Charles Bonnet syndrome (CBS) is a rare condition characterized by visual impairment associated with complex visual hallucinations in elderly people. Although studies suggested that visual hallucinations may be caused by brain damage in the visual system in CBS patients, alterations in specific brain regions in the occipital cortex have not been studied. Functional connectivity during resting-state functional magnetic resonance imaging  in CBS patients, has never been explored. We aimed to investigate brain structural and functional changes in a patient with CBS, as compared with late blind (LB) and normally sighted subjects. We employed voxel-based morphometry and cortical thickness analyses to investigate alterations in grey matter characteristics, and rs-fMRI to study changes in functional brain connectivity. Decreased grey matter volume was observed in the middle occipital gyrus and in the cuneus in the CBS patient, and in the middle occipital gyrus and in the lingual gyrus within LB subjects, compared to their respective control groups. Reductions in cortical thickness in associative and multimodal cortices were observed in the CBS patient when comparing with LB subjects. The precuneus exhibited increased functional connectivity with the secondary visual cortex in the CBS patient compared to the controls. In contrast, LB patients showed decreased functional connectivity compared to sighted controls between the DMN and the temporo-occipital fusiform gyrus, a region known to support hallucinations. Our findings suggest a reorganization of the functional connectivity between regions involved in self-awareness and in visual and salience processing in CBS that may contribute to the appearance of visual hallucinations. Charles Bonnet syndrome (CBS) is a rare syndrome characterized by complex and recurrent visual hallucinations in people without psychological disorder. This syndrome typically occurs in people who have a visual deficit, generally resulting from macular degeneration, optic neuritis, cataracts, retinitis pigmentosa, glaucoma or diabetic retinopathy . TypicalHere, we investigated a late-onset visually-impaired patient with CBS who experiences complex visual hallucinations with a structural-functional imaging approach. In order to discern the findings strictly related to the visual impairment from those related to visual hallucination in our patient, we included three control samples for comparison: one consisting of a group of normal sighted subjects with the CBS patient, a second one consisting of a group of late blind (LB) subjects without CBS, and a third group of normal sighted subjects matched in age and sex with the LB. We used voxel-based morphometry (VBM) to study differences in grey matter density, and cortical thickness analysis to investigate structural cortical rearrangement in CBS  from the visual pathways). We further investigated functional connectivity patterns by means of rs-fMRI in order to detect changes in functional connectivity patterns underlying this syndrome. To this end, we used both a seed-based approach focusing on brain areas implicated in visual consciousness and salience networks.An 85-year-old man with visual impairment and no psychiatric history presented to the neurological department of the University Hospital Centre of Liège (Belgium). He reported his five-year history of increasing frequency of visual hallucinations and was able to give a detailed and coherent description of his hallucinatory experiences. The patient suffered from retinitis pigmentosa, a degenerative eye disease causing severe vision impairment due to progressive degeneration of the rod photoreceptors in the retina . At the This man started experiencing visual hallucinations at the age of 80. Visual hallucinations gradually became more frequent and occurred many times during the day. At the time of the visit, he repeatedly described seeing bilateral visual hallucinations with vivid details. The hallucinations reported by this patient were well formed, ranging from simple flashes or colored background to more complex with the appearance of common faces, objects and bodies of people, or landscapes. The hallucinations varied in size and color, and were binocular, covering the entire visual field. However, animations (i.e. scenes in motion) were only present in the right visual field. The visual hallucinations were always perceived as pleasant; they generally occurred with the eyes open and did not disappear when closing the eyes and were never accompanied by abnormal perception in any other sensory modality. The patient was fully aware of their unreal nature but he was not able to consciously control their occurrence or content. Based on his clinical history and the diagnostic exams he underwent, a diagnosis of CBS was made by the neurologist. Indeed, the patient fulfilled the four diagnostic criteria for CBS: (1) hallucinations must be complex, repetitive, and persistent; (2) awareness that the hallucinations are not real; (3) no additional delusions; and (4) absence of additional hallucinations in the other senses .The patient underwent a neuropsychological examination, including the Mattis Dementia Rating Scale  and the The patient underwent an ophthalmologic examination with, notably, measurements of visual acuity and visual evoked potentials.p = .03; Sokal and Rohlf )In order to investigate if these structural alterations were paralleled by functional alterations, we carried out a resting state functional connectivity study. Our analysis showed a functional reorganization of the brain connectivity between regions involved in self-awareness and in visual and salience processing, when observing the respective findings obtained with the CBS patient and the LB subjects. The precuneus showed increased connectivity