This Research Topic contains proceedings of the final conference for COST Action BM1101 “Network of dystonia syndromes”. The topic highlights consolidated knowledge and unmet needs in a field that is evolving very fast.

Catholic University of the Sacred Heart

Frontiers in Neurology

Movement Disorders

Unmet needs in dystonia

The Editorial on the Research Topic<a href="http://journal.frontiersin.org/researchtopic/4314">Unmet Needs in Dystonia</a>The need for a cooperation on dystonia at the European level has been pursued for years. This movement disorder has been extensively studied in Europe, where important advances in knowledge have repeatedly taken place. The pioneering clinical physiologic approach led by David Marsden has deeply characterized European research on dystonia and more recently the clinical and genetic complexity of dystonia has been clarified.In 2011, the European Cooperation in Science and Technology (COST) office approved a European Concerted Research Action designated as COST Action BM1101: European network for the study of dystonia syndromes. The original applicants were from 18 European countries, but later increased to encompass 24 European countries and the United States. By the end of the Action, in 2015, the countries involved were: Belgium, Bulgaria, Croatia, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Latvia, Republic of Macedonia, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, and United Kingdom. Clinicians and researchers from these countries have interacted on research and clinical activities during the 4-year duration of the Action. The European Dystonia Federation (now Dystonia Europe) has been a fundamental partner and has also served as administrative grant holder.The European dystonia players have been deeply engaged by this concerted activity, and our research and personal ties have been reinforced along time. The Action has involved industry partners in additions to patients, doctors, and researchers. This research topic is the Action final publication, following a final conference held on October 2015 at the campus of Humanitas Research Hospital in Rozzano. The title &#x201c;Unmet needs in dystonia&#x201d; was proposed by Kailash Bathia and adopted by the Steering committee to signify the complexity of this area of knowledge that is still characterized by more questions than answers. We consider that this leitmotiv represents well the current state-of-art of dystonia.The common theme of this publication is lumping vs splitting. How many dystonia syndromes exist clinically, genetically, neurophysiologically, etc.?The first chapter in this Research Topic, by <a href="https://doi.org/10.3389/fneur.2017.00018">Albanese</a>, is a clinical and historical review ending with a proposal on the new diagnostic criteria for dystonia syndromes. The descriptions of dystonia from post-medieval ages till now are reported. This exercise accounts for innovative clinical observations and scholar thinking. The second chapter by <a href="https://doi.org/10.3389/fneur.2016.00241">Verbeek and Gasser</a> reviews the genetic heterogeneity of dystonia syndromes. Whole-exome sequencing and genome-wide association studies have allowed the discovery of novel genes and risk factors for dystonia. How to combine clinical and genetic heterogeneity is a matter for future research.The third chapter by <a href="https://doi.org/10.3389/fneur.2016.00045">Valls-Sole and Defazio</a> is an update on blepharospasm. Phenomenology and electrophysiology are reviewed for this simple, yet complex, focal dystonia. A chapter by <a href="https://doi.org/10.3389/fneur.2017.00035">Contarino et al.</a> reviews the complex management of cervical dystonia, the most common focal dystonia syndrome. In this area, we expect several innovations, including treatment of non-motor features and functional neurosurgery. Evidence-based recommendations for the treatment of cervical dystonia with botulinum toxin are reviewed in the fifth chapter. Cervical dystonia is an area where we expect most innovation in management with botulinum neurotoxins. Injection of deep cervical muscles, usage of ultrasound, and EMG combined are rewriting current clinical practice. The next chapter by <a href="https://doi.org/10.3389/fneur.2016.00226">Lin and Nardocci</a> reviews the complex issue of childhood dystonia that is often combined with other movement disorders or neurodevelopmental issues. Finally, the needs and requirements of modern biobanks, an issue extensively discussed within the COST Action, are reviewed by <a href="https://doi.org/10.3389/fneur.2017.00009">Lohmann et al.</a>We hope that these contributions will be helpful to clinicians, researchers, and patients. Altogether they offer a glimpse on dystonia that is not available elsewhere.This effort (and all the activities covered by the COST Acton) have been possible thanks to the dedication of Alistair Newton and Monika Benson (from Dystonia Europe), who deserve all our thanks. Their long-standing friendship under the name of dystonia and their stubborn dedication turned so many common initiatives, including this COST Action, into a success. The author also wish to thank the COST Office (now COST Association) and particularly Inga Dadeshidze and Jeannette Nchung Oru, who assisted us as Science and Administrative Officers.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Supported by COST Action BM1101.

