Segmental Dystonia Research Articles

Rest and other types of tremor in adult-onset primary dystonia

IntroductionKnowledge regarding tremor prevalence and phenomenology in patients with adult-onset primary dystonia is limited. Dystonic tremor is presumably under-reported, and we aimed to assess the prevalence and the clinical correlates...

No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia

Recently, using a whole exome sequencing approach, mutations in GNAL were identified as a novel cause of primary dystonia by one group[1] and subsequently confirmed by another.[2] Mutations in this gene appear to cause autosomal dominant, primary dystonia with a cervical predilection and evidence of incomplete penetrance.[1] The initial discovery paper by Fuchs et al reported GNAL mutations in 6 out of 39 families screened (~15%). However, in the subsequent study by Vemula et al, only 3 GNAL mutations were detected in 760 subjects with familial or sporadic primary dystonia (<0.5%). An accurate estimate of the prevalence of GNAL mutations is important as a mutation frequency of ~15% would justify early and widespread genetic testing of GNAL in familial dystonia, whereas a frequency of <0.5% would not. We screened GNAL by Sanger sequencing using the DNA samples from 192 probands (136 female and 56 male) with either familial or sporadic cervical dystonia, selected from a library of research samples on the basis of a clinical description of focal or segmental dystonia that included the cervical region. Local ethics committee approval was obtained for the study. A family history, defined as one or more first or second-degree relatives with dystonia, was recorded in 84 cases. Tremor was recorded in 53 cases. All familial cases had been screened for TOR1A, THAP1 and ANO3 mutations and were negative. Primers were designed to amplify all exons, the exon/intron boundaries and the 5′UTRs of both major isoforms of GNAL (ENS0334049 and ENS0423027). We identified only two novel single nucleotide variations in GNAL in three individuals in our case cohort. The first was a missense mutation in exon 2 of the gene (cDNA.1053C>T; P149S in ENS0334049) that was detected in one individual with onset of cervical dystonia in the 4th decade, with a similarly affected father, suggesting autosomal dominant inheritance. However, segregation analysis revealed the variant had in fact been inherited from his unaffected mother and was also present in his unaffected brother (see Fig. 1A), ruling it out as the cause of the dystonia in this family. The second variant, located in the 5′UTR of isoform 2 (cDNA.199C>T in ENS0423027), was found in two individuals in our cohort exhibiting onset of cervical dystonia in the 6th decade. One individual was a sporadic case whereas the other was part of family with multiple affected members (see Fig.1B-C). Despite affecting a highly conserved base (PhyloP score = 4.158), the variant failed to segregate with disease in the family, being absent in two affected individuals (see Fig. 1C). Figure 1 Family trees for individuals with novel variants in GNAL. In summary, we did not identify any mutations in GNAL that could be a cause of the dystonia in 192 cases drawn from the United Kingdom, including 84 familial cases. Our own data suggest that GNAL mutations do not represent a common cause of dystonia — in the U.K. population at least — and that the overall frequency of GNAL mutations may be closer to the figure obtained by Vemula et al[2] than the 15% initially reported by Fuchs et al.[1] This study also emphasises the importance of segregation analysis in establishing the pathogenicity or otherwise of novel variants and suggests that other novel genetic causes of dystonia remain to be identified.

Treatment of dystonia.

Selecting the appropriate treatment for dystonia begins with proper classification of disease based on age, distribution, and underlying etiology. The therapies available for dystonia include oral medications, botulinum toxin, and surgical procedures. Oral medications are generally reserved for generalized and segmental dystonia. Botulinum toxin revolutionized the treatment of focal dystonia when it was introduced for therapeutic purposes in the 1980s. Surgical procedures are available for medication-refractory dystonia, markedly affecting an individual's quality of life.

