Objective
Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome‐associated autoinflammatory syndrome ...(CANDLE/PRAAS), stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI), and Aicardi‐Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of “points to consider” to improve diagnosis, treatment, and long‐term monitoring of patients with these rare diseases.
Methods
Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, “points to consider” to guide patient management were developed.
Results
The Task Force devised consensus and evidence‐based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long‐term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS.
Conclusion
These points to consider represent state‐of‐the‐art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.
Faces hold a substantial value for effective social interactions and sharing. Covering faces with masks, due to COVID-19 regulations, may lead to difficulties in using social signals, in particular, ...in individuals with neurodevelopmental conditions. Daily-life social participation of individuals who were born preterm is of immense importance for their quality of life. Here we examined face tuning in individuals (aged 12.79 ± 1.89 years) who were born preterm and exhibited signs of periventricular leukomalacia (PVL), a dominant form of brain injury in preterm birth survivors. For assessing the face sensitivity in this population, we implemented a recently developed experimental tool, a set of Face-n-Food images bordering on the style of Giuseppe Arcimboldo. The key benefit of these images is that single components do not trigger face processing. Although a coarse face schema is thought to be hardwired in the brain, former preterms exhibit substantial shortages in the face tuning not only compared with typically developing controls but also with individuals with autistic spectrum disorders. The lack of correlations between the face sensitivity and other cognitive abilities indicates that these deficits are domain-specific. This underscores impact of preterm birth sequelae for social functioning at large. Comparison of the findings with data in individuals with other neurodevelopmental and neuropsychiatric conditions provides novel insights into the origins of deficient face processing.
Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), ...stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases.
Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed.
The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS.
These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.
Cerebral palsy is a non-progressive syndrome due to a pre-, peri- or postnatal brain injury, which frequently involves an impairment of non-motor abilities. The aim of this paper was to examine ...visuospatial attention and inhibitory control of prepotent motor responses in children with cerebral palsy showing a normal IQ or mild cognitive impairment, measuring their performance in oculomotor tasks. Ten children (9-16 year-old) with spastic cerebral palsy and 13 age-matched, typically developing children participated in the study. Subjects performed a simple visually-guided saccade task and a cue-target task, in which they performed a saccade towards a peripheral target, after a non-informative visual cue was flashed 150 ms before the imperative target, either at the same (valid) or at a different (invalid) spatial position. Children with cerebral palsy showed severe executive deficits in maintaining sustained attention and complying with task instructions. Furthermore, saccadic inhibitory control appeared to be significantly impaired in presence of both stimulus-driven and goal-directed captures of attention. In fact, patients showed great difficulties in suppressing saccades not only to the cue stimuli, but also to the always-present target placeholders, which represented powerful attentional attractors that had to be covertly attended throughout the task execution. Moreover, impairment did not affect in equal manner the whole visual field, but showed a marked spatial selectivity in each individual subject. Saccade latencies in the cue-target task were faster in the valid than in the invalid condition in both child groups, indicating the preservation of low-level visuospatial attentive capabilities. Finally, this study provides evidence that these impairments of executive skills and in inhibitory control, following early brain injuries, manifest in childhood but recover to virtually normal level during adolescence.
Cerebral visual impairment (CVI) is a brain based visual disorder associated with the maldevelopment of central visual pathways. Individuals with CVI often report difficulties finding a target of ...interest in cluttered and crowded visual scenes. However, it remains unknown how manipulating task demands and other environmental factors influence visual search performance in this population.
We developed a novel and naturalistic virtual reality (VR) based static visual search task combined with eye tracking called the “virtual toy box” to objectively assess visual search performance in CVI.
A total of 38 individuals with CVI (mean age 13.18 years ± 3.58 SD) and 53 controls with neurotypical development (mean age 15.25 years ± 5.72 SD) participated in the study. In a first experiment, study subjects were instructed to search for a preselected toy presented among a varying number of surrounding distractor toys (set size ranging from 1 to 36 items). In a second experiment, we assessed the effects of manipulating item spacing and the size of the visual area explored (field of view; FOV).
