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

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252825
Author(s):  
Susanne Hopf ◽  
Julia B. Hennermann ◽  
Alexander K. Schuster ◽  
Norbert Pfeiffer ◽  
Susanne Pitz
Keyword(s):  
Mixed Model ◽  
Linear Mixed Model ◽  
Peak Velocity ◽  
Clinical Investigation ◽  
Outer Nuclear Layer ◽  
Head Movements ◽  
Retinal Layer ◽  
Type C ◽  
Niemann Pick ◽  
Retinal Thinning

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.

scholarly journals Ocular motor biomarkers in Niemann-Pick disease type C: A prospective cross-sectional multicontinental study in 72 patients

2020 ◽  
Author(s):  
Tatiana Bremova-Ertl ◽  
Larry Abel ◽  
Mark Walterfang ◽  
Ettore Salsano ◽  
Anna Ardissone ◽  
...  
Keyword(s):  
Smooth Pursuit ◽  
Peak Velocity ◽  
Disease Type ◽  
Ocular Motor ◽  
Cross Sectional ◽  
Vertical Saccades ◽  
Type C ◽  
Niemann Pick ◽  
Gaze Palsy ◽  
Pursuit Gain

Niemann-Pick type C (NPC) is a rare lysosomal storage disorder with ocular motor involvement. In a multi-continental cross-sectional study we characterized ocular motor function in 72 patients from twelve countries by means of video-oculography. We also searched for ocular motor biomarkers interlinking with disease severity. Study protocol comprised reflexive and self-paced saccades, smooth pursuit, and gaze-holding in both planes. 158 healthy controls acted as data comparison. The Modified Disability Rating Scale, Scale for Assessment and Rating of Ataxia, Spinocerebellar Ataxia Functional Index, and Montreal Cognitive Assessment were also performed. In contrast to previous publications and the common belief that the downward saccadic system degenerates to greater extent than the upward one, our measurements of vertical saccades demonstrated that the involvement in both directions was similar. Mean saccadic peak velocity to 20 deg stimulus was 63.5 deg/s (SD, 95% CIs of the mean: 59.5, [47.9-79.2]) in NPC patients and 403.1 deg/s (69.0, [392.0-414.2 deg/s]) in healthy subjects (p<0.001). Downward saccades yielded 51 deg/s (68.9, [32.7-69.3]), whilst upward 78.8 deg/s (65.9, [60.8-96.8]) (p<0.001). Vertical position smooth pursuit gain was 0.649 (0.33, [0.554-0.744]) in NPC and 0.935 (0.149 [0.91-0.959]) in HC (p<0.001). The number of patient-specific saccadic patterns, incl. slow-pursuit like, hypometric and staircase-pattern saccades suggest varying involvement of the saccadic system with fragmentation of the velocity profile as a sign of omnipause neuron dysfunction. Observed compensating strategies, such as blinks to elicit saccades, head and upper body movements to overcome the gaze palsy, should be used clinically to establish a diagnosis. Vertical reflexive saccades were more impaired and slower than self-paced ones. Ocular motor performance depended on age of onset and disease duration. We found that peak velocity and latency of horizontal saccades, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials, as they showed the strongest correlation to disease severity. By comparing saccadic with pursuit movements, we showed that 98.2% of patients generated vertical saccades (both up and down) that were below the 95% confidence intervals of the controls peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% of healthy controls. Vertical supranuclear saccade palsy and not vertical supranuclear gaze palsy is the hallmark of NPC disease. The distinction between saccadic and gaze palsy is also important in other neurodegenerative diseases and inborn errors of metabolism with ocular motor involvement, such as progressive supranuclear palsy or Gaucher disease type 3.

scholarly journals Retinal Sensitivity and Ganglion Cell-Related Retinal Layer Thickness in the Normal Aging Process 

2021 ◽  
Author(s):  
Makoto Araie ◽  
Makoto Fujii ◽  
Yuko Ohno ◽  
Yuki Tanaka ◽  
Tsutomu Kikawa ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Layer Thickness ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Plexiform Layer ◽  
Retinal Layer ◽  
Inner Plexiform Layer ◽  
Fiber Layer ◽  
Nerve Fiber Layer Thickness ◽  
Ocular Media

