Diagnostic flowcharts for Dystonia: (1) In adults (2) In children & adolescents

Transcription

1 Diagnostic flowcharts for Dystonia: (1) In adults (2) In children & adolescents Published by ERN-RND: 11 th February 2019

2 Introduction to the European Reference Network for Rare Neurological Diseases (ERN-RND): ERN-RND is a European Reference Network established and approved by the European Union. ERN-RND is a healthcare infrastructure which focuses on rare neurological diseases (RND). The three main pillars of ERN-RND are (i) network of experts and expertise centres, (ii) generation, pooling and dissemination of RND knowledge, and (iii) implementation of e- health to allow the expertise to travel instead of patients and families. ERN-RND unites 32 of Europe s leading expert centres in 13 Member States and includes highly active patient organizations. Centres are located in Belgium, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Lithuania, Netherlands, Poland, Slovenia, Spain and the UK. The following disease groups are covered by ERN-RND: Ataxias and Hereditary Spastic Paraplegias Atypical Parkinsonism and genetic Parkinsons Disease Dystonia, Paroxysmal Disorder and Neurodegeneration with Brain Ion Accumulation Frontotemporal Dementia Huntingtons Disease and other Choreas Leukodystrophies Specific information about the network, the expert centres and the diseases covered can be found at the networks web site Recommendation for clinical use: The European Reference Network for Rare Neurological Diseases developed the Diagnostic Flowcharts for Dystonia to help guide the diagnosis of Dystonia patients. The Reference Network recommends the use of these Diagnostic Flowcharts. This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND). ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States. The ERNs are co-funded by the European Commission (ERN-RND: 3HP ). Page 2

3 Disclaimer: Clinical practice guidelines, practice advisories, systematic reviews and other guidance published, endorsed or affirmed by ERN-RND are assessments of current scientific and clinical information provided as an educational service. The information (1) should not be considered inclusive of all proper treatments, methods of care, or as a statement of the standard of care; (2) is not continually updated and may not reflect the most recent evidence (new information may emerge between the time information is developed and when it is published or read); (3) addresses only the question(s) specifically identified; (4) does not mandate any particular course of medical care; and (5) is not intended to substitute for the independent professional judgement of the treating provider, as the information does account for individual variation among patients. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ERN-RND provided this information on an as is basis, and makes no warranty, expressed or implied, regarding the information. ERN-RND specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ERN-RND assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions. METHODOLOGY The development of the Diagnostic Flowcharts for Dystonia was done by the Disease group for Dystonia, Paroxysmal Disorder and NBIA of ERN-RND. Disease group for Dystonia, Paroxysmal Disorder and NBIA: Disease group coordinators: Alberto Albanese 1 ; Thomas Klopstock 2 ; Marie Vidailhet 3 Disease group members: Enrico Bertini 4 ; Kailash Bhatia 5 ; Elena Chorbadgieva 6 ; Yaroslau Compta 7 ; Adrian Danek 2 ; Alejandra Darling 7 ; Tom de Koning 8 ; Marina de Koning-Tijssen 8 ; Malgorazate Dec-Cwiek 9 ; Maria Teresa Dotti 10 ; Antonio Elia 11 ; Antonio Federico 10 ; Dusan Flisar 12 ; Thomas Gasser 13 ; Kathrin Grundmann 13 ; Kinga Hadzsiev 14 ; Christine Klein 15 ; Jiri Klempir 16 ; Maja Kojovic 17 ; Norbert Kovacs 14 ; Bernhard Landwehrmeier 18 ; Ebba Lohmann 13 ; Sebastian Löns 15 ; Maria Jose Marti 7 ; Maria Judit Molnar 19 ; Alexander Münchau 15 ; Juan Dario Ortigoza Escobar 7 ; Damjan This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND). ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States. The ERNs are co-funded by the European Commission (ERN-RND: 3HP ). Page 3

4 Osredkar 12 ; Sebastian Paus 20 ; Belén Pérez Dueñas 21 ; Bart Post 22 ; Evžen Růžička 23 ; Sinem Tunc 15 ; Michel Willemsen 22 ; Giovanna Zorzi 11 1 IRCCS Clinical Institute Humanitas Rozzano, Italy; 2 Klinikum der Universität München, Germany; 3 Assistance Publique- Hôpitaux de Paris, Hôpital Pitié-Salepétrière, France: Reference Centre for Rare Diseases 'Neurogenetics'; 4 Pediatric hospital Bambino Gesù, Rome, Italy; 5 University College London Hospitals NHS Foundation Trust, United Kingdom; 6 University Neurological Hospital St. Naum Sofia, Bulgaria; 7 Hospital Clínic i Provincial de Barcelona y Hospital de Sant Joan de Déu, Spain; 8 University Medical Center Groningen, Netherlands; 9 University Hospital in Krakow, Poland; 10 AOU Siena, Italy; 11 Foundation IRCCS neurological institute Carlo Besta Milan, Italy; 12 University Medical Centre Ljubljana, Slovenia; 13 Universitätsklinikum Tübingen, Germany; 14 University of Pécs, Hungary; 15 Universitätsklinikum Schleswig-Holstein, Germany; 16 General University Hospital in Prague, Czech Republic; 17 University Medical Centre Ljubljana, Slovenia; 18 Universitätsklinikum Ulm, Germany; 19 Semmelweis University, Hungary; 20 Universitätsklinikum Bonn, Germany; 21 Hospital Universitari Vall d'hebron, Spain; 22 Stichting Katholieke Universiteit, doing business as Radboud University Medical Center Nijmegen, Netherlands; 23 Motol University Hospital, Czech Republic Flowchart development process: Development of flowcharts June November 2017 Discussion/Revision in ERN-RND disease group November 2017 June 2018 Consent on diagnostic flowcharts during ERN-RND annual meeting /06/2018 Consent on document by whole disease group 26/09/2018 This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND). ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States. The ERNs are co-funded by the European Commission (ERN-RND: 3HP ). Page 4

5 Diagnostic flowchart for Dystonia in adults (according to A. Albanese, M. Di Giovanni and S. Lalli: Dystonia: Diagnosis and Management, Eur J Neurol Jul 23. doi: /ene [Epub ahead of print]) This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND). ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States. The ERNs are co-funded by the European Commission (ERN-RND: 3HP ). Page 5

6 Diagnostic flowchart for Dystonia in children and adolescents (according to van Egmond ME, Kuiper A, Eggink H, et al. J Neurol Dystonia in children and adolescents: a systematic review and a new diagnostic algorithm Neurosurg Psychiatry 2015;86: ) This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND). ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States. The ERNs are co-funded by the European Commission (ERN-RND: 3HP ). Page 6

7 Annex - Original publications This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND). ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States. The ERNs are co-funded by the European Commission (ERN-RND: 3HP ). Page 7

8 REVIEW ARTICLE Dystonia: diagnosis and management A. Albanese a,b, M. Di Giovanni a and S. Lalli a,b a Unita Operativa di Neurologia, IRCCS Istituto Clinico Humanitas, Rozzano, Milano; and b Istituto di Neurologia, Universita Cattolica del Sacro Cuore, Milano, Italy Keywords: classification, diagnosis, dystonia, genetics, phenotypes Received 28 February 2018 Accepted 20 July 2018 European Journal of Neurology 2018, 0: 1 13 doi: /ene Introduction More than 100 years have passed since Oppenheim first introduced the term dystonia [1], and more than 40 since David Marsden and Stanley Fahn first attempted to define and classify different dystonia syndromes [2,3]. Meanwhile, the phenomenology of dystonia has been described in great detail and several genetic forms have been recognized. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures or both [4]. Dystonic movements are typically patterned, twisting and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. The hyperkinetic disorder of dystonia is not always easy to recognize, and it is often misdiagnosed [5]. Clinical practice in dystonia has greatly evolved in recent years; a synthetic review on patient management is provided here. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures or both. A recent classification has innovated clinical practice and serves as guidance for clinical assessment: Axis I describes clinical features, whereas Axis II indicates etiology. Dystonia presents with different syndromic aggregations with varied somatic involvement and some common features. There are five recognizable physical signs of dystonia: two main signs (dystonic postures and movements) and three additional signs (gestes antagonistes or tricks, mirror dystonia and overflow dystonia). There is still no validation of diagnostic criteria for the different dystonia syndromes, and many cases with mild phenomenology remain undiagnosed. Patients with dystonia also present non-motor features that are variably combined with the movement disorder. The features of the most common inherited and acquired dystonia syndromes are reviewed here. There is clear evidence of genetic environmental interaction in the determinism of dystonia. The diagnostic process is guided by clinical examination and based on specific laboratory examinations. Symptomatic treatments are available for dystonia: botulinum neurotoxin injections are the primary choice for most focal dystonia syndromes; deep brain stimulation is useful in some generalized and non-generalized syndromes. Additional treatment strategies are currently being assessed. Dystonia shares some features with parkinsonian states: it causes bradykinesia [6], may coexist with parkinsonism, and is observed in Parkinson s disease (PD) as an off-related phenomenon or a transition dyskinesia [7,8]. The physical signs of dystonia are easy to recognize when combined into a full-house syndromic association, but instead more difficult when mild or isolated. Epidemiology Attempts to assess the overall epidemiology of dystonia have led to uncertain figures because of its wide heterogeneous expression. Overall, dystonia is not a rare disease, but several inherited or idiopathic dystonia syndromes fall into the current definition of rare chronic debilitating diseases. 1 Published epidemiological studies have probably EUROPEAN JOURNAL OF NEUROLOGY Correspondence: A. Albanese, Istituto Clinico Humanitas, Via A. Manzoni, 56, Rozzano Milano, Italy (tel.: ; fax: ; alberto.albanese@unicatt.it). 1 See for example the definition of rare diseases provided by the European Commission ( icy_en) EAN 1

9 2 A. ALBANESE ET AL. underestimated the prevalence of dystonia in the general population when accounting for cases per [9,10]. A classic population study in Rochester (Minnesota) reported a similar crude prevalence rate for all focal dystonia syndromes [11]. In a study of a random sample of the population over 50 years of age, the prevalence of isolated dystonia was estimated to be 732 per , suggesting that in the aging population dystonia is a common neurological disorder [12]. The reported variability amongst epidemiological studies denotes a difficulty in ascertaining the diagnosis of dystonia, given the lack of validated criteria and the occurrence of a significant proportion of patients with mild phenomenology who do not request a medical consultation. Women are affected about twice as often as men. Of note, although the genetic causes of dystonia especially for adult-onset focal forms are still largely elusive, a positive family history is reported in about 20% of dystonia sufferers [13 15]. Adult-onset focal dystonia syndromes are by far the most frequent presentations. In two recent studies on focal syndromes, the majority of patients had cervical dystonia (69%) or blepharospasm (17%) [15,16], whilst other forms were much rarer: limb dystonia (3% 7%), spasmodic dysphonia (1% 3%), musician s dystonia (3%) and oromandibular dystonia (1%). Classification The recent classification of dystonia has greatly innovated clinical practice and serves as a guide for clinical assessment [4]. Axis I depicts clinical features and provides a synthetic snapshot of the patient s clinical condition at the time of examination, whereas Axis II accommodates etiology (Fig. 1). Five descriptors are listed under Axis I: age at onset, body distribution, temporal pattern, cooccurrence of other movement disorders or of other neurological manifestations. Five age groups are distinguished for age at dystonia onset: infancy (birth to 2 years), childhood (3 12 years), adolescence (13 20 years), early adulthood (21 40 years) and late adulthood (>40 years). The body distribution can be focal, segmental, multifocal, generalized (with or without leg involvement) or unilateral (hemidystonia). The temporal pattern includes the disease course, which may be Figure 1 Hierarchical organization of Axis I (clinical characteristics) and Axis II (etiology) of the dystonia classification EAN