Dystonia

The purpose of this review is to provide an update on the classification, phenomenology, pathophysiology, and treatment of dystonia. A revised definition based on the main phenomenologic features of dystonia has recently been developed in an expert consensus approach. Classification is based on two main axes: clinical features and etiology. Currently, genes have been reported for 14 types of monogenic isolated and combined dystonia. Isolated dystonia (with dystonic tremor) can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), PRKRA (DYT16), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25). Combined dystonias (with parkinsonism or myoclonus) are further subdivided into persistent (GCHI [DYT5], SGCE [DYT11], and ATP1A3 [DYT12], with TAF1 most likely but not yet proven to be linked to DYT3) and paroxysmal (PNKD [DYT8], PRRT2 [DYT10], and SLC2A1 [DYT18]). Recent insights from neurophysiologic studies identified functional abnormalities in two networks in dystonia: the basal ganglia-sensorimotor network and, more recently, the cerebellothalamocortical pathway. Besides the well-known lack of inhibition at different CNS levels, dystonia is specifically characterized by maladaptive plasticity in the sensorimotor cortex and loss of cortical surround inhibition. The exact role (modulatory or compensatory) of the cerebellar-cortical pathways still has to be further elucidated. In addition to botulinum toxin for focal forms, deep brain stimulation of the globus pallidus internus is increasingly recognized as an effective treatment for generalized and segmental dystonia. The revised classification and identification of new genes for different forms of dystonia, including adult-onset segmental dystonia, enable an improved diagnostic approach. Recent pathophysiologic insights have fundamentally contributed to a better understanding of the disease mechanisms and impact on treatment, such as functional neurosurgery and nonpharmacologic treatment options.

Comparison of double monopolar and interleaving stimulation modes in the treatment of primary generalized and segmental dystonia

Comparison of double monopolar and interleaving stimulation modes in the treatment of primary generalized and segmental dystonia

Komplikationsanalyse von spinalen Eingriffen bei adulten zentralen Bewegungsstörungen und Skoliosen

Adult central movement disorders, malpostures, and scolioses can have their cause in various neurological underlying diseases such as Morbus Parkinson, Pisa syndrome, or segmental dystonia. Important clinical characteristics are marked postural distortions such as camptocormia (bent spine) or laterocollis. In cases of these adult scolioses, surgical spine treatment puts high demands on the surgeon. Surgery in Parkinson's disease, for example, is associated with serious surgery-specific as well as general complications. The more rarely occurring Pisa syndrome is an entity primarily requiring medical therapy. A series of ten case reports of patients with Morbus Parkinson and Pisa syndrome who underwent spinal surgery is presented and discussed. From these reports, treatment recommendations have been derived and complemented by references from the literature. An extensive MEDLINE search was performed for this purpose. In patients suffering from Parkinson's disease, even minor surgical interventions can lead to instability of whole spine segments or even the entire spine. Implant loosening, adjacent segment instability, general perioperative complications, and progressive malposture due to disease progress can bring forth disastrous treatment courses. Spinal fixation should be performed long-segmented in combination with ventral stabilisation. Due to osteoporosis, pedicle screw cement augmentation is recommended in this collective. If the diagnosis of Pisa syndrome is established, an optimised preoperative preparation should be initiated in close cooperation with neurologists. In many cases medical therapy is sufficient and surgical interventions can be avoided.

Acute Pisa Syndrome After Administration of a Single Dose of Mirtazapine

Mirtazapine is an antidepressant with an adequate safety profile used in major depression. Adverse effects have been reported in the field of movement disorders, but none as truncal segmental dystonia (Pisa syndrome). We describe the case of a woman who developed Pisa syndrome after a single dose of mirtazapine.

What's new in surgical treatment for dystonia?