with the secondary visual cortex in the CBS patient. This is consistent with Kazui and colleagues’  study deIn this study, we observed an increase of resting-state negative connectivity between the DMN and a cluster including the occipital fusiform gyrus in the LB subjects, whereas no such significant functional connectivity changes were identified between the CBS patient and the associated controls. This might suggest that a functional connectivity reorganization in the visual network is taking place for LB subjects but not in CBS. The fusiform gyrus is known to support hallucinations of faces in CBS patients  and otheThe present results offer evidence of cortical network reorganization between the salience network and some specific  regions in both the CBS patient and the LB as compared with respective matched sighted controls. Some studies have associated both activity and connectivity changes in the salience network, and more specifically in the dorsal prefrontal cortex, with the presence of phantom percepts e.g., –41) and  and 41])primum movens to the hallucination or only a result of them is not clear now.It has been debated to which extent CBS could be caused by sensory deprivation as a result of eye deficits or some brain lesions . Some auThe present study is not free of limitations. The main limits are represented by the small number of patients  and the fact that CBS and LB groups were examined using two different scanners. In addition, the LB group include different eye pathologies. For these reasons the current findings cannot be generalized to the entire LB population and should be interpreted cautiously. The age difference between the CBS patient and the comparison groups is also a limitation, however, we used the factor age as a regressor in the present analyses to limit the potential bias. Further studies should investigate functional connectivity in a greater number of CBS patients and with LB subjects acquired on the same scanner; nonetheless, this syndrome is relatively rare. Although hallucinations in CBS are visual in the majority of cases, few CBS patients also report somatosensory  hallucinations –50, whicIn conclusion, our overall resting state investigation showed brain connectivity changes specific to the CBS case, notably in visual related and salience networks. A functional connectivity reorganization following alterations in visual brain structures may contribute to visual hallucinations in CBS. Nonetheless, the explanation of this phenomenon remains incomplete. CBS symptoms can last for many years and have negatives consequences in around a third of CBS population , thus a S1 Figp-FWE <0.05 and primary threshold p-uncorrected <0.001.Cluster-mass (TIFF)Click here for additional data file.


Specialized research networks are essential to achieve drug approvals for rare pediatric diseases. Such networks help realize the potential of global legislation enacted upon the recognition that most children are treated with drugs whose most beneficial dose and regimen have not been established in pediatric patients. The Pediatric Rheumatology Collaborative Study Group (PRCSG) is a North American clinical trials network that is specialized in the performance of clinical trials of new therapies for pediatric populations with rheumatic diseases. This review provides an overview of the strategies employed by this research network to achieve drug and biologic approvals for children with pediatric rheumatic diseases, particularly juvenile idiopathic arthritis.Clinical trial conduct in rare pediatric diseases has required global recruitment. Supported or led by the PRCSG, highly responsive, validated, composite measures have been established to assess drug efficacy. For pediatric orphan diseases with high disease burdens, specialized investigative sites and study designs are needed to complete adequately powered trials at the high standard necessary to enable drug labeling by regulatory agencies. Novel trial designs have been utilized for more efficient testing of innovative drug candidates. All these have been developed or co-developed by the PRCSG research network.Specialized research networks in pediatric rheumatology, such as the PRCSG, have changed the landscape of available therapies and improved overall disease outcomes for children with pediatric rheumatic diseases. There remains a profound unmet medical need for the effective and safe treatment of pediatric rheumatic diseases. As these diseases are rare, highly specialized and experienced research networks are best suited to support therapeutic trials of new drug compounds. The Pediatric Rheumatology Collaborative Study Group (PRCSG) has an over 40-year long track record of successfully supporting the design, conduct, analysis, and publication of such therapeutic trials in close collaboration with industry sponsors. The PRCSG has intensely focused on ensuring that clinical trial designs have scientific rigor, are practical for enrollment by pediatric rheumatologists, and acceptable to families of children with pediatric rheumatic diseases. Studies conducted in collaboration with the PRCSG changed the landscape of pediatric rheumatology care over the past decades. The objective of this review is to highlight the history of the PRCSG, including approaches developed and used by the research network that made effective therapies available to children with pediatric rheumatic diseases.The Food and Drug Administration (FDA) is the federal agency charged with overseeing drug manufacturing, labeling, advertisement, and safety of medications and biological products  in the UActivism by professional organizations, families, and networks, such as the PRCSG, resulted in legislation that markedly changed the landscape of drug therapy for children. In the