10 DYSTONIA: DIAGNOSIS AND MANAGEMENT 3 static or progressive, and the variability of symptoms, which may be persistent, fluctuating, action specific or paroxysmal. Associated features indicate whether dystonia is combined with another movement disorder (e.g. myoclonus dystonia) or with other neurological or systemic manifestations. If a patient s condition progresses, its description along Axis I will vary over time and the sequence of consecutive observations will describe progression. Instead, for the etiological classification (Axis II), the most recent information available will be used. Clinical features The motor features of dystonia were originally observed in generalized cases and later recognized to occur also in focal syndromes with cervical or limb involvement [17]. The features of dystonia encompass two main physical signs that can be recognized by expert neurological assessment (Table 1). Since the diagnosis is based on clinical observation and there are no supportive laboratory measures, the clinical recognition is easier when there is a full-house phenomenology, more difficult instead when dystonic movements occur in isolation. Tremor may be an isolated dystonic movement; therefore, isolated tremor syndromes may be misdiagnosed as non-dystonic tremor syndromes (see below). Additional clinical signs, such as a geste, may support a diagnosis of dystonia, but the clinical picture may still remain below a threshold of diagnostic confidence. People with mild focal phenomenology may have no complaint or may not consult a doctor; hence, it is not uncommon to recognize a focal dystonia in unaware or uncomplaining subjects. The diagnosis of dystonia can be delayed or missed more frequently than that of other hyperkinetic movement disorders. The physical signs listed in Table 1 are commonly observed in patients with cervical or limb involvement. Additional signs observed in patients with blepharospasm are the presence of stereotyped, bilateral and synchronous spasms of the orbicularis oculi muscles. Spasms may be brief or sustained and may induce narrowing or closure of the eyelids, but of course have no torsional attitude [18]. In the case of laryngeal dystonia, instrumental examination can reveal spasmodic contractions of the vocal folds (abductor or adductor dysphonia), also without overt torsional appearance [19]. In muscle tension dysphonia, instead, the involuntary contractions affect the accessory phonation muscles without necessarily involving the vocal folds. In addition to producing the positive motor phenomena listed in Table 1, dystonia may also present failure of willed activity to occur. This has been documented in blepharospasm (where the so-called apraxia of eyelid opening is in fact an inability of voluntary eyelid opening) [20], upper limb dystonia [21] and cervical dystonia [22]. Finally, dystonia is associated with slowing of movement (dystonic bradykinesia) [23], to be distinguished from parkinsonian bradykinesia [24]. Dystonia is called isolated when it is the sole motor feature. The observation of tremor, representing a dystonic movement, is compatible with the definition of isolated dystonia. If additional movement disorders occur, dystonia is called combined. Typical combined dystonia syndromes are myoclonus dystonia or dystonia parkinsonism. When dystonia is associated with other neurological or systemic manifestations, these are annotated as associated features (Fig. 1). Transition from old to new terminology The recent introduction of a new classification system of dystonia [4] has occasionally raised uncertainties on how to translate the old terminology. The newly introduced definitions provide better clarity of language and meaning but are not exactly synonymous with older terms. The traditional expression primary dystonia is now discouraged and can be translated as isolated idiopathic or isolated inherited dystonia. Pure dystonia is an obsolete denomination for isolated dystonia. Dystonia plus and heredodegenerative dystonia can be translated, respectively, to combined dystonia or dystonia associated with neurological/systemic manifestations. The newer expressions are sometimes longer; still, they hold the advantage of conveying more detailed information than older terms. Non-motor features of dystonia Recent studies have revealed that, in addition to the movement disorder, there are other, non-motor, features in patients with isolated dystonia. Sensory abnormalities may present months before the movement disorder develops, as mild neck discomfort preceding cervical dystonia, irritation or dry eyes before the development of blepharospasm, or throat irritation heralding the onset of spasmodic dysphonia [25]. Pain is reported in nearly 70% of patients with cervical dystonia and in up to 30% of those with focal hand dystonia or writer s cramp [26]. Dystonia is also associated with neuropsychiatric abnormalities, such as depressive disorders, that are more frequent in cervical dystonia, blepharospasm, laryngeal dystonia and focal hand dystonia compared to healthy controls. A family history of depression, anxiety and social anxiety is more common in 2018 EAN

11 4 A. ALBANESE ET AL. Table 1 The five physical signs of dystonia syndromes are recognized in most patients with dystonia Physical sign Description Main physical signs Dystonic postures Dystonic movements Muscle contractions may be continuous, forcing limbs and trunk into sustained postures (not available for blepharospasm or laryngeal dystonia) A body part is flexed or twisted along its longitudinal axis Slowness and clumsiness for skilled movements is associated with sensation of rigidity and traction in the affected part Additional physical signs Gestes antagonistes ( tricks ) Mirror dystonia Overflow dystonia These features have to be looked for in all movement disorders, either fast or slow, also when the immediate impression is that of a tremor, tic, chorea or myoclonus Tremor is a feature of dystonic movements and may appear as isolated tremor Movements are repetitive and patterned (i.e. consistent and predictable) or twisting Movements are often sustained at their peak to lessen gradually in a preferred posture (usually opposite to the direction of movement) Voluntary actions performed by patients that reduce or abolish the abnormal posture or the dystonic movements. They are usually simple movements involving, or directed to, the body region affected by dystonia These movements are natural and graceful, not consisting of forceful opposition to the phenomenology of dystonia The movement does not push or pull the affected body part but simply touches it ( sensory trick ) or accompanies it during alleviation of dystonia Alleviation of dystonia occurs during the geste movement, usually soon after its start Alleviation may last for as long as the geste or slowly reverses spontaneously before its end To be distinguished from geste-like voluntary movements It is evaluated in the upper or lower limbs. At least three different types of repetitive tasks (e.g. finger sequence, normal writing or piano-like movements) are performed at low and fast speed in the non-affected limb It is a unilateral posture or movement with the same or similar characteristics to the patient s dystonia (usually postures and some movements) that can be elicited, usually in the more severely affected side, when contralateral movements or actions are performed To be distinguished from non-dystonic mirror movements It is observed at least once, usually ipsilaterally, in coincidence with the peak of dystonic movements It is an unintentional muscle contraction accompanying the most prominent dystonic movement that are observed in an anatomically distinct neighboring body region Dystonic postures are not observed in patients with blepharospasm; mirror dystonia is only observed when the limbs are affected. Modified from [69]. dystonia than in controls [27]. Some specific inherited dystonia syndromes have clear association with nonmotor features, as observed, for example, in aggregated cohorts of patients with DYT11 dystonia [28]. In isolated dystonia syndromes, whether idiopathic or inherited, there are usually no cognitive abnormalities; by contrast, cognitive abnormalities are often found in combined (whether inherited or idiopathic) syndromes (Table 2). Etiology Classification by etiology is listed under Axis II. This is an evolving area, particularly concerning genetic discoveries. Evidence of degeneration, at the macroscopic, microscopic or imaging level, provides a useful tool to identify degenerative dystonias. Degeneration is defined as a progressive structural abnormality, such as neuronal loss, related to the occurrence of dystonia. Static lesions are non-progressive neurodevelopmental anomalies or acquired lesions. Incidental findings, unrelated to the observed dystonia phenotype, are not taken into account. In cases of isolated dystonia, usually there is no evidence of either degeneration or structural lesion under Axis II. Axis II specifies whether dystonia is acquired (due to a known specific cause), inherited (due to a pathogenic genetic mutation) or idiopathic (possibly related to a yet undiscovered genetic defect). Inherited dystonia syndromes The number of inherited syndromes is continuously increasing. They can present with isolated dystonia or with a combination of dystonia plus another movement disorder (Table 2). Some common syndromic associations are highlighted hereafter. Isolated dystonia Dystonia is the only disease manifestation with the possible occurrence of tremor. The best characterized form is DYT1 dystonia, also called DYT-TOR1A 2018 EAN

