Dystonia: Then and now.

INTRODUCTION: Dystonia is a rare disorder that has undergone extensive scientific investigation leading to a transformation of understanding over the past century. METHODS: This manuscript was prepared through a review of relevant literature for each topic. RESULTS: Historically dystonia was considered the manifestation of psychiatric disorders. Subsequently, investigations have firmly established this as a neurological disorder. Though electrophysiological and imaging, dystonia is thought to arise from a loss inhibition of motor programs, defective sensorimotor integration and abnormal plasticity. The genetic studies in dystonia have revealed the hereditary nature of many forms of familial dystonia. Treatment of dystonia has focused primarily on botulinum toxin for focal and segmental dystonia and deep brain stimulation of the globus pallidus interna for generalized and medically refractory focal dystonia. CONCLUSION: The progress in dystonia in the past century has revised the concepts of this disorder, increased knowledge of genetics and underlying pathophysiology, and provides new therapeutic targets. To promote future research the development of diagnostic criteria, biomarkers and validated rating scales for each form of dystonia is essential.

Art and dystonia.

Dystonia has a recent history in medicine. Focal dystonia was described in the 19th century by classic authors including Gowers, whilst generalized dystonia was described at the turn of the century. However, it is possible to find precise descriptions of dystonia in art, centuries before the medical definition. We have reviewed several pieces of art (sculpture, painting and literature) across the history that might represent descriptions of dystonia, from ancient period to nowadays. In classic times, the first reference to abnormal postures can be tracked back to the new Empire of Egypt (equinus foot), not to mention some recently described examples of dystonia from the Moche sculptures in Peru or Veracruz culture from Mexico. In Middle Ages it is possible to find many examples of sculptures in European cathedrals representing peasants with dramatic, presumably dystonic postures that coexist with amputation of limbs. This unique combination of dystonia and limb amputation probably represents ergotism. The painters Brueghel, Ribera and Velazquez also represented figures with postures likely to be dystonic. Literature is also a source of precise pre-neurological descriptions, especially during the 19th century. In David Copperfield, Dickens depicts characters with generalized dystonia (Uriah Heep), cervical dystonia (Mr. Sharp) and spasmodic dysphonia (Mr Creakle). Finally, even in modern Art (19th and 20th centuries), there are dramatic descriptions of abnormal postures that are likely to be dystonic, such as painful cervical dystonia (Brancusi), cervical dystonia with sensory trick (Modigliani) and upper limb dystonia (Wyspianski). However some postures presented in works of art may simply be a form of artistic expression and only bear unintentional resemblance to the dystonic postures. Art may be a source of neurological information, and that includes primary and secondary dystonia.

Evolution of the concept of dystonia.

The term dystonia was proposed by Hermann Oppenheim in 1911, but reports of cervical dystonia are finding since the Roman Empire. The differentiation of the dystonia between a neurological and a psychiatric disease turned a lot. Sometimes was proposed, further, the exclusion of the dystonia as a different phenomenon among the movement disorders. The hypothesis of emotional etiology of the dystonias increase in the decade of 1960 and the conclusion of the etiology of dystonia only happened in the decades of 1970 and 1980 with a series of works of Charles David Marsden. These researches defined dystonia as a movement disorder caused by lesion in the basal ganglia. In February of 1984, a committee of members of Scientific Advisory Board of the Dystonia Medical Research Foundation developed the definition for dystonia accepts until 2013 when an international committee developed the new concept.

Evolution of the concept of dystonia / Evolução do conceito de distonia

The term dystonia was proposed by Hermann Oppenheim in 1911, but reports of cervical dystonia are finding since the Roman Empire. The differentiation of the dystonia between a neurological and a psychiatric disease turned a lot. Sometimes was proposed, further, the exclusion of the dystonia as a different phenomenon among the movement disorders. The hypothesis of emotional etiology of the dystonias increase in the decade of 1960 and the conclusion of the etiology of dystonia only happened in the decades of 1970 and 1980 with a series of works of Charles David Marsden. These researches defined dystonia as a movement disorder caused by lesion in the basal ganglia. In February of 1984, a committee of members of Scientific Advisory Board of the Dystonia Medical Research Foundation developed the definition for dystonia accepts until 2013 when an international committee developed the new concept.