Abstract Aging-associated changes in visual field (VF) sensitivity were compared prospectively and longitudinally with the circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and macular ganglion cell-inner plexiform layer thickness (GCIPLT) changes in the corresponding retinal areas of the same eyes (72 eyes of 37 normal Japanese subjects; mean age, 51.3 years). The Humphrey Field Analyzer 24-2 test (HFA 24-2) and spectral-domain optical coherence tomography (SD-OCT) measurements of the cpRNFLT and GCIPLT in a 0.6-mm-diameter circle corresponding to the four central points of HFA 24-2 adjusted for retinal ganglion cell displacement (GCIPLT4TestPoints) were performed every 3 months for 3 years. The tiem changes of the mean sensitivity over the entire field (VFmean) and the four central points (VF4TestPoints), cpRNFLT, and GCIPLT4TestPoints were analyzed using a linear mixed model. The aging-associated decline rates of VFmean and VF4TestPoins were 0.12 and 0.19 decibels/year (p<0.001), which significantly accelerated with increased subjects’ age (0.009 and 0.010 decibels/year, p<0.001, respectively) without changes in the ocular media. Those of the CpRNFLT and GCIPLT4TestPoints were not significant in both (p>0.114), but significantly accelerated with increased subjects’ age (0.021 and 0.010 mm/year, p=0.001 and 0.004, respectively). These results have implications in studying physiological aging- or desease-related changes in these parameters.

Neuroretinal atrophy following resolution of macular oedema in retinal vein occlusion

2018 ◽  
Vol 103 (1) ◽  
pp. 36-42 ◽  
Author(s):  
Dominika Podkowinski ◽  
Ana-Maria Philip ◽  
Wolf-Dieter Vogl ◽  
Jutta Gamper ◽  
Hrvoje Bogunovic ◽  
...  
Keyword(s):  
Retinal Vein Occlusion ◽  
Macular Oedema ◽  
Pigment Epithelium ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Retinal Layer ◽  
Inner Plexiform Layer ◽  
Vein Occlusion ◽  
Retinal Atrophy ◽  
Retinal Thinning

Background/aimsTo characterise neuroretinal atrophy in retinal vein occlusion (RVO).MethodsWe included patients with central/branch RVO (CRVO=196, BRVO=107) who received ranibizumab according to a standardised protocol for 6 months. Retinal atrophy was defined as the presence of an area of retinal thickness (RT) <260 µm outside the foveal centre. Moreover, the thickness of three distinct retinal layer compartments was computed as follows: (1) retinal nerve fibre layer to ganglion cell layer, (2) inner plexiform layer (IPL) to outer nuclear layer (ONL) and (3) inner segment/outer segment junction to retinal pigment epithelium. To characterise atrophy further, we assessed perfusion status on fluorescein angiography and best-corrected visual acuity (BCVA), and compared these between eyes with/without atrophy.Results23 patients with CRVO and 11 patients with BRVO demonstrated retinal atrophy, presenting as sharply demarcated retinal thinning confined to a macular quadrant. The mean RT in the atrophic quadrant at month 6 was 249±26 µm (CRVO) and 244±29 µm (BRVO). Individual layer analysis revealed pronounced thinning in the IPL to ONL compartment. Change in BCVA at 6 months was similar between the groups (BRVO, +15 vs +18 letters; CRVO, +14 vs +18 letters).ConclusionsIn this exploratory analysis, we describe the characteristics of neuroretinal atrophy in RVO eyes with resolved macular oedema after ranibizumab therapy. Our analysis shows significant, predominantly retinal thinning in the IPL to ONL compartment in focal macular areas in 11% of patients with RVO. Eyes with retinal atrophy did not show poorer BCVA outcomes.

scholarly journals Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

2020 ◽  
Author(s):  
Dario Carradori ◽  
Hsintsung Chen ◽  
Beat Werner ◽  
Aagam Shah ◽  
Chiara Leonardi ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
High Doses ◽  
Niemann Pick ◽  
Stable Forms ◽  
Pick Disease