12 DYSTONIA: DIAGNOSIS AND MANAGEMENT 5 Table 2 Common inherited dystonia syndromes, grouped according to Axis I criteria Progressive listing (gene/protein) Proposed name [29] Inheritance Phenomenology Inherited isolated dystonia syndromes DYT1 (TOR1A/torsinA) DYT-TOR1A AD Early-onset generalized dystonia. Typically, there is limb onset and sparing of face and neck. Alternative phenotypes have been described DYT4 (TUBB4/tubulin beta 4A class IVa) DYT-TUBB4A AD Rare form of dystonia presenting more commonly with spasmodic dysphonia, with craniocervical involvement and possible later generalization DYT6 (THAP1/THAP domain containing apoptosis-associated protein 1) DYT-THAP1 AD Adolescent or young adult onset, generalized or segmental involvement with predominance of craniocervical and laryngeal features DYT24 (ANO3/anoctamin 3) DYT-ANO3 AD Adult-onset tremulous craniocervical dystonia with laryngeal involvement and upper limb tremor DYT25 (GNAL/guanine nucleotide-binding protein subunit alpha L) DYT-GNAL AD Adult-onset focal craniocervical dystonia, typically progressing to involve larynx, trunk and limbs Inherited combined syndromes DYT5a (GCH1/GTP cyclohydrolase 1) DYT/PARK-CGH1 AD Childhood- or young adult-onset dopa-responsive dystonia with parkinsonism and diurnal fluctuations DYT5b (TH/tyrosine hydroxylase) DYT/PARK-TH AR Milder form of dopa-responsive dystonia with infantile or early childhood onset DYT3 (TAF1/TATA box-binding protein-associated factor 1) DYT12 (ATP1A3/ATPase Na + /K + transporting subunit alpha 3) DYT/PARK-TAF1 XD Segmental or generalized dystonia with marked oromandibular involvement and parkinsonism unresponsive to levodopa. Endemic in Panay, Philippines, where it is known as Lubag DYT/PARK- ATP1A3 AD Different phenotypes, including bridging forms, have been described: rapid-onset dystonia parkinsonism, alternating hemiplegia of childhood and CAPOS syndrome DYT8 (MR1/myofibrillogenesis regulator 1) PxMD-PNKD AD Attacks of paroxysmal non-kinesigenic dystonia, chorea, athetosis or ballismus precipitated by specific factors such as alcohol, caffeine, stress, hunger, fatigue or tobacco PxMD-SLC2A1 AD Paroxysmal exertion-induced chorea and dystonia in excessively exercised body regions DYT18 (SLC2A1/glucose transporter protein type 1) Inherited combined syndromes associated with additional neurological abnormalities SCA3 (ATXN3/ataxin-3) SCA-ATXN3 AD Ataxic syndrome that may present with parkinsonism, dystonia, chorea, spasticity, neuropathy or lower motor neuron involvement SCA17 (TBP/TATA box binding protein) SCA-TBP AD Ataxic syndrome that may present chorea and dystonia; it may be associated with dementia and psychosis N/A (TIMM8A/mitochondrial import inner membrane translocase subunit Tim8 A) N/A (DCAF17/nuclear transmembrane protein) DYT-TIMM8A XD Mohr Tranebjaerg syndrome: dystonia plus additional clinical features such as sensorineural deafness, visual or cognitive impairment, behavioral problems, pyramidal signs PARK2 (parkin/e3 ubiquitin ligase) PARK-Parkin AR Young-onset parkinsonian syndrome with sustained response to dopaminergic treatment and prominent leg dystonia DYT11 (SGCE/epsilon-sarcoglycan) DYT-SGCE AD Myoclonus dystonia with predominant neck and upper limb involvement N/A (NKX2.1/homeobox protein Nkx-2.1) CHOR-NKX2-1 AD Onset with chorea which can be replaced by a myoclonus dystonia phenotype during the disease course N/A (ADCY5/adenylate cyclase 5) CHOR-DYT- ADCY5 AD Varied phenotype, including childhood-onset paroxysmal or persistent chorea and dystonia DYT10 (PRRT2/proline-rich transmembrane protein 2) PxMD-PRRT2 AD Paroxysmal dystonia and choreoathetosis NBIA/DYT- DCAF17 AR Woodhouse Sakati syndrome: dystonia and additional clinical features such as dysarthria, deafness, seizures, cognitive impairment, hypogonadism, alopecia, diabetes mellitus, thyroid dysfunction (continued) 2018 EAN

13 6 A. ALBANESE ET AL. Table 2 (Continued) Progressive listing (gene/protein) Proposed name [29] Inheritance Phenomenology NBIA1 or PKAN (PANK2/pantothenate kinase 2) NBIA2, PARK14 or PLAN (PLA2G6/A2 phospholipase) NBIA/DYT- PANK2 NBIA/DYT/ PARK-PLA2G6 AR AR Dystonia with onset in childhood or adolescence, combined dysarthria, rigidity, pyramidal signs and cognitive impairment (previously called Hallervorden Spatz disease) Dystonia often combined with chorea, parkinsonism, dementia, pyramidal signs and psychiatric features This listing is not exhaustive. AD, autosomal dominant; AR, autosomal recessive; XD, X-linked dominant; N/A, not available. [29]. DYT1 dystonia is caused by mutations in the TOR1A gene, encoding torsina, a member of the ATPases family. Almost all cases are caused by a specific mutation, a 3-base pair deletion (delgag) in the coding region. This is the prototype of inherited isolated generalized dystonia with limb onset, and it is believed that Oppenheim s original description included patients with this inherited form [30]. Symptoms usually start in childhood with lower limb dystonia and later spread to generalization. The face and neck are typically not involved, a useful clue for clinical orientation. By contrast, there are inherited isolated syndromes with a prominent craniocervical onset. DYT6 dystonia (DYT-THAP1) may remain segmental or generalized, and often has a striking laryngeal involvement. DYT25 dystonia (DYT-GNAL) also causes adultonset cervical or cranial dystonia, often with prominent tremor. Other generalized syndromes are still debated and not yet confirmed, such as DYT4 (DYT- TUBB4A), a rare generalized dystonia often with laryngeal onset and cranial cervical involvement, and DYT23 dystonia (DYT-CIZ1), associated with adultonset autosomal dominant cervical dystonia and tremor. DYT24 (DYT-ANO3) is a cervical isolated dystonia syndrome due to mutations of the ANO3 gene that encodes a transmembrane protein belonging to a family of calcium-activated chloride channels. Dystonic tremor has been described as a key feature of DYT24 dystonia, appearing most commonly as head or arm tremor, and may precede the appearance of dystonic postures. Generalization has been described in approximately 10% of cases [31]. Isolated dystonia may be the presenting feature of combined syndromes that can remain isolated for a significant amount of time before another movement disorder appears. An isolated dystonia may be the long-standing presenting feature of PARK2 parkinsonism (PARK-Parkin) [32], of rapid-onset dystonia parkinsonism (DYT12, DYT-ATP1A3) [33], of Lubag disease (DYT3, DYT/PARK-TAF1) [34] and of doparesponsive dystonia (DYT5a, DYT-GCH1 [35] or DYT5b, DYT-TH [36]). In most cases, a full-house syndrome of combined dystonia will develop in time, whilst in some cases the phenotype will remain limited to isolated dystonia. Dystonia combined with myoclonus The term myoclonus dystonia is used to indicate the occurrence of true myoclonus (particularly as lightning jerks ) in combination with typical features of dystonia in patients without evidence of degeneration or structural lesion; this sets a difference with myoclonic dystonia, a rather old term referring to cases of isolated dystonia where very fast and brief dystonic movement has a myoclonus-like appearance. Actioninduced, alcohol-responsive myoclonic jerks of subcortical origin are typically combined with dystonia in DYT11 myoclonus dystonia (DYT-SGCE). The myoclonic jerks typically are brief, lightning-like and often affecting prevalently the neck, the trunk and the upper limbs. Dystonia occurs in about two-thirds of patients, usually in the form of mild cervical dystonia and writer s cramp. Some patients with myoclonus dystonia carry no SGCE gene mutations and may have other gene defects (e.g. ANO3, GCH1, TH, CACNA1B, TITF1, TOR1A), with few cases remaining genetically unidentified [37]. Dystonia combined with parkinsonism In cases with childhood onset, dystonia dominates and may be the only motor sign, whereas parkinsonism becomes more prominent with increasing age. Several forms have a disorder of dopamine metabolism, diurnal fluctuation of symptoms and a sustained response to levodopa. Dopa-responsive dystonia (DRD) syndromes include autosomal dominant DYT5a (DYT/PARK-GCH1) and autosomal recessive syndromes with more severe phenotypes, such as DYT5b (DYT/PARK-TH) or sepiapterin reductase deficiency (DYT/PARK-SPR) EAN

14 DYSTONIA: DIAGNOSIS AND MANAGEMENT 7 In some patients, parkinsonism dominates; in others dystonia prevails, particularly in the legs. The differential diagnosis is with inherited juvenile PD, particularly autosomal recessive parkinsonisms, such as PARK2 (PARK-Parkin), PARK7 (PARK-DJ1) or PARK6 (PARK-PINK1). In the latter cases, both dystonia and parkinsonism improve with dopaminergic medication [32]. In addition, there are combined dystonia parkinsonism syndromes that are partially responsive to levodopa, such as rapid-onset dystonia parkinsonism (DYT12, DYT-ATP1A3), DYT3 (DYT-TAF1, Lubag disease) and DYT16 (DYT-PRKRA) (Table 2). Dystonia combined with ataxia Several autosomal dominant spinocerebellar ataxias (SCAs) can have dystonia as a part of the phenotype and occasionally as the presenting feature. Dystonia is most commonly observed in SCA1, SCA2, SCA3, SCA6 and SCA17 [38,39]. Acquired dystonia syndromes It is remarkable that dystonia syndromes indistinguishable from idiopathic may be caused by discrete brain lesions [40]. Lesions causing acquired dystonia are prevalently located in the basal ganglia, thalamus, corticospinal tract or cerebellum and have a varied etiology (Table 3). Frequent etiologies include vascular or traumatic lesions, perinatal brain injury and neuroleptic usage. Table 3 Main categories of acquired dystonia syndromes Pathophysiology Dystonic cerebral palsy Drug-induced Toxic Brain lesion Infection Immunemediated Metabolic Etiology Perinatal brain injury Neuroleptics, dopamine blockers, anticonvulsants, calcium channel blockers Heroin inhalation, methanol, carbon monoxide, disulfiram, cyanide, manganese, cobalt, 3-nitropropionic acid Ischaemic, hemorrhagic, arteriovenous malformation, neoplasms, radiotherapy, head trauma, brain surgery (including ablations and stereotactic lesions), electrical injury Viral encephalitis, subacute sclerosing panencephalitis, human immunodeficiency virus, encephalitis lethargica, prion disease Acquired disseminated encephalomyelitis (ADEM), autoimmune or paraneoplastic encephalitis (most frequently NMDAR antibody-associated encephalitis) Hypoglycemia, hyperglycemic hyperosmolar state, hypocalcemia, hypoparathyroidism, hyperthyroidism, hepato-cerebral degeneration, uremia Common phenotypes of acquired dystonia encompass hemidystonia, which is caused by static brain lesions in the contralateral hemisphere; Vogt s double athetosis caused by cerebral palsy; and axial dystonia caused by neuroleptics. By contrast, cervical dystonia is most often idiopathic or inherited, although it has been occasionally described also in acquired cases [41]. There is no altogether reliable clinical clue to distinguish acquired from non-acquired dystonia syndromes. Genetic environmental interplay Dystonia syndromes are evidently influenced by both genetic and environmental factors. This interaction is particularly evident in isolated dystonia. An epidemiological study performed in Australia showed that anxiety disorders, tremor, cigarette smoking and head injuries with a loss of consciousness were associated with increased risk of idiopathic isolated dystonia [42]. The first two factors may be either causative or secondary to dystonia, whereas the last two are probably contributing environmental variables. Similar results have been found in focal dystonia syndromes. Not surprisingly, spasmodic dysphonia is associated with several endogenous and exogenous factors [43], and musician s dystonia is probably caused by skilled perfectionist training in genetically predisposed individuals [13]. It has also been shown that environmental factors may facilitate or worsen different focal dystonia syndromes, such as exposure to bright light for blepharospasm [44] or repeated skilled exercise for task-specific dystonia [45]. Differences in prevalence, age of onset and gender are probably correlated with different exposures to environmental factors on a background of genetic susceptibility. Environmental factors play a role also in inherited dystonia syndromes. A first evidence is provided by the observation of incomplete penetrance: in DYT- TOR1A penetrance is quite low, around 30% 40% [46], whereas in DYT-THAP1 it is about 60% [47]. This suggests that yet unknown environmental and lifestyle factors can influence the expression of pathogenic mutations even in early-onset dystonia syndromes. Diagnosis The phenomenology of dystonia is a collection of physical signs, including tremor, that require expert neurological assessment [48,49]. The first diagnostic criteria were proposed by Herz [50], who recognized that dystonic movements and postures are the hallmark phenomenology of dystonia. They constitute the 2018 EAN