O termo distonia foi proposto por Hermann Oppenheim em 1911, porém, quadros de distonia cervical são encontrados desde a antiguidade. A categorização da distonia entre uma doença neurológica ou psiquiátrica mudou muitas vezes sendo proposta, inclusive, a retirada da distonia como um fenômeno distinto entre os distúrbios do movimento. A etiologia emocional das distonias teve grande força na década de 1960 e o fim da discussão etiológica da distonia somente ocorreu nas décadas de 1970 e 1980 com uma série de trabalhos de Charles David Marsden colocando a distonia como um distúrbio do movimento por lesão nos gânglios da base. Em fevereiro de 1984, um comitê formado de membros da Scientific Advisory Board of the Dystonia Medical Research Fundation desenvolveu a definição para distonia aceita até 2013 quando um comitê internacional desenvolveu a definição aceita atualmente.

Genetics in dystonia.

While Hermann Oppenheim probably described the first cases of genetic (DYT1) dystonia in 1911, the 'modern history' of dystonia genetics dates back to 1994 when mutations in the GTP cyclohydrolase I gene were discovered to cause dopa-responsive dystonia. Due to the advent of next-generation sequencing, the field of dystonia genetics has been evolving very rapidly over the past two years, resulting in the reporting of 'DYT1-25' and, for the first time, in the identification of genes associated with adult-onset focal/segmental dystonia. However, three of these putative new genes still await independent confirmation (TUBB4/DYT4; CIZ1/DYT23; ANO3/DYT24) and only 11 'DYT' genes have been unequivocally demonstrated to cause different forms of dystonia. Based on a recent consensus approach, dystonias are subdivided on clinical grounds into isolated (with or without tremor) and combined (with other movement disorders) forms. Confirmed genes for isolated dystonias include TOR1A/DYT1; THAP1/DYT6; GNAL/DYT25. In the combined forms, dystonia is accompanied by parkinsonism (GCH1/DYT5a; TH/DYT5b; ATP1A3/DYT12; TAF1/DYT3) or myoclonus (SGCE/DYT11). Persistent and paroxysmal forms are distinguished according to their temporal pattern. The paroxysmal forms of dystonia/dyskinesias present with a mixed pattern of hyperkinetic movement disorders (PRRT2/DYT10; MR-1/DYT8; SLC2A1/DYT18).

Milestones in dystonia.

The last 25 years have seen remarkable advances in our understanding of the genetic etiologies of dystonia, new approaches into dissecting underlying pathophysiology, and independent progress in identifying effective treatments. In this review we highlight some of these advances, especially the genetic findings that have taken us from phenomenological to molecular-based diagnoses. Twenty DYT loci have been designated and 10 genes identified, all based on linkage analyses in families. Hand in hand with these genetic findings, neurophysiological and imaging techniques have been employed that have helped illuminate the similarities and differences among the various etiological dystonia subtypes. This knowledge is just beginning to yield new approaches to treatment including those based on DYT1 animal models. Despite the lag in identifying genetically based therapies, effective treatments, including impressive benefits from deep brain stimulation and botulinum toxin chemodenervation, have marked the last 25 years. The challenge ahead includes continued advancement into understanding dystonia's many underlying causes and associated pathology and using this knowledge to advance treatment including preventing genetic disease expression.

Adult-onset dystonia.