U.S., medication labeling and drug studies are governed largely by two sections of the FD&C Act: section 505A pertains to The Best Pharmaceuticals for Children Act (BPCA)  and sectIntegration of pediatric planning and exclusivity requests are now a part of regular new drug and biologic product development programs at pharmaceutical companies. Key documents to be developed include the initial Pediatric Study Plan (iPSP) for submission to and approval by the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) at FDA .Importantly, the EMA passed similar legislation concerning pediatric drug testing and approval. Like the iPSP, a Pediatric Investigational Plan (PIP) must be submitted to the Paediatric Committee (PDCO), EMA’s scientific committee that is responsible for activities concerning medicine testing in children. PDCO oversees the labeling of such medicines in the European Union. One difference between the U.S. and the European legislation is that PIP submission to PDCO takes place by the end of Phase I development in adults, while iPSP submission to FDA is expected to occur later around the end of Phase II development in adults.It has been a long-term initiative of the FDA to facilitate international standardization in drug testing and drug approval (“harmonization”). Various FDA Centers coordinate regular conferences with colleagues in Europe, Japan, Canada, and Australia. The benefits of harmonization of drug and biologic DMARD testing in pediatric rheumatic diseases include a decrease of unnecessary exposure to placebo or potentially unsafe new medications. Harmonization efforts are especially evident in the context of pediatric drug trials. This is achieved by international agreement between the various regulatory agencies on the design and performance of only a single blinded controlled pediatric trial, rather than several studies.http://www.prcsg.org) is to foster, facilitate, and conduct high quality clinical research in the field of pediatric rheumatology. The PRCSG Advisory Council provides oversight of the network’s activities. Its members are established clinical investigators, a junior clinical investigator, and representatives of foundations, organizations, and government agencies pertinent to the mission of the network, such as the National Institutes of Health and FDA.Founded in 1973, the PRCSG is a research network of nearly 90 academic clinical pediatric rheumatology centers. At present, there are over 180 pediatric rheumatology investigators in North America and Puerto Rico who are members of the PRCSG. The mission of the PRCSG (http://printo.it) [The impact of the PRCSG extends beyond North America. The PRCSG leadership was involved in the training of the leadership of the Paediatric Rheumatology International Trials Organisation  , a reseaStudies in pediatric rheumatic diseases often require complex response measures; necessitate adjustment of background medications; and rules for early discontinuation of subjects for added safety. To ensure that study protocols are closely followed by the investigative sites, the PRCSG and PRINTO Coordinating Centers have developed standardized operating procedures, custom software, electronic data capture systems and databases, as well as data security and back-up systems. This robust infrastructure allows the Coordinating Centers to provide real-time feed-back to investigative sites throughout the world and across all time zones. Although focused on pharmaceutical supported trials, the PRCSG Coordinating Center also supports investigator-initiated studies , 12.During the Cold War era, and as part of a Scientific Collaboration Treaty between the State Departments of the U.S. and the Union of Soviet Socialist Republics (USSR), the PRCSG conducted trials of popular traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs) with pediatric rheumatologists in the U.S. and the USSR. The motivation behind the Scientific Collaboration Treaty was that the fostering of scientific collaboration between the two countries was hoped to promote collaborations in other realms. Dr. Earl Brewer, the founder and first chairman of the PRCSG, considered the Scientific Collaboration Treaty a unique opportunity to obtain federal funding for clinical trials in JIA.Facilitated by the Scientific Collaboration Treaty, three large, pivotal Phase III randomized, double-blind, placebo-controlled trials of DMARDs were successfully performed through the collaborative efforts of pediatric rheumatologists in the U.S. and the USSR. The first study compared the efficacy of D-penicillamine and hydroxychloroquine to placebo in polyarticular JIA . Despite2 body surface area (BSA) once per week, but not the lower weekly dose of 5 mg/m2 BSA, proved to be superior to placebo in JIA. The results of this study were specifically used for the subsequent labeled indication of methotrexate in reducing signs and symptoms of polyarticular JIA.The third trial was of methotrexate versus placebo in active polyarticular JIA . Only orOther trials performed by the PRCSG were of various nonsteroidal anti-inflammatory drugs (NSAIDs), which were formerly the cornerstone of JIA treatments –23. Thesn = 69) was fully enrolled within 3 months from sites in North America because many children with JIA had failed all available medications. When the first JIA patient was dosed with etanercept, only about 300 adult patients with RA had been treated with this drug. Etanercept remains the first and presently only biologic DMARD that achieved regulatory approval by the FDA using the “fast track” approach. Eventually, world-wide approval of etanercept for polyarticular JIA was achieved based on the results of this PRCSG trial. However, given its small sample size and short duration of follow-up, the FDA required the Sponsor to establish