Primary focal dystonia is an idiopathic neurological disorder causing involuntary muscle contraction. Its pathophysiology probably involves the basal ganglia and cortical-basal pathways. Primary dystonia appears to be associated with significant obsessive-compulsive symptoms, but evidence remains scarce and contradictory. We addressed the following research questions: (1) Do primary dystonia patients have high obsessive-compulsive symptom scores? (2) Are these symptoms more severe in dystonia than in controls with equivalent peripheral neurological disorders? and (3) Is psychopathology different in botulinum toxin-treated and -untreated dystonia patients? This work was a cross-sectional, descriptive, controlled study comprising 45 consecutive patients with primary focal dystonia (i.e., blepharospasm, spasmodic torticollis, or writer's cramp) 46 consecutive patients with hemifacial spasm, cervical spondylarthropathy, or carpal tunnel syndrome, and 30 healthy volunteers. Assessment included the DSM-IV based psychiatric interview, Symptom Checklist 90R, Yale-Brown Obsessive-Compulsive Scale and Checklist, and the Unified Dystonia Rating Scale. Dystonia patients had higher Yale-Brown Obsessive-Compulsive Symptom scores than both control groups. Dystonia patients with obsessive-compulsive symptom scores above cut-off for clinical significance predominantly developed hygiene-related symptoms. Major depression and generalized anxiety disorder were the most frequent psychiatric diagnoses in primary focal dystonia. Obsessive-compulsive disorder frequency was 6.7%. Primary focal dystonia patients have higher obsessive-compulsive symptom scores than individuals with similar functional disabilities resulting from other neurological disorders, suggesting that obsessive-compulsive symptoms in dystonia are not reactive to chronic disability. Dystonic muscle contractions and obsessive-compulsive symptoms may share a common neurobiological basis related to cortical-basal dysfunction. Psychopathology, especially obsessive-compulsive symptoms, should be actively explored and treated in primary focal dystonia.

Adult-onset primary torsion dystonia (AOPTD) is an autosomal dominant disorder with markedly reduced penetrance. Sensory abnormalities are present in AOPTD and also in unaffected relatives, possibly indicating non-manifesting gene carriage (acting as an endophenotype). The temporal discrimination threshold (TDT) is the shortest time interval at which two stimuli are detected to be asynchronous. We aimed to compare the sensitivity and specificity of three different TDT tasks (visual, tactile and mixed/visual-tactile). We also aimed to examine the sensitivity of TDTs in different AOPTD phenotypes. To examine tasks, we tested TDT in 41 patients and 51 controls using visual (2 lights), tactile (non-painful electrical stimulation) and mixed (1 light, 1 electrical) stimuli. To investigate phenotypes, we examined 71 AOPTD patients (37 cervical dystonia, 14 writer's cramp, 9 blepharospasm, 11 spasmodic dysphonia) and 8 musician's dystonia patients. The upper limit of normal was defined as control mean +2.5 SD. In dystonia patients, the visual task detected abnormalities in 35/41 (85%), the tactile task in 35/41 (85%) and the mixed task in 26/41 (63%); the mixed task was less sensitive than the other two (p = 0.04). Specificity was 100% for the visual and tactile tasks. Abnormal TDTs were found in 36 of 37 (97.3%) cervical dystonia, 12 of 14 (85.7%) writer's cramp, 8 of 9 (88.8%) blepharospasm, 10 of 11 (90.1%) spasmodic dysphonia patients and 5 of 8 (62.5%) musicians. The visual and tactile tasks were found to be more sensitive than the mixed task. Temporal discrimination threshold results were comparable across common adult-onset primary torsion dystonia phenotypes, with lower sensitivity in the musicians.