Editorial: Unmet Needs in Dystonia

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Clinical Practice: Evidence-Based Recommendations for the Treatment of Cervical Dystonia with Botulinum Toxin

Literary reports on dystonia date back to post-Medieval times. Medical reports are instead more recent. We review here the early descriptions and the historical establishment of a consensus on the clinical phenomenology and the diagnostic features of dystonia syndromes. Lumping and splitting exercises have characterized this area of knowledge, and it remains largely unclear how many dystonia types we are to count. This review describes the history leading to recognize that focal dystonia syndromes are a coherent clinical set encompassing cranial dystonia (including blepharospasm), oromandibular dystonia, spasmodic torticollis, truncal dystonia, writer’s cramp, and other occupational dystonias. Papers describing features of dystonia and diagnostic criteria are critically analyzed and put into historical perspective. Issues and inconsistencies in this lumping effort are discussed, and the currently unmet needs are critically reviewed.

Literary reports on dystonia date back to post-Medieval times. Medical reports are instead more recent. We review here the early descriptions and the historical establishment of a consensus on the clinical phenomenology and the diagnostic features of dystonia syndromes. Lumping and splitting exercises have characterized this area of knowledge, and it remains largely unclear how many dystonia types we are to count. This review describes the history leading to recognize that focal dystonia syndromes are a coherent clinical set encompassing cranial dystonia (including blepharospasm), oromandibular dystonia, spasmodic torticollis, truncal dystonia, writer&#x2019;s cramp, and other occupational dystonias. Papers describing features of dystonia and diagnostic criteria are critically analyzed and put into historical perspective. Issues and inconsistencies in this lumping effort are discussed, and the currently unmet needs are critically reviewed.

How Many Dystonias? Clinical Evidence

Dystonia belongs to a group of rare diseases (RDs) characterized by etiologic heterogeneity, affection often in childhood, severe and variable clinical manifestation. The burden of this disease is aggravated by the lack of effective and specific treatment. In the field of dystonia as in other RDs the number of available biospecimens is, in general, limited. Here, we report a new approach to collect clinical and genetic data in biospecimens maintained collaboratively by researchers and their associated institutions in a decentralized system. Allowing researchers to have access to significant numbers of samples and corresponding clinical data, biobanking in dystonia might not only provide a powerful tool in the identification of disease genes but also the classification of variants detected in known genes with respect to their clinical relevance. Growing data in genetics due to the technical progress demand for well-annotated and well-managed biobanks, which in near future hold even the potential for biomarker research and generating medical treatment based on clinical and genetic data currently summarized as “personalized medicine.”

Dystonia belongs to a group of rare diseases (RDs) characterized by etiologic heterogeneity, affection often in childhood, severe and variable clinical manifestation. The burden of this disease is aggravated by the lack of effective and specific treatment. In the field of dystonia as in other RDs the number of available biospecimens is, in general, limited. Here, we report a new approach to collect clinical and genetic data in biospecimens maintained collaboratively by researchers and their associated institutions in a decentralized system. Allowing researchers to have access to significant numbers of samples and corresponding clinical data, biobanking in dystonia might not only provide a powerful tool in the identification of disease genes but also the classification of variants detected in known genes with respect to their clinical relevance. Growing data in genetics due to the technical progress demand for well-annotated and well-managed biobanks, which in near future hold even the potential for biomarker research and generating medical treatment based on clinical and genetic data currently summarized as &#x201c;personalized medicine.&#x201d;

Needs and Requirements of Modern Biobanks on the Example of Dystonia Syndromes

Genetic findings of the past years have provided ample evidence for a substantial etiologic heterogeneity of dystonic syndromes. While an increasing number of genes are being identified for Mendelian forms of isolated and combined dystonias using classical genetic mapping and whole-exome sequencing techniques, their precise role in the molecular pathogenesis is still largely unknown. Also, the role of genetic risk factors in the etiology of sporadic dystonias is still enigmatic. Only the systematic ascertainment and precise clinical characterization of very large cohorts with dystonia, combined with systematic genetic studies, will be able to unravel the complex network of factors that determine disease risk and phenotypic expression.

Genetic findings of the past years have provided ample evidence for a substantial etiologic heterogeneity of dystonic syndromes. While an increasing number of genes are being identified for Mendelian forms of isolated and combined dystonias using classical genetic mapping and whole-exome sequencing techniques, their precise role in the molecular pathogenesis is still largely unknown. Also, the role of genetic risk factors in the etiology of sporadic dystonias is still enigmatic. Only the systematic ascertainment and precise clinical characterization of very large cohorts with dystonia, combined with systematic genetic studies, will be able to unravel the complex network of factors that determine disease risk and phenotypic expression.

Unmet Needs in Dystonia: Genetics and Molecular Biology—How Many Dystonias?