15 8 A. ALBANESE ET AL. main physical signs and are complemented by three other physical signs: gestes antagonistes ( tricks ), mirror dystonia and overflow dystonia. Fahn first noticed that dystonic movements are the most common type of involuntary movements to be misdiagnosed [51], are highly variable (either fast or slow, and irregular) and may manifest as isolated tremor without other clues suggesting dystonia. This may delay recognition of dystonia in patients with an isolated tremor syndrome [48]. The minimal requirements for diagnosing dystonia in specific body regions are still for the most part undefined and, whilst the full-house phenomenology remains unquestionable, mild or incomplete expressions, in the past called formes frustes [52], may remain undiagnosed. There is no consensus on diagnostic criteria for focal dystonia syndromes; therefore, only general diagnostic criteria are currently available. A set of proposed diagnostic criteria for blepharospasm [53] still needs validation and refinement; a concerted effort for consensus on diagnostic criteria for cervical dystonia is currently under way. Tremor in dystonia Traditionally, tremor was considered a separate movement disorder from dystonia, although the recent consensus classification has ratified that dystonic movements can present as isolated tremor [4]. In patients with dystonia, tremor commonly involves the head or the arms, where it can be postural/kinetic or at rest [54]. Head tremor is quite specific of dystonia, but isolated arm tremor can be mistaken for essential or parkinsonian tremor [48]. Upper limb tremor is observed in a significant proportion of patients with otherwise isolated focal dystonia syndromes, such as cervical dystonia, focal upper limb dystonia or spasmodic dysphonia [15]. It is accepted that patients with dystonia may have a classic essential tremor phenomenology and later may develop dystonic postures to compose a full-house clinical picture. It is not uncommon that patients with isolated upper limb postural/kinetic tremor are misclassified as having classic essential tremor if upper limb tremor is the presenting sign and the patients are observed before they develop any other signs of dystonia. The expression isolated upper limb tremor is increasingly used to describe patients who cannot be definitely classified as having essential or instead dystonic tremor. Patients with adult-onset dystonic tremor can also be misdiagnosed as having PD, particularly if they have upper limb dystonic resting tremor and are not assessed by dopaminergic imaging. Large clinical trials on PD have shown that a percentage between 10% and 15% of clinically diagnosed PD patients have normal dopaminergic binding (scans without evidence of dopaminergic deficit) [55,56]. Some of these patients have adult-onset isolated dystonia [57] that is particularly difficult to recognize when dystonic bradykinesia causes reduced arm swing while walking [58]. Investigations The diagnosis of dystonia is primarily clinical, and investigations are needed particularly for Axis II classification. After outlining a syndromic description according to Axis I, syndrome-specific investigations are performed to establish an etiological diagnosis according to Axis II (Fig. 2). In some cases, clinical examination may prompt specific investigations. For example, the observation of a Kayser Fleischer ring may lead to a study of copper metabolism or the observation of myoclonus dystonia may warrant specific genetic testing. Electromyography (EMG) mapping may provide a complement to clinical examination, allowing some typical neurophysiological phenomenology to be recognized. The usual EMG features observed in dystonia are as follows: prolonged bursts ( ms), simultaneous contractions (cocontraction) of agonist and antagonist muscles, involuntary activation of contiguous muscles (overflow) [59]. Most patients will undergo an imaging study, usually starting with brain magnetic resonance imaging (MRI), to identify whether there is a degenerative condition, a static lesion or no evidence of brain lesions. Results of imaging studies may prompt further investigations. For example, a suspicion of neurodegeneration with brain iron accumulation or a cerebellar atrophy may lead to specific genetic testing. In dystonia parkinsonism syndromes, by contrast, brain imaging may be abnormal and shows accumulation of metals: manganese, as in Kufor Rakeb syndrome (PARK-ATP13A2) [60]; calcium, as in primary familial brain calcifications [61]; iron, as in neurodegenerations with brain iron accumulation [62]. A brain computed tomography scan is preferable if calcifications are suspected; otherwise MRI is the neuroimaging of choice. As a rule, brain MRI should include iron-sensitive sequences [63]. In patients where the workup has ruled out evidence for an acquired or inherited dystonia syndrome, a provisional diagnosis of idiopathic dystonia is made. The high degree of phenotypic overlap has facilitated the diffusion of multi-gene diagnostic dystonia panels [64] EAN

16 DYSTONIA: DIAGNOSIS AND MANAGEMENT 9 Figure 2 Clinical strategy from examination to treatment plan. Following examination, phenomenology guides diagnostic testing. The information collected allows a treatment plan, whether symptomatic or mechanism specific, to be defined. A listing of specific diseasemodifying treatments for dystonia syndromes has recently been compiled [94]. BoNT, botulinum neurotoxin; DBS, deep brain stimulation; NGS, next-generation sequencing. [Colour figure can be viewed at wileyonlinelibrary.com] Metabolic and blood testing (e.g. acanthocytes, ceruloplasmin, serum and urinary copper, uric acid, serum pyruvate, and lactate levels) and other complementary investigations (e.g. slit-lamp examination) are usually performed in specific cases to reach a diagnostic confirmation. DAT scan scintigraphy allows reduced binding to dopaminergic terminals to be identified, indicating a parkinsonian syndrome. Treatment/management Anticholinergic medications have proved useful in patients with generalized and focal isolated dystonia syndromes, whereas levodopa is effective in some patients with dopa-responsive dystonia parkinsonism. Other agents that have been used in dystonia are baclofen, carbamazepine and benzodiazepines, either alone or in combination [65]. Botulinum toxin treatment Botulinum neurotoxin (BoNT) is a potent poison produced by Clostridium botulinum that causes local muscle weakness. Its efficacy is due to partial peripheral denervation [66] with a contribution of central effects [67]. Botulinum neurotoxin is the first-line treatment for patients with blepharospasm and cervical dystonia (spasmodic torticollis) [68]. It is also effective in laryngeal and limb dystonia. Three BoNT/A serotypes and one BoNT/B serotype are commercially available worldwide. They have received individual generic names and are currently considered individual products that are only partly interchangeable [69]. In addition, other BoNT products are available in specific countries and others are under development [70] EAN

17 10 A. ALBANESE ET AL. Cervical dystonia There is class A evidence of efficacy for Abo BoNT/A and Rima BoNT/B and class B evidence for Ona BoNT/A and Inco BoNT/A in cervical dystonia [71]. BoNT/A products are commonly used as first-line therapy for cervical dystonia. The efficacy of BoNT products in cervical dystonia has been confirmed by several systematic reviews. BoNT/A is more effective than placebo [72] and anticholinergic oral treatment [73]. BoNT/B has also proven efficacious in cervical dystonia [74]; a comparison of BoNT/A and BoNT/B showed significant improvement from baseline without difference between the median duration of benefit [75]. There is no standard procedure for performing BoNT injections in cervical dystonia: muscle selection, BoNT dilution and dosing, and targeting techniques (whether to use EMG or ultrasound guidance) vary significantly amongst centers, which probably brings some heterogeneity in outcome. Two recent consensus publications have provided a first attempt to develop practice guidelines for BoNT treatment in cervical dystonia [76,77]. Blepharospasm There is class B evidence on the efficacy of Ona BoNT/A and Inco BoNT/A and class C evidence for Abo BoNT/A in blepharospasm [71]. BoNT/A is the first-line treatment in this condition, with an expected success rate approaching 100% if injections are placed in the pretarsal portion of the orbicularis oculis muscle [78,79]. Other focal dystonias Botulinum neurotoxin type A is probably effective for the treatment of focal upper limb dystonia (including writer s cramp) and adductor spasmodic dysphonia (adductor laryngeal dystonia) [80], whilst abductor laryngeal dystonia responds less predictably [68]. Notwithstanding, BoNT/A is the treatment of choice also for these conditions given the lack of alternative treatments. Most patients with dystonia have a long-term response to BoNT after repeated treatment cycles [81]. However, in some patients the efficacy of BoNT treatment may lessen to the extent that a patient may be considered to have lost a tangible benefit. This condition, called secondary non-response, is caused almost always by wrong muscle targeting, possibly due to changes in the muscle activation pattern over time. The development of neutralizing antibodies is a theoretical possibility that is considered exceptional: after longterm treatment with ona BoNT/A, only <2% of the patients were positive for neutralizing antibodies [82]. Transcranial magnetic stimulation Repetitive, low frequency transcranial magnetic stimulation can enhance intracortical inhibition, a neural process deemed to be altered in dystonia. Although single-session studies have been reported to be ineffective, there is preliminary evidence that cumulative effects can be obtained by repeated stimulation over consecutive days [83]. Deep brain stimulation Deep brain stimulation (DBS) of the internal globus pallidus (GPi) has emerged as the surgical treatment of choice for children and adults with disabling idiopathic isolated dystonia. The efficacy of DBS has been well documented in patients with inherited generalized dystonia, particularly DYT1 dystonia which cannot be managed with oral medications or BoNT. This therapeutic approach has been extended more recently to focal dystonia syndromes, which are commonly treated with BoNT. Evidence of the efficacy of bilateral DBS of the GPi on DYT1 dystonia is confirmed by several studies [84,85]. Compared to patients with idiopathic (not inherited) isolated dystonia, DYT1 patients had earlier and greater improvement [86]. The efficacy of GPi DBS on other inherited isolated dystonia syndromes is less consistent than observed in DYT1. Patients with DYT6 dystonia respond less favorably to GPi DBS than DYT1 mutation carriers [86,87]. There is insufficient evidence of the efficacy of GPi DBS on patients with DYT24 tremulous-prominent cervical dystonia [31], although it is generally believed that dystonic tremor responds to GPi DBS implants [88]. The efficacy of GPi DBS has been consistently reported in DYT11 (DYT-SGCE) myoclonus dystonia and in DYT3 (DYT/PARK-TAF1 or Lubag) X- linked dystonia parkinsonism. In DYT11, both dystonia and myoclonus improve and a sustained benefit has been reported after 10 years [89]; in Lubag, instead, dystonia can improve more than parkinsonism but long-term assessments are lacking [90]. In other inherited combined syndromes, however, there is no clear indication of DBS efficacy. In DYT12 dystonia, instead, there is evidence of inefficacy for GPi DBS [33]. Globus pallidus internus DBS has also proved efficacious in acquired dystonia syndromes. The response of drug-induced, tardive, dystonia may be very rapid and occurs within days or weeks after bilateral GPi implants. In most cases, patients with generalized or segmental tardive dystonia have been 2018 EAN

