Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients

Background: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. Methods: An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available

Retinal vessel tortuosity as a prognostic marker for disease severity in Fabry disease

Purpose!#!The aim of this case control study was to evaluate the prognostic value of automatically quantified retinal vessel tortuosity from fundus images and vessel density from OCT-A in Fabry disease and to evaluate the correlation of these with systemic disease parameters.!##!Methods!#!Automatically quantified perimacular retinal vessel tortuosity (MONA REVA software), acquired by fundus imaging, and perifoveal retinal vessel density, acquired by optic coherence tomography angiography (OCT-A) were compared between 26 FD patients and 26 controls. Gender and FD phenotype were analyzed to the obtained retinovascular data and correlated to the Mainz severity score index (MSSI) and plasma lyso-Gb3.!##!Results!#!Automatically quantified retinal vessel tortuosity indices of FD patients were significantly lower, reflecting an increased vessel tortuosity, compared to controls (p = 0.008). Males with a classical phenotype showed significantly lower retinal vessel tortuosity indices compared to males with an oligosymptomatic phenotype and females with a classical or oligosymptomatic phenotype (p < 0.001). The retinal vessel tortuosity index correlated significantly with systemic disease severity parameters [global MSSI (r = - 0.5; p < 0.01), cardiovascular MSSI (r = - 0.5; p < 0.01), lyso-Gb3 (r = - 0.6; p < 0.01)].!##!Conclusion!#!We advocate fundus imaging based automatically quantified retinal vessel tortuosity index over OCT-A imaging as it is a quick, non-invasive, easily assessable, objective and reproducible marker

Intravitreal Co-Administration of GDNF and CNTF Confers Synergistic and Long-Lasting Protection against Injury-Induced Cell Death of Retinal Ganglion Cells in Mice

We have recently demonstrated that neural stem cell-based intravitreal co-administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) confers profound protection to injured retinal ganglion cells (RGCs) in a mouse optic nerve crush model, resulting in the survival of ~38% RGCs two months after the nerve lesion. Here, we analyzed whether this neuroprotective effect is long-lasting and studied the impact of the pronounced RGC rescue on axonal regeneration. To this aim, we co-injected a GDNF- and a CNTF-overexpressing neural stem cell line into the vitreous cavity of adult mice one day after an optic nerve crush and determined the number of surviving RGCs 4, 6 and 8 months after the lesion. Remarkably, we found no significant decrease in the number of surviving RGCs between the successive analysis time points, indicating that the combined administration of GDNF and CNTF conferred lifelong protection to injured RGCs. While the simultaneous administration of GDNF and CNTF stimulated pronounced intraretinal axon growth when compared to retinas treated with either factor alone, numbers of regenerating axons in the distal optic nerve stumps were similar in animals co-treated with both factors and animals treated with CNTF only

Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients.

BackgroundCLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition.MethodsAn expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. Individuals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria.ResultsTwenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality).ConclusionThis program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available

Zusammenarbeit mit klinischen Auftragsforschungsinstituten

Clinical trials with pharmaceuticals or medical devices make complex demands on sponsors and participating centers. During the past two decades, sponsors have increasingly delegated regulatory and organizational tasks to clinical research organizations (CRO). As a rule, these companies are the main interface for the collaboration with the participating study centers. The main purpose of the participation is the support of the study centers for achieving an optimal study quality. The study centers involved in the DOG working group on clinical study centers perceived varying experiences in the collaboration with CROs. In the future these experiences will be systematically assessed at the participating study centers and analyzed by the coordinating investigator. Reflecting these experiences to the respective CROs and the delegating sponsors will contribute to the quality of support by CROs and herewith to the quality of clinical trials. This paper presents which areas of collaboration will be assessed and analyzed