fat keratic precipitation in all eyes. The findings were bilateral in 10 patients. Time between initiation of brimonidine treatment and presentation was 1 week to 49 months. Glaucoma sub-types were mostly pseudo-exfoliative and primary open angle glaucoma. Brimonidine treatment was stopped immediately. Additionally, topical corticosteroids were prescribed in 18 eyes and tapered down during the following 4 weeks. Thirteen eyes did not need surgical or laser treatment (median follow-up time 15 months). No patient showed recurrence of inflammation after cessation of brimonidine. CONCLUSIONS: This type of anterior uveitis is an uncommon but important manifestation which should always be considered in glaucoma patients on brimonidine treatment. Although treatable at its root cause, problems may persist, especially with respect to IOP control. The latter may necessitate glaucoma surgery after the resolved episode of the uveitis.

Saccadic reaction time and ocular findings in phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is an inherited metabolic disorder characterized by reduced activity of phenylalanine hydroxylase resulting in elevated blood phenylalanine (Phe) concentration. Despite some obvious ocular changes, the disorder has been poorly recognized by ophthalmologists. Neurophysiologic tests imply prolonged reaction time correlating with increased phenylalanine blood concentrations. We aimed to test saccadic reaction time in PKU patients in dependency of blood phenylalanine concentrations. METHODS: Nineteen biochemically diagnosed PKU patients and 100 controls completed comprehensive ophthalmologic and orthoptic examinations including saccadometry by infrared based video-oculography. Peak velocity, gain, and particularly latency of reflexive saccades were compared to controls, and regression analysis was performed. RESULTS: Latency of reflexive saccades was not associated with the current phenylalanine concentration. Although in 10 out of 19 patients phenylalanine concentrations were outside the age-related therapeutic range, latency differed little between PKU patients and the controls, as well as peak velocity and gain. Ocular findings occurred as partial hypopigmentation of the iris in one late diagnosed patient aged 36 years, and as bilateral cataracts (possibly due to steroid intake) with refractive amblyopia, strabismus, high myopia, and glaucoma in another late diagnosed patient aged 46 years. Visual acuity was reduced in eight PKU patients. CONCLUSIONS: Saccadometry, particularly saccadic reaction time, is not useful in the monitoring of phenylketonuria. Ophthalmic examination is recommended in PKU patients, as the occurrence of ocular pathologies was relatively high.

The impact of intraocular pressure fluctuations and other factors on conversion of ocular hypertension to primary open-angle glaucoma.

PURPOSE: To evaluate the role of intraocular pressure (IOP) fluctuations and other factors on conversion of ocular hypertension to open-angle glaucoma (OAG) within a retrospective, longitudinal cohort study. PATIENTS AND METHODS: The study population included patients with ocular hypertension defined by IOP > 21 mmHg with normal appearing optic discs and no visual field defect. IOP fluctuation, mean and maximum were examined in 61 eyes over a follow-up period of 36 months (standard deviation (SD) 24). All patients underwent at least two 48-h IOP profiles including night-time IOP measurements in the supine position, visual field examinations, Heidelberg retina tomograph analyses (HRT) and optic disc photographs. Regression analyses were performed to demonstrate the impact of IOP parameters, myopia, sex, cup/disc ratio and visual field results on conversion to glaucoma. RESULTS: While IOP fluctuation and mean did not impact conversion, myopia proved to be a risk factor (HR 14.4; 95% CI: [3.9-53.0]; p ≤ 0.001). Over an average of three years, 6/61 converted to OAG. The study yielded a mean long-term IOP over all available pressure profiles of 18.1 mmHg (SD 3.2) and an IOP fluctuation of 1.9 mmHg (SD 1.1) within a mostly treated cohort. Conversion-free five-year rate was 59.8%. CONCLUSIONS: The amount of fluctuation we measured in our study sample did not result in the development of glaucoma in treated ocular hypertension patients. Myopic subjects with ocular hypertension are at a higher risk for glaucoma conversion than non-myopic ocular hypertensive subjects are.