18 DYSTONIA: DIAGNOSIS AND MANAGEMENT 11 treated. The available data are mainly uncontrolled case reports, and prospective systematic studies are needed instead. Dystonic cerebral palsy without prominent spasticity has also been shown to respond to GPi DBS. Most data collected are retrospective series or case reports that indicate a significant potential efficacy for DBS and call attention to the need for properly designed prospective controlled trials [91]. The subthalamic nucleus (STN) has recently been proposed as a potential DBS target, alternative to GPi in patients with dystonia. A 3-year follow-up study provided class IV evidence that STN DBS decreases long-term severity in patients with medically refractory isolated dystonia [92]. Overall, the available data suggest that DBS has great potential for different dystonia syndromes, whether idiopathic or inherited, isolated or combined. The outcome is influenced by a number of Axis I features, such as body distribution, age of onset, and by the relative prevalence of dystonic movements or postures. The genetic status is also important, with two extremes represented by DYT1 dystonia (consistently excellent outcome) and DYT12 dystonia (consistent lack of efficacy). Physical treatments A variety of physical treatments have been proposed for dystonia, including motor learning exercises, passive or active mobilization techniques, stretching of dystonic muscles, relaxation and electrotherapy (e.g. EMG biofeedback or transcutaneous electrical nerve stimulation). Different rehabilitation strategies have been combined with BoNT to improve disability and pain compared to BoNT treatment alone. This is still a debated topic that has particularly regarded patients with cervical dystonia and has not yet reached a consensus level [93]. Disclosure of conflict of interest The authors declare no financial or other conflict of interests. References 1. Oppenheim H. Uber eine eigenartige Krampfkrankheit des kindlichen und jugendlichen Alters (Dysbasia lordotica progressiva, Dystonia musculorum deformans). Neurologische Centralblatt 1911; 30: Marsden CD. Dystonia: the spectrum of the disease. Res Publ Assoc Res Nerv Ment Dis 1976; 55: Fahn S, Eldridge R. Definition of dystonia and classification of the dystonic states. Adv Neurol 1976; 14: Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013; 28: Lalli S, Albanese A. The diagnostic challenge of primary dystonia: evidence from misdiagnosis. Mov Disord 2010; 25: Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson s disease. Brain 2001; 124: Del Sorbo F, Albanese A. Levodopa-induced dyskinesias and their management. J Neurol 2008; 255(Suppl. 4): Dolhun R. Dystonia and Parkinson s disease. Pract Neurol 2015; 15: Epidemiological Study of Dystonia in Europe Collaborative Group. A prevalence study of primary dystonia in eight European countries. J Neurol 2000; 247: Steeves TD, Day L, Dykeman J, Jette N, Pringsheim T. The prevalence of primary dystonia: a systematic review and meta-analysis. Mov Disord 2012; 27: Nutt JG, Muenter MD, Aronson A, Kurland LT, Melton LJ 3rd. Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord 1988; 3: Muller J, Kiechl S, Wenning GK, et al. The prevalence of primary dystonia in the general community. Neurology 2002; 59: Schmidt A, Jabusch HC, Altenmuller E, et al. Etiology of musician s dystonia: familial or environmental? Neurology 2009; 72: Groen JL, Kallen MC, van de Warrenburg BP, et al. Phenotypes and genetic architecture of focal primary torsion dystonia. J Neurol Neurosurg Psychiatry 2012; 83: Williams L, McGovern E, Kimmich O, et al. Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland. Eur J Neurol 2017; 24: Wang L, Chen Y, Hu B, Hu X. Late-onset primary dystonia in Zhejiang province of China: a service-based epidemiological study. Neurol Sci 2016; 37: Albanese A. How many dystonias? Clinical evidence Front Neurol 2017; 8: Defazio G, Hallett M, Jinnah HA, Conte A, Berardelli A. Blepharospasm 40 years later. Mov Disord 2017; 32: Hintze JM, Ludlow CL, Bansberg SF, Adler CH, Lott DG. Spasmodic dysphonia: a review. Part 2: Characterization of pathophysiology. Otolaryngol Head Neck Surg 2017; 157: Krack P, Marion MH. Apraxia of lid opening, a focal eyelid dystonia: clinical study of 32 patients. Mov Disord 1994; 9: Cohen LG, Hallett M. Hand cramps: clinical features and electromyographic patterns in a focal dystonia. Neurology 1988; 38: Mezaki T. Dystonia redefined as central non-paretic loss of control of muscle action: a concept including inability to activate muscles required for a specific movement, or negative dystonia. Med Hypotheses 2007; 69: Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain 1998; 121(Pt 7): EAN

19 12 A. ALBANESE ET AL. 24. Rao G, Fisch L, Srinivasan S, et al. Does this patient have Parkinson disease? JAMA 2003; 289: Patel N, Jankovic J, Hallett M. Sensory aspects of movement disorders. Lancet Neurol 2014; 13: Kuyper DJ, Parra V, Aerts S, Okun MS, Kluger BM. Nonmotor manifestations of dystonia: a systematic review. Mov Disord 2011; 26: Berman BD, Junker J, Shelton E, et al. Psychiatric associations of adult-onset focal dystonia phenotypes. J Neurol Neurosurg Psychiatry 2017; 88: Peall KJ, Dijk JM, Saunders-Pullman R, et al. Psychiatric disorders, myoclonus dystonia and SGCE: an international study. Ann Clin Transl Neurol 2016; 3: Marras C, Lang A, van de Warrenburg BP, et al. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force. Mov Disord 2016; 31: Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol 1998; 78: Stamelou M, Charlesworth G, Cordivari C, et al. The phenotypic spectrum of DYT24 due to ANO3 mutations. Mov Disord 2014; 29: Elia AE, Del Sorbo F, Romito LM, Barzaghi C, Garavaglia B, Albanese A. Isolated limb dystonia as presenting feature of Parkin disease. J Neurol Neurosurg Psychiatry 2014; 85: Albanese A, Di Giovanni M, Amami P, Lalli S. Failure of pallidal deep brain stimulation in DYT12-ATP1A3 dystonia. Parkinsonism Relat Disord 2017; 45: Lee LV, Pascasio FM, Fuentes FD, Viterbo GH. Torsion dystonia in Panay, Philippines. Adv Neurol 1976; 14: Dobricic V, Tomic A, Brankovic V, et al. GCH1 mutations are common in Serbian patients with dystonia-parkinsonism: challenging previously reported prevalence rates of DOPA-responsive dystonia. Parkinsonism Relat Disord 2017; 45: Katus LE, Frucht SJ. An unusual presentation of tyrosine hydroxylase deficiency. J Clin Mov Disord 2017; 4: Balint B, Bhatia KP. Isolated and combined dystonia syndromes an update on new genes and their phenotypes. Eur J Neurol 2015; 22: Hagenah JM, Zuhlke C, Hellenbroich Y, Heide W, Klein C. Focal dystonia as a presenting sign of spinocerebellar ataxia 17. Mov Disord 2004; 19: Manto MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 2005; 4: Marsden CD, Obeso JA, Zarranz JJ, Lang AE. The anatomical basis of symptomatic hemidystonia. Brain 1985; 108(Pt 2): Strader S, Rodnitzky RL, Gonzalez-Alegre P. Secondary dystonia in a botulinum toxin clinic: clinical characteristics, neuroanatomical substrate and comparison with idiopathic dystonia. Parkinsonism Relat Disord 2011; 17: Newman JR, Boyle RS, O Sullivan JD, Silburn PA, Mellick GD. Risk factors for idiopathic dystonia in Queensland, Australia. J Clin Neurosci 2014; 21: Tanner K, Roy N, Merrill RM, Sauder C, Houtz DR, Smith ME. Case control study of risk factors for spasmodic dysphonia: a comparison with other voice disorders. Laryngoscope 2012; 122: Hallett M, Evinger C, Jankovic J, Stacy M, International Workshop. Update on blepharospasm: report from the BEBRF International Workshop. Neurology 2008; 71: Torres-Russotto D, Perlmutter JS. Task-specific dystonias: a review. Ann N Y Acad Sci 2008; 1142: Grundmann K, Laubis-Herrmann U, Bauer I, et al. Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia. Arch Neurol 2003; 60: Saunders-Pullman R, Raymond D, Senthil G, et al. Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites. Am J Med Genet A 2007; 143A: Albanese A, Del Sorbo F. Dystonia and tremor: the clinical syndromes with isolated tremor. Tremor Other Hyperkinet Mov (N Y) 2016; 6: Albanese A. Classifying tremor: language matters. Mov Disord 2018; 33: Herz E. Dystonia I. Historical review: analysis of dystonic symptoms and physiologic mechanisms involved. Arch Neurol Psychiatry 1944; 51: Fahn S. The varied clinical expressions of dystonia. Neurol Clin 1984; 2: Zeman W, Kaelbling R, Pasamanick B. Idiopathic dystonia musculorum deformans. II. The formes frustes. Neurology 1960; 10: Defazio G, Hallett M, Jinnah HA, Berardelli A. Development and validation of a clinical guideline for diagnosing blepharospasm. Neurology 2013; 81: Gigante AF, Berardelli A, Defazio G. Rest tremor in idiopathic adult-onset dystonia. Eur J Neurol 2016; 23: Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003; 54: Marek K, Seibyl J, Eberly S, et al. Longitudinal followup of SWEDD subjects in the PRECEPT study. Neurology 2014; 82: Schneider SA, Edwards MJ, Mir P, et al. Patients with adult-onset dystonic tremor resembling parkinsonian tremor have scans without evidence of dopaminergic deficit (SWEDDs). Mov Disord 2007; 22: Albanese A, Lalli S. Distinguishing scan without evidence of dopaminergic depletion patients with asymmetric resting tremor from Parkinson s disease: a clinical diagnosis of dystonia is required. Mov Disord 2010; 25: Albanese A, Lalli S. Is this dystonia? Mov Disord 2009; 24: Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006; 38: Kostic VS, Petrovic IN. Brain calcification and movement disorders. Curr Neurol Neurosci Rep 2017; 17: Amaral LL, Gaddikeri S, Chapman PR, et al. Neurodegeneration with brain iron accumulation: clinicoradiological approach to diagnosis. J Neuroimaging 2015; 25: Fung VS, Jinnah HA, Bhatia K, Vidailhet M. Assessment of patients with isolated or combined dystonia: an update on dystonia syndromes. Mov Disord 2013; 28: EAN