It is now established that pallidal deep brain stimulation (DBS) is effective in the treatment of generalized and segmental primary dystonia, although there is still insufficient evidence to support its benefit in focal and secondary dystonia. Because several studies have demonstrated that pallidal DBS improves quality of life (QoL), reduced QoL and disability that are nonresponsive to medical treatment are probably the main factors guiding the decision to consider surgery. Some studies have indicated that young patients with primary dystonia who have shorter disease duration and less severe dystonia are likely to have the best outcome from DBS. Therefore, surgery should not be delayed when disability and QoL are impaired to the extent that justifies the surgical risk. A case-by-case approach is recommended in patients who have secondary dystonia. The globus pallidus internus is considered the best target for dystonia. There are still not enough data about the effectiveness of thalamic, subthalamic nucleus, and premotor cortex stimulation. Targeting with multiple electrodes and intra-individual comparisons of outcomes may help determine which target would be more beneficial. With regard to the role of lesions, pallidotomy for dystonia is still performed in several countries and can play a role in selected patients. New technologies are already available to improve the stimulation programming for DBS patients and to increase battery longevity. In the near future, it is possible that we will be able to shape stimulation settings according to disease type and symptoms. © 2013 Movement Disorder Society.

Secondary and primary dystonia: pathophysiological differences

Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.

THU0478 MRI Quantitative Analysis of Fatty Infiltration of Paravertebral Muscles in Patients with Primary Camptocormia

BackgroundCamptocormia also referred to as “bent spine syndrome” is characterized by an abnormal trunk posture with marked flexion of the thoraco-lumbar spine. These clinical signs are most prominent on standing...

Myoclonus‐dystonia syndrome associated with Russell Silver syndrome

Myoclonus-Dystonia Syndrome (MDS, DYT11) is a movement disorder characterized by myoclonus predominant in upper body regions and focal or segmental dystonia. MDS typically results from autosomal dominant loss-of-function mutations in the epsilon-sarcoglycan gene (SGCE) on chromosome 7q2112. We describe MDS due to maternal uniparental disomy of chromosome 7 (mUPD7) associated with Russell Silver Syndrome (RSS), rather than SGCE gene mutation. A 7-year-old girl with RSS presented for evaluation of involuntary movements of two years’ duration. Parents described generalized and multi-focal jerks of the head, limbs, and trunk, worsened by intercurrent illness and fatigue. The jerks sometimes resulted in accidental dropping or throwing of items. The involuntary movements were neither suppressible nor associated with premonitory sensation. Cognition, behavior, and mood were normal. Development was notable for mild gross and fine motor delays. The diagnosis of RSS was made at age 1 year based on intrauterine growth restriction, post-natal failure to thrive, and characteristic facial features. Microsatellite marker testing on the patient and her parents was indicative of maternal uniparental disomy for the entirety of chromosome 7. There was no known family history of similar symptoms. On examination, the patient was small for age with preserved head size (head circumference 50th%ile, length and weight <5th%ile). She had a triangular-shaped face, mild frontal bossing, scooped nasal bridge, small mouth, flat philtrum, and mild lower limb size asymmetry, all consistent with RSS. There was diffuse hypotonia with diminished muscle bulk, but full strength. Multifocal myoclonus was present at rest and worsened with action without stimulus sensitivity. The myoclonus was most prominent in the head, shoulders, torso, and upper extremities. Focal dystonia of the right upper extremity was elicited with prolonged writing. Dystonia was not evident in other body regions. Clinical evaluation included electroencephalogram, which showed generalized spike-wave discharges but no electrographic change during the periods of myoclonus. SGCE analysis did not identify any deletions. Treatment of the involuntary movements with medication was not pursued.

The Genetics of Segawa Disease

Segawa disease is a dopa-responsive generalized dystonia, caused by abnormalities of the gene GCH-1 located on chromosomes 14q22.1–q22.2. Clinically, there are two types, postural type and action type, depending on the family. Cases of action type show focal or segmental dystonia after adolescence. In families of action type, there are cases starting with focal or segmental dystonia in adulthood or parkinsonism in older age. Both types show symptoms of dopamine decrement due to the deficiency of tyrosine hydroxylase in the terminal of the nigrostriatal dopamine neuron, which is caused by GCH-1 deficiency. With an onset in childhood, stagnation of body length develops. For these symptoms, L-dopa demonstrates dramatic effects. In early-onset cases, tryptophan hydroxylase is also affected and patients show symptoms of serotonine deficiency. More than 100 mutations of the GCH-1 gene are detected; they are particular for each family. However, there is no particular mutation for postural and action type.