AbstractNiemann-Pick Disease Type C (NPC) is a severe neurovisceral disorder that is pathophysiologically characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and multiple sphingolipids, including sphingosine. The compound 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a compound with high cholesterol complexation capacity and is currently under clinical investigation for the treatment of NPC. However, due to its short blood half-life, high doses are required to produce a therapeutic effect. It has been reported in mice that HPβCD’s circulation time and efficacy can be improved by increasing its size via polymerization, but the biodegradable nature of these systems did not allow the contribution of the macromolecule to the activity to be determined. In this work, stable forms of polymerized HPβCD were generated (via epichlorohydrin crosslinking) to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8-312 kDa) displayed a 10-fold greater complexation capacity towards cholesterol than monomeric HPβCD but were taken up by cells to a lower extent (in a size-dependent fashion), resulting in an overall comparable in vitro effect on intracellular cholesterol accumulation that was dependent on cholesterol complexation. When tested in vivo, the crosslinked 19.3 kDa HPβCD exhibited a longer terminal half-life than the monomeric HPβCD. However, it did not increase the life span of Npc1 mice, possibly due to reduced organ penetration and brain diffusion consequence of its large molecular weight. This could be circumvented by the application of magnetic resonance imaging-guided low intensity-pulsed focused ultrasound (MRIg-FUS), which increased the brain penetration of the CD. In conclusion, stable forms of polymerized HPβCD constitute valuable tools to elucidate CDs’ mechanism of action. Moreover, the use of MRIg-FUS to maximize CDs tissue penetration warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the treatment of NPC.Graphical abstractThe 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a well-established pharmaceutical excipient that can complex cholesterol and is currently under clinical investigation to treat Niemann-Pick Disease Type C (NPC). However, high doses of the drug are needed to achieve a therapeutic effect. Using stable and long circulating crosslinked HPβCDs, this study attempts to further understand the mechanisms behind CDs’ activity.

Analyzing discontinuities in longitudinal count data: A multilevel generalized linear mixed model.

2020 ◽  
Author(s):  
James L. Peugh ◽  
Sarah J. Beal ◽  
Meghan E. McGrady ◽  
Michael D. Toland ◽  
Constance Mara
Keyword(s):  
Count Data ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Generalized Linear Mixed Model ◽  
Longitudinal Count Data

ANALYSIS OF CHOLESTEROL AND OXYSTEROL LEVELS IN NIEMANN PICK DISEASE TYPE C MICE AND PATIENTS

2006 ◽  
Vol 37 (S 1) ◽  
Author(s):  
S Tay ◽  
X He ◽  
AM Jenner ◽  
BS Wong ◽  
WY Ong
Keyword(s):  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

Predicting bycatch hotspots based on suitable habitat derived from fishery-independent data

2020 ◽  
Vol 641 ◽  
pp. 159-175
Author(s):  
J Runnebaum ◽  
KR Tanaka ◽  
L Guan ◽  
J Cao ◽  
L O’Brien ◽  
...  
Keyword(s):  
Habitat Suitability ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Gulf Of Maine ◽  
Homarus Americanus ◽  
Management Tool ◽  
American Lobster ◽  
Suitable Habitat ◽  
Climate Conditions ◽  
Suitability Index

Bycatch remains a global problem in managing sustainable fisheries. A critical aspect of management is understanding the timing and spatial extent of bycatch. Fisheries management often relies on observed bycatch data, which are not always available due to a lack of reporting or observer coverage. Alternatively, analyzing the overlap in suitable habitat for the target and non-target species can provide a spatial management tool to understand where bycatch interactions are likely to occur. Potential bycatch hotspots based on suitable habitat were predicted for cusk Brosme brosme incidentally caught in the Gulf of Maine American lobster Homarus americanus fishery. Data from multiple fisheries-independent surveys were combined in a delta-generalized linear mixed model to generate spatially explicit density estimates for use in an independent habitat suitability index. The habitat suitability indices for American lobster and cusk were then compared to predict potential bycatch hotspot locations. Suitable habitat for American lobster has increased between 1980 and 2013 while suitable habitat for cusk decreased throughout most of the Gulf of Maine, except for Georges Basin and the Great South Channel. The proportion of overlap in suitable habitat varied interannually but decreased slightly in the spring and remained relatively stable in the fall over the time series. As Gulf of Maine temperatures continue to increase, the interactions between American lobster and cusk are predicted to decline as cusk habitat continues to constrict. This framework can contribute to fisheries managers’ understanding of changes in habitat overlap as climate conditions continue to change and alter where bycatch interactions could occur.

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