Dystonia is defined as involuntary sustained muscle contractions producing twisting or squeezing movements and abnormal postures. The movements can be stereotyped and repetitive and they may vary in speed from rapid to slow; sustained contractions can result in fixed postures. Dystonic disorders are classified into primary and secondary forms. Several types of adult-onset primary dystonia have been identified but all share the characteristic that dystonia (including tremor) is the sole neurologic feature. The forms most commonly seen in neurological practice include cranial dystonia (blepharospasm, oromandibular and lingual dystonia and spasmodic dysphonia), cervical dystonia (also known as spasmodic torticollis) and writer's cramp. These are the disorders that benefit most from botulinum toxin injections. A general characteristic of dystonia is that the movements or postures may occur in relation to specific voluntary actions by the involved muscle groups (such as in writer's cramp). Dystonic contractions may occur in one body segment with movement of another (overflow dystonia). With progression, dystonia often becomes present at rest. Dystonic movements typically worsen with anxiety, heightened emotions, and fatigue, decrease with relaxation, and disappear during sleep. There may be diurnal fluctuations in the dystonia, which manifest as little or no involuntary movement in the morning followed by severe disabling dystonia in the afternoon and evening. Morning improvement (or honeymoon) is seen with several types of dystonia. Patients often discover maneuvers that reduce the dystonia and which involve sensory stimuli such as touching the chin lightly in cervical dystonia. These maneuvers are known as sensory tricks, or gestes antagonistes. This chapter focuses on adult-onset focal dystonias including cranial dystonia, cervical dystonia, and writer's cramp. The chapter begins with a review of the epidemiology of focal dystonias, followed by discussions of each major type of focal dystonia, covering clinical phenomenology, differential genetics, and diagnosis. The chapter concludes with discussions of the pathophysiology, the few pathological cases published of adult-onset focal dystonia and management options, and a a brief look at the future.

Egon Schiele and dystonia.

Egon Schiele was a leading Austrian Expressionist painter who, after the era of Gustav Klimt, strongly influenced the artistic scene in Vienna in the early 20th century. Schiele's depiction of his body in his self-portraits in a twisted, contorted, dystonia-like pose raised questions about the possibility of his suffering from dystonia. However, there are no grounds whatsoever for such a hypothesis. Schiele's conception of distorted, at times bizarre, body postures reflects a concourse of the Expressionist formal style of displaying extroverted emotions and psychic confl icts with the emerging perception of photographs of patients with movement disorders in Vienna's art scene and intellectual circles. There are reliable indications that Schiele knew the images of diseases published in the 'Iconographie Photographique de la Salpetriere' and the later 'Nouvelle Iconographie de la Salpetriere' including hysterical and dystonic postures. The brevity of Schiele's life adds to the popular fantasy of the outlaw who lived fast and died young. In fact, however, his drawings sold well to discerning collectors, and his exhibitions were a financial success, so the myth of Schiele as a sacrificial outcast does not tell the whole story. It may be speculated that the figuration of the pathological body in Schiele's self-portraiture was part of modernist strategizing.

How psychogenic is dystonia? Views from past to present.

In the last few centuries, there has been a constant sway between organic and psychogenic explanations for dystonia. In the current study, we investigate this history, assuming the perspective of a spectrum from organic to psychogenic, between which ideas were moving. We have focussed on (i) primary generalized dystonia, (ii) cervical dystonia, (iii) writer's cramp and (iv) fixed dystonia related to complex regional pain syndrome. We have studied medical texts published since the 19th century and their references. Jean-Martin Charcot advocated the concept of hysteria, disorders in which, besides predisposition, environmental factors were involved in their pathogenesis. Sigmund Freud introduced psychoanalysis as an explanatory therapy for psychic disorders. Previous theories, together with the lack of an organic substrate for dystonia, made a strong case for psychogenic explanations. Consequently, many dystonia patients were told that they suffered from psychological conflicts and were treated for them. However, after the description of new hereditary cases in the 1950s, the limited efficacy of psychotherapy in torsion dystonia, the effects of surgical treatments and the lesion studies in the 1960s, more physicians became convinced of the organic nature. The culminating point was the discovery of the DYT1 gene in 1997. In the meantime, experts had already convinced the neurological community that cervical dystonia and writer's cramp were focal dystonias, i.e. minor forms of generalized dystonia, and therefore organic disorders. In contrast, the pathophysiology of fixed dystonia related to complex regional pain syndrome remained controversial. Knowledge of this history, which played on the border between neurology and psychiatry, is instructive and reflects the difficulty in discriminating between them. Today, new insights from functional imaging and neurophysiological studies again challenge the interpretation of these disorders, while the border between psychogenic and organic has become more blurred. Abnormalities of sensorimotor integration and cortical excitability that are currently supposed to be the underlying cause of dystonia bring us back to Sherringtonian physiology. We suggest that this may lead to a common explanation of the four afflictions of which we have traced the history.