20 DYSTONIA: DIAGNOSIS AND MANAGEMENT van Egmond ME, Lugtenberg CHA, Brouwer OF, et al. A post hoc study on gene panel analysis for the diagnosis of dystonia. Mov Disord 2017; 32: Jankovic J. Treatment of dystonia. Lancet Neurol 2006; 5: Tighe AP, Schiavo G. Botulinum neurotoxins: mechanism of action. Toxicon 2013; 67: Caleo M, Restani L. Direct central nervous system effects of botulinum neurotoxin. Toxicon 2018; 147: Albanese A, Asmus F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 2011; 18: Albanese A. Clinical guidelines: no more mistaken identities for botulinum neurotoxins. Nat Rev Neurol 2016; 12: Cocco A, Albanese A. Recent developments in clinical trials of botulinum neurotoxins. Toxicon 2018; 147: Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2016; 86: Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database Syst Rev 2005: CD Costa J, Espirito-Santo C, Borges A, Ferreira JJ, Coelho M, Sampaio C. Botulinum toxin type A versus anticholinergics for cervical dystonia. Cochrane Database Syst Rev 2005: CD Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev 2005: CD Costa J, Borges A, Espirito-Santo C, et al. Botulinum toxin type A versus botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev 2005: CD Albanese A, Abbruzzese G, Dressler D, et al. Practical guidance for CD management involving treatment of botulinum toxin: a consensus statement. J Neurol 2015; 262: Contarino MF, Van Den Dool J, Balash Y, et al. Clinical practice: evidence-based recommendations for the treatment of cervical dystonia with botulinum toxin. Front Neurol 2017; 8: Albanese A, Bentivoglio AR, Colosimo C, Galardi G, Maderna L, Tonali P. Pretarsal injections of botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry 1996; 60: Cakmur R, Ozturk V, Uzunel F, Donmez B, Idiman F. Comparison of preseptal and pretarsal injections of botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neurol 2002; 249: Simpson DM, Blitzer A, Brashear A, et al. Assessment: botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008; 70: Ramirez-Castaneda J, Jankovic J. Long-term efficacy, safety, and side effect profile of botulinum toxin in dystonia: a 20-year follow-up. Toxicon 2014; 90: Naumann M, Carruthers A, Carruthers J, et al. Metaanalysis of neutralizing antibody conversion with onabotulinumtoxina (BOTOX(R)) across multiple indications. Mov Disord 2010; 25: Erro R, Tinazzi M, Morgante F, Bhatia KP. Non-invasive brain stimulation for dystonia: therapeutic implications. Eur J Neurol 2017; 24: 1228 e Cif L, Vasques X, Gonzalez V, et al. Long-term followup of DYT1 dystonia patients treated by deep brain stimulation: an open-label study. Mov Disord 2010; 25: Panov F, Gologorsky Y, Connors G, Tagliati M, Miravite J, Alterman RL. Deep brain stimulation in DYT1 dystonia: a 10-year experience. Neurosurgery 2013; 73: 86 93; discussion Vidailhet M, Jutras MF, Grabli D, Roze E. Deep brain stimulation for dystonia. J Neurol Neurosurg Psychiatry 2013; 84: Bruggemann N, Kuhn A, Schneider SA, et al. Shortand long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia. Neurology 2015; 84: Fasano A, Bove F, Lang AE. The treatment of dystonic tremor: a systematic review. J Neurol Neurosurg Psychiatry 2014; 85: Roze E, Vidailhet M, Hubsch C, Navarro S, Grabli D. Pallidal stimulation for myoclonus-dystonia: ten years outcome in two patients. Mov Disord 2015; 30: Patel AJ, Sarwar AI, Jankovic J, Viswanathan A. Bilateral pallidal deep brain stimulation for X-linked dystonia-parkinsonism. World Neurosurg 2014; 82(241): e241 e Koy A, Timmermann L. Deep brain stimulation in cerebral palsy: challenges and opportunities. Eur J Paediatr Neurol 2017; 21: Ostrem JL, San Luciano M, Dodenhoff KA, et al. Subthalamic nucleus deep brain stimulation in isolated dystonia: a 3-year follow-up study. Neurology 2017; 88: Contarino MF, Smit M, van den Dool J, Volkmann J, Tijssen MA. Unmet needs in the management of cervical dystonia. Front Neurol 2016; 7: Jinnah HA, Factor SA. Diagnosis and treatment of dystonia. Neurol Clin 2015; 33: EAN

21 Movement disorders Additional material is published online only. To view please visit the journal online ( jnnp ). 1 University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, The Netherlands 2 University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands 3 University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands Correspondence to Dr Tom J de Koning, University of Groningen, University Medical Center Groningen, Department of Genetics, PO Box , Groningen 9700 RB, The Netherlands; t.j.de.koning@umcg.nl Received 28 July 2014 Revised 22 October 2014 Accepted 28 October 2014 Published Online First 13 November 2014 To cite: van Egmond ME, Kuiper A, Eggink H, et al. J Neurol Neurosurg Psychiatry 2015;86: REVIEW Dystonia in children and adolescents: a systematic review and a new diagnostic algorithm Martje E van Egmond, 1 Anouk Kuiper, 1 Hendriekje Eggink, 1 Richard J Sinke, 2 Oebele F Brouwer, 1 Corien C Verschuuren-Bemelmans, 2 Deborah A Sival, 3 Marina A J Tijssen, 1 Tom J de Koning 2,3 ABSTRACT Early aetiological diagnosis is of paramount importance for childhood dystonia because some of the possible underlying conditions are treatable. Numerous genetic and non-genetic causes have been reported, and diagnostic workup is often challenging, time consuming and costly. Recently, a paradigm shift has occurred in molecular genetic diagnostics, with next-generation sequencing techniques now allowing us to analyse hundreds of genes simultaneously. To ensure that patients benefit from these new techniques, adaptation of current diagnostic strategies is needed. On the basis of a systematic literature review of dystonia with onset in childhood or adolescence, we propose a novel diagnostic strategy with the aim of helping clinicians determine which patients may benefit by applying these new genetic techniques and which patients first require other investigations. We also provide an up-to-date list of candidate genes for a dystonia gene panel, based on a detailed literature search up to 20 October While new genetic techniques are certainly not a panacea, possible advantages of our proposed strategy include earlier diagnosis and avoidance of unnecessary investigations. It will therefore shorten the time of uncertainty for patients and their families awaiting a definite diagnosis. INTRODUCTION Dystonia is a movement disorder characterised by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures or both. 1 For dystonia in children and adolescents, here referred to as dystonia of childhood (DC), the list of possible genetic and non-genetic causes is extensive. 2 3 For clinicians encountering a young patient with dystonia, an important practical question is how to manage the diagnostic workup, which is often challenging, time consuming and costly. Recently, a paradigm shift has occurred in molecular genetic diagnostics, with next-generation sequencing (NGS) techniques now allowing us to analyse hundreds of genes simultaneously. NGS diagnostic strategies are particularly effective in heterogeneous conditions, including movement disorders, significantly increasing the diagnostic yield at lower costs. 4 5 As a significant proportion of DC cases is estimated to be genetic, a genetics first diagnostic approach for all patients with DC seems logical and appealing. However, there are 774 van Egmond ME, et al. J Neurol Neurosurg Psychiatry 2015;86: doi: /jnnp two groups of patients for whom another initial approach should be considered. First, in children and adolescents who may have acquired dystonia, and second, in patients in whom the cause may be a treatable inborn error of metabolism (IEM), because for most of these IEMs biochemical investigations will be a faster diagnostic method than genetic testing. We first provide a systematic literature review of the phenomenology, classification and aetiology of DC. We then propose a novel diagnostic strategy that will help clinicians determine which patients may benefit from NGS technologies and which patients require other initial investigations. Finally, we give an up-to-date list of dystonia gene candidates to enhance the development of NGS diagnostics for DC (see online supplement 1). METHODS We systematically reviewed all papers regarding DC up to 20 October 2014, both genetic and nongenetic, in three age groups (infancy, childhood and adolescence), as proposed in the latest dystonia classification. 1 For details of our systematic search, see online supplement 2. DYSTONIA IN CHILDREN AND ADOLESCENTS: STATE OF THE ART Phenomenology: Is it dystonia? The first step in diagnosing DC is the identification of a hyperkinetic movement as being dystonic. Dystonia is defined as a movement disorder characterised by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures or both. Dystonic movements are typically patterned or twisting, and may be tremulous. They are often initiated or worsened by voluntary action and associated with overflow muscle activation. 1 This definition of dystonia is identical for adults and children 1 3 and similar to the definition of dystonia published by the Taskforce on Childhood Movement Disorders. 6 In children, dystonia is more often generalised compared with adult-onset dystonia. Correct identification of dystonia involves both an understanding of classification systems and visual pattern recognition. Three important, characteristic, clinical features of dystonia are: (1) patterned, predictable contractions of the same muscles; (2) exacerbation when performing voluntary movements (eg, walking, running, writing) and J Neurol Neurosurg Psychiatry: first published as /jnnp on 13 November Downloaded from on 5 September 2018 by guest. Protected by copyright.

22 (3) the so-called geste antagoniste, or sensory trick. This phenomenon is characterised by the relief of dystonic movements by lightly touching the relevant or adjacent part of the body. A sensory trick is particularly frequent in cranial and cervical dystonia, whereas limb and trunk involvement more often predominate in children. Therefore, a sensory trick is not an obligatory feature in DC; however, when observed, it strongly favours a diagnosis of dystonia. 16 In children, movements should be evaluated in relation to their developmental age. For instance, a healthy toddler can have normal overflow movements that may look like dystonia, diminishing as the child s development progresses. 3 In addition to these normal movements, abnormal movements may also mimic dystonia (table 1). For example, children with focal, stereotyped movements of the eyelids, face or neck are more likely to have tics than focal dystonia. 78 Reliable diagnostic criteria for different body localisations of dystonia are needed to help clinicians accurately differentiate dystonia from conditions mimicking dystonia. Recently, a Table 1 Type of dystonia Mimics of facial dystonia Mimics of dystonia in children and adolescents Mimics of cervical dystonia (head tilt) Mimics of trunk dystonia Mimics of limb dystonia (posturing) Mimics of generalised dystonia Mimics Tics Stereotypies Functional Tics Stereotypies Trochlear nerve palsy Vestibulopathy Spasmus nutans Acquired nystagmus Congenital muscular torticollis Sternocleidomastoid injuries Benign paroxysmal torticollis of infancy Posterior fossa tumours Tumours in the pineal region Chiari malformation Atlanto axial subluxation (eg, syndrome of Grisel) Cervical tumours (in cervical cord, bone or soft tissue) Upper spinal cord syringomyelia Juvenile rheumatoid arthritis Sandifer syndrome Klippel-Feil syndrome Functional Scoliosis Stiff person syndrome Functional Overflow movements in toddlers (normal developmental movements) Stereotypies Shoulder subluxation Dystonic (tonic) tics Myotonia Neuromyotonia Cramp Satoyoshi syndrome Rigidity Spasticity Focal tonic seizures Spasms (hypocalcaemia, hypomagnesaemia, alkalosis) Deafferentation (pseudoathetosis) Functional Self-stimulation Opisthotonus Stiff person syndrome Functional Movement disorders diagnostic guideline for diagnosing blepharospasm has been validated; 9 however, blepharospasm is a form of focal dystonia that rarely occurs in childhood or adolescence. For other body localisations of dystonia, specific diagnostic criteria are an unmet need. Classification of dystonia The most recent general classification scheme of dystonia identifies two distinct axes: axis I clinical characteristics, and axis II aetiology. 1 Axis I describes the clinical features by (1) age at onset, (2) body distribution, (3) temporal pattern, (4) coexistence of other movement disorders and (5) other neurological or systemic manifestations. Axis II addresses the aetiology via two components: (1) nervous system pathology and (2) whether the dystonia is inherited or acquired. Classification of aetiology into the categories inherited or acquired differs from traditional classification schemes in which dystonia was classified into primary genetic dystonia or secondary dystonia. 1 The reason for this change was that primary dystonias, heredodegenerative dystonias and dystonia-plus syndromes are all in fact genetic disorders. 1 These three categories are now considered together as inherited. In this review, we elaborate on this recent change in aetiological classification. Aetiology of dystonia There are many possible aetiologies of DC. For this review, we highlight acquired dystonias and treatable IEMs because an initial approach other than NGS testing needs to be considered for these conditions. All other genetic causes can be tested at the same time by means of NGS diagnostics. Acquired dystonias We focus on acquired forms of dystonia that are relatively common and/or treatable. Drugs and toxic agents that may cause DC are listed in table 2. For other causes of acquired DC, clinical clues and recommended investigations are summarised in table 3. Drugs and toxic agents DC can be induced by certain drugs and toxic agents, most commonly neuroleptics and antiemetics (table 2). 7 8 Drug-induced dystonias are categorised into acute dystonic reactions and tardive (chronic use) dystonia. The latter is a well-recognised disorder in adults, but may also occur in children. 7 Acute forms of dystonia may arise after taking a few doses or even after one administration or accidental ingestion. 8 The dystonia usually disappears rapidly on withdrawing the offending drug. Cerebral palsy Dyskinetic cerebral palsy (CP) is the most common cause of acquired DC. 10 CP is a clinical diagnosis, encompassing a group of permanent disorders that cause impairment of movement and posture, attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. 11 Dyskinetic CP is characterised by the presence of choreoathetosis and dystonia 11 and possible aetiologies are heterogeneous. 812 It is most common in children, born at term, who have experienced adverse perinatal effects, since the basal ganglia are particularly vulnerable to pathogenic events towards the end of gestation. 12 There are guidelines to help identify whether an acute intrapartum event was the likely cause of any particular case of CP. 13 Owing to the aggressive treatment of perinatal hyperbilirubinaemia, it is now rare to see kernicterus as a cause of dyskinetic CP. 12 In dyskinetic CP, the hyperkinetic movements are usually bilateral and mostly begin after the first year of life, and progress van Egmond ME, et al. J Neurol Neurosurg Psychiatry 2015;86: doi: /jnnp J Neurol Neurosurg Psychiatry: first published as /jnnp on 13 November Downloaded from on 5 September 2018 by guest. Protected by copyright.