Role of basal ganglia: Vesalius and Piccolomini distinguished subcortical nuclei from cortex and white matter in the 16th century. Willis' mistaken concept in the late 17th century that the corpus striatum was the seat of motor power persisted for 200 years and formed the basis of mid-19th-century localizations of movement disorders to the striatum (chorea by Broadbent and Jackson, and athetosis by Hammond). By the late 19th century, many movement disorders were described but for most no pathologic correlate was known. Tremor: Descriptions of tremors progressed from Galen's definition in the 2nd century; to Galileo's physiologic tremor in 1610; separation of involuntary movements during action and at rest in the 17th and 18th centuries by de la Boë Sylvius and van Sweiten; description of Parkinson's disease by Parkinson, discrimination of the rest tremor of Parkinson's disease from the intention tremor of multiple sclerosis by Charcot, and recognition of familial action tremors by Dana and others in the late 19th century; and recognition of autosomal dominant essential tremor in the mid-20th century. Parkinsonism: Pathologic changes in Parkinson's disease were recognized in the substantia nigra by Blocq and Marinescu in the late 19th century, and around 1920 Trértiakoff established Lewy bodies in the substantia nigra as a pathologic hallmark while the Vogts instead emphasized pathologic changes in the striatum; it was only in the mid-1960s that a nigrostriatal dopaminergic pathway was demonstrated and found to be critical to pathogenesis. Early treatment approaches with anticholinergic medications or crude neurosurgical ablation procedures were eclipsed in the 1960s by the advent of L-DOPA therapy due to the work of Carlsson and colleagues, Birkmayer and Hornykiewicz, Barbeau, and Cotzias. Later progress in understanding and treating Parkinson's disease included recognition of neuroleptic-induced parkinsonism beginning in the 1950s, development of dopamine agonists and elaboration of different dopamine receptors beginning in the 1960s, recognition of MPTP-induced parkinsonism in 1982 and subsequent development of experimental models of MPTP-induced parkinsonism. Since the 1980s, stereotactic neurosurgical ablation procedures such as stereotactic pallidotomy were revisited and improved, and stimulation or ablation procedures that modulate subthalamic nucleus activity were developed. Since 1990, rare genetic forms of Parkinson's disease were discovered, which accelerated progress in understanding pathogenesis, and established roles for alpha synuclein and the ubiquitin-proteasome proteolytic system. Separation of atypical forms of parkinsonism (e.g. Wilson's disease, multisystem atrophy, progressive supranuclear palsy, and corticobasal degeneration) from Parkinson's disease in the 20th century also led to important discoveries of basal ganglia function, and in the case of Wilson's disease to recognition of genetic mutations and effective treatments. Choreoathetosis: Since the middle ages, the term chorea has been used to describe both organic and psychological disorders of motor control. Paracelcus introduced the concept of chorea as an organic medical condition in the 16th century. Sydenham's description of childhood chorea (1686) was followed by recognition in the 19th and 20th centuries that Sydenham's chorea was a manifestation of rheumatic fever; by the 1930s, rheumatic fever was recognized as a sequel of group A streptococcal pharyngitis, which could be effectively prevented with sulfonamides. Athetosis was described by Hammond (1871) and later linked by him to a malignant growth in the contralateral corpus striatum; nevertheless, athetosis has been controversial and often dismissed as a form of post-hemiplegic chorea or part of a continuum between chorea and dystonia. Huntington's classic description of adult-onset hereditary chorea (1872) was followed a century later by demonstration that Huntington's disease is caused by an unstable CAG trinucleotide repeat expansion in the Huntington disease gene on chromosome 4; this triggered a surge in research, development of various animal models, and numerous important discoveries of cell function and disease pathogenesis. Hemiballismus and the subthalamic nucleus: The relationship between a lesion of the subthalamic nucleus of Luys and contralateral hemiballismus was first convincingly demonstrated by Martin in 1927; this led 20 years later to development of an animal model by Whittier and Mettler, who produced experimental hemichorea-hemiballismus in monkeys by lesioning the contralateral subthalamic nucleus. Since the late 1980s, the neurochemistry and neurophysiology of the subthalamic nucleus have been substantially revised with the demonstration that the subthalamic nucleus is not fundamentally inhibitory but instead provides excitatory glutaminergic inputs to the globus pallidus, and appreciation that the subthalamic nucleus serves an important role in both hyperkinetic and hypokinetic movement disorders. Dystonia: Dystonias were often interpreted in psychological or psychiatric terms since the original descriptions of generalized dystonia by Barraquer Roviralta (1897), and familial forms of generalized primary tortion dystonia by Schwalbe (1908) and Oppenheim (1911). Although Oppenheim had first insisted that dystonia was an organic disease, it was only in the late-20th century that an organic framework was firmly established with the identification of genetic mutations in some families with dystonia and with the demonstration that the basal ganglia were often damaged contralateral to acquired hemidystonia. Focal and segmental forms of dystonia, including writer's cramp, other occupational dystonias, and torticollis, were also recognized in the 19th century. Writer's cramp was clearly described in the 1830s by Bell and Kopp, and increasingly recognized in the late 19th century due in part to Solly's influential lectures on "scriviner's palsy" in the 1860s, and to increasing prevalence because of the increase in writing using primitive writing instruments. Myoclonus: In 1903, Lundborg proposed a classification of myoclonus that remains in use, with primary (essential), epileptic, and secondary or symptomatic categories: essential myoclonus was described by Friedrich in 1881; forms of myoclonic epilepsy were described beginning in the late 19th century by West (1861), Unverricht (1891), and Lundberg (1903); and secondary multifocal myoclonus was recognized in a wide variety of disorders beginning in the 1920s. Asterixis was described in patients with hepatic encephalopathy by Adams and Foley in 1949 and found to result from electrically silent pauses in muscle activity, which led to the concept of negative myoclonus in the 1980s. Posthypoxic action myoclonus (Lance-Adams syndrome) was described by Lance and Adams in 1963 and found to incorporate both positive and negative components. Startle syndromes: Early descriptions of pathologic startle syndromes included Beard's description of the jumping Frenchmen of Maine (1878) and Hammond's description of miryachit (1884), both of which may have had psychological origins. In contrast, hyperekplexia or "startle disease" was described in the late 1950s and early 1960s, and genetic forms were later found to result from various mutations affecting glycinergic synapses. Tics: Tic disorders were described by Itard (1825) and Trousseau (1873), but only gained wider recognition in the late 19th century after Charcot presented cases before his classroom audiences and after Gilles de la Tourette's classic description in 1885. Gilles de la Tourette and Charcot initially considered tic disorders and startle syndromes to be similar if not identical, but these disorders were later recognized as distinct. Psychodynamic and psychological theories or etiology gave way in the 1960s to biological theories supporting an important role for dopamine in pathogenesis, particularly with the discovery that neuroleptic medications could be useful in treatment.