Prevalence of myopic maculopathy in the German population: results from the Gutenberg health study.

AIMS: To determine the prevalence of myopic maculopathy in the general population in Germany and to analyse potential associations with ocular and systemic factors. DESIGN: The Gutenberg Health Study is a population-based study, including 15 010 participants aged 35-74 years. METHODS: Myopic maculopathy was graded in phakic eyes with spherical equivalent ≤-6 D by assessing fundus photographs according to a recent international photographic classification system (META-PM). 801 eyes of 519 participants (mean age 51.0±0.77 years) met the conditions and had gradable fundus photographs. Age-specific prevalence estimates were computed. Multivariable logistic regression analysis was used to assess associated factors with myopic maculopathy. RESULTS: Myopic maculopathy was present in 10.3% (95% CI 7.9 to 13.3) study participants. The prevalence was 8.6% (95% CI 6.1% to 11.9%) in the 397 right eyes and 8.7% (95% CI 6.2% to 12.0%) in the 404 left eyes. The most common type of pathology was diffuse atrophy (8.1%), followed by patchy atrophy (1.3%) and macular atrophy (0.5%); plus lesions were present in 3% (right eyes). Age (OR 1.07 per year, 95% CI 1.03 to 1.11, p<0.001), higher myopic refractive error (p<0.001), and male gender (p=0.02) were associated with myopic maculopathy, while cardiovascular risk factors and socioeconomic factors were not. CONCLUSIONS: The prevalence of myopic maculopathy in the German population was 0.5%, and 10% in high myopic participants, aged 35-74 years. These population-based data are the first in Europe. Myopic maculopathy was related to severity of myopic refractive error and age.

A comprehensive monocentric ophthalmic study with Gaucher disease type 3 patients: vitreoretinal lesions, retinal atrophy and characterization of abnormal saccades.

BACKGROUND: The differentiation between Gaucher disease type 3 (GD3) and type 1 is challenging because pathognomonic neurologic symptoms may be subtle and develop at late stages. The ophthalmologist plays a crucial role in identifying the typical impairment of horizontal saccadic eye movements, followed by vertical ones. Little is known about further ocular involvement. The aim of this monocentric cohort study is to comprehensively describe the ophthalmological features of Gaucher disease type 3. We suggest recommendations for a set of useful ophthalmologic investigations for diagnosis and follow up and for saccadometry parameters enabling a correlation to disease severity. METHODS: Sixteen patients with biochemically and genetically diagnosed GD3 completed ophthalmologic examination including optical coherence tomography (OCT), clinical oculomotor assessment and saccadometry by infrared based video-oculography. Saccadic peak velocity, gain and latency were compared to 100 healthy controls, using parametric tests. Correlations between saccadic assessment and clinical parameters were calculated. RESULTS: Peripapillary subretinal drusen-like deposits with retinal atrophy (2/16), preretinal opacities of the vitreous (4/16) and increased retinal vessel tortuosity (3/16) were found. Oculomotor pathology with clinically slowed saccades was more frequent horizontally (15/16) than vertically (12/16). Saccadometry revealed slowed peak velocity compared to 100 controls (most evident horizontally and downwards). Saccades were delayed and hypometric. Best correlating with SARA (scale for the assessment and rating of ataxia), disease duration, mSST (modified Severity Scoring Tool) and reduced IQ was peak velocity (both up- and downwards). Motility restriction occurred in 8/16 patients affecting horizontal eye movements, while vertical motility restriction was seen less frequently. Impaired abduction presented with esophoria or esotropia, the latter in combination with reduced stereopsis. CONCLUSIONS: Vitreoretinal lesions may occur in 25% of Gaucher type 3 patients, while we additionally observed subretinal lesions with retinal atrophy in advanced disease stages. Vertical saccadic peak velocity seems the most promising "biomarker" for neuropathic manifestation for future longitudinal studies, as it correlates best with other neurologic symptoms. Apart from the well documented abduction deficit in Gaucher type 3 we were able to demonstrate motility impairment in all directions of gaze.

Correction: Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium.