a large post-marketing Phase IV JIA registry to document the continued effectiveness, benefits on quality of life, and longer-term safety of etanercept in routine clinical use, including usage in younger children [The first biologic DMARD studied in JIA was etanercept, a fusion protein targeting tumor necrosis factor alpha (TNFα) . The effchildren . These schildren , 26–30.In the last decade, PRCSG investigators also participated in clinical trials in systemic JIA (SJIA) –33. The With the advent of designer drugs that target pathways only relevant to some rare JIA subsets, the corresponding clinical trials in children constitute an even larger challenge. Examples are drugs that inhibit the IL-17 or IL-12/23 pathways which are expected to only benefit children with juvenile psoriatic arthritis and /or enthesitis-related JIA. The PRCSG has also been involved in the planning and conduct of the pediatric clinical trials of the anti-B lymphocyte stimulator monoclonal antibody, belimumab, in systemic lupus erythematosus (SLE), and the anti-CD20 monoclonal antibody, rituximab, in anti-neutrophil cytoplasmic antibody associated vasculitis.Since 2000, JIA medication trials generally involved pediatric rheumatology centers located all over the world, including in developing countries where access to affordable biologic DMARDs remains limited. The PRCSG and PRINTO have adopted the guiding principle that, irrespective of regulatory approval in the child’s country, study participants must be provided long-term access to the study agent, as long as it is deemed medically beneficial to the child. The mechanism by which medication is provided to former study participants varies country by country. Despite the added cost, to date, all pharmaceutical companies have agreed to this request of the PRCSG and PRINTO.sine-qua-non for the successful conduct of clinical trials. Members of the PRCSG Advisory Council have held the view that it is unethical and scientifically unacceptable to proceed with large scale trials, if validated response criteria [The PRCSG published the first guidance papers concerning medication studies in JIA , 35. Mancriteria  are unavcriteria –41. The criteria –47 and jcriteria , 48, 49.Pediatric rheumatic diseases are uncommon, and almost all affect fewer than 200,000 individuals in the US, which is compared to 1.3 million adult patients diagnosed with RA . PediatrUse of traditional double-blind placebo-controlled parallel design may be considered in pediatric rheumatic diseases if (1) the new drug is fast-acting, hence the duration of placebo exposure is expected to be very short; (2) the new drug is not dosed continuously or has a very prolonged effect and therefore awaiting disease flare after therapy withdrawal would be impractical; or (3), there are safety concerns with sudden drug discontinuation of study drug in Part 2 of the RWD trials . WheneveIn addition to placebo-controlled studies, the PRCSG uses open-label designs of studies for drug labeling purposes, provided the mechanism of action of a given drug is known to consistently result in improvement of a rheumatic disease in both children and adults, considering earlier controlled studies . Open-laModification of the above-mentioned controlled and uncontrolled study designs include elements considered in adaptive trial designs. Examples are the reduction of sample size following planned interim analyses, the tapering of corticosteroids during the RWD trial of canakinumab in SJIA ; and proTaken together, the PRCSG advocates study designs for new drugs that minimize placebo and background medication exposures. Nonetheless, any study by the PRCSG maintains sufficient scientific rigor needed for subsequent drug approval by regulatory agencies. Another prerequisite of PRCSG trials is that large-scale Phase III studies only proceed after the delineation of the dosing regimen that provides comparable drug exposure to those known to be efficacious in the related adult rheumatic disease. If the pathogenesis of the pediatric disease is distinct from the approved adult disease , dose-finding Phase II studies must be performed prior to the initiation of the Phase III trials used for achieving marketing approval . Phase IBesides optimizing study designs, the PRCSG is actively engaged in the training of pediatric rheumatology investigators. This includes formal training and certification of quantitated reporting of the joint evaluation in children (Joint Assessor Certification)  and the It is the intent of the PRCSG to facilitate translational research studies in pediatric rheumatic diseases. This has proven to be difficult as pharmaceutical firms are determined to minimize trial costs and logistic demands. Generally, the collection of biological samples during studies paid for by biopharmaceutical companies focus on the demands of regulatory agencies and the pharmaceutical sponsor in-house research portfolio. To make matters worse, there were no internationally-accepted standard protocols for the collection, shipping, processing, and storage of pediatric rheumatology biological samples until recently. This short-coming has been addressed by the international consortium UCAN (Understanding Childhood Arthritis Network) , 59. TheSince the 1970’s, the PRCSG has contributed to the methodology of performing trials in pediatric rheumatic diseases. Closely collaborating with PRINTO and industry sponsors, 25 drugs and biologic agents have been studied by the network, resulting in 13 drug and biologic therapies achieving labeling for JIA by the FDA and/or EMA as of 2018. These drugs have dramatically improved the outcomes of children with polyarticular and systemic forms of JIA, leading to improved growth, quality of life, and possibly reduced radiographic joint erosions –65. Upco