Conclusion:

In the last two centuries, neuroscientists and clinicians contributed greatly to our understanding of basal ganglia anatomy and physiology, as well as to movement disorder semiology, pathophysiology, treatment, and prevention. The development of animal models, and the increasing use of genetic and molecular biological techniques will lead to further advances in the coming years.

Dystonia can occasionally be found in idiopathic Parkinson's disease. It is very uncommon in untreated patients and is more frequently seen as a complication of its treatment. In this review, the various types of dystonia occurring in PD, the differential diagnosis with other parkinsonian syndromes associated with dystonia and treatments available are revised. Dystonia unrelated to treatment can be typical (blepharospasm, torticollis), atypical (parkinsonian writer's cramp, camptocormia, anismus), or occurring in earlyonset Parkinson disease (the so-called kinesigenic foot dystonia, considered a hallmark of early-onset Parkinson's disease). Early and prominent dystonia in untreated patients with parkinsonism should raise the suspicion of other entities other than Parkinson's disease, such as progressive supranuclear palsy, multiple system atrophy or corticobasal degeneration. In patients on chronic dopaminergic treatment, peak-dose dystonia, diphasic dystonia and off-dystonia can be seen. The later constitutes the major dystonic feature of chronic levodopa therapy, and a wide variety of strategies are available to manage this complication. Among them, deep brain stimulation of the subthalamic nucleus has proved to be the most effective one. Dystonic reactions (mainly involving oculomotor cranial nerves and limbs) in operated patients (especially carriers of deep brain stimulation (DBS) devices) are increasingly being reported, constituting a new type of dystonia in patients with Parkinson's disease: dystonia linked to surgical treatment.

An epidemiological survey of primary focal dystonias in the western area of Tottori Prefecture in Japan was conducted in 2003, and the results were compared with those of a previous survey in 1993. The service-based prevalence of primary focal dystonia was 13.7 per 100,000 population, representing an increase from that found in the 1993 survey. In 1997, botulinum toxin type A was approved for use in Japan to treat blepharospasm, and the increased number of patients now being evaluated and diagnosed with focal dystonias at medical centers throughout Japan may be responsible for this increased prevalence. Prevalence by subtype per 100,000 population was as follows: facial dystonia, 6.5; spasmodic torticollis, 2.0; writer's cramp, 4.4; and other focal dystonias; 0.8. Facial dystonia showed the most marked increase in service-based prevalence among these subtypes.

Animal models indicate that the abnormal movements of focal dystonia result from disordered sensorimotor integration. Sensorimotor integration involves a comparison of sensory information resulting from a movement with the sensory information expected from the movement. Unanticipated sensory signals identified by sensorimotor processing serve as signals to modify the ongoing movement or the planning for subsequent movements. Normally, this process is an effective mechanism to modify neural commands for ongoing movement or for movement planning. Animal models of the focal dystonias spasmodic torticollis, writer's cramp, and benign essential blepharospasm reveal different dysfunctions of sensorimotor integration through which dystonia can arise. Animal models of spasmodic torticollis demonstrate that modifications in a variety of regions are capable of creating abnormal head postures. These data indicate that disruption of neural signals in one structure may mutate the activity pattern of other elements of the neural circuits for movement. The animal model of writer's cramp demonstrates the importance of abnormal sensory processing in generating dystonic movements. Animal models of blepharospasm illustrate how disrupting motor adaptation can produce dystonia. Together, these models show mechanisms by which disruptions in sensorimotor integration can create dystonic movements.