Corrigendum: Unmet Needs in the Management of Cervical Dystonia

Dystonia in childhood may be severely disabling and often unremitting and unrecognized. Considered a rare disorder, dystonic symptoms in childhood are pervasive in many conditions including disorders of developmental delay, cerebral palsy (CP), autism, neurometabolic, neuroinflammatory, and neurogenetic disorders. Collectively, there is a need to recognize the role of early postures and movements which characterize phases of normal fetal, infant, and child development as a backdrop to the many facets of dystonia in early childhood neurological disorders and to be aware of the developmental context of dystonic symptoms. The role of cocontraction is explored throughout infancy, childhood, young adulthood, and in the elderly. Under-recognition of pervasive dystonic disorders of childhood, including within CP is reviewed. Original descriptions of CP by Gowers are reviewed and contemporary physiological demonstrations are used to illustrate support for an interpretation of the tonic labyrinthine response as a manifestation of dystonia. Early recognition and molecular diagnosis of childhood dystonia where possible are desirable for appropriate clinical stratification and future precision medicine and functional neurosurgery where appropriate. A developmental neurobiological perspective could also be useful in exploring new clinical strategies for adult-onset dystonia disorders focusing on environmental and molecular interactions and systems behaviors.

Dystonia in childhood may be severely disabling and often unremitting and unrecognized. Considered a rare disorder, dystonic symptoms in childhood are pervasive in many conditions including disorders of developmental delay, cerebral palsy (CP), autism, neurometabolic, neuroinflammatory, and neurogenetic disorders. Collectively, there is a need to recognize the role of early postures and movements which characterize phases of normal fetal, infant, and child development as a backdrop to the many facets of dystonia in early childhood neurological disorders and to be aware of the developmental context of dystonic symptoms. The role of cocontraction is explored throughout infancy, childhood, young adulthood, and in the elderly. Under-recognition of pervasive dystonic disorders of childhood, including within CP is reviewed. Original descriptions of CP by Gowers are reviewed and contemporary physiological demonstrations are used to illustrate support for an interpretation of the tonic labyrinthine response as a manifestation of dystonia. Early recognition and molecular diagnosis of childhood dystonia where possible are desirable for appropriate clinical stratification and future precision medicine and functional neurosurgery where appropriate. A developmental neurobiological perspective could also be useful in exploring new clinical strategies for adult-onset dystonia disorders focusing on environmental and molecular interactions and systems behaviors.

Recognizing the Common Origins of Dystonia and the Development of Human Movement: A Manifesto of Unmet Needs in Isolated Childhood Dystonias

Cervical dystonia (CD) is a movement disorder which affects daily living of many patients. In clinical practice, several unmet treatment needs remain open. This article focuses on the four main aspects of treatment. We describe existing and emerging treatment approaches for CD, including botulinum toxin injections, surgical therapy, management of non-motor symptoms, and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed.

Cervical dystonia (CD) is a movement disorder which affects daily living of many patients. In clinical practice, several unmet treatment needs remain open. This article focuses on the four main aspects of treatment. We describe existing and emerging treatment approaches for CD, including botulinum toxin injections, surgical therapy, management of non-motor symptoms, and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed.

Unmet Needs in the Management of Cervical Dystonia

Blepharospasm (BSP) is a rather distressing form of focal dystonia. Although many aspects of its pathophysiological mechanisms are already known, we lack fundamental evidence on etiology, prevention, and treatment. To advance in our knowledge, we need to review what is already known in various aspects of the disorder and use these bases to find future lines of interest. Some of the signs observed in BSP are cause, while others are consequence of the disorder. Non-motor symptoms and signs may be a cue for understanding better the disease. Various cerebral sites have been shown to be functionally abnormal in BSP, including the basal ganglia, the cortex, and the cerebellum. However, we still do not know if the dysfunction or structural change affecting these brain regions is cause or consequence of BSP. Further advances in neurophysiology and neuroimaging may eventually clarify the pathophysiological mechanisms implicated. In this manuscript, we aim to update what is known regarding epidemiology, clinical aspects, and pathophysiology of the disorder and speculate on the directions of research worth pursuing in the near future.

Blepharospasm (BSP) is a rather distressing form of focal dystonia. Although many aspects of its pathophysiological mechanisms are already known, we lack fundamental evidence on etiology, prevention, and treatment. To advance in our knowledge, we need to review what is already known in various aspects of the disorder and use these bases to find future lines of interest. Some of the signs observed in BSP are cause, while others are consequence of the disorder. Non-motor symptoms and signs may be a cue for understanding better the disease. Various cerebral sites have been shown to be functionally abnormal in BSP, including the basal ganglia, the cortex, and the cerebellum. However, we still do not know if the dysfunction or structural change affecting these brain regions is cause or consequence of BSP. Further advances in neurophysiology and neuroimaging may eventually clarify the pathophysiological mechanisms implicated. In this manuscript, we aim to update what is known regarding epidemiology, clinical aspects, and pathophysiology of the disorder and speculate on the directions of research worth pursuing in the near future.