[Segawa disease].

The first report of Segawa disease was a report of two girls, cousin each other, with dystonic posture, under the title of "Hereditary progressive basal ganglia disorder" in 1971. After accumulation of cases with an adult case, I confirmed this disease does not transform to Parkinson's disease in adulthood and published with a nomenclature of "Hereditary progressive dystonia with marked diurnal fluctuation" in 1976. Polysomnographical examination for evaluating the sleep effects and correlation of the natural course to the age variation of the tyrosine hydroxylase activities in the striatum, these speculated this is a particular disorder caused by non-progressive decrement of the tyrosine hydroxylase at the terminal of the nigrostriatal dopamine neuron. This was supported by PET studies in early 1990's. Evaluation of pteridine metabolites in cerebrospinal fluid revealed partial decrement of the GTP cyclohydrolase I as the cause of this disease and induced the discovery of the causative gene. After the discovery of the gene, an autopsied case with dopa-responsive dystonia was confirmed as Segawa disease and the neuropathological and histochemical findings confirmed the hypothesis. Furthermore, these showed rather selective involvement the D1-direct pathways in the disease. However, it was also clarified existence of two types, one, classic type, postural dystonia and the other action dystonia with vigorous dystonic movements besides dystonic posture, which, is postulated to be caused by the dopamine neuron innervating to the subthalamic nucleus with D1 neuron. Existence of these two phenotypes also provides phenotypical variation of Segawa disease.

Early cinematographic studies of generalized dystonia.

Among movement disorders, dystonia is a particularly complex phenomenon and difficult to describe. For this reason, cinematographic documents were particularly important to the establishment of this disorder within the neurological nosology. The seminal 1944 article on dystonia by E. Herz anchored its arguments in moving film documentation, published with frame-by-frame demonstrations of dystonic patients. Although the original films that comprised the basis of this article have not been located, two related contemporaneous films, one by Herz in association with T.J. Putnam, and one by S.P. Goodhart and B.H. Balser, have been located. Incorporating standard and several innovative filming techniques, these films and their accompanying text material capture the particular movements of dystonia, revealing the anatomical patterns of the twisting spasms, and emphasize their action exacerbation. The films demonstrate the variety of dystonic movements appreciated during this period, consider psychogenic, postencephalitic, and hereditary forms, and refer to the treatment of dystonia by surgery and plaster casts.

Movement disorders associated with encephalitis lethargica: a video compilation.

Encephalitis lethargica (EL; epidemic encephalitis; von Economo's disease) often presented with a movement disorder, and the motor consequences of postencephalitic parkinsonism (PEP) were characteristic of the chronic sequelae of this condition. PEP was similar to Parkinson's disease but was more variable and had some distinct features such as oculogyric crises. Although two previous publications have included video images of the movement disorders associated with EL and PEP, the sequences presented were typically short, showed only a few patients, and did not include the work of several neurologists who had the foresight to preserve filmed images of their patients. We describe the most complete record of EL and PEP moving images that have been preserved and make them available in edited form.

Fifty years of brain surgery for dystonia: revisiting the Irving S. Cooper's legacy, and looking forward.

As dystonia may represent a severe disease with possible fatal outcome or physical or social incapacity, and considering the limited efficacy of drug treatments (excepted doparesponsive dystonia), efforts have been made since the 1950s to propose alternative treatment. In this paper, an overview of the works done by neurosurgeons over fifty years to treat severe dystonia is presented. In this area of therapeutical research, the pioneering contribution of Irving Cooper is presented and discussed, and the way his publications were evaluated emphasized. Undoubtedly, Cooper observed striking improvement after performing basal ganglia lesions in patients with generalized dystonia, even in the long term. It should be noted that he early made almost the same statements as today's preliminary observations regarding the clinical criteria for the selection of good responders to brain functional surgery. However, the message was lost, given the amount of critics Cooper received, and probably, the way he required to present them. This point emphasize the need we are today to carry out carefully designed, controlled, double-blind studies in this area.