Functional neuroimaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), provides a valuable technique for detecting regional changes in brain metabolic activity associated with human disease. These techniques have been applied in different dystonic disorders including primary generalized dystonia and dopa-responsive dystonia (DRD), as well as focal dystonic syndromes such as torticollis, writer's cramp, and blepharospasm. A common finding is abnormality of the basal ganglia and associated outflow pathways to sensorimotor cortex and other regions involved with motor performance. Other recent imaging research has utilized diffusion-based MRI techniques to localize distinct microstructural abnormalities in dystonia patients and gene carriers. This presentation will focus on an integrated approach to understanding the pathophysiology of this genetic and biochemically diverse disorder.

A questionnaire about the treatment of dystonia was sent out to 585 councilors of Societas Neurologica Japonica. One hundred and sixty-eight replies (28.7%) were collected, although some of them were excluded from the analysis because of inappropriateness. 1) The number of patients previously experienced was < 10; 37 respondents (22.7%), 10-50; 83 (50.9%), 50-100; 26 (16.0%), and > 100; 17 (10.4%). 2) Oral medication was most often the first line treatment in either of generalized dystonia, blapharospasm, cervical dystonia, and writer's cramp. Botulinum toxin injection was the first or the second line treatment in 147 (87.5%) and 116 (69.0%) respondents for blepharospasm and cervical dystonia, respectively. In these two conditions, the more experienced doctors tended to prefer botulinum toxin injection to the other treatments as the first choice (Cochran-Armitage analysis; p = 0.003 for blepharospasm and p = 0.002 for cervical dystonia). 3) Among the oral drugs, anticholinergics, especially trihexyphenidyl, were the most frequent choice in generalized dystonia, cervical dystonia, and writer's cramp. For blepharospasm, clonazepam was most favored. Sedatives, especially diazepam, were also often the drug of choice in either of these disorders. The favored drugs were not related to the respondent's experience. 4) The success rate of treatment, designated as the percentage of patients who improved through any treatment so much that the respondent was satisfied with it, was the highest in blepharospasm (65.4 +/- 24.1; mean +/- SD), followed by cervical dystonia (41.2 +/- 23.4), writer's cramp (32.9 +/- 22.5), and generalized dystonia (20.4 +/- 19.8). Only in cervical dystonia, the rate was significantly higher in more experienced respondents (regression analysis; p = 0.008). In blepharospasm (p < 0.001) and cervical dystonia (p = 0.002), regression analysis indicated that the success rate was higher in the group who preferred botulinum toxin injection to oral medication as the first line treatment. These results indicate that in Japan the treatment of choice for dystonia does not always follow the therapeutic guidelines for dystonia proposed in some foreign countries. Adopting more evidence-based rationale of treatment is encouraged, because the recent progress about the treatment of dystonia, e.g. botulinum toxin injection or the stereotaxic surgery, is reshaping dystonia from a devastating to a treatable disorder.

We describe 2 patients, one with cervical dystonia (CD) combined with focal hand dystonia (writer's cramp) and another with idiopathic CD, who were unresponsive to oral medications and became resistant to botulinum toxin type A and B injections. Both patients were successfully treated with high cervical (C1-3) continuously infused intrathecal baclofen (ITB). Neck range of motion (ROM) was measured by using a 3-dimensional electromagnetic cervical ROM system. Pain, disability, and severity were assessed by using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). The patient with CD and writer's cramp did well on a continuous baclofen dose of 186.1 microg/d. Her total TWSTRS score improved significantly, her electromagnetic measurements showed an increased in total neck flexion and extension, and her handwriting improved. Unfortunately, this patient (a heavy smoker) developed small cell carcinoma of the lung and died 9 months after her pump was placed. Total TWSTRS score and electromagnetic measurements also significantly improved after pump implant in the patient with CD. He continues to do well on a periodic bolus dose using a combination of 50 microg of baclofen and 25 microg of hydromorphone (Dilaudid) every 4 hours. Our findings suggest the potential usefulness of this therapy in other patients with focal dystonia. To our knowledge, this is the first reported successful treatment of CD and CD combined with writer's cramp with high cervical continuously infused ITB.

Botulinum toxin has been a useful treatment in many movement disorders and more recently in other non-neurological motor dysfunctions for more than 15 years. Here, we review the various indications in neurology, mainly in the field of movement disorders. From 1973 to 2002, we searched the Medline database on this topic. We selected the most useful and relevant papers, with a special interest in dystonia. We summarized the results in the main indications (spasmodic torticollis, bleparospasm, hemifacial spasm) and in other manifestations such as writer's cramp, oromandibular dystonia, tremor, tics and myoclonus. We discuss the data of literature and compare them with the experience of the French movement disorders groups.