23 Movement disorders Table 2 Drugs and toxic agents that may cause dystonia in children and adolescents Drugs Dopamine receptor blocking drugs Dopamine depleting drugs Dopamine receptor stimulants Antihistaminic drugs Tricyclic antidepressants Serotonin reuptake inhibitors Cholinergic agonists Antiepileptic drugs Antimalarials Calcium channel blockers Disulfiram Lithium Cocaine Toxins Carbon monoxide Cyanide Manganese Methanol Organophosphate (Neuroleptics, antiemetics) (eg, Tetrabenazine) (L-dopa, dopamine receptor agonists) (eg, Trihexyphenidyl) (Especially phenytoin and carbamazepine) (eg, Chloroquine, amodiaquine) Main source Smoke inhalation, poorly functioning heating systems or fuel-burning devices Inhalation of smoke, ingestion of toxic household and workplace substances or cyanogenic foods Drinking water with a high concentration of manganese, long-term parenteral nutrition Ingestion of certain industrial products such as antifreeze solution or cleaners Exposure to or ingestion of insecticides slowly for several years. 7 8 In children with severe CP, dystonia may be so profound and sustained that it manifests as hypertonia rather than abnormal involuntary movements. 3 Brain MRI Table 3 Clinical clues suggesting acquired dystonia demonstrates abnormal findings in about 80% of individuals with CP. 14 Genetic analysis is recommended in those cases where no specific cause can be determined, as several monogenic disorders can present with clinical features similar to CP. 15 Acquired structural lesions Structural lesions, such as stroke, neoplasms or structurally abnormal vessels including arteriovenous malformations, may result in unilateral DC (focal or hemidystonia). 7 8 Childhood stroke may result in dystonia if the caudate, lenticular nucleus or thalamus are involved. 78 In most cases, the dystonia develops months or even years after the incident. Autoantibody-associated and autoimmune disorders Several autoantibody-associated and autoimmune disorders can lead to DC (table 3). 16 We put emphasis on two autoantibodyassociated disorders, as early recognition and timely therapy can improve the outcome significantly in these conditions. 16 Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children is characterised by a combination of seizures, movement disorders, psychiatric symptoms and encephalopathy. 16 The first symptom is often non-psychiatric. 17 In addition to dystonia, multiple movement disorders can be seen in the same patient, 16 the most characteristic being orofacial dyskinesias. 17 Young children often present with temper tantrums, hyperactivity or irritability, whereas in older patients anxiety, psychosis and altered personality are the main psychiatric features observed. 17 Recognition of the combination of symptoms should prompt testing for anti-nmdar antibodies, both in serum and cerebrospinal fluid (CSF). 17 Brain MRI, EEG and CSF may all show non-specific abnormalities An underlying neoplasm is found in approximately 6% of girls younger than 12 years but rarely in boys, whereas the association with an ovarian teratoma increases in adolescent girls. 18 Treatment Clinical clue Differential diagnosis Recommended initial investigations Acute onset dystonia or rapidly progressive course Unilateral dystonia Psychiatric symptoms (de novo) Seizures (de novo) Signs of meningo-encephalitis or encephalitis Structural lesion External insult* Autoantibody-associated movement disorder ADEM Infection Structural lesion External insult* Autoantibody-associated movement disorder Demyelinating disease Antiphospholipid syndrome CP Autoantibody-associated movement disorder Infection Structural lesion Autoantibody-associated movement disorder Rasmussen s syndrome Infection Autoantibody-associated movement disorder Infection Neuroimaging Neuroimaging Autoantibodies in serum and CSF Neuroimaging, CSF Neuroimaging, serum, CSF Neuroimaging Neuroimaging Autoantibodies in serum and CSF Neuroimaging, CSF Serum investigations Neuroimaging Autoantibodies in serum and CSF Neuroimaging, serum, CSF Neuroimaging Autoantibodies in serum and CSF Neuroimaging Neuroimaging, serum, CSF Autoantibodies in serum and CSF Neuroimaging, serum, CSF Abnormal birth or perinatal history CP Neuroimaging Local signs of autonomic disturbances and pain CRPS I Clinical diagnosis** *External insults include head trauma and hypoxic insults caused by near-drowning, cardiac arrest or status epilepticus. Unilateral dystonia comprises either focal or hemidystonia. Demyelinating diseases including ADEM, multiple sclerosis and neuromyelitis optica. Antiphospholipid syndrome with or without associated rheumatic disease such as systemic lupus erythematosus should be considered in all children with hemidystonia of unknown origin. In Rasmussen s syndrome, dystonia can be an accompanying sign or the presenting feature. **Criteria for CRPS are described by Mersky et al, see online supplemental references (supplement 4). ADEM, acute disseminated encephalomyelitis; CP, cerebral palsy; CRPS I, complex regional pain syndrome type I. 776 van Egmond ME, et al. J Neurol Neurosurg Psychiatry 2015;86: doi: /jnnp J Neurol Neurosurg Psychiatry: first published as /jnnp on 13 November Downloaded from on 5 September 2018 by guest. Protected by copyright.

24 consists of immunotherapy and oncological treatment in those patients with a clinically detectable tumour. 18 Outcome is good in the majority of patients treated early enough. 18 Autoimmune basal ganglia encephalitis is a syndrome characterised by extrapyramidal movement disorders including dystonia and parkinsonism, sleep disturbance, dysautonomia and psychiatric symptoms. 16 Approximately 70% of cases have serum antidopamine-2 receptor antibodies. 16 Many patients have MRI T2 hyperintense basal ganglia abnormalities and show signs of CSF inflammation including oligoclonal bands. 16 Immune therapy is the mainstay of treatment In the past, encephalitis with dominant involvement of the basal ganglia was given a variety of names, including encephalitis lethargica and (infantile) bilateral striatal necrosis. 16 These disorders and autoimmune basal ganglia encephalitis may all be part of the same clinical entity. 16 Infections DC caused by infection is relatively rare, but has been reported in children with viral infections, tuberculosis, mycoplasma or toxoplasmosis. 19 Infection by flaviviruses is an important cause of DC, the most common being Japanese encephalitis. 19 Other viruses associated with DC include influenza viruses, herpes viruses (including herpes simplex and herpes zoster) and measles viruses, which may lead to subacute sclerosing panencephalitis. 7 8 The main bacterial infections are tuberculosis and infection by Mycoplasma pneumoniae. 8 Infection should be suspected in any child with dystonia and pre-existing immunodeficiency or signs of meningoencephalitis or encephalitis. Detecting the infectious agent may be important for the type of therapy chosen, and therefore serum and CSF investigations are indicated in addition to neuroimaging. Treatable IEMs IEMs are highly heterogeneous. For most clinicians who do not work daily with IEMs, it will be virtually impossible to recognise all these often extremely rare conditions. Fortunately, since all IEMs can be detected with NGS diagnostics, early identification is only necessary for those IEMs where timely treatment can improve the outcome. 20 In general, an important clue for an IEM is a complex clinical picture comprising both neurological and non-neurological features. An overview of treatable IEMs associated with DC is provided in online supplement 3. We defined treatable as the availability of a therapy that might lead to the improvement or prevention of symptoms. We will highlight five significant subgroups of treatable IEMs that may cause DC. Organic acidurias Organic acidurias can present both acutely and intermittently and are associated with intoxication-like non-specific symptoms, such as vomiting and anorexia, progressing towards encephalopathy. Episodes are frequently triggered by intercurrent illness, dietary changes or prolonged fasting. 21 When the underlying enzymatic defect is severe, onset will be in the newborn period. Milder phenotypes may present later as a slowly progressive disorder or with an intermittent course. Examples of organic acidurias associated with DC are propionic aciduria, methylmalonic aciduria, cobalamin defects and glutaric aciduria type I. 22 GLUT-1 deficiency GLUT-1 deficiency, caused by mutations in the SCL2A1 gene, can give rise to paroxysmal dystonia triggered by prolonged exercise. 23 This phenotype is also referred to as paroxysmal exertion-induced dystonia. The SCL2A1 gene encodes for the glucose transport protein 1, and mutations in this gene compromise glucose transport to the brain. Paroxysmal dystonia can be the sole feature, but developmental delay, spasticity, ataxia and epilepsy can also be part of the phenotype. A ketogenic diet is the current gold standard for treatment and has proven to be beneficial in most cases. 23 Metal storage Wilson s disease (WD) and dystonia with brain manganese accumulation (DBMA), caused by SLC30A10 mutations, are both metal storage disorders in which symptoms can be fully or partly prevented by timely treatment In both disorders, a combination of neurological symptoms and hepatic involvement is usually present. Other manifestations are psychiatric symptoms and a corneal Kayser-Fleischer ring in WD and parkinsonism and polycythaemia in DBMA. Indicative biochemical findings include low serum copper and ceruloplasmin in WD and hypermanganesaemia in DBMA. Lysosomal storage Niemann Pick type C is a clinically heterogeneous disorder in which the presenting phenotype depends on the age of onset. Infants can present with ascites and liver or pulmonary disease. The classic presentation in mid to late childhood consists of ataxia, a supranuclear vertical gaze palsy, psychiatric symptoms, dystonia and dementia, whereas the clinical picture in adults is dominated by psychiatric symptoms and cognitive decline. 26 Recently, treatment with miglustat has been shown to stabilise the progression of neurological symptoms, including in paediatric patients. 27 Dopa-responsive dystonias Dopa-responsive dystonias (DRD) are a group of disorders with a more insidious onset, probably representing 5% of childhood dystonias. 28 The autosomal dominant form, GTP-cyclohydrolase deficiency, is most common. This form is also known as Segawa s disease and shows an excellent and sustained response to low doses of levodopa. 29 Typically, there is a diurnal fluctuation of symptoms, and associated parkinsonism. Furthermore, two autosomal recessive forms of DRD have been identified: tyrosine hydroxylase deficiency and sepiapterin reductase deficiency, both often accompanied by intellectual disability and ophthalmological problems like oculogyric crisis, upward gaze and ptosis. 30 Since DRD features can be non-specific and can show considerable phenotypic variability, DRDs are frequently misdiagnosed as CP. 30 This may result in a considerable delay in diagnosis and Movement disorders adequate treatment. In addition to biochemical and molecular studies, a levodopa trial can be used as a diagnostic procedure. However, it should be noted that a positive response on a levodopa trial is not specific for the classic DRDs, but can also be seen in other disorders such as ataxia telangiectasia and GLUT deficiency. Classification of genetic dystonias The genetic forms of dystonia including IEMs may be categorised into two groups. The first group consists of the monogenetic forms of dystonia with assigned genetic loci identified as DYT1 25, formerly named primary dystonias and dystonia plus syndromes. These disorders are characterised by isolated dystonia, or dystonia combined with parkinsonism or myoclonus. 1 The second group consists of genetic disorders in which van Egmond ME, et al. J Neurol Neurosurg Psychiatry 2015;86: doi: /jnnp J Neurol Neurosurg Psychiatry: first published as /jnnp on 13 November Downloaded from on 5 September 2018 by guest. Protected by copyright.