[This corrects the article DOI: 10.1371/journal.pone.0220143.].

Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium.

PURPOSE: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). METHODS: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). RESULTS: In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. CONCLUSIONS: Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

Myopia is associated with education: Results from NHANES 1999-2008.

PURPOSE: Myopia is increasing worldwide and possibly linked to education. In this study, we analyse the association of myopia and education in the U.S. and investigate its age-dependency. METHODS: We conducted a secondary data analysis using the public use files from the cross-sectional study National Health and Nutrition Examination Survey of the period from 1999 to 2008. 19,756 participants aged 20 to 85 years were included with data on education and ophthalmic parameters (distance visual acuity, objective refraction and keratometry). Spherical equivalent, astigmatism, corneal power and corneal astigmatism were evaluated for an association with education using linear regression analysis with adjustment of potential confounders. RESULTS: Analysis revealed an association between spherical equivalent and educational level in the univariate analysis (P < .001), and in the adjusted model (P < .001). Subjects who attend school to less than 9th grade had a mean spherical equivalent of 0.34 D, subjects with 9-11th grade -0.14 D, subjects that finished high school -0.33 D, subjects with partial college education -0.70 D, subjects that graduated from college or a higher formal education -1.22 D. Subjects that graduated from college or above were -1.47 D more myopic compared to subjects that completed less than 9th grade school in the adjusted analyses. Astigmatism and corneal curvature was not associated with education. CONCLUSIONS: Myopia is associated with higher education in the U.S. Our analysis shows that corneal curvature does not contribute to this association, therefore axial elongation or lens power are likely to contribute to myopia.

Age dependent normative data of vertical and horizontal reflexive saccades.

PURPOSE: There is some controversy whether or not saccades change with age. This cross-sectional study aims to clarify the characteristics of reflexive saccades at various ages to establish a normative cohort in a standardized set-up. Second objective is to investigate the feasibility of saccadometry in daily ophthalmological practice. METHODS: One hundred healthy participants aged between 6 and 76 years underwent an ophthalmologic examination and saccadometry, using an infrared video-oculography device, sampling at 220 Hz. The reflexive saccades were evoked in four directions and three target displacements each (5°/15°/30° horizontally and of 5°/10°/20° vertically). Saccadic peak velocity, gain (amplitude/target displacement) and latency were measured. RESULTS: Mean peak velocity of saccades was 213°/s (± 29°/s), 352°/s (± 50°/s) and 455°/s (± 67°/s) to a target position 5°, 15°and 30° horizontally, respectively, and 208°/s (± 36°/s), 303°/s (± 50°/s) and 391°/s (± 71°/s) to a target position 5°, 10° and 20° vertically. The association between peak velocity and eccentricity proved to be present at any age in all four directions. We found no relevant effect of age on peak velocity, gain and latency in a fitted linear mixed model. However, latency becomes shorter during childhood and adolescence, while in adulthood it is relatively stable with a slight trend to increase in the elderly. Saccades are more precise when the target displacement is small. Isometric saccades are most common, followed by hypometric ones. All children and elderly were able to perform good quality saccadometry in a recording time of approximately 10 minutes. CONCLUSION: The presented data may serve as normative control for further studies using such a video-oculography device for saccadometry. The means of peak velocity and the gain can be used independently from age respecting the target displacement. Latency is susceptible to age.

Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene.