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene

A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.

Role of Gα(olf) in familial and sporadic adult-onset primary dystonia

The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ~10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.

The syndrome of deafness‐dystonia: Clinical and genetic heterogeneity

The syndrome of deafness-dystonia is rare and refers to the association of hearing impairment and dystonia when these are dominant features of a disease. Known genetic causes include Mohr-Tranebjaerg syndrome, Woodhouse-Sakati syndrome, and mitochondrial disorders, but the cause frequently remains unidentified. The aim of the current study was to better characterize etiological and clinical aspects of deafness-dystonia syndrome. We evaluated 20 patients with deafness-dystonia syndrome who were seen during the period between 1994 and 2011. The cause was identified in only 7 patients and included methylmalonic aciduria, meningoencephalitis, perinatal hypoxic-ischemic injury, large genomic deletion on chromosome 7q21, translocase of inner mitochondrial membrane 8 homolog A (TIMM8A) mutation (Mohr-Tranebjaerg syndrome), and chromosome 2 open reading frame 37 (C2orf37) mutation (Woodhouse-Sakati syndrome). The age of onset and clinical characteristics in these patients varied, depending on the etiology. In 13 patients, the cause remained unexplained despite extensive work-up. In the group of patients who had unknown etiology, a family history for deafness and/or dystonia was present the majority of patients, suggesting a strong genetic component. Sensory-neural deafness always preceded dystonia. Two clinical patterns of deafness-dystonia syndrome were observed: patients who had an onset in childhood had generalized dystonia (10 of 13 patients) with frequent bulbar involvement, whereas patients who had a dystonia onset in adulthood had segmental dystonia (3 of 13 patients) with the invariable presence of laryngeal dystonia. Deafness-dystonia syndrome is etiologically and clinically heterogeneous, and most patients have an unknown cause. The different age at onset and variable family history suggest a heterogeneous genetic background, possibly including currently unidentified genetic conditions.

A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia

Brain-derived neurotrophic factor (BDNF) modulates neuroplasticity. A functional polymorphism [Val66Met (G196A)] in BDNF has been reported to modify cortical plasticity in humans. Physiologic investigations have revealed that dystonia might be a consequence of the pathologic plasticity of the sensorimotor cortex. We aimed to investigate the role of the Val66Met polymorphism in a cohort of Serbian patients with adult-onset primary focal and segmental dystonia (PTD). One hundred and forty-nine patients with primary adult-onset PTD, 194 patients with Parkinson's disease (PD), and 366 healthy control subjects were recruited for the study. Patients with PTD and PD, as well as healthy controls had a similar distribution of genotypes and allele frequencies. There was no any significant difference in the allelic distribution at the Val66Met SNP of the BDNF gene among patients with adult-onset PTD, PD, and healthy volunteers from the same geographic areas. In addition, the presence of the Met allele did not influence the clinical characteristics of PTD patients. Patients with the Met variant did not differ by age at onset, number of affected regions, and efficacy of a sensory trick. Met66Met is not associated with an increased risk of dystonia.