Behavioral outcomes collected were success rate, reaction time, gaze error, visual search area, and off-screen percent (an index of task compliance). Compared to age-matched controls, participants with CVI showed an overall impairment with respect to all the visual search outcomes of interest. Specifically, individuals with CVI were less likely and took longer to find the target, and search patterns were less accurate and precise compared to controls. Visual search response profiles were also comparatively less efficient and were associated with a slower initial pre-search (visual orienting) response as indexed by higher slope and intercept values derived from the analysis of reaction time × set size functions. Search performance was also more negatively affected in CVI at the smallest as well as largest spacing conditions tested, while increasing FOV was associated with greater decreased gaze accuracy and precision
These results are consistent with a general profile of impaired visual search abilities in CVI as well as worsening performance with increased visual task demands and an overall sensitivity to visual clutter and crowding. The observed profile of impaired visual search performance may be associated with dysfunctions related to how visual selective attention is deployed in individuals with CVI.
•Higher order visual perceptual abilities are typically not assessed as part of a standard ophthalmological exam.•Visual search performance in CVI was characterized by using a novel virtual reality-based task combined with eye tracking.•Compared to age-matched controls, participants with CVI showed an overall impairment in performance on all visual search outcomes of interest.•The general profile observed in CVI was consistent with worsening performance with increased visual task demands and sensitivity to visual clutter and crowding.
Individuals with cerebral visual impairment (CVI) have difficulties identifying common objects, especially when presented as cartoons or abstract images. In this study, participants were shown a ...series of images of ten common objects, each from five possible categories ranging from abstract black & white line drawings to color photographs. Fifty individuals with CVI and 50 neurotypical controls verbally identified each object and success rates and reaction times were collected. Visual gaze behavior was recorded using an eye tracker to quantify the extent of visual search area explored and number of fixations. A receiver operating characteristic (ROC) analysis was also carried out to compare the degree of alignment between the distribution of individual eye gaze patterns and image saliency features computed by the graph-based visual saliency (GBVS) model. Compared to controls, CVI participants showed significantly lower success rates and longer reaction times when identifying objects. In the CVI group, success rate improved moving from abstract black & white images to color photographs, suggesting that object form (as defined by outlines and contours) and color are important cues for correct identification. Eye tracking data revealed that the CVI group showed significantly greater visual search areas and number of fixations per image, and the distribution of eye gaze patterns in the CVI group was less aligned with the high saliency features of the image compared to controls. These results have important implications in helping to understand the complex profile of visual perceptual difficulties associated with CVI.
Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during ...preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control.
Other issues related to the reproductive journey have emerged as “unmet needs”, such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper.
Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.
Individuals with Down syndrome (DS) are widely believed to possess considerable socialization strengths. However, the findings on social cognition capabilities are controversial. In the present ...study, we investigated whether individuals with DS exhibit shortage in face tuning, one of the indispensable components of social cognition. For this purpose, we implemented a recently developed Face-n-Food paradigm with food-plate images composed of food ingredients such as fruits and vegetables. The key benefit of such face-like non-face images is that single elements do not facilitate face processing. In a spontaneous recognition task, 25 children with DS aged 9 to 18 years were presented with a set of Face-n-Food images bordering on the Giuseppe Arcimboldo style. The set of images was administered in a predetermined order from the least to most resembling a face. In DS individuals, thresholds for recognition of the Face-n-Food images as a face were drastically higher as compared not only with typically developing controls, but also with individuals with autistic spectrum disorders and Williams-Beuren syndrome. This outcome represents a significant step toward better conceptualization of the visual social world in DS and neurodevelopmental disorders in general.
Summary Background Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes ( TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1 , and ADAR ). The disease is ...severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven 27% of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r =−0·604; serum, r =−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding European Union's Seventh Framework Programme; European Research Council.
Different pathologic processes (especially demyelination, hypomyelination, and combinations of these) may underlie leukoencephalopathies. Leukoencephalopathies pose a particular diagnostic problem ...when they occur in children. To seek associated, non-neurologic signs is of fundamental importance in hypomyelinating leukoencephalopathies, because these can help clarify the diagnostic picture. Two new types of leukoencephalopathy have emerged, one classified as ataxia, delayed dentition, and hypomyelination, and the other as hypomyelination with hypogonadotropic hypogonadism and hypodontia. Initially described as distinct entities, they were recently brought together in the Online Mendelian Inheritance in Man database under a single code. However, the literature describes only two patients with the characteristics of both these clinical pictures. We present the extended clinical and neuroradiologic follow-up of a patient with ataxia, delayed dentition, and hypomyelination, as well as hypogonadotropic hypogonadism. This patient reinforces the idea that the two syndromes should actually be considered the same disorder, and prompted us to conduct a critical review of the literature on disorders in which hypomyelinating leukoencephalopathy is associated with cerebellar atrophy or hypogonadism.