25 Movement disorders dystonia is an important feature among several other neurological and systemic features. On axis I of the latest dystonia classification, these co-occurring neurological or systemic manifestations are classified as associated features. 1 Important associated features in children include: ataxia, epilepsy, mental retardation, spasticity, hypotonia, abnormal eye movements, neuropathy, deafness, ophthalmological signs, hepatosplenomegaly, psychiatric and dysmorphic features. These features are decisive for accurate phenotyping and a prerequisite for correct interpretation of NGS results. NGS methodology Genetic techniques using massive parallel sequencing are called NGS. With these new techniques, sequencing the entire genome of a patient (whole-genome sequencing; WGS), the coding regions (exons) of every gene (whole-exome sequencing; WES) or targeting specific disease-causing genes (targeted resequencing; TRS) have all become a reality in DNA diagnostics. Technical details of the specific methods fall outside the scope of this review, but are described elsewhere. 33 It is important to recognise that with WGS or WES approaches, information for all genes will become available, including those not relevant to the diagnostic question. These genes need to be excluded to restrict the data analysis to a list of known genes that might explain the phenotype. If the phenotype is unique and no mutation is found in the selected genes, the information about the excluded genes may be used to hunt for new disease-causing genes. The drawbacks of WGS and WES are high costs, the risk of unsolicited findings, and coverage that is usually less than in TRS panels, compromising the diagnostic accuracy. In TRS panels, a preselected list of several known genes that cause dystonia are tested. By sequencing only preselected genes, the coverage increases significantly, contributing to diagnostic accuracy, and unsolicited findings are minimised, at significantly lower costs. The important benefits of NGS diagnostics compared with regular biochemical procedures are that shipping DNA to referral centres is relatively cheap and straightforward, without stringent shipping conditions. In contrast, the costs and conditions of shipping samples, for instance, for (CSF) biochemical tests can be a serious hurdle in the present diagnostic process. It is to be expected that in the near future the widespread use of NGS, both in research and in clinical diagnostics, will lead to many more reports of dystonia-associated genes, and the list of associated genes will grow rapidly. However, it is important that independent confirmation of the causal relationship between gene variants and dystonia is performed because, in some of the recently annotated dystonia genes, variants in these genes also occur with high frequency in the general population. 34 A NEW DIAGNOSTIC ALGORITHM Owing to the extraordinarily broad range of possible causes of DC, several algorithms have been developed to assist clinicians in making diagnostic decisions These algorithms are not widely applicable as they mainly focus on (rare) neurometabolic causes and do not make use of the availability of NGS methodologies. On the basis of our systematic literature review and our own clinical experience, we propose a new diagnostic algorithm with five steps (figure 1). Step 1: Is it dystonia? The first step in the algorithm is to record a careful history and perform a physical and neurological examination to determine that dystonia is an important feature. Movement disorders that may be misdiagnosed as dystonia are listed in table 1. In general, these pseudodystonias have a known or presumed cause that is thought to differ from the causes of the broader dystonia group. 1 Applying the algorithm and using NGS testing is not advised in these conditions. Step 2: Could the dystonia be medication-induced or caused by toxic agents? The second step is to verify exposure to any medication or toxic agents that could be causing the dystonia (table 2). Treatment consists of discontinuing medication or prevention of further toxic exposure and, if possible, detoxification. Step 3: Clinical clues suggesting acquired dystonia? Step 3 is to consider whether the dystonia could be acquired. In table 3, we indicate red flags for acquired disorders with the main subgroups. These red flags are only defined to guide clinicians to a limited number of disorders in which immediate diagnosis and treatment is necessary to identify treatable disorders, preventing insults to the brain during the diagnostic process. Step 4: Biochemical investigations and levodopa trial In any child with dystonia without obvious clues for an acquired cause, we recommend performing a laboratory workup (table 4) aimed at identifying the treatable forms, before moving on to NGS testing. Of course, this recommendation only applies for those centres where biochemical diagnostics will provide faster results than NGS testing, depending on the local facilities. CSF investigations are only recommended in selected patients (table 4) because otherwise the diagnostic yield of CSF investigations is likely to be rather low In addition to the laboratory investigations, we recommend that all patients receive a trial of levodopa with carbidopa. 30 The primary goal of the trial is diagnostic. However, an additional advantage is that levodopa can also give symptom relief in non-drd dystonia. 39 The recommended starting dose of levodopa is 1 mg/kg/day, to be gradually increased until complete benefit, or until dose-limiting side effects occur. 7 Most individuals respond to 4 5 mg/kg/day in divided doses. 40 Levodopa should be given for 3 months before considering the trial a failure. 39 Step 5: NGS Simultaneously with the biochemical investigations and the initiation of the levodopa trial, all possible genetic causes can be approached by using NGS diagnostic technologies. To facilitate this, we provide a list of DC-associated genes (see online supplement 1). For those cases that remain unsolved after NGS testing, referral to a tertiary referral centre is recommended to further explore the possibilities to obtain an aetiological diagnosis. DISCUSSION We provide a comprehensive overview of DC and propose a new diagnostic algorithm (figure 1). This five-step approach provides guidance for clinicians to determine which patients may benefit from innovative genetic tests and those for whom other investigations are required first, while taking into account the importance of early recognition of acquired and treatable causes of DC. Our proposed flow chart (figure 1) differs from existing algorithms in that certain commonly used processing steps have been omitted, such as age at onset, temporal pattern (eg, persistent or paroxysmal), associated features and mode of 778 van Egmond ME, et al. J Neurol Neurosurg Psychiatry 2015;86: doi: /jnnp J Neurol Neurosurg Psychiatry: first published as /jnnp on 13 November Downloaded from on 5 September 2018 by guest. Protected by copyright.

26 Figure 1 Diagnostic algorithm of dystonia in children and adolescents (IEM, inborn error of metabolism). inheritance Indeed, pattern recognition based on these features has been important in the delineation of dystonia disorders and can still be successful in identifying classical phenotypes, especially by experts in the field. 1 8 However, these features were not included in our algorithm because many clinicians will have limited experience with these rare disorders and specific clinical patterns will easily remain unrecognised. In addition, recent insights from more widely applied NGS testing demonstrate that the clinical heterogeneity of many disorders is much larger than expected, so clinical pattern recognition of milder, intermediate and unusual phenotypes remains problematic. Nevertheless, careful clinical phenotyping still remains indispensable for two reasons. First, clinicians need to define, on the basis of these clinical parameters, the a priori risk that the patient is indeed suffering from a genetic disorder. NGS methodology should not be used when the a priori risk is low, because the numerous genes being tested increase the chance that variants will be misinterpreted as disease-causing, in genes that are unlikely to explain the clinical phenotype. Second, closely related to the first reason, detailed phenotyping is key when the results of NGS diagnostic strategies are available and need to be interpreted. As Hennekam and Biesecker 41 clearly Movement disorders stated, NGS and computers will not magically make patient diagnoses for us. Instead, there will be a shift from a pre-ngs-test differential diagnostic mode to a post-ngs-test diagnostic assessment mode. 41 Thus, the diagnostic skills of clinicians will be integrated into the evaluation of NGS test results to make molecular diagnoses together with laboratory staff. Notably, clinicians using NGS diagnostics should be aware that there are some technical pitfalls in the application of NGS diagnostics such as a limited ability to detect large structural rearrangements. In DC, this is particularly relevant if no causative mutation in a gene can be identified by NGS techniques, while at the same time the clinical picture is compatible with, for example, myoclonus dystonia or paroxysmal kinesigenic dyskinesia, both disorders that may be caused by deletions (in SCGE and PRRT2, respectively). In these cases, additional genetic tests detecting deletions are still required, such as multiplex ligation-dependent probe amplification or arraycomparative genomic hybridisation (array-cgh). 42 At present, we live in a period of transition between emerging NGS diagnostic tests and changing costs, budgets and availability of diagnostic procedures. In the future, NGS tools will become increasingly available in many areas of clinical diagnostics and clinical decision-making, and will be incorporated in van Egmond ME, et al. J Neurol Neurosurg Psychiatry 2015;86: doi: /jnnp J Neurol Neurosurg Psychiatry: first published as /jnnp on 13 November Downloaded from on 5 September 2018 by guest. Protected by copyright.