OBJECTIVE: PDZD7 was identified in 2009 in a family with apparent nonsyndromic sensorineural hearing loss. However, subsequent clinical reports have associated PDZD7 with digenic Usher syndrome, the most common cause of deaf-blindness, or as a modifier of retinal disease. No further reports have validated this gene for nonsyndromic hearing loss, intuitively calling correct genotype-phenotype association into question. This report describes a validating second case for biallelic mutations in PDZD7 causing nonsyndromic mild to severe sensorineural hearing loss. It also provides detailed audiometric and ophthalmologic data excluding Usher syndrome in both the present proband (proband 1) and the first proband described in 2009 (proband 2). DESIGN: Proband 1 was sequenced using a custom-designed next generation sequencing panel consisting of 151 deafness genes. Bioinformatics analysis and filtering disclosed two PDZD7 sequence variants (c.1648C>T, p.Q550* and c.2107del, p.S703Vfs*20). Segregation testing followed in the family. For both probands, audiograms were collected and analyzed for progressive hearing loss and detailed ophthalmic evaluations were performed including electroretinography. RESULTS: Proband 1 demonstrated a prelingual, nonsyndromic, sensorineural hearing loss that progressed in the higher frequencies between 4 and 9 years old. PDZD7 segregation analysis confirmed biallelic inheritance (compound heterozygosity). Mutation analysis determined the c.1648C>T mutation as novel and reported the c.2107del deletion as rs397516633 with a calculated minor allele frequency of 0.000018. Clinical evaluation spanning well over a decade in proband 2 disclosed bilateral, nonprogressive hearing loss. Both probands showed healthy retinas, excluding Usher syndrome-like changes in the eye. CONCLUSIONS: PDZD7 is confirmed as a bona fide autosomal recessive nonsyndromic hearing loss gene. In both probands, there was no evidence of impaired vision or ophthalmic pathology. As the current understanding of PDZD7 mutations bridge Mendelian and complex phenotypes, the authors recommend careful variant interpretation, since PDZD7 is one of many genes associated with both Usher syndrome and autosomal recessive nonsyndromic hearing loss. Additional reports are required for understanding the complete phenotypic spectrum of this gene, including the possibility of high-frequency progression, as well as noise-induced hearing loss susceptibility in adult carriers. This report rules out all forms of Usher syndrome with an onset before 12 and 15 years old in probands 1 and 2, respectively. However, due to the young ages of the probands, this report is uninformative regarding older patients.

Species- and concentration-dependent differences of acetyl- and butyrylcholinesterase sensitivity to physostigmine and neostigmine.

Previous and more recent studies show that cholinesterase inhibitors (ChE-Is) are an important possibility for therapeutic intervention in Alzheimer's Disease, sepsis and other inflammatory syndromes. ChE-Is maintain high levels of acetylcholine (ACh) determining beneficial effects on the disease process. Despite numerous efforts to identify the appropriate choice of agents and dose of ChE-Is, a common protocol regarding concentration- and species-dependent differences in inhibitory potency (IC 50) of clinical relevant ChE-Is is still not available. To evaluate the in vitro sensitivity of Acetyl- and Butyrylcholinesterase (AChE, BChE), we compared the concentration-response effects of physostigmine and neostigmine on cholinesterases in whole blood from rat and human. A spectrophotometrical test system based on in vitro Ellman's reagent has been used to determine the kinetic properties of clinical relevant ChE-Is. In vitro, the enzyme activity of human AChE and BChE was inhibited in a concentration-dependent manner until a residual activity of 4-6% for AChE and 20-30% for BChE (IC 50 human AChE: 0.117 ± 0.007 µM physostigmine, 0.062 ± 0.003 µM neostigmine; IC 50 human BChE: 0.373 ± 0.089 µM neostigmine; 0.059 ± 0.012 µM physostigmine). The inhibition curve of rat BChE in contrast showed no concentration-dependency for physostigmine and neostigmine (87% residual activity even at high inhibitor concentrations). Rat AChE was inhibited in a concentration-dependent manner until a residual activity of 53%. The results suggest that cholinesterases from human and rat show marked species- and inhibitor-dependent differences in sensitivity to physostigmine and neostigmine. Knowledge of such differences may be critical in assessing the possible therapeutic effects of ChE-Is in both species and may guide researchers in the optimal design of future experiments regarding the application of ChE-Is.

The effect of perchlorate medication on point-of-care testing.