Tremor associated with focal and segmental dystonia

Background and purposeTremor occurs in 10–85% of patients with focal dystonia as so-called dystonic tremor or tremor associated with dystonia. The aim of this study was to assess the incidence and to characterize parameters of tremor accompanying focal and segmental dystonia. Material and methodsOne hundred and twenty-three patients with diagnosis of focal and segmental dystonia together with 51 healthy controls were included in the study. For each participant, clinical examination and objective assessment (accelerometer, electromyography, graphic tablet) of hand tremor was performed. Frequency and severity of tremor were assessed in three positions: at rest (rest tremor); with hands extended (postural tremor); during ‘finger-to-nose’ test and during Archimedes spiral drawing (kinetic tremor). Based on the mass load test, type of tremor was determined as essential tremor type or enhanced physiological type. ResultsThe incidence of tremor was significantly higher in dystonic patients as compared to controls (p = 0.0001). In clinical examination, tremor was found in 50% of dystonic patients, and in instrumental assessment in an additional 10–20%. The most frequent type of tremor was postural and kinetic tremor with 7 Hz frequency and featured essential tremor type. In the control group, tremor was detected in about 10% of subjects as 9-Hz postural tremor of enhanced physiological tremor type. No differences were found between patients with different types of dystonia with respect to the tremor incidence, type and parameters (frequency and severity). No correlations between tremor severity and dystonia severity were found either.

Phenotypes and Genotypes of Patients with Pantothenate Kinase-Associated Neurodegeneration in Asian and Caucasian Populations: 2 Cases and Literature Review

Objectives. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease caused by pantothenate kinase 2 (PANK2, OMIM 606157) mutations. This study is aimed to investigate clinical presentations, pathologies, and genetics in patients with PKAN. Methods. Two patients with PKAN were reported. We reviewed the literature to include additional 19 patients with PKAN in Eastern Asia. These patients were divided into classic and atypical groups by the age of onset. We compared the data on PKAN patients of Asian and Caucasian populations. Results. We found iron deposits in the globus pallidus in our Patient 1 and a heterozygous truncating mutation (c.1408insT) in Patient 2. Literature review shows that generalized dystonia and bulbar signs are more common in classic PKAN patients, whereas segmental dystonia and tremors are more specific to atypical ones. Asian patients have less complex presentations—lower prevalence of pyramidal signs, mental impairment, and parkinsonism—than Caucasians. D378G in exon 3 is the most frequent mutation (28%) in Asians. Conclusions. Our study demonstrates that the distribution of dystonia is the major distinction between subgroups of PKAN. Caucasian patients have more complex presentations than Asians. Exon 3 and 4 are hot spots for screening PANK2 mutations in Asian patients.

14 Prevalence of dementia in Parkinson’s disease (PDD)

Background The Center for Neurodegenerative Diseases of the Department of Neurology of the Ospedali Riuniti of Foggia deals with the diagnosis and treatment of patients suffering from major forms of dementia and movement disorders from Foggia and from neighboring towns for many years. The prevalence (prevalence) of dementia in Parkinson’s disease (PD dementia) is reported in 40% of patients. Methods We describe the population of patients referred to the clinic for movement disorders. Data collection took place through the outpatient consultation folders that collect the personal details of patients, all medical and clinical records. Results Flow to the Center for Movement Disorders, every three months 389 patients with a diagnosis of movement disorders. Patients had the following characteristics: 300 patients with Parkinson’s disease (146 males and 154 females); 66 cases of essential tremor with high familiarity (32 males and 34 females); 12 cases of restless legs syndrome (8 males and 4 females); 6 cases of focal and segmental dystonia; 6 cases of other neurodegenerative diseases (Chorea, MSA, PSP, etc.). There is a distribution to the almost similar for all movement disorders between the sexes (191 males and 198 females). In the context of the population of patients with Parkinson’s disease related to the clinic only 27 patients were diagnosed with Parkinson’s dementia and of these 11 men and 16 women. With a prevalence of dementia, accounting for 9% of the population in question. The vast majority of these patients being treated with rivastigmine at doses ranging between 6 and 12 mg per day. In our small series the drug efficacy has shown good. Conclusions More likely than patients described have cognitive impairment, but most often are misunderstood or not the same as evidenced by patients who are used to focus their attention on movement disorders and much less on non-motor disorders. In view of the effectiveness of rivastigmine, even in our small population would be desirable to implement all appropriate diagnostic procedures to reach an early diagnosis of dementia in Parkinson’s disease in these patients to ensure a better quality of life.

Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial

Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. Medtronic.