BACKGROUND: To create awareness for mismeasurements of ion-selective electrodes caused by patients' medications and to prevent severe consequences in an intensive care therapy. CASE PRESENTATION: A 73-year-old woman presented with severe carbimazol-induced toxic epidermal necrolysis. After replacement of carbimazol by sodiumperchlorate, we detected a huge discrepancy in the measurement of ionised calcium by two different Point-of-Care (POCT) systems. While Siemens Rapidlab 865 showed a severe hypocalcemia at all times, the Radiometer 600 system first presented a severe hypercalcemia and, in the course of the following days, also a hypocalcemia but with significantly (p < 10 to the -45) higher values than the Rapidlab system. Furthermore, the POCT systems detected a pseudohypocalcemia at times where we think there was a normo- or even hypercalcemia which led to incorrect therapy with excessive substitution of ionised calcium. CONCLUSIONS: The substance sodiumperchlorate, which is well established in Europe for hyperthyreosis therapy, caused malfunctions of analyses of ionised calcium by POCT systems.

Comparison of point-of-care testing glucose results from intensive care patients measured with network-ready devices.

BACKGROUND: Fast and reliable glycemic control is of tremendous importance in intensive care units. Point-of-care devices used in professional care have to be precise and of low variability, and their connectivity has to outrange the abilities of home-care equivalents. In particular, the meter's efficiency should be tested not only with spiked blood samples from healthy donors but also with blood from intensive care unit patients because of their special matrix conditions as low hematocrit, oxygen pressure variability, or medication. METHODS: Four types of network-ready glucose meters were tested. Data, obtained from native or maltose/xylose-spiked intensive care patients' blood, were compared (oxygen, hematocrit, glucose, and maltose and xylose dependencies) with those from a YSI 2300 STAT Plus™ glucose and lactate analyzer (YSI Life Sciences, Yellow Springs, OH). According to ISO 15197 (2003) acceptance of glucose meter results was determined. Quality control results were investigated considering a new calculation type in German guidelines. RESULTS: Three of the meters fulfill the overall acceptance criterions. Two of the meters achieved accuracies above 93% in all oxygen, hematocrit, and glucose subgroups. Maltose generates deviations leading to accuracies from 71.1% to 100%, and xylose causes accuracies of 33.3% to 100%. CONCLUSIONS: State of the art for manufacturing small network point-of-care testing glucose meters has reached a new level of precision, but the devices still have to be handled with care, and in particular the staff of an intensive care unit still needs knowledge about possible interferences.

Perchlorate (Irenat®) may falsely lower measured ionised calcium.

BACKGROUND: Discrepancies in ionised calcium concentrations between results from several point-of-care devices derived from intensive care unit (ICU) patients were postulated to be caused by perchlorate, a thyroid blocking agent. The deviations were serious concerning the diagnosis of hyper- or hypocalcaemia and administration of calcium infusions. METHODS: The problem was studied from three perspectives. First: quantification of ionised calcium in heparinised blood samples spiked with sodium perchlorate from healthy volunteers measured using five blood gas analysers (BGAs from IL, Radiometer, Roche and Siemens). Second: verification of clinical concentrations of perchlorate in blood samples after routine use for blood gas analysis from ICU patients. Third: retrospective analysis of data stored from patients during their stay in general ICU of the Departments of Anesthesiology and General Surgery by a patient data management system. RESULTS: Category 1: three of the point-of-care testing devices measure clinically relevant falsely low ionised calcium concentrations when exposed to concentrations perchlorate >0.1 mmol/L. Two were not able to identify hypercalcaemia of up to 4 mmol/L ionised calcium when specific perchlorate concentrations are exceeded. Category 2: measured clinical concentrations of perchlorate ranged between the lower limit of quantification [LOQ=0.03 mmol/L and 2.75 mmol/L (median=0.29 mmol/L; mean=0.585 mmol/L)]. A concentration above 0.1 mmol/L perchlorate was found in 74.3% of all samples that tested positive. Category 3: between February 2006 and July 2009, 42 patients per year (2.2%) received sodium perchlorate with a median length of treatment of 25 days. CONCLUSIONS: Perchlorate causes clinically relevant lowering of measured ionised calcium in BGAs from two providers at concentrations obtained in samples from ICU patients (affecting about 1.1